Professional Documents
Culture Documents
ENDOCRINOLOGY Handbook of Obesity 2003 PDF
ENDOCRINOLOGY Handbook of Obesity 2003 PDF
iv
fat accumulation associated with treatment with proteases and we have added a chapter to cover this area
(Chap. 19). The importance of visceral and total body
fat continues to expand. One of the key new developments of the 1990s was the recognition that the fat cell
is one of the most important endocrine cells in the body.
We have recognized this with several chapters on adipose tissue (Chaps. 17, 18, 20, 21, and 22). We have also
recognized the importance of obesity in the function of
the classical endocrine glands such as the adrenal,
thyroid, pituitary and gonads (Chaps. 25, 26, and 27).
The other side of the energy balance from food intake is
energy expenditure. This subject too receives substantial discussion in several chapters (Chaps. 23, 24, and
28). Muscle metabolism and nutrient partitioning are
the nal two chapters in this section.
Obesity has a myriad of eects on the health of
human beings. Obesity increases the risk of death, as
discussed in Chapter 31. The metabolic syndrome, as a
collection of ndings that predict health risks, has
become considerably more important in the past decade
approaches to obesity, which has been aided by advances in molecular biology. There follow three chapters
on the intake of food. One of these deals with this
problem in humans, the second with the problem in
animals, and the third with the neural basis for the
intake of food in both humans and animals. Together
these chapters provide a vivid view of the current standing of the eld of nutrient intake.
Our understanding of the importance of adipose
tissue has steadily increased, from regarding it as a
simple storage organ to recognizing it as a secretory
organ as well. The important dierences between white
and brown adipose tissue have also been elucidated, and
their role in the development and maintenance of
human obesity dened. These concepts are developed
in the next four chapters. The nal group of chapters in
the second section deals with energy expenditure. There
is a chapter on energy expenditure and thermogenesis
during rest and one on physical activity and its relation
to obesity and food intake. Finally, the roles of the
endocrine system, the autonomic nervous system, and
substrate handling are discussed. From this second
section the reader should obtain a detailed understanding of the genetic basis of obesity; the role and control of
food intake in the development of obesity; the way fat
cells function as a storage, thermogenic, secretory organ; and, nally, the way in which energy expenditure is
controlled and involved in the development of obesity.
v
vi
the evaluation of the overweight patient. The cornerstones for treatment of obesitybehavior therapy, diet,
and exerciseare presented in three separate chapters.
These are followed by three important chapters on the
management of diabetes, hypertension, and hyperlipidemia in the obese individual. Finally, there is a chapter on the current status of pharmacological treatment
of obesity and a chapter on the surgical approaches
that can be used for an individual for whom other
approaches to treatment have failed.
The preparation of this volume has required the work
of many people. First, we want to thank the authors and
their secretarial assistants for submitting the chapters so
promptly. This will make the entire volume timely.
Several individuals in the editors oce have also played
key roles in moving this forward. We want to thank
especially Ms. Millie Cutrer and Terry Hodges in Baton
Rouge, Ms. Karen Horth and Ms. Diane Drolet in
Quebec City, and Ms. Jean James in Aberdeen. The
guiding hand at Marcel Dekker, Inc., who has been so
valuable in nudging and cajoling us along when we
needed, is Ms. Lia Pelosi. We thank you all and hope
that the readers appreciate the important role each of
you, and others we have not mentioned, including
especially our long-suering families, has made to the
success of this volume.
George A. Bray
Claude Bouchard
Contents
iii
v
xi
33
81
93
109
117
135
149
PART II
ETIOLOGY
vii
157
viii
Contents
10.
Molecular Genetics of Rodent and Human Single Gene Mutations Aecting Body Composition
Streamson Chua, Jr., Kathleen Graham Lomax, and Rudolph L. Leibel
201
11.
255
12.
283
13.
301
14.
373
15.
427
16.
Central Integration of Peripheral Signals in the Regulation of Food Intake and Energy Balance:
Role of Leptin and Insulin
L. Arthur Campeld, Francoise J. Smith, and Bernard Jeanrenaud
461
17.
481
18.
515
19.
533
20.
Uncoupling Proteins
Daniel Ricquier and Leslie P. Kozak
539
21.
559
22.
589
23.
Resting Energy Expenditure, Thermic Eect of Food, and Total Energy Expenditure
Yves Schutz and Eric Jequier
615
24.
631
25.
655
26.
671
27.
693
28.
705
Contents
ix
29.
733
30.
Nutrient Partitioning
Samyah Shadid and Michael D. Jensen
753
PART III
PATHOPHYSIOLOGY
31.
767
32.
787
33.
813
34.
825
35.
845
36.
873
37.
899
38.
919
39.
935
40.
953
41.
967
42.
983
43.
Index
1005
1023
Contributors
Gerard Ailhaud, Ph.D. Professor, Department of Biochemistry, Unite Mixte de Recherche 6543, Centre
National de la Recherche Scientique, Nice, France
Jeanine Albu, M.D. Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Columbia University College of Physicians and Surgeons, and
St. Lukes-Roosevelt Hospital Center, New York, New
York, U.S.A.
Claude Bouchard, Ph.D. Executive Director, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
George A. Bray, M.D. Boyd Professor, Chronic Disease Prevention, Pennington Biomedical Research
Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
Richard N. Baumgartner, Ph.D. Professor, Department of Internal Medicine, University of New Mexico
School of Medicine, Albuquerque, New Mexico, U.S.A.
Streamson Chua, Jr., M.D., Ph.D. Associate Professor, Division of Molecular Genetics, Department of
Pediatrics, Columbia University College of Physicians
and Surgeons, New York, New York, U.S.A.
Per Bjorntorp, M.D., Ph.D., F.R.C.P.(Edin) Professor, Department of Heart and Lung Diseases, University of Goteborg, Goteborg, Sweden
xi
xii
Contributors
Graham A. Colditz, M.D., Dr.PH. Professor, Departments of Medicine and Epidemiology, Harvard School
of Public Health, Harvard Medical School, and Brigham & Womens Hospital, Boston, Massachusetts,
U.S.A.
Contributors
xiii
xiv
Contributors
Steven R. Smith, M.D. Associate Professor, Endocrinology Laboratory, Pennington Biomedical Research
Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
1
Historical Framework for the Development of Ideas
About Obesity
George A. Bray
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
INTRODUCTION
Religions dissipate like fog, kingdoms vanish, but
the works of scientists remain for eternity.
Ulug Beg, 15th century
(cited in Uzbekistan:
Macleod and Maghew, p 17.)
We do not live in our own time alone; we carry our
history within us.
Gaarder (1:152)
The goal of historical scholarship is said to be to
reconstruct the past, but the only past available for
reconstruction is that which we can see from the
present. The nature of science as an analytical
discipline, involved at one and the same time in the
uncertainties of discovery and in the accumulation
of a body of objective knowledge, raises some
special problems of historical reconstruction.
Crombie (2:4)
Bray
PREHISTORIC MEDICINE
(f3000 BC)
Paleomedicine
Paleolithic Artifact
Table 1
Obesity
Place found
Number
found
Height
Composition
One
Many
11 cm
11.4 cm
Limestone
Terracotta
One
One
Many
Many
Many
Many
24 cm
14.7 cm
Serpentine
Ivory
Terracotta
Terracotta
Ivory
Ivory
Willendorf, Austria
Dolni Vestonice,
Czeckoslovakia
Savignano, Italy
Lespugue, France
Grimaldi, France
Laussel, France
Kostenki, Russia
Gagarino, Russia
40 cm
47 cm
Neolithic Artifacts
Historical Framework
Figure 1 Map showing location of the paleolithic Venus gurines. Note that obese gurines have been found throughout
Europe and in the Middle East.
standing, or lying. One of the most famous from Catalhoyuk is 20 cm tall. She sits on a throne with two lions
serving as her arm rests. The gurines from this period
show exaggeration of the hips, belly, and breasts, with
genital areas indicated by triangular decoration, symbolizing motherhood and womankind, attributes which
are shared by later Mother Goddess gurines from
Kybele to Artemis. It is important to note that no deity
or mythological gure has ever borne as many dierent
names as the Mother Goddess. On the Kultepe tablets
(1800 BC) she is known as Kubaba; the Lydians called
her Kybebe; the Phrygians, Kybele; and the Hittites,
Hepat. In ancient Pontic Comana (near Tokat) and
Cappadocian Comana (Kayseri), she was known by the
ancient Anatolian name of Ma. She was Marienna and
Lat to the Sumerians, Arinna to the people of the Late
Hittite period, Isis to the Egyptians, Rhea to the Greeks,
Artemis to the Ephesians, and Venus to the Romans.
The name Kybele has even survived into modern times
as the Anglo-Saxon Sybil and its variants, and Turkish
III
Bray
Egyptian Medicine
Mesopotamian Medicine
Historical Framework
Meso-American medicine
Prior to the discovery of the New World by Columbus in 1492, there were three high cultures in the Meso-
Greco-Roman Medicine
From the vantage point of Western civilization, GrecoRoman medicine has been the major source of our
medical tradition. The health hazards associated with
obesity were clearly noted in the medical writings of
Hippocrates, where he states, Sudden death is more
common in those who are naturally fat than in the lean
(58). These traditions also note that obesity was a cause
of infertility in women and that the frequency of menses
was reduced in the obese.
Galen was the leading physician of Roman times.
His inuence on medicine and medical teaching lasted
more than 1000 years. He identied two types of obesity, one he called moderate and the other immoderate. The former is regarded as natural and the other
as morbid.
Descriptions of sleep apnea associated with obesity
also date from Roman times. Dionysius, the tyrant of
Heracleia of Pontius, who reigned ca 360 BC, is one of
the rst historical gures aicted with obesity and
somnolence. This enormously fat man frequently fell
asleep. His servants used long needles inserted through
his skin and fat to awaken him when he fell asleep.
Kryger cites a second case of Magas, King of Cyrene,
who died in 258 BC. He was a man weighted down
Bray
Arabic Medicine
IV
SCIENTIFIC MEDICINE
(1500 TO PRESENT)
Anatomy
Historical Framework
Figure 3 Timeline for developments in science, obesity, and contemporary events in the 16th century.
Bray
Figure 4 Timeline for developments in science, obesity, and contemporary events in the 17th century.
Historical Framework
Figure 5 Timeline for developments in science, obesity, and contemporary events in the 18th century.
10
Bray
Figure 6 Timeline for developments in science, obesity, and contemporary events in the 19th century.
Historical Framework
Figure 7 Timeline for developments in science, obesity, and contemporary events in the 20th century.
11
12
Bray
Physiology
Historical Framework
13
14
Bray
(piqure) to the hypothalamus could produce glycosuria. His scientic philosophy was one of gradualism.
Scientic theory would naturally lead to step-by-step
progress, a concept that was a dominant element in
the 19th-century philosophy of science. This concept
of gradualism is in sharp contrast to the concept of
paradigm shifts (120) and scientic revolutions (121)
(see Sec. V).
Claude Bernards contemporary in Germany was
Liebig. His concept that the carbohydrates, proteins,
and fat were all that were needed for human nutrition
served as the basis for nutritional science during much
of the 19th century. Overthrow of this theory by the
discovery of vitamins at the turn of the 20th century
gave birth to a new and broader eld of nutrition
(122). The development of nutrition through the rst
half of the 20th century is epitomized by the discovery
of vitamins and their function. This era largely closed
in 1948 with the elucidation of the structure of vitamin
B12. With the closing of this era, the impact of macronutrients again took center stage through the recognition of the role of dietary fats and obesity as causes
of chronic disease (123,124).
The 20th century saw an explosion in the application
of chemical and biochemical techniques to the study of
obesity. Sophistication in the measurement of body
components has greatly expanded. The work by Benke,
Feen, and Wellman applied the techniques of density
for quantitating the fat and nonfat compartments of
the body (125). This methodology has been supplemented since World War II by the application of
radioactive isotopes (126) to the study of body composition by many workers (127). New techniques have
continued to provide ever better ways of characterizing
the human body. Radioactive isotopes have largely
been replaced by stable isotopes. The introduction of
ultrasound for measuring fat thickness, of computed
axial tomographic (CT) scans, and magnetic resonance
imaging (MRI) scans to measure regional fat distribution, the use of dual-energy x-ray absorptiometry to
measure body fat, lean body compartments, and bone
mineral, and the use of whole body neutron activation
have provided sophisticated techniques for accurate
and detailed determination of body composition in
vivo (128).
E
Historical Framework
Pharmacology
15
Amphetamine was a second product of the synthetic organic chemical industry that was used for
treatment of obesity. In the 1930s, dextroamphetamine, which was synthesized in 1887 (155), was
shown to produce weight loss in individuals being
treated for narcolepsy (156). Because amphetamine is
addictive, it fell into disrepute and led to a negative
view of all drugs with a similar chemical structure.
However, the similarity of chemical structure on
paper proved misleading pharmacologically. The hphenethylamine chemical structure is the backbone of
amphetamine (a-methyl-h-phenethylamine). Amphetamine aects two neurotransmitters, dopamine and
norepinephrine. Modifying the h-phenethylamine
structure can completely change the eect on neurotransmitters. Phentermine is a h-phenethylamine
cousin of amphetamine that aects primarily norepinephrine. Fenuramine, another h-phenethylamine
cousin, is pharmacologically unrelated to amphetamine since it only aects serotonin.
G
Neuroscience
16
Bray
the thermogenic component of the sympathetic nervous system in heat generation in small animals and in
inhibiting food intake, has been central to the development of h-adrenergic drugs as potential agents for
treating obesity (169).
The discovery of a number of peptides that are
present in both the brain and the gastrointestinal tract
has brought together the areas of neuroscience and
physiology in the control of body fat and obesity.
Secretin was the rst GI hormone found (170). Subsequently, cholecystokinin was found to stimulate contraction of the gallbladder and then to reduce food
intake (171). Of the many peptides now known, neuropeptide-Y is among the more interesting because it will
stimulate food intake and produce obesity when given
continuously (172).
H
Gender
M
M
M
M
M
M
M
F
M
F
F
M
F
M
M
M
F
Age at
death
Maximum
weight (kg)
39
335
280
462
332
385
318
332
381
385
367
338
343
318
350
485
411
408
381
59
22
39
36
29
27
31
28
23
37
35
32
38
46
35
Ref.
(1)
(182)
(3)
(174)
(3)
(2)
(2)
(2)
(174)
(2)
(2)
(2)
(2)
(2)
(3)
(3)
(3)
(3)
Sporadic cases of obesity have been noted since antiquity. Gould and
Pyle (174) describe a large number of cases of massive obesity in
children and adults. They cite the writings of Athenaeus who
described Denys, the tyrant of Heraclea, as so enormous that he was
in constant danger of suocation, which was treated by putting
needles in the back of his chair. Several other very fat people
identied by Gould and Pyle are William the Conqueror; Charles le
Gros; Louis le Gros; Humbert II, Count of Maurienne; Henry I,
King of Navarre; Henry III, Count of Champagne; Conan III, Duke
of Brittany; Sancho I, King of Leon; Alphonse II, King of Portugal;
the Italian poet Bruni who died in 1635; Vivonne, a general under
Louis XIV; Frederick I, King of Wurtemberg, and Louis XVII.
Historical Framework
17
Treatment of Obesity
18
Bray
Historical Framework
19
Protein
Fat
Carbohydrate
Minimal
Maximal
120 g (4 oz)
492 cal
30 g (1 oz)
280 cal
100 g (3 1/3 oz)
410 cal
1182 cal
180 g (6 oz)
738 cal
30 g (1 oz)
280 cal
120 g (4 oz)
492 cal
1510 cal
20
Bray
Behavior Modication
Following the introduction of psychoanalytic techniques by Freud and his colleagues (223), several theories
were proposed suggesting that obesity might result from
personality disorders. These were carefully tested and
found to be wanting (224). That obesity had important
social components, however, became clear from its
relation to socioeconomic status (225). The prevalence
of obesity was found to be much higher in the lower
social and economic groups than in the higher social and
economic groups in the seminal Manhattan study.
Although psychoanalytic approaches were unproductive as a basis for treatment, other avenues of
behavioral research were productive. One of these ows
from the work on conditioned reexes by Pavlov and
his followers (226), and another from the work on
operant behavior by Skinner (227,228). It was an
adaptation of these latter techniques that was used by
Stuart (229) in his classic study in 1967. Stuart treated
11 patients, 8 of whom were available for follow-up at
the end of the year. In this group, weight losses using
techniques of monitoring food intake and manipulating
the environment in which it was eaten were indeed
striking. Subsequent to this seminal work, the principles of behavior modication have been widely applied,
and some would consider them to have been central to
the treatment of obesity in the late 20th century.
3
Pharmacotherapy
Historical Framework
Surgery
21
22
Bray
French
German
Maccary (177)
Dancel (300)
Worthington
(301)
Kisch (302)
Ebstein (303)
Leven (313)
Haeckel (314)
Le Noir (315)
Boivin (316)
Cref and
Herschberg
(317)
Historical Framework
23
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
REFERENCES
25.
1.
26.
27.
28.
29.
30.
24
31. Bray GA. Commentary on Atwater classic. Obes Res
1993;1(3):223227.
32. Bray GA. Letter on corpulence. Obes Res 1993;1:153
163.
33. Bray GA. Commentary on Banting letter. Obes Res
1993;1(2):148152.
34. Martinie J. Notes sur lHistoire de lObesite. Thesis de
Paris 1934. Paris: Les Presses Universitaires de France,
1934.
35. Schwartz H. Never Satised. A Cultural History of
Diets, Fantasies and Fat. New York: Doubleday,
1986.
36. Needham J. Science and Civilization in China. Cambridge: Cambridge University Press, 1988, 6 vols.
37. Singer C, Homyard EJ, Hall AR, Williams TI. A
History of Technology. New York: Oxford University
Press, 19541958, 5 vols.
38. Ackerknecht EH. Medicine at the Paris Hospital.
Baltimore: Johns Hopkins University Press, 1967.
39. Foucault M. The Birth of the Clinic. An Archaeology
of Medical Perception. New York: Vintage Books,
1973.
40. Gamble C. The Palaeolithic Settlement of Europe.
Cambridge: Cambridge University Press, 1986.
41. Stephen-Chauvet. La Medicine chez les Peuples
Primitifs. Paris: Librairie Maloine, 1936.
42. Beller AS. Fat & Thin. A Natural History of Obesity.
New York: Farrar, Straus and Giroux, 1977.
43. Hautin RJR. Obesity. Conceptions actuelles The`se
pour le Doctorat en Medicine. Bordeaux: Imprimerie
Bier, 1939.
44. Kulacoglu, B. Gods and Goddesses. (Translated by J.
Ozturk.) Anhura: Museum of Anatolian Civilizations,
1992.
45. Garrison F. An Introduction to the History of Medicine. Philadelphia: W.B. Saunders, 1914.
46. Contenau G. La medicine en Assyrie et en Babylonie.
Paris: Librairie Maloine, 1938.
47. Spycket A. Kassite and middle Elamite sculpture. In:
Later Mesopotamia and Iran. Tribes and Empires
1600538 BC. London: British Museum Press, 1995, p
30 plate 18.
48. Smith E. The Edwin Smith Surgical Papyrus.
(Published in facsimile and hieroglyphic transliteration with translation and commentary in two volumes
by James Henry Breasted.) Chicago: University of
Chicago Press, 1930. Classics of Medicine, Special
Edition, 1984.
49. Darby WJ, Ghalioungui P, Grevetti L. Food: The Gift
of Osiris. London: Academic Press, 1977, p 60.
50. Nunn JF. Ancient Egyptian Medicine. London:
British Museum Press, 1996.
51. Reeves C. Egyptian Medicine. London: Shire Publications, 1992.
52. Eiler I. Egyptian Bookshelf Disease. London: British
Museum Press, 1995.
Bray
53. Alphen JV, Aris A. Oriental Medicine: An Illustrated
Guide to the Asian Arts of Healing. Boston: Shambhala, 1996.
54. Tibetan Medical Paintings. Illustrations to the Blue
Beryl Treatise of Sangye Gyamtso. (16351705). New
York: Henry N. Abrams, 1992.
55. Iason AH. The Thyroid Gland in Medical History.
New York: Frobin Press, 1946.
56. Ortiz de Montellano BR. Aztec Medicine, Health and
Nutrition. New Brunswick: Rutgers University Press,
1990.
57. Vogel VJ. American Indian Medicine. Norman:
University of Oklahoma Press, 1970.
58. Hippocrates. Oeuvres Comple`tes dHippocrate. (Traduction nouvelle avec le texte grec en regard. . .par E.
Littre.) Paris: J.B. Ballie`re, 1839.
59. Kryger MH. Sleep apnea. From the needles of
Dionysius to continuous positive airway pressure.
Arch Intern Med 1983;143:23012303.
60. Kryger MH. Fat, sleep, and Charles Dickens: literary
and medical contributions to the understanding of
sleep apnea. Clin Chest Med 1985;6:555562.
61. Campbell D. Arabian medicine and its inuence on the
Middle Ages. London: Kegan Paul, Trench, Trubner
& Co, 1926, 2 vols.
62. Beaujouan G. Motives and opportunities for science
in the medieval universities. In: Scientic Change.
Historical Studies in the Intellectual, Social and
Technical Conditions for Scientic Discovery and
Technical Invention, from Antiquity to the Present.
Crombie AC, ed. New York: Basic Books, 1963, pp
232234.
63. Vesalius A. De humani corporis fabrica. Basileae: ex
o. Joannis Oporini, 1543.
64. Copernicus N. De revolutionibusorbium colestium.
Libri VI. Norimberg: Apud Ioh. Petrium, 1543.
65. Bonetus T. Sepulchretum, sive anatomia practica, ex
cadaveribus morbo denatis, proponens historias omnium humani corporis aectum. Genevae: Sumptibus
Cramer & Perachon, 1700.
66. Morgagni GB. De sedibus, et causis morborum per
anatomen indagatis libriquinque. Venetiis: typog.
Remordiniana, 1761.
67. Haller A. Corpulence ill cured; large cryptae of the
stomach (etc). Path Observ 1756;4449.
68. Haller A. Elementa physiologiae corporis humani.
Lausanne: MarciMichael Boursquet & Sociorum,
1757.
69. Wadd W. Comments on corpulency lineaments of
leanness mems on diet and dietetics. London: John
Ebers & Co., 1829.
70. Malpighi M. Opera Omnia. Londini: R. Scott, 1686.
71. Hooke R. Micrographia or some physiological
descriptions of minute bodies made by magnifying
glasses; with observations and inquiries thereupon.
London: J. Martyn & J. Allestry, 16651667.
Historical Framework
72. Van Leeuwenhoek A. The Select Works of Antony
van Leeuwenhoek, Containing His Microscopical Discoveries in Many of the Works of Nature. (Translated
from the Dutch and Latin editions by Samual Hoole.)
London: G. Sidney, 1800.
73. Schwann T. Mikroscopische Untersuchungen uber di
Ubereinstimmung in der Struktur un dem Wachstum
der Thiere und Panzen. Berlin: Sander, 1839.
74. Schleiden MJ. Beitrage zur Phytogenesis. Arch Anat
Physiol Wiss Med 1839;137176.
75. Henle FGJ. Allgemeine Anatomie. Leipzig: L. Voss,
1841.
76. Hassall A. The microscopic anatomy of the human
body, in health and disease. London: Samuel Highley,
1849.
77. Hoggan G, Hogan FE. On the development and retrogression of the fat cell. J R Microsc Soc 1879;2:353.
78. Hassall A. Observations on the development of the fat
vesicle. Lancet 1849;i:6364.
79. Bjurlf P. Atherosclerosis and body build with special
reference to size and number of subcutaneous fat cells.
Acta Med Scand 1959;166 (suppl 349):99.
80. Hirsch J, Kittle JL. Cellularity of obese and
nonobese human adipose tissue. Fed Proc
1970;29:15161521.
81. Bjorntorp P, Sjostrom L. Number and size of adipose
tissue fat cells in relation to metabolism in human
obesity. Metabolism 1971;20:703713.
82. Virchow R. Die Cellularpathologiein inrer Begrundung auf physiologische and pathologische Gewebelehre. Berlin: August Hirschwald, 1858.
83. Knoll M, Ruska E. Beitrag zur geometrischen Electronenoptik. Ann Physik 1932;12:607661.
84. Renold AE, Cahill GF, eds. Handbook of Physiology.
Section 5. Adipose Tissue. Bethesda, MD: American
Physiological Society, 1965.
85. Harvey W. The Anatomical Exercises of Dr. William
Harvey. De Motu Cordis 1628: De Circulatione
Sanguinis 1649. (The rst English text of 1653 edited
by Georey Keynes.) London: Nonesuch Press, 1928.
86. Osler W. The Evolution of Modern Medicine. New
Haven: Yale University Press, 1921.
87. Santorio S. A new art of Physick. Contained in eight
sections of aphorisms, concerning insensible perspiration; being a vapor of breathing from the body.
Plainly shewing that health and sickness is best
discerned by weighing the body. (Translated by
Abdiah Cole.) London: Peter Cole, 1663.
88. Santorio, Santorio. Medicina Statica: Being the
aphorisms of Sanctorius, translated into English with
large explanations. The second edition. To which is
added Dr. Keils Medicina statica Britannica, with
comparative remarks and explanations. As also medicphysical essays. . .by John Quincy. London: W. and J.
Newton, A. Bell, W. Taylor and J. Osborne, 1720.
89. Newburgh LH, Johnston MW. The exchange of
25
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
26
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
Bray
energy expenditure in humans using a respiration
chamber. Am J Clin Nutr 1983;989998.
Garrow J. Energy Balance and Obesity in Man, 2d ed.
Amsterdam: Elsevier/North Holland, 1978.
Ravussin E, Swinburn BA. Pathophysiology of
obesity. Lancet 1992;340:404408.
Schoeller DA, Van Santen E, Peterson DW, Dietz W,
Jaspan J, Klein PD. Total body water measurement in
humans with O and H labeled water. Am J Clin Nutr
1980;33:26862693.
Lichtman SW, Pisarska K, Berman ER, et al.
Discrepancy between self-reported and actual caloric
intake and exercise in obese subjects. N Engl J Med
1992;327:18931898.
Wohler F. Ueber kunstliche Bildung des Harnstos.
Ann Phys Chem (Leipzig) 1828;12:253256.
Bernard C. Sur le mechanisme de la formation du
sucre dans le foie. C R Acad Sci 1855;41:461469.
Magendie F. Precis ElEmentaire de Physiologie. Paris:
Mequignon-Marvis, 1816.
Liebeg JV. Chemistry and its application to agriculture
and physiology. (Translated by Lyon Playfair.) London: Taylor and Walton, 1842.
Bernard C. Memoire sur le pancreas et sur le role du
suc pancreatique dans les phenome`nes digestif. Suppl
C R Acad Sci (Paris)1856;1:379563.
Kuhn TS. The Structure of Scientic Revolutions.
Chicago: University of Chicago Press, 1962.
McCollum EV. A history of nutrition. The sequence of
ideas in nutrition investigations. Boston: Houghton
Miin, 1957.
Select Committee on Nutrition and Human Needs
(hearing) of the United States Senate 95th Congress.
Diet Related to Killer Diseases. Washington: Government Printing Oce, 1977. Vols VI, VII (2VI, 2VII).
Society of Actuaries. Build Study of 1979. City
Recording and Statistical Corp, 1980.
Behnke AR Jr, Feen BG, Welham WC. The specic
gravity of healthy men. Body weight divided by volume
as an index of obesity. JAMA 1942;118:495498.
Hevesy G. Radioactive Indicators. Their Application
in Biochemistry, Animal Physiology, and Pathology.
New York: Interscience Publishers, 1948.
Moore FD, Olesen KH, McMurrey JD, Parker HV,
Ball MR, Boyden CM. The Body Cell Mass and Its
Supporting Environment. Philadelphia: W.B. Saunders, 1963.
Wang Z, Pierson RN, Heymseld SB. The ve-level
model: a new approach to organizing body composition. Am J Clin Nutr 1992;56(1):1928.
Darwin C. On the Origin of Species by Means of
Natural Selection or the Preservation of Favoured
Races in the Struggle for Life. London: John Murray,
1859.
Bateson W. Mendels Principles of Heredity: A
Defence. London: Cambridge University Press, 1902.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
Historical Framework
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
27
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
28
182.
Coe T. A letter from Dr. T. Coe, Physician at Chelmsford in Essex, to Dr. Cromwell Mortimer, Secretary
R. S. concerning Mr. Bright, the fat man at Malden in
Essex. Phil Trans 17511752;47:188193.
183. Don WG. Remarkable case of obesity in a Hindoo
boy aged twelve years. Lancet 1859;1:363.
184. Eschenmeyer. Beschreibung eines monstrosen fett
Madchen, das in einem Alter von 10 jahren starb,
nach dem es eine hohe van 5 fuss 3 zoll und ein
Gewicht von 219 pfund erreicht hatte. Tubing Bl
Naturw Arznk 1815;1:261285.
185. Gordon S. Art. XV.Reports of rare cases. IV. Case
of extensive fatty degeneration in a boy 14 years of
age. Death from obstructed arterial circulation.
Dublin Q J Med Sci 1862; 33:340349.
186. McNaughton J. Cases of Polysarcia Adiposa in Childhood. New York: C.S. Francis, 1829: 317322.
187. Wood T. A sequel to the case of Mr. Thomas Wood,
of Billericay, in the Country of Essex, by the same.
Med Trans 1785;3:309318.
188. Linnaeus Cv. Species Plantarum, Stockholm: Salvius,
1753.
189. Sauvages FB. Nosologia methodica sistens morborum
classes juxta Sydenhami menen and botanicorum
ordinem. Amstelodami: Fratrum de Tournes, 1768, 2
vols.
190. Cullen W. First Lines of the Practice of Physic, by
William Cullen, M.D., Late Professor of the Practice
of Physic in the University of Edinburgh, and
Including the Denitions of the Nosology; with
Supplementary Notes Chiey Selected from Recent
Authors, Who Have Contributed to the Improvement
of Medicine by Peter Reid, M.D. Edinburgh: Abernethy and Walker, 1810, 2 vols.
191. Burwell CS, Robin ED, Whaley RD, Bickelman AG.
Extreme obesity associated with alveolar hypoventilation: a Pickwickan syndrome. Am J Med 1956;
21:811818.
192. Robin ED, ed. Claude Bernard and the Internal Environment. A Memorial Symposium. New York; Marcel
Dekker, 1979.
193. Russell J. A case of polysarka, in which death resulted
from decient arterialisation of the blood. Br Med J
1866; i:220221.
194. Cushing H. The Pituitary Body and Its Disorders.
Clinical States Produced by Disorders of the Hypophysis Cerebri. Philadelphia: J.B. Lippincott, 1912.
195. Cushing H. The basophil adenomas of the pituitary
body and their clinical manifestations. Pituitary basophilism. Bull Johns Hopkins Hosp 1932; L:137195.
196. Quetelet A. Sur lHomme et le Developpement de ses
Facultes, ou Essai de Physique Sociale. Paris: Bachelier, 1835.
197. Dawber TR. The Framingham Study: The Epidemiology of Atherosclerotic Disease. Cambridge: Harvard
University Press, 1980.
Bray
198. Keys A, Aravanis C, Blackburn HW, et al. Epidemiological studies related to coronary heart disease:
Characteristics of men aged 4059 in seven countries.
Acta Med Scand Suppl 1966;460:1392.
199. Lew EA, Garnkel L. Variations in mortality by
weight among 750,000 men and women. J Chronic Dis
1979; 32:563576.
200. Waaler HT. Height, weight and mortality: the Norwegian experience. Acta Med Scand 1984; 679:156.
201. Manson JE, Willett WC, Stampfer MJ, et al. Body
weight and mortality among women. N Engl J Med
1995;333:677685.
202. Vague J. La dierenciation sexuelle. Facteur determinant des furmes de lobesite. Presse Med 1947;55:339
340.
203. Carter HS, Howe PE, Mason HH. Nutrition and
Clinical Dietetics. Philadelphia: Lea and Febiger, 1917.
204. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson
CL. Overweight and obesity in the United States:
prevalence and trends, 19601994. Int J Obes Relat
Metab Disord 1998; 22(1):3947.
205. Precope J. Hippocrates on Diet and Hygiene. London:
Zeno, 952.
206. Green RM. A Translation of Galens Hygiene (De
Sanitate Tuenda). Springeld, IL: Charles C. Thomas,
1951.
207. Gruner OC. A Treatise on the Canon of Medicine of
Avicenna Incorporating a Translation of the First
Book. London: Luzac, 1930.
208. Harington J. The School of Salernum Regimen
Sanitatis Salernitanum. New York: Paul Hoeber, 1920.
209. Tweedie J. Hints on Temperence and Exercise,
Shewing Their Advantage in the Cure of Dyspepsia,
Rheumatism, Polysarcia, and Certain States of Palsy.
London: T. Rickaby, 1799.
210. Cornaro L. Sure and Certain Methods of Attaining a
Long and Healthful Life: With Means of Correcting a
Bad Constitution. London: D. Midwinter, 1737, 5th
English ed, p 11.
211. Brillat-Savarin JA. The Physiology of Taste or,
Meditations on Transcendental Gastronomy. (Translated from the French by M.F.K. Fisher.) San
Francisco: Arion Press, 1994.
212. Banting W. A Letter on Corpulence Addressed to the
Public. London: Harrison and Sons, 1863.
213. Harvey W. On Corpulence in Relation to Disease:
With Some Remarks on Diet. London: Henry Renshaw, 1872.
214. Gulick A. A study of weight regulation in the adult
human body during over-nutrition. Am J Physiol
1922;60:371395.
215. Neumann RO. Experimentel Beitrage zur Lehre von
dem taglichen Nahrungsbedarfdes Menschen unter
besonderer Berucksichtigung der notwendigen Eiweifsmenge. Arch Hyg 1902;45:187.
216. Wiley FH, Newburgh LH. The doubtful nature of
Historical Framework
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
229.
230.
231.
232.
233.
234.
29
and edited by F. Rosner, MD.) New York: Hebrew
Publishing Company, 1978.
235. Kremen AJ, Linner JH, Nelson CH. Experimental
evaluation of nutritional importance of proximal and
distal small intestine. Ann Surg 140:439448, 1954.
236. Payne JH, DeWind LT, Commons RR. Metabolic
observations in patients with jejunocolic shunts. Am J
Surg 1963;106:273289.
237. Mason EE, Ito C. Gastric bypass. Ann Surg 1970;
170:329339.
238. Sjostrom CD, Lissner L, Wedel H, Sjostrom L.
Reduction in incidence of diabetes, hypertension and
lipid disturbances after intentional weight loss induced
by bariatric surgery: the SOS Intervention Study. Obes
Res 1999;7(5):477484.
239. Sarton G. The History of Science and the New
Humanism. New York: Henry Holt, 1931.
240. Sarton G. A History of Science. Ancient Science
Throughout the Golden Age of Greece. Cambridge,
MA: Harvard University Press, 1952.
241. Schenkio MM. De pinguedinis in animalibut generatione et concretione. In: Erastus Th. Philosophi et
Medici Celeberrimi Disputationum et Episolarum
Medicalium, Volumen Doctissimum. Tiguri: Johan
Wolphium, 1595.
242. Ettmueller M. Pratique de Medicine Speciale . . . sur les
Maladies Propres des Hommes, des Femmes & des
Petits Enfants, avec des Dissertations . . . sur lEpilepsie,
lYvresse, le Mal Hypochondriaque, la Douleur
Hypochondriaque, la Corpulence, & la Morsure de la
Vipe`re (trad. nouv.) Lyon: Thomas Amaulry, 1691.
243. Gosky AU. Disputatio solennis de marasmo, sive
marcore: macilentia item & gracilitate sanorum;
macilentia & gracilitate aegrotatium; crassitie &
corpulentia sanorum naturali; crassitie & magnitudine
corporis morbosa aegrorum. Argentinae: Typis Eberhardii Welperi, 1658.
244. Held JF. Disputationem medica de corpulentia nimia.
Publicae. . .censurae. . .submittit. Jenae: Nisianis, 1670.
245. Leisner KC. Dissertatio medica de obesitate exsuperante. Jenae: Typ Gollnerianis, 1683.
246. Widemann GM. Disputatio medica de corpulaentia
nimia. Lipsiae: typ Krugerianus, 168l.
247. Vaulpre JM. De obesitate, comodis et noxis. Montepellier: Joannem-Franciscum Picot, 1782.
248. Fecht EH. Disputatio medica inauguralis de obesitate
nimia. Rostochi: J. Wepplingii, 1701.
249. Triller DW. De pinguedine seu succo nutritio superuo. Halae: Type C. Henklii, 1718.
250. Bass G. Dissertationem inauguralem medicam de
obesitate nimia. Erfordiae: Preolo Heringii, 1740.
251. Bertram JW. Dissertatio inauguralis medica de pinguedine. Halae Magdeb: J.C. Hilligeri, 1739.
252. Bon J. Dissertatio medica inauguralis. De mutatione
pinguedinis. Harderovici: Apud Johannem Moojen,
1742.
30
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
Bray
Bougourd O. An obesis somnus brevis salubrior?
Paris: 1733 [thesis].
Dissertatio inauguralis medica de obesitate: Viennae:
Typis Joan Thomae Nobil. de Trattnern, 1776.
Ebart FCW. Dissertatio inauguralis medica de obesitate nimia et morbis inde orindus. Small quarto ed.
Gottingen: Lit J.H. Schulzii, 1780.
Hoelder FB. Obesitatis corporis humani nosologia.
Tubingae: Lit Schrammianis, 1775.
Homeroch CF. De pinguedine ejusque sede tam
secundum quam preaeter naturam constitutis. Lipsiae:
Ex Ocian Langenhemiana, 1996.
Hulsebusch JF. Dissertatio inauguralis medica sistens
pinguedinis corporis humani, sive panniculi adiposi
veterum, hodie membranae cullulosae dictae fabricam,
ejusque, & contenti olei historiam, usum, morbos.
Lugduni Batavorum: Joh Arnold Langerak, 1728.
Jansen WX. Pinguedinis animalis consideratio physiologica et pathologica. Lugduni Batavorum: J. Hazebroek, A. van Houte et Ardream Koster, 1784.
Kroedler JS. Theses inauguralis medicae de eo quod
citius moriantur obesi, quam graciles secundum
Hippocratis aphorismum XLIV. Sect II. Erfordiae:
Typis Groschianis, 1724.
La Sone JMF. An in macilentis liberior quam in obesis
circulatio. Paris: Quillau, 1740.
Locke SCJ. De celeri corporum incremento causa
debilitatis in morbis. Lipsiae: ex ocina Langenhemia,
1760.
Lohe AW. Exhibens de morbis adipis humani principia generalia. Duisburg, 1772.
Muller PA. Dissertatio physiologica de pinguedine
corporis. Hafniae: Typis Andreae Hartvigi Godiche,
1766.
Oswald JH. Obesitatis corporis humani therapia.
Tubingae: Litteris Schrammianis, 1775.
Person C. An parcior obesis, quam macilentis sanguinis missio. Paris: Quillau, 1748.
Pohl JC. Dissertationem inauguralem de obesis et
voracibus eorumque vitae incommodis ac morbis.
Lipsiae: J.C. Langenhemii, 1734.
Polonus SI. Dissertatio medica inauguralis de pinguedine. Harderovici: Typis Everardi Tyho, 1797.
Quabeck KJ. Dissertatio inauguralis medica de
insolito corporis augmento frequenti morborum futurorum signo. Halae Magdeb: J.C. Hendelii, 1752.
Redhead J. Dissertatio physiologica-medica, inauguralis, de adipe, quam annuente summo numine.
Edinburgh: Balfour et Smellie, 1789.
Riegels ND. De usu glandularum superrenalium
in animalibus nec non de origine adipis. Hafniae, 1790.
Reussing HCT. Dissertatio inauguralis medica de
pinguedine sana et morbosa. Jenae: Ex Ocina Fiedleriana, 1791.
Riemer JA. De obesitatis causis praecipuis. Halae and
Salem: Stanno Hendeliano, 1778.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
292.
Historical Framework
293.
294.
295.
296.
297.
298.
299.
300.
301.
302.
303.
31
304.
305.
2
Evaluation of Total and Regional Adiposity
Steven B. Heymsfield, Wei Shen, and ZiMian Wang
Columbia University College of Physicians and Surgeons and St. Lukes-Roosevelt Hospital, New York,
New York, U.S.A.
Richard N. Baumgartner
University of New Mexico School of Medicine, Albuquerque, New Mexico, U.S.A.
David B. Allison
The University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
Robert Ross
Queens University, Kingston, Ontario, Canada
INTRODUCTION
34
II
Heymseld et al.
ADIPOSITY COMPONENTS
man obesity. Each body composition level of the individual has a representation of adiposity (3). We now
review the main features of the ve body composition
levels with a focus on adiposity-related components.
A
Atomic Level
Molecular Level
The main atomic level elements, including trace elements that occur in low but essential concentrations,
combine to form various chemical compounds that may
be grouped into the broad classes that dene the molecular level of body composition. The main components
of the molecular level are shown in Figure 4 and include
water, lipids, proteins, minerals, and glycogen (3). Each
of the nonaqueous components represents many dier-
35
ent but closely related chemical compounds. For example, the protein component consists of several hundred dierent specic proteins.
Lipid is the main molecular-level component of
interest in the study of human obesity. The term lipid
refers to all chemical compounds that are insoluble or
weakly soluble in water, but are soluble in organic
solvents such as chloroform and diethyl ether (5). Lipids
isolated from human tissues include triglycerides,
sphyngomyelin, phospholipids, steroids, fatty acids,
Carbon
Hydrogen
Oxygen
77.4
75.9
76.9
76.7
76.7
11.8
12.2
11.9
12.1
12.0
10.9
11.9
11.2
11.2
11.3
36
Heymseld et al.
Component
Water
Protein
0.99371 at 36jC
0.9934 at 37jC
1.34 at 37jC
Glycogen
1.52 at 37jC
Minerals
Bonea
3.042
2.982 at 36-36.7jC
Nonbone
Lipid
Adipose tissue
extracts
3.317
0.9007 at 36jC
Elemental
stoichiometry
0.111 H; 0.889 O
0.532 C; 0.070 H;
0.161 N; 0.227 O;
0.01 S
0.444 C; 0.062 H;
0.494 O
0.398 Ca; 0.002 H;
0.185 P; 0.414 O
0.767 C; 0.120 H;
0.113 O
a
Calculated from the largest component of bone mineral, calcium
hydroxyapatite [Ca3(PO4)2]3Ca(OH)2. Other small elemental contributions to bone, such as Na, are recognized.
Sources: Refs. 46.
1
2
Cellular Level
37
Internal adipose tissue is found in the visceral compartment and in nonvisceral sites. The most important
internal adipose tissue component in the obesity eld is
found in the visceral compartment. The word viscera is
Latin for organs in the cavities of the body, usually
applied to the heart and lungs as thoracic viscera and the
stomach and intestines as abdominal viscera. Since
there are three main body cavitiesthoracic, abdominal, and pelvicthere are three corresponding visceral
adipose tissue (VAT) components (Table 3). However,
the medical literature varies widely in dening VAT
based on imaging methods. This topic is reviewed in the
section on imaging methods. Very few human studies in
the obesity eld examine intrathoracic VAT, including
pericardial, epicardial, and periaortic adipose tissue.
Of the nonvisceral internal adipose tissue, interstitial
adipose tissue is interspersed within the cells of a tissue
(e.g., skeletal muscle) so tightly that it may be included
with the tissue/organ at dissection. Adipose tissue is
almost absent in some anatomic sites such as the penis,
Figure 6
Ref. 3.)
38
Heymseld et al.
MEASUREMENT METHODS
Body Weight and Stature
Standardized methods have been described for measuring weight and stature, as well as other anthropometric
variables (19). For most clinical research purposes, it is
desirable to measure body weight to the nearest F 0.1 kg
using a high-quality calibrated beam-balance or electronic scale. Subjects should be measured either nude
or wearing standardized light clothing of known weight.
Whole-Body Level
39
and
W aSb
40
Heymseld et al.
with sex = 1 for male and 0 for female (38). Body fat in
this investigation was evaluated using a four-component model as the reference method. The percent fat
prediction formula is applicable in Caucasians and
African Americans and a separate equation is available
for use in Asian subjects.
B
Body composition methods vary in several characteristics including cost, safety, technical complexity, port-
40
K Counting
41
(K/FFM)i
Fat-free
f FFMi
mass (kg) f FFMi (K/FFM)i
2.34
1.13
3.00
5.46
8.10
0.99
0.29
0.095
0.30
0.09
1.68
27.38
0.18
1.25
52.29
0.041
0.020
0.053
0.096
0.143
0.018
0.005
0.002
0.005
0.002
0.030
0.483
0.003
0.022
0.922
24.0
33.9
40.9
41.2
47.4
49.1
52.0
53.8
61.4
65.4
68.5
78.5
79.6
85.9
0.98
0.68
2.17
3.96
6.77
0.88
0.26
0.11
0.31
0.13
2.06
37.90
0.24
1.89
58.34
A group of methods referred to as whole-body counting/in vivo neutron activation analysis can be used to
estimate adiposity-related components. The methods
share in common the ability to quantify all main
elements at the atomic body composition level in vivo
including H, C, N, O, P, Ca, Cl, K, and Na (3). Once
these elements are known, it is possible to calculate,
42
Heymseld et al.
8
9
10
11
where all units are in kg, and TBC, TBN, and TBCa
represent total body carbon, nitrogen, and calcium,
respectively. Solving the simultaneous equations for
fat mass,
total body fat 1:30 TBC 4:45 TBN
0:06 TBCa
12
This last equation indicates that the total body carbon method measures total body fat as a function of
three elements, C, N, and Ca.
There are two important issues to consider with
respect to Eq. (12) are the coecients constant, and
can total-body carbon, nitrogen, and calcium be
measured accurately? Equation (8) includes the proportions of total body carbon as fat, protein, glycogen, and bone mineral. Equations (9), (10), and (11)
include the ratios between protein and nitrogen,
glycogen and protein, and carbon and calcium in
bone mineral. All of the ratios in Eqs. (9)(11) are
assumed constant, and it is useful to consider this
assumption in some detail.
Although triglycerides extracted from human tissues
vary in fatty acid composition, their carbon/triglyceride
ratios (C/TG) are very close to 0.77 (Tables 1 and 2).
The various stoichiometries indicate that the C/TG
ratio varies within a narrow range (0.7590.774). It is
therefore reasonable to assume a constant C/TG ratio
of 0.77 in Eq. (8), (13).
Total-body protein can be calculated from total
body nitrogen, and nitrogen can be measured by
prompt-g neutron activation analysis. This calculation
is based on the assumption that a constant ratio (0.16)
exists between nitrogen and protein [Eq. (9)]. Protein
includes almost all compounds containing nitrogen,
varying from simple amino acids to complex nucleoproteins (45). The current suggested chemical formula
for protein is C100H159N26O32N0.7. The C/protein and
N/protein ratios in this widely accepted formula are
0.532 and 0.16, respectively. Chemical analysis conrmed the ratios validity for most proteins analyzed,
although a few specic proteins have N contents that
43
48
b
!
Ca n ! Ca! Sc* !49 Sc
49
c 3:084 MeV
49
15
Hydrometry
16
17
18
where DC and DP* are the measured unknown component mass and tracer property, respectively. Combining
this formula with the above equation, a dilution model
is derived,
C P*DC=AP*
19
44
Heymseld et al.
Table 5 Fat-Free Body Mass Hydration (TBW/FFM) Evaluated in Nine Adult Human Cadavers
Gender
M
M
M
M
F
F
M
M
F
Mean
SD
Age (yr)
BM (kg)
TBW (kg)
FFM (kg)
TBW/FFM
Cause of death
46
60
25
63
59
42
48
35
67
49
14
53.8
73.5
71.8
58.6
25.9
45.1
62.0
70.6
43.4
50.1
15.8
29.7
37.2
44.4
35.0
13.3
25.3
43.9
47.9
32.0
34.3
10.8
43.3
53.0
61.1
48.0
18.2
34.5
59.3
61.7
39.6
46.6
14.5
0.686
0.702
0.726
0.729
0.731
0.733
0.740
0.776
0.808
0.737
0.036
Skull fracture
Heart attack
Uremia
Esophageal cancer
Extreme cachexia
Drowning
Infective endocarditis
Mitral insuciency
Advanced malignancy
BM, body mass; F, female; FFM, fat-free body mass; M, male; TBW, total body water; TBW/FFM, ratio of total body water to fat-free body
mass.
Source: Ref. 10.
Hydrodensitometry/Air Displacement
Plethysmography
a. Hydrodensitometry
Hydrodensitometry, often referred to as underwater weighing, is one of the oldest in vivo methods of
analyzing human body composition as a two-component (i.e., fat and FFM) model (58).
Hydrodensitometry is based on the Archimedean
principle that a solid object submerged in water is
subject to a buoyant force that is equal to the weight
of the water displaced by the object, or the loss in
weight of the object when it is weighed while submerged
in the water. Thus, the specic gravity or density of
the object can be determined from the weight of the
object divided by the loss in weight when submerged in
water. The human body generally has a density close to
that of water (i.e., 1.0 g/cm3). Individual deviations
from this value are mainly due to the amount of fat in
the body. Because fat is less dense than water, the lower
the body density, the greater the amount of body fat.
Behnke was the rst to show that this method could be
used to deduce the percentage of weight that is fat from
body density using a simple two-component model that
assumes specic densities for fat and fat-free fractions
of body weight (13,59).
Lipid extracts of human adipose tissue, which are
mostly triglycerides, have a mean density of 0.9007 g/
cm3 at body temperature (60) (Table 2). The density of
FFM has been estimated to be 1.100 g/cm3 based on
data from cadaver studies (61). Fat-free body mass is
assumed to be composed of constant proportions of
water (73.2%), minerals (6.8%), and protein (19.5%)
with residual amounts (<1%) of other chemical components (e.g., glycogen). The densities of these individual chemical components are also considered to be
constants at body temperature (Table 2). Human body
45
46
Heymseld et al.
47
Figure 10 Schematic representation of DXA system (left) and three-component model consisting of bone mineral, lean soft
tissue, and fat. (From Ref. 17.)
48
Heymseld et al.
theoretical calculations suggests that percent fat estimates by DXA are minimally inuenced by changes in
hydration within the physiological range (79). Observational studies have compared DXA, with favorable
outcomes, to estimates from hydrodensitometry, total
body water, and multicomponent models in subject
groups over wide ranges of body fatness (80,81). It is
important to note that few studies were specically
designed to test the accuracy of DXA in moderately or
severely obese subjects.
Most studies show that DXA estimates of body
composition are highly reproducible. This has been
evaluated in a variety of experiments. Reported technical errors for estimates of percent fat ranged from 0.3%
to 1.4%; errors for FFM range from 0.3 to 0.9 kg
(69,80). Reported coecients of variation range from
0.5% to 4% for percent body fat, 1% to 1.7% for fat
mass, and 0.7%, to 1.0% for FFM (78,82). Although
there is substantial evidence that DXA estimates lose
accuracy with increasing body thickness, reports are
conicting as to whether thickness results in a systematic bias toward either over- or underestimation of body
fatness (76). These conicting results might be attributable to the use of dierent scanners and versions of
software incorporating dierent calibration standards
and thickness corrections. In any event, it is reasonable
to expect that DXA estimates will lose both accuracy
and precision in thicker obese subjects.
The DXA approach is rapidly becoming the most
available and established of the reference body composition methods as systems are well designed and
provide accurate and reproducible results, studies in
children are possible, and there exists the possibility of
transporting systems in a mobile van. The disadvantages of DXA are that it cannot be used in pregnant
women, the cost of purchasing and operating the
system is relatively high, and very large or obese
subjects cannot be easily accommodated on most
available systems. An ongoing and unresolved debate
centers on the superiority of fan beam versus pencil
beam systems, and on other system characteristics that
dier among manufacturers.
The application of DXA to the body composition
analysis of obese patients is subject to additional practical limitations. Many obese individuals will simply be
too wide for the scan eld (f190 60 cm) as the soft
tissue falling outside of the scan eld will not be included
in the body composition analysis, resulting in biased
estimates. As a result, DXA manufacturers generally do
not recommend scanning individuals >100 kg body
weight. This represents a serious limitation to the application of DXA body composition analysis, and it also
49
Imaging Methods
Imaging methods, such as CT and MRI, are considered the most accurate means available for in vivo
quantication of body composition on the tissue system level. Although access and expenses remain
obstacles to routine use, these imaging approaches
are now used extensively in body composition research. CT and MRI are the methods of choice for
calibration of eld methods designed to measure adipose tissue and skeletal muscle in vivo, and are the only
methods available for measurement of internal tissues
and organs. More recently both methods have been
employed to measure the quality of various tissues, in
particular, skeletal muscle tissue.
Multicomponent Models
a.
Computed Tomography
50
Heymseld et al.
Lohman (54)
Properties
BW, BV
BW, BV
BW, BV
Components
Water
BW=FM+water +protein+mineral
Mineral
BV=FM/0.900+water/0.994
+protein/1.34+mineral/3.04
protein=2.40mineral
BW=FM+water+protein+mineral
Water,
TBBM
BV=FM/0.9007+water/0.994
+protein/1.34+mineral/3.04 water
=4.00protein
BW=FM+water+protein+
TBBM+Ms
Selinger (89)
BW, BV
Water,
TBBM
Heymseld (90)
BW, BV
Water,
TBBM
Wang (86)
BW, BV
Simultaneous equations
Water,
Mo, MS
BV=FM/0.9007+water/0.994
+protein/1.34+TBBM/2.982
+Ms/3.317
Ms=0.235TBBM
BW=FM+water+protein
+TBBM+Ms
BV=FM/0.9007+water/0.994
+protein/1.34+TBBM/2.982
+Ms/3.317
Ms=0.0105BW
BW=FM+water+TBBM+residual
BV=FM/0.9907+water/0.99371
+TBBM/2.982+residual/1.404
BW=FM+water+protein
+Mo+Ms
BV=FM/0.9007+water/0.99371
+Protein/1.34+Mo/2.982
+Ms/3.317
FM=6.386BV+3.961
mineral6.09BW
FM=2.75BV 0.714
water+1.148mineral
2.05BW
FM=2.75BV0.714
water
+1.129TBBM2.037
BW
FM=2.513BV 0.739
water
+0.947TBBM1.79
BW
FM=2.748BV0.715
water+
1.129Mo+1.222Ms
2.051BW
Abbreviations: BV, body volume (liter); BW, body weight (kg); FM, fat mass (kg); Mo, osseous mineral; Ms, soft tissue mineral (kg); TBBM
(kg)=ashed bone from DXA1.0436.
Source: Ref. 15.
51
52
Heymseld et al.
Figure 11 CT images of the proximal thigh for a lean (left) and obese (right) subject. The darker-appearing pixels within the
skeletal muscle tissue of both subjects have attenuation values (Hounseld Units) between 0 and 100. Skeletal muscle attenuation
is determined by measuring the mean attenuation value from all pixels within the range of 0 to 100 HU. The lower the mean
attenuation value, the greater the inltration of lipid within the muscle. The mean attenuation value of the skeletal muscle of the
obese subject is lower (i.e., darker pixels) by comparison to the lean subject.
by the MRI systems instrumentation. Hydrogen protons have a nonzero magnetic moment which cause
them to behave like tiny magnets. When a subject is
placed inside the magnet of a magnetic resonance
imager, where the eld strength is typically 10,000 times
stronger than the earths, the magnetic moments of the
protons align themselves with the magnetic eld. Having aligned the H protons in a known direction, a pulsed
radiofrequency eld (RF) is applied to the body tissues
causing a number of hydrogen protons to absorb
energy. When the RF is turned o, the protons gradually return to their original positions, releasing in the
process the energy that they absorbed in the form of an
RF signal. It is this signal that is used to generate the
magnetic resonance images by computer.
Foster et al. (117) were among the rst to illustrate
the applicability of MRI to body composition analysis.
Hayes et al. (118) rst demonstrated the quantication
of subcutaneous adipose tissue distribution in human
subjects using MRI. A variety of studies have subsequently used MRI to quantify adipose tissue and/or
lean tissue areas or volumes in children (119), normal
males and females (120122), obese males and females
(123,124), diabetics (124), and elderly people (125). To
date several groups have employed MRI to evaluate
whole body adipose tissue and lean tissue distribution in
human subjects (120122c).
Historically, an important problem with the application of MRI to body composition analysis has been
the substantial time needed to obtain images of
sucient quality and resolution for reliable measurements. For example, depending on the pulse sequence
used, the acquisition of a set of MRI images for the
abdomen could require between 8 (120) and 16 min
(126). Recent advances in MRI technology have
reduced the time needed to obtain the same quality
images of the abdomen to f25 sec, and a series of
images for whole body analysis can be acquired in
<30 min (127). These advances should make MRI a
much more accessible instrument for body composition studies in the future.
A multislice MRI protocol for whole body analysis is
illustrated in Figure 5 (127). The pulse sequence used to
obtain images of the abdomen in this protocol requires
26 sec. During this time the subject must hold his/her
breath to reduce the eects of respiratory motion on
image quality.
A factor that has impeded the use of MRI in body
composition analysis has been the availability of
appropriate image analysis software. In contrast to
CT, this software is not generally included on most
MRI control consoles. As a result, MRI image data
usually must be translated and downloaded to a
separate workstation with image analysis software.
Once this is accomplished, the approach to the analysis of MRI images is similar to that used for CT
images. The perimeter of the tissue of interest can be
traced using a light pen or mouse-controlled pointer,
and the area within the perimeter can be calculated by
multiplying the number of pixels in the highlighted
region by their known area (128,129). Alternatively,
image segmentation algorithms can be used that highlight all pixels within a selected range of intensities
believed to be representative of a specic tissue. The
latter approach, however, is considered more problematic when applied to MRI than to CT images for three
reasons: (1) the distributions of pixel intensity (gray
scale) values for dierent tissues overlap more for
MRI than for CT images; (2) noise due to respiratory
motion blurs the borders between tissues in the abdomen to a greater extent in MRI than in CT; and (3)
inhomogeneity in the magnetic eld can produce
shading at the peripheries of MRI images.
Once tissue areas have been quantied from MRI
images, volumes (cm3) and masses may be calculated in
a manner similar to that described above for CT. Ross
(120), however, has dened a somewhat dierent mathematical formula for deriving tissue volumes from
measurements of a series of axial MRI images. This
formula recognizes that each image has a slice thickness
and that the pixels identied for a tissue are actually
volume elements, or voxels. Thus, the formula is based
53
54
Heymseld et al.
Subjects (N)
Comparison with CT
Seidell et al. (126)
Sobel et al. (132)
Ross et al. (130)
Comparison with cadavers
Engstrom et al. (131)
Mitsiopoulos et al. (133)
IV
SCAT
Visceral AT
Total AT
SM
Human (7)
Human (11)
Rats (21)
Midabdomen
Umbilicus
Whole body
0.79 (4.9)
0.98 (8)
0.98 (12)
0.79 (12.8)
0.93 (20)
0.98 (13.6)
0.99 (4.4)
0.99 (8.7)
Human (3)
Human
0.99 (7.6)
0.99
0.97 (10)
AT, adipose tissue; IV, independent variable; SC, subcutaneous; SEE, standard error of estimate; SM, skeletal muscle; SCAT, subcutaneous
adipose tissue; %, percent; CSA, cross-sectional area.
Source: Ref. 129a.
Subject (N)
Staten et al.
Seidell et al. (134)
Garard et al. (138)
Ross et al. (130)
Ross et al. 1993 (139)
Sohlstrom et al. (121)
Ross et al. (140)
Abate et al. (129)
Ross et al. (141)
Mitsiopoulos et al. (133)
a
MRI Sequence
Anatomical position
SCAT
Visceral AT
Total AT
LT
Human (6)
Human (7)
Human (4)
Rats (11)
Human (3)
0.5
1.5
1.5
1.5
1.5
SE
IR
SE
SE
SE
Human (3)
Human (11)
Cadavers (3)
Human (19)
Cadavers (6)
0.02
1.5
0.35
1.5
1.5
SR
SE
SE
SE
SE
Midabdomen
Umbilicus
6 Abd. images
Whole body
L4-L5
Whole body
Whole body
Proximal thigh
Abdomen
L4-L5
Arm and leg slices
5.0
10.1
3.0
1.1
1.7
2.2
2.5
10.0
10.6
9.0
5.5
5.3*
6.0
3.0
5.4
4.3
2.5
1.5
1.2
1.0
2.6
55
Figure 12 Illustration of the MRI protocol used to acquire axial images throughout the whole body. Both sequences employ a
T1-weighted spin-echo scheme. The principal dierence is that the abdomen sequence uses a one-half Fourier transformation
pulse sequence (l/2 NEX). Using these parameters reduces the time required to obtain the data set to 26 sec during which the
subject is asked to hold his/her breath. Although the signal-to-noise ratio is decreased using this scheme, the limitation is oset by
the reduction in respiratory motion artifact normally associated with the acquisition of MR images in the abdomen region.
56
Heymseld et al.
Figure 13 Illustration of conventional T1-weighted image (left) with corresponding water suppressed lipid images (right)
obtained from a normal weight subject. The lipid image is obtained using a spiral MR imaging scheme for direct quantication of
the lipid MRI signal in skeletal muscle.
57
Figure 14 (Left) CT image of the abdomen illustrating the subdivision of abdominal subcutaneous adipose tissue (AT) into
deep and supercial depots using the fascia supercialis (highlighted for clarity). The deep layer surrounds the abdomen
but the majority of deep subcutaneous AT is located posteriorly. (Right) MRI image of the abdomen at the L4-L5 level. The
fascia supercialis on MR images is often dicult to observe using standard acquisition sequences thus, an arbitrary line is drawn
horizontally using the vertebral disk as an anatomical landmark to divide abdominal subcutaneous AT into anterior and
posterior depots. In men posterior AT is analogous to deep subcutaneous AT because a majority the deep AT is located
in the posterior region. This assumption is likely untrue for women.
58
Heymseld et al.
Imaging Summary
Anthropometry
59
adipose tissue that are taken using calipers at standardized locations on the body. The essential technique is to pinch and elevate a skinfold at specic
anatomical sites using the thumb and ngers and to
measure the thickness of the fold with specially designed
calipers. These measurements are correlated with, but
are not directly representative of, the actual thickness of
subcutaneous adipose tissue. This has been illustrated
by comparisons of skinfold thickness measurements
with radiographic and ultrasound measurements of
subcutaneous adipose tissue thickness at dierent anatomical sites (51,162,163). Because f7090% of total
adipose tissue is subcutaneous, skinfold thicknesses can
be used to grade or predict total body fat (164). In
addition, since the thickness of subcutaneous adipose
tissue varies among anatomical locations, skinfold
thicknesses are useful for describing subcutaneous adipose tissue distribution or fat patterning. They are
not useful, however, for predicting amounts of intraabdominal adipose tissues.
Carefully standardized methods of measuring skinfold thicknesses have been developed and it is important
to adhere strictly to these to ensure reliable measurements that are comparable with published tables of
reference data, and that can be used in appropriate
equations for predicting body fat (165). A variety of
skinfold calipers are available and measurements may
dier systematically among brands depending on quality and the control of pressure between the jaws of the
calipers. Jaw pressure is important because skinfolds
vary within and between individuals in compression
when measured (162,165). Variability in compression
is a major factor aecting the reliability of skinfold
thickness measurements. Calipers with dierent jaw
pressures will produce systematically dierent readings,
and those with manually controlled jaw pressures will be
less reliable than those with built-in spring mechanisms.
As a result, the use of dierent brands of skinfold
calipers within a study is not recommended unless their
systematic dierences are known. Research-quality calipers (e.g., Holtain, Lange, Harpenden) exert a constant
pressure of 10 g/cm3 between the jaws and have a ner
scale of measurement (i.e., 0.1-mm intervals) than the
inexpensive, plastic calipers marketed for clinical use
(165).
In theory, skinfold thicknesses can be measured anywhere on the body that a double fold of skin and subcutaneous adipose tissue can be pinched and elevated. In
practice, only a few standard sites are commonly measured based on their accessibility, ease of measurement,
and high correlation with measures of total body fat.
The triceps and subscapular sites meet these criteria best
60
Heymseld et al.
Ultrasound
Circumferences
Body circumferences are useful in that, unlike skinfold thicknesses, they can always be measured, even in
extremely obese subjects. Circumferences reect internal as well as subcutaneous adipose tissue, but are also
inuenced by variation in muscle and bone. As a result,
the interpretation of circumference measurements, and
especially circumference ratios, is often not straightforward. As for all anthropometric variables, body circumferences should be measured with close attention to
standardized procedures (19). Flexible, inelastic cloth
or steel tapes are recommended.
The most useful circumferences for grading or predicting body fat and for describing adipose tissue distribution are upper arm, chest, waist or abdomen, hip or
buttocks, proximal or midthigh, and calf (19,165).
Waist or abdomen circumferences are usually very
highly correlated with total fat mass and percent body
fat in men (r>.85); in women, hip or thigh circumferences may have slightly higher correlations. Correlations of upper arm, thigh, and calf circumferences with
measures of body fat are somewhat lower, and these
circumferences tend to be more strongly inuenced by
variation in appendicular skeletal muscle.
d.
61
62
Heymseld et al.
63
fourth lumbar vertebrae, or the iliac crests. It is important to note that the choice between these landmarks
will result in measurements at very dierent levels on the
trunk or abdomen. Sliding calipers with long, parallel
blades are necessary for this measurement.
Although sagittal trunk thickness may be taken with
the participant standing, measurement in the supine
recumbent position may be preferred to maximize the
association with the latent variable, intra-abdominal
adipose tissue volume. Theoretically, when a person
with an enlarged intra-abdominal adipose tissue mass
lies supine, the mass shifts cranially, causing anterior
projection of the abdomen, which is measured as
increased sagittal thickness (189). When a person is
standing, gravity pulls the intra-abdominal adipose
tissue mass downward, and the maximum sagittal thickness may be located somewhat lower. It is important to
keep in mind that the level of the maximum measurable
diameter, either supine or standing, will likely vary
among some subjects. The extent to which these measurements are inuenced by the amount of subcutaneous
abdominal adipose tissue, and shifts in its distribution
between supine and standing measurements, is not
well established.
Results for the use of sagittal thickness to grade or
predict VAT volume in several Swedish studies have
been summarized by Sjostrom (189). VAT volume was
estimated using seven cross-sectional CT scans of the
abdomen. Sagittal thickness was measured on the CT
image at the level of L4-L5. VAT volume was regressed
on sagittal thickness (ST) in 17 men producing an
equation, VAT (L)=0.731ST (cm)-11.5, (R2=0.81).
This equation was later cross-validated in two independent samples of 7 and 13 men, respectively, with virtually
indistinguishable results. A similar regression equation
was developed using data for 10 women and crossvalidated in nine independently selected women: VAT
(L) = 0.370 ST(cm) 4.85, (R2 = .80). Sjostrom and
associates also showed that changes in VAT volume
were accurately tracked by changes in sagittal thickness
in six patients with Cushings disease during treatment.
Pouliot et al. (185) analyzed associations of sagittal
thickness with VAT area on CT images at L4-L5 in 81
men and 70 women, 3042 years of age. Sagittal thickness correlated better with VAT area than waist/hip
ratio in both sexes; however, it was also correlated
strongly with subcutaneous abdominal adipose tissue
area. Taken together, the results of the studies by
Sjostrom et al. (189) and Pouliot et al. (185) indicate
that sagittal thickness is somewhat more sensitive than
conventional indices such as waist/hip ratio for grading
or predicting the amounts of VAT.
64
Heymseld et al.
Bioimpedance Analysis
Bioimpedance analysis (BIA) is a technique for predicting body composition based on the electrical conductive
properties of the human body. The ability of the body to
conduct an electric current is due to the presence of free
ions, or electrolytes, in the body water. The amount of
electricity that can be conducted is determined mainly
by the total volume of electrolyte-rich uid in the body.
Measures of bioelectric conductivity are therefore proportional to TBW and to body composition com-
65
21
ERRORS OF ESTIMATION
66
Heymseld et al.
VI
REFERENCE VALUES
67
Table 9 Selected Anthropometric and Impedance Measures According to Age and Sex for Non-Hispanic Whites: NHANES III
(unpublished data)
Non-Hispanic white males
Age (years)
1213.9
1415.9
1617.9
1819.9
2029.9
3039.9
4049.9
5059.9
6069.9
7079.9
Anthropometric
measure
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Mean
Standard
deviation
Standard
error
88
51.7
159.6
20.1
31.3
18.4
68.3
172.2
23.0
40.6
18.4
70.9
177.0
22.6
43.1
17.7
73.1
176.9
23.3
43.2
19.6
79.2
177.5
25.1
45.5
21.8
84.0
177.8
26.5
47.2
23.6
86.0
177.3
27.3
48.0
24.2
86.9
176.7
27.8
47.9
25.1
84.9
175.3
27.6
46.2
26.2
79.3
172.4
26.7
44.0
25.1
12.3
8.4
3.5
6.3
7.3
20.5
7.6
6.3
7.0
8.3
13.8
7.9
4.0
6.2
6.8
15.0
6.7
4.2
5.8
6.9
16.6
6.7
4.9
6.9
6.2
17.1
6.8
4.6
7.6
5.8
17.0
6.7
4.9
7.8
5.7
15.0
6.2
4.6
6.5
6.0
14.7
6.3
4.2
6.6
5.5
13.3
6.7
4.0
6.4
5.5
1.5
0.9
0.4
0.8
1.0
2.5
0.8
0.8
0.9
1.2
1.6
0.8
0.5
0.8
0.9
1.9
0.8
0.6
0.8
1.0
0.9
0.3
0.3
0.4
0.4
0.9
0.3
0.3
0.4
0.4
0.9
0.3
0.3
0.5
0.4
0.8
0.3
0.3
0.4
0.4
0.8
0.3
0.2
0.4
0.3
0.7
0.3
0.2
0.4
0.3
82
96
76
384
436
410
396
465
447
Mean
Standard
deviation
Standard
error
101
52.1
157.8
20.9
28.5
24.8
57.8
162.6
21.9
29.9
29.1
61.1
164.5
22.5
30.7
30.7
63.7
164.9
23.4
31.9
30.8
63.2
163.6
23.6
31.8
31.0
69.1
164.6
25.5
33.5
33.0
70.7
163.4
26.6
33.3
35.4
73.9
162.4
28.0
33.8
37.3
70.3
160.8
27.2
32.5
36.9
67.1
158.3
26.7
31.6
35.9
13.3
8.2
4.7
4.2
9.7
10.5
6.0
3.8
3.7
6.5
14.5
6.6
4.9
4.0
6.9
15.0
5.8
5.5
4.2
7.9
14.3
6.7
5.1
4.5
7.5
18.0
6.3
6.5
5.1
8.5
16.8
6.1
6.5
5.2
6.9
17.4
6.0
6.4
5.1
7.1
15.1
6.1
5.6
4.8
6.9
14.5
6.8
5.3
4.9
6.9
1.6
1.0
0.6
0.6
1.2
1.2
0.7
0.4
0.5
0.8
1.7
0.8
0.6
0.5
0.9
1.9
0.7
0.7
0.6
1.0
0.8
0.4
0.3
0.3
0.5
0.9
0.3
0.3
0.3
0.5
1.0
0.3
0.4
0.3
0.4
1.0
0.3
0.4
0.3
0.4
0.9
0.4
0.3
0.3
0.4
0.8
0.4
0.3
0.3
0.4
120
104
90
426
543
454
454
447
538
68
Heymseld et al.
Table 10 Selected Anthropometric and Impedance Measures According to Age and Sex for Non-Hispanic Blacks: NHANES
III (unpublished data)
Non-Hispanic black males
Age
(years)
Anthropometric
measure
1213.9
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
1415.9
1617.9
1819.9
2029.9
3039.9
4049.9
5059.9
6069.9
7079.9
Mean
124
52.1
157.9
20.7
30.7
19.5
64.4 171.5
21.8
38.9
17.8
131
126
118
462
454
339
191
258
145
68.7
173.8
22.7
41.2
18.6
74.7
176.6
23.8
44.1
19.9
82.9
177.1
26.3
46.1
23.7
82.9
177.2
26.4
46.5
23.6
83.6
176.5
26.8
46.1
24.9
83.7
175.2
27.2
45.9
25.1
80.9
173.6
26.8
44.7
24.9
77.0
171.6
26.2
43.2
24.3
Standard
deviation
Standard
error
16.7
10.1
5.2
7.0
8.9
15.4
7.7
4.7
6.7
7.5
14.5
7.2
4.1
6.6
6.4
16.4
7.2
4.4
7.5
6.0
20.5
7.4
5.8
8.0
7.0
17.9
6.6
5.4
7.7
6.7
17.2
7.3
4.8
7.5
6.1
19.4
6.6
5.7
8.5
6.7
16.2
6.6
4.9
7.7
6.6
15.5
7.1
4.8
7.4
6.3
1.5
1.0
0.5
0.7
1.1
1.4
0.8
0.4
0.7
9.0
1.3
0.7
0.4
0.7
0.8
1.5
0.7
0.4
0.8
0.8
1.0
0.4
0.3
0.4
0.4
0.9
0.3
0.3
0.4
0.4
1.0
0.4
0.3
0.5
0.5
1.4
0.5
0.4
0.7
0.7
1.0
0.5
0.3
0.5
0.6
1.3
0.7
0.4
0.7
0.7
Mean
Standard
deviation
Standard
error
156
55.1
159.6
21.5
29.3
26.9
62.0
163.1
23.2
30.9
30.9
64.0
163.9
23.8
31.0
32.6
65.8
163.6
24.6
31.4
33.3
70.4
163.7
26.2
32.8
35.5
76.7
163.7
28.6
34.4
38.0
81.5
164.2
30.2
35.8
39.4
80.7
162.5
30.6
35.2
40.0
77.6
161.1
29.9
34.0
39.8
74.0
159.4
29.1
33.4
38.5
13.3
7.3
4.4
4.1
8.8
16.3
7.1
5.3
5.3
8.0
15.8
7.0
5.7
4.2
8.5
18.6
6.3
6.7
5.5
8.7
16.7
6.1
6.0
4.9
7.5
20.2
6.7
7.4
5.8
7.7
21.1
6.1
7.4
6.0
7.0
19.4
5.8
7.1
5.8
7.5
18.3
6.3
7.0
5.6
6.9
16.5
5.7
6.3
5.3
6.7
1.2
0.7
0.4
0.4
0.8
1.8
0.8
0.6
0.7
0.9
1.6
0.7
0.6
0.5
0.9
2.0
0.7
0.8
0.7
1.0
0.8
0.3
0.3
0.3
0.4
1.0
0.3
0.4
0.3
0.4
1.2
0.4
0.4
0.4
0.4
1.5
0.5
0.6
0.5
0.6
1.3
0.5
0.5
0.4
0.5
1.5
0.6
0.6
0.6
0.6
102
126
110
510
569
395
231
258
149
69
Table 11 Selected Anthropometric and Impedance Measures According to Age and Sex for Mexican-Americans: NHANES III
(unpublished data)
Mexican-American males
Age
(years)
Anthropometric
measure
1213.9
Mexican-American females
Mean
Standard
deviation
Standard
error
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
132
52.7
156.0
21.4
30.2
22.0
62.5
167.2
22.2
37.2
18.8
67.9
170.5
23.3
39.6
21.3
72.8
171.9
24.6
41.5
22.7
73.9
170.0
25.6
41.6
24.1
78.4
170.6
26.9
43.4
25.4
82.0
169.7
28.4
44.7
26.6
14.1
9.2
4.6
6.2
8.2
16.6
8.5
5.1
6.9
7.7
12.2
6.7
3.7
5.5
5.4
13.9
6.3
4.4
5.9
5.7
13.9
6.4
4.2
6.1
6.0
14.2
7.0
4.3
6.5
5.4
14.5
6.3
4.4
6.6
5.3
5059.9
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
165
82.6
169.3
28.7
45.0
26.7
6069.9
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
Weight (kg)
Stature (cm)
BMI (kg/m2)
TBW (L)
%fat
301
78.2
168.3
27.6
42.6
26.7
72.3
165.5
26.3
39.9
26.1
1415.9
1617.9
1819.9
2029.9
3039.9
4049.9
7079.9
108
126
109
631
443
361
118
Mean
Standard
deviation
Standard
error
1.5
0.9
0.5
0.7
1.0
1.9
0.9
0.6
0.9
1.1
1.3
0.7
0.4
0.6
0.7
1.6
0.7
0.5
0.7
0.8
0.7
0.3
0.2
0.3
0.4
0.8
0.4
0.2
0.4
0.4
0.9
0.4
0.3
0.5
0.4
139
53.3
155.4
21.9
27.9
28.6
56.2
157.7
22.5
28.1
31.8
62.2
159.3
24.5
30.2
33.3
59.6
157.7
23.9
28.9
33.5
64.8
157.6
26.1
30.5
35.8
70.6
156.9
28.6
32.2
38.0
73.4
157.2
29.7
32.6
39.9
12.3
6.5
4.5
4.2
7.6
10.7
6.0
3.7
3.7
6.3
15.5
5.8
5.7
4.5
7.1
13.1
5.7
4.9
3.7
6.8
14.5
6.2
5.5
4.3
7.0
17.1
6.3
6.4
4.8
7.1
13.9
5.4
5.6
4.3
5.5
1.2
0.7
0.5
0.5
0.8
1.2
0.7
0.4
0.4
0.7
1.7.
0.7
0.7
0.6
0.8
1.6
0.7
0.6
0.5
0.9
0.8
0.3
0.3
0.2
0.4
1.0
0.4
0.4
0.3
0.4
0.9
0.4
0.4
0.3
0.4
15.1
6.0
4.5
7.1
5.3
1.4
0.5
0.4
0.7
0.6
171
71.3
155.7
29.5
32.1
39.4
13.7
5.4
5.5
4.4
5.7
1.2
0.5
0.5
0.4
0.5
12.7
6.0
4.0
5.9
5.2
12.5
5.7
4.0
6.3
5.2
0.9
0.4
0.3
0.4
0.4
1.4
0.6
0.4
0.7
0.7
278
70.0
154.3
29.5
31.6
39.4
65.0
153.0
27.8
30.1
37.8
14.1
5.9
5.9
4.6
5.7
13.0
5.9
5.5
4.4
6.8
1.0
0.4
0.4
0.4
0.4
1.5
0.7
0.7
0.6
0.8
113
112
90
509
451
334
101
70
Heymseld et al.
VII
APPENDIX
Monographs on Body Composition Research Published
Since 1985
Norgan NG, ed. Human Body Composition and Fat
Distribution. EUR-NUT Report 8, 1985.
Roche AF, ed. Body-Composition Assessments in
Youth and Adults. Columbus, OH: Ross Laboratory, 1985.
Forbes GB. Human Body Composition: Growth,
71
Table 12 Main Qualitative Features of Available Body Composition Methods Used to Evaluate Adiposity-Related
Components
40
Accurate?
Reproducible?
Cost to purchase?
Cost to operate?
Technician training?
Radiation exposure?
Requires subject participation
Transportable?
Regional estimates?
Appropriate for:
Very obese adults?
Children?
Elderly?
IVNA
TBWa
UWW
ADP
DXA
MCM
MRIb
CTc
ANTH
BIA
...
....
...
...
...
...
....
....
....
..
..
..
..
..
..
....
...
...
...
....
....
....
..
...
...
...
....
....
...
...
..
..
..
..
..
...
...
..
..
..
..
..
..
..
...
...
..
....
..
..
....
...
..
...
....
..
..
....
....
YM
YM
NX
NX
NX
YM
NX
YM
YM
YM
YM
NM
YM
YM
NM
NX
YM
YM
YM
YM
YM
YM
YM
NX
YM
YM
NX
YM
YM
YX
YM
YM
NX
YM
YM
NX
NX
NM
YX
YM
YM
YM
YM
YM
Abbreviations: ANTH, anthropometry; ADP, air displacement plethysmography; BIA, bioimpedance analysis; CT, computerized axial
tomography; DXA, dual-energy x-ray absorptiometry; IVNA, in vivo neutron activation analysis; K, potassium; MCM, multicomponent models;
MRI, magnetic resonance imaging; N, no; TBW, total body water; UWW, underwater weighing; Y, yes.
Scale: . (least or none).... (most).
a
Assumes stable isotope.
b
Assumes four or more components and stable isotope for TBW.
Marriott BM, Grumstrup-Scott J, eds. Body Composition and Physical Performance: Applications for the
Military Services. Washington: National Academy
Press, 1992.
Lohman TG. Advances in Body Composition Assessment. Champaign, IL: Human Kinetics, 1993.
Ellis KJ, Eastman JD, eds. Human Body Composition:
In Vivo Methods, Models, and Assessment. New
York: Plenum, 1993.
Kral JG, VanItallie TB, eds. Recent Development in
Body Composition Analysis: Methods and Applications. London: Smith-Gordon, 1993.
Kreitzman SN, Howard AN, eds. The Swansea Trial:
Body Composition and Metabolic Studies with a
Very-Low-Calorie Diet (VLCD). London: SmithGordon, 1993.
WHO Expert Committee. Physical Status: The Use
and Interpretation of Anthropometry. Geneva:
WHO Technical Report Series 854, 1995.
Davies PSW, Cole TJ, eds. Body Composition Techniques in Health and Disease. Cambridge: Cambridge University Press, 1995.
Heyward VH, Stolarczyk L. Applied Body Composition Assessment. Champaign, IL: Human Kinetics,
1996.
Roche AF, Heymseld SB, Lohman TG, eds. Human
Body Composition: Methods and Findings. Champaign, IL: Human Kinetics, 1996.
Grimnes S, Martinsen G. Bioimpedance and Bioelectricity Basics. San Diego: Academic Press, 2000.
Yasamura S, Wang J, Pierson RN Jr, eds. In Vivo
Body Composition Studies. New York: New York
Academy of Sciences, 2000.
Pierson RN Jr, ed. Quality of the Body Cell Mass:
Body Composition in the Third Millenium. New
York: Springer-Verlag, 2000.
REFERENCES
1.
2.
3.
4.
5.
6.
72
Heymseld et al.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
73
sium, sodium, sulfate, and tritium space in 58 adults.
J Chron Dis 1982; 35:419428.
52. Culebras JM, Moore FD. Total body water and the
exchangeable hydrogen. 1. Theoretical calculation of
nonaqueous exchangeable hydrogen in man. Am J
Physiol 1997; 232:R54R59.
53. Wong WW, Cochran WJ, Klish WJ, Smith EO, Lee
LS, Klein PD. In vivo isotope-fractionation factors
and the measurement of deuterium, and oxygen-18
dilution spaces from plasma, urine, saliva, respiratory
water vapor, and carbon dioxide. Am J Clin Nutr
1988; 47:16.
54. Lohman TG. Applicability of body composition
techniques and constants for children and youths.
Exerc Sport Sci Rev 1986; 14:325357.
55. Waki M, Kral JG, Mazariegos M, Wang J, Pierson
RN Jr, Heymseld SB. Relative expansion of extracellular uid in obese vs. nonobese women. Am J
Physiol 1991; 261:E199E203.
56. Deurenberg P, Leenen R, Van der Kooy K, Hautvast
JGAJ. In obese subjects the body fat percentage
calculated with Siris formula is an overestimate. Eur J
Clin Nutr 1989; 43:569575.
57. Kooy KVD, Leenen R, Deurenberg P, Seidell JC,
Westerterp KR, Hautvast JGAJ. Changes in fat-free
mass in obese subjects after weight loss: a comparison
of body composition measures. Int J Obes 1992;
16:675683.
58. Wang ZM, Heshka S, Pierson RN Jr, Heymseld SB.
Systematic organization of body composition methodology: overview with emphasis on component-based
methods. Am J Clin Nutr 1995; 61:457465.
59. Behnke AR, Wilmore JH. Evaluation and Regulation
of Body Build and Composition. Englewood Clis,
NJ: Prentice-Hall, 1974.
60. Fidanza F, Keys A, Anderson JT. Density of body fat
in man and other mammals. J Appl Physiol 1953;
6:252256.
61. Brozek J, Grande F, Anderson T, Keys A. Densitometric analysis of body composition: a revision of some
assumptions. Ann NY Acad Sci 1963; 110:113140.
62. Siri WE. Body composition from uid spaces and
density. In: Brozek J, Henschel A, eds. Techniques in
the Measurement of Body Composition. Washington:
National Academy of Sciences, 1961:223244.
63. Murgtroyd PR, Coward WA. An improved method
for estimating changes in whole-body fat and protein
mass in man. Br J Nutr 1989; 62:311314.
64. Sawka MN, Weber H, Knowlton RG. The eect of
total body submersion on residual lung volume and
body density measurements in man. Ergonomics 1978;
21:8994.
65. Lohman TG. Advances in Body Composition Assessment. Champaign, IL: Human Kinetics, 1992.
66. McCrory MA, Gomez TD, Bernauer EM, Mole PA.
Evaluation of a new air displacement plethysmograph
74
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
Heymseld et al.
for measuring human body composition. Med Sci
Sports Exerc 1995; 27(12):16861691.
Collins MA, Millard-Staord ML, Sparling PB, Snow
TK, Rosskopf LB, Webb SA, Omer J. Evaluation of
the BOD POD for assessing body fat in collegiate
football players. Med Sci Sports Exerc 1999; 31(9):
13501356.
Wells JCK, Fuller NJ. Precision of measurement and
body size in whole-body air-displacement plethysmography. Int J Obes Relat Metab Disord 2001; 25:1161
1167.
Mazess RB, Barden HS, Bisek JP, Hanson J. Dualenergy x-ray absorptiometry for total-body and
regional bone-mineral and soft-tissue composition.
Am J Clin Nutr 1990; 51:11061112.
Pietrobelli A, Formica C, Wang ZM, Heymseld SB.
Dual-energy x-ray absorptiometry body composition
model: review of physical concepts. Am J Physiol
1996; 271: E941E951.
Van Loan MD, Keim NL, Berg K, Mayclin PL.
Evaluation of body composition by dual energy x-ray
absorptiometry and two dierent software packages.
Med Sci Sport Exerc 1995; 27:587591.
Brunton JA, Bayley HS, Atkinson SA. Validation and
application of dual-energy x-ray absorptiometry to
measure bone mass and body composition in small
infants. Am J Clin Nutr 1993; 58:839845.
Ellis KJ, Shypailo RJ, Pratt JA, Pond WG. Accuracy
of dual energy x-ray absorptiometry for body-composition measurements in children. Am J Clin Nutr 1994;
60:660665.
Svendsen OL, Haarbo J, Hassager C, Christiansen C.
Accuracy of measurements of body composition by
dual-energy x-ray absorptiometry in vivo. Am J Clin
Nutr 1993; 57:605608.
Heymseld SB, Wang J, Heshka S, Kehayias JJ,
Pierson RN. Dual-photon absorptiometry: comparison of bone mineral and soft tissue mass measurements in vivo with established methods. Am J Clin
Nutr 1989; 49:12831289.
Laskey MA, Lyttle KD, Flaxman ME, Barber RW.
The inuence of tissue depth and composition on the
performance of the Lunar dual-energy x-ray absorptiometer whole-body scanning mode. Eur J Clin Nutr
1992; 46:3945.
Snead DB, Birge SJ, Kohrt WM. Age-related dierences in body composition by hydrodensitometry and
dual-energy x-ray absorptiometry. J Appl Physiol
1993; 74:770775.
Going SB, Massett MP, Hall MC, Bare LA, Root PA,
Williams DP, Lohman TG. Detection of small changes
in body composition by dual-energy x-ray absorptiometry. Am J Clin Nutr 1993; 57:845850.
Testolin CG, Gore R, Rivkin T, Horlick M, Arbo J,
Wang ZM, Chiumello G, Heymseld SB. Dual-energy
x-ray absorptiometry: analysis of pediatric fat estimate
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
75
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
76
Ross R, Leger L, Morris DV, De Guise J, Guardo R.
Quantication of adipose tissue by, MRI: relationship
wit anthropometric variables. J Appl Physiol 1992;
72(2):787795.
121. Sohlstrom A, Wahlund LO, Forsum E. Adipose tissue
distribution and total body fat by magnetic resonance
imaging, underwater weighing, and body-water dilution in healthy women. Am J Clin Nutr 1993; 58:830
838.
122. Thomas EL, Saeed N, Hajnal JV, Brynes A, Goldstone
AP, Frost G, Bell JD. Magnetic resonance imaging of
total body fat. J Appl Physiol 1998; 85(5):17781785.
122a. Busetto L, Tregnaghi A, Bussolotto M, Sergi G,
Beninca P, Ceccon A, Giantin V, Fiore D, Enzi G.
Visceral fat loss evaluated by total body magnetic
resonance imaging in obese women operated with
laparascopic adjustable silicone gastric banding. Int J
Obes 2000; 24(1):6069.
122b.LeBlanc A, Lin C, Shackelford L, Sinitsyn V, Evans H,
Belichenko O, Schenkman B, Kozlovskaya I, Oganov
V, Bakulin A, Hedrick T, Feeback D. Muscle volume,
MRI relaxation times (T2), and body composition after
spaceight. J Appl Physiol 2000; 89(6):21582164.
122c. Heymseld SB, Gallagher D, Kotler DP, Wang Z,
Allison DB, Heshka S. Body-size dependence of
resting energy expenditure can be attributed to nonenergetic homogeneity of fat-free mass. Am J Physiol
Endocrinol Metab 2002: 282(1):E132E138.
123. Ross R, Shaw KD, Rissanen J, Martel Y, De Guise J,
Avruch L. Sex dierences in lean and adipose tissue
distribution by magnetic resonance imaging: anthropometric relationships. Am J Clin Nutr 1994; 59:1277
1285.
124. Gray D, Fujioka K, Colletti PM, Kim H, Devine W,
Cuyegkeng T, Pappas T. Magnetic-resonance imaging
used for determining fat distribution in obesity and
diabetes. Am J Clin Nutr 1991; 54:623627.
125. Baumgartner RN, RL Rhyne C, Troup S, Wayne,
Garry PJ. Appendicular skeletal muscle areas assessed
by magnetic resonance imaging in older persons.
J Gerontol 1992; 47:M67M72.
126. Seidell JC, Bakker CJC, Van der Kooy K. Imaging
techniques for measuring adipose-tissue distribution
a comparison between computed tomography and 1.5T magnetic resonance. Am J Clin Nutr 1990; 51:953
957.
127. Ross R, Pedwell H, Rissanen J. Eects of energy
restriction and exercise on skeletal muscle and adipose
tissue in women as measured by magnetic resonance
imaging. Am J Clin Nutr 1995; 61:11791185.
128. Fowler PA, Fuller MF, Glasbey CA, Cameron GG,
Foster MA. Validation of the in-vivo measurement of
adipose tissue by magnetic resonance imaging of lean
and obese pigs. Am J Clin Nutr 1992; 56:713.
129. Abate N, Burns D, Peshock RM, Garg A, Grundy
SM. Estimation of adipose tissue mass by magnetic
Heymseld et al.
120.
129a.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
77
155.
Hood R, Allen C. Lipogenic enzyme activity in adipose tissue during the growth of swine with dierent
propensities to fatten. J Nutr 1973; 103: 353362.
156. Goodpaster BH, Kelley DE, Wing RR, Meier A,
Thaete FL. Eects of weight loss on regional fat
distribution and insulin sensitivity in obesity. Diabetes
1999; 48:839847.
157. Misra A, Garg A, Abate N, Peshock R, Stray-Gundersen J, Grundy S. Relationship of anterior and
posterior subcutaneous abdominal fat to insulin sensitivity in nondiabetic men. Obes Res 1997; 5:9399.
158. Abate N, Garg A, Peshock R, Stray-Gundersen J,
Adama-Huet B, Grundy S. Relationship of generalized and regional adiposity to insulin sensitivity in men
with NIDDM. Diabetes 1996; 45:16841693.
159. Rissanen J, Hudson R, Ross R. Visceral adiposity,
androgens and plasma lipids in obese men. Metabolism 1994; 43(10):13181323.
160. Fowler PA, Fuller MF, Glasby CA, Foster MA,
Cameron GG, McNiel G, Maughan RJ. Total and
subcutaneous adipose tissue distribution in women:
the measurement of distribution and accurate prediction of quantity by using magnetic resonance imaging.
Am J Clin Nutr 1991; 54:1825.
161. Roche AF, Baumgartner RN, Guo S. Anthropometry:
classical and modem approaches. In: Whitehead RG,
Prentice A, eds. New Techniques in Nutritional
Research. New York: Academic Press, 1991:241260.
162. Himes JH, Roche AF, Siervogel RM. Compressibility
of skinfolds and the measurement of subcutaneous
fatness. Am J Clin Nutr 1979; 32:17341740.
163. Jackson AS, Pollock ML. Generalized equations for
predicting body density of women. Med Sci Sports
Exerc 1980; 12:175182.
164. Durnin JVGA, Womersely J. Body fat assessment
from total body density and its estimation from
skinfold thickness: measurements on 481 men and
women aged 16 to 72 years. Br J Nutr 1974; 32:7797.
165. Roche AF, Guo S. Development, testing and use of
predictive equations for body composition measures.
In: Kral JG, VanItallie TB, eds. Recent Developments
in Body Composition Analysis: Methods and Applications. London: Smith-Gordon, 1993:116.
166. Armellini F, Zamboni M, Rigo L, Tedesco T,
Bergamo-Andreis IA, Procacci C, Bosello O. The contribution of sonography to the measurement of intraabdominal fat. J Clin Ultrasound 1990; 18:563567.
167. Bellisari A, Roche AF, Siervogel RM. Reliability of Bmode ultrasonic measurements of subcutaneous adipose tissue and intra-abdominal depth: comparisons
with skinfold thicknesses. Int J Obes 1993; 17:475480.
168. Bjorntorp P. Visceral obesity: a civilization syndrome. Obes Res 1993; 1:206222.
169. Garn SM. Relative fat patterning: an individual
characteristics. Hum Biol 1955; 27:7589.
170. Bouchard C. Introductory notes on the topic of fat
78
distribution. In: Bouchard C, Johnston F, eds. Fat
Distribution During Growth and Later Health Outcomes. New York: Alan R. Liss, 1988:18.
171. Bailey SM, Garn SM, Katch VL, Guire KE. Taxonomic identication of human fat patterns. Am J Phys
Anthrop 1982; 59:361366.
172. Mueller WH, Stallones L. Anatomical distribution of
subcutaneous fat: skinfold site choice and construction
of indices. Hum Biol 1981; 53:321335.
173. Baumgartner RN, Roche AF, Guo S, Lohman TG,
Boileau RA, Slaughter M. Adipose tissue distribution:
the stability of principal components by sex, ethnicity
and maturation stage. Hum Biol 1986; 58:719735.
174. Lapidus L, Bengtsson C, Larsson B, Pennart K,
Rybo E, Sjostrom L. Distribution of adipose tissue
and risk of cardiovascular disease and death: a 12
year follow up of participants in the population study
of women in Gothenburg, Sweden. Br Med J 1984;
289:12571261,
175. Larsson BK, Svardsudd L, Welin L, Wilhelmsen, Bjorntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity and risk of cardiovascular disease and
death: 13 year follow up of participants in the study of
men born in 1913. Br Med J 1984; 288:14011404.
176. Ohlson LO, Larsson B, Svardsudd K, Welin L,
Eriksson H, Wilhelmsen L, Bjorntorp P, Tibblin G.
The inuence of body fat distribution on the incidence
of diabetes mellitus, 13.5 years of follow-up of the
participants of the study of men born in 1913.
Diabetes 1985; 34:10551058.
177. Seidell JC, Deurenberg P, Hautvast JGAJ. Obesity
and fat distribution in relation to healthcurrent
insights and recommendations. World Rev Nutr Diet
1987; 50:5791.
178. Kissebah AH. Insulin resistance in visceral obesity. Int
J Obes 1991; 15:109115.
179. Despres JP. Lipoprotein metabolism in visceral
obesity. Int J Obes 1991; 15:4552.
180. Bray GA. Pathophysiology of obesity. Am J Clin Nutr
1992; 55:488S494S.
181. Filipovsky J, Ducimetiere P, Darne B, Richard JI.
Abdominal body mass distribution and elevated blood
pressure are associated with increased risk of death
from cardiovascular diseases and cancer in middleaged men. The results of a 15-20-year follow-up in the
Paris prospective study I. Int J Obes 1993; 17:197203.
182. Houmard JA, Wheeler WS, McCammon MR, Wells
JM, Truitt N, Hamad SF, Holbert D, Israel RG,
Barakat HA. An evaluation of waist to hip ratio measurement methods in relation to lipid and carbohydrate
metabolism in men. Int J Obes 1991; 15:181188.
183. Vague J. The degree of masculine dierentiation of
obesities: a factor determining predisposition to
diabetes, atherosclerosis, gout and uric calculous
diseases. Am J Clin Nutr 1956; 4:2034.
184. Kekes-Szabo T, Hunter GR, Nyikos I, Nicholson C,
Heymseld et al.
185.
185a.
185b.
185c.
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
79
199.
200.
201.
3
Ethnic and Geographic Influences on Body Composition
Paul Deurenberg and Mabel Deurenberg-Yap
Health Promotion Board, Singapore, Republic of Singapore
INTRODUCTION
81
82
Indirect
Doubly indirect
Densitometry
Dilution techniques, e.g., deuterium oxide dilution
Dual-energy x-ray absorptiometry (DXA)
More compartment models
CT/MRI scanning
CT, computed tomography; MRI, magnetic resonance imaging; BMI, body mass index.
II
constant composition of the fat-free mass, the densitometric method has a methodological error of maximally
23%. This was conrmed, for example, in a study by
Heymseld et al. (6) Deuterium dilution results in about
the same level of error. For example, if an obese,
edematous subject is weighed underwater, the normal
calculation formula to convert body density into body
fat could overestimate body fat percent by two or three
percentage points (due to a larger amount of body water
in the fat free mass its density is <1.100 kg/L). In the
same subject deuterium oxide dilution would, however,
underestimate body fat percent by some two or three
percentage points.
With the development of new body composition
techniques such as IVNAA and dual-energy x-ray absorptiometry (DXA), and their combined use with
densitometry and deuterium oxide dilution, it has
become possible to measure body composition using
chemically dened multicompartment models (11). The
most popular models are a three-compartment model
(fat mass, water, and dry fat-free mass) in which variation of the water fraction in the fat-free mass is
accounted for, and a four-compartment model (fat
mass, water, minerals, and protein). In the latter model,
the variation of both the water and the mineral fraction
in fat-free mass is accounted for. Although the technical
error of these multicompartment models is not lower
compared to two-compartment models (15), they do
have a smaller methodological error, as the variation in
the composition of the fat-free mass is accounted for.
This makes the three- and especially the four-compartment model suitable as a reference when it comes to
comparing groups in which the composition of the fatfree mass might dier. Such dierences are known to
exist between age groups (children vs. adults vs. elderly),
males and females, and also ethnic groups.
Table 2 provides examples for females from various
ethnic groups for body fat percent measured by densitometry alone, (assuming a density of the fat-free mass
of 1.1 kg/L) and a four-compartment model. As can be
seen, body fat calculated from the Siri formula is gen-
83
Ref.
BF2c
BF4c
Difference
17
18
8
10
9
9
9
17
18
8
10
21.2
26.5
35.1
26.7
30.3
35.5
35.9
24.2
30.2
30.2
27.7
21.8
28.1
35.3
29.7
33.5
38.2
37.8
23.6
29.3
30.5
28.9
+0.6
+1.6
+0.2
+3.0
+3.2
+2.7
+1.9
0.6
0.9
+0.3
+1.2
a
BF2c: body fat from two-compartment model; BF4c: body fat from
four-compartment model.
III
Doubly indirect methods rely on a statistical relationship between easily measurable body parameters and
body composition as measured by a direct or an
indirect method. There are many examples of such
methods, and the most often used for the prediction
or assessment of body fat are skinfold thickness measurements, bioelectrical impedance measurements, and
weight/height indices. All these methods have in common that the standard error of estimate (SEE) of the
equation is f45 percentage body fat points and that
the prediction equations are not general but are
population specic. It has to be kept in mind that a
SEE of 5% means, that, even if the mean bias is zero in
34% of the population, the dierences between measured and predicted body fat percent will exceed 5 or
+5 percentage body fat points. In 5% of the population, the error will be higher than 10 or +10 percentage points. Thus, for individual assessments, these
methods are not very reliable. Unfortunately, many
prediction formulas also have a systematic bias if
applied to other populations than the one in which
they were developed.
Table 3 gives for three methods an example of
systematic bias. In this table, the predictive values
from a BMI-based prediction formula (19), an impedance-based formula (20) and a skinfold based formula (21) are compared in Indonesian and Caucasian
males and females of comparable age. It is obvious
that in Caucasians the dierences between measured
and predicted values are much lower than in Indonesians. This is not surprising, as the formulas used to
predict were all developed in Caucasians. These data
show that the interpretation of predicted values from
formulas developed in other populations has to be
approached with caution.
The reasons for those systematic biases are easy
to understand from the principles of the predictive
84
Table 3 Measured and Predicted Body Fat Percent in Dutch and Indonesian Adult Males and Females
Females
Indonesian (51)
Age (years)
BMI (kg/M2)
BF deuterium %
BF BMI (%)
BF imp (%)
BF skfd (%)
Males
Dutch (42)
Indonesian (59)
Dutch (64)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
35
22.7
36.0
29.8
27.4
32.6
9
4.7
6.4
7.1
8.9
6.4
34
24.4
33.2
31.7
33.1
33.9
8
4.9
9.2
7.0
6.9
5.2
41
24.3
28.3
22.3
22.3
27.3
7
3.3
6.2
4.9
4.9
6.6
40
26.2
26.5
24.4
26.4
25.8
8
3.6
7.6
5.7
7.3
6.1
BMI: body mass index; BF deuterium, body fat from deuterium oxide dilution; BF BMI: body fat predicted from body mass index using a sexand age-specic Caucasian prediction formula (19); BF imp: body fat predicted from bioelectrical impedance (20); BF skfd: body fat
predicted from skinfolds (21).
Figure 1 Body build and composition data from a Caucasian (Dutch) subject and a Chinese (Singaporean) subject.
BMI, body mass index; BF4c, body fat from four-compartment model. (From Ref. 1.)
85
despite its easy and convenient application. Standardization is very important, not only regarding body
position but also regarding environmental temperature.
In addition dierent machines give dierent readings,
and the correct type of electrodes is important as well.
However, when compared to skinfold measurements,
less experience is needed to perform an accurate measurement. A report of a consensus meeting on the use of
bioelectrical impedance in body composition studies has
been published (28).
Both the impedance methodology and skinfold
thickness measurements are portable methods, which
can be used in large population studies. Skinfold measurements have the disadvantage that the subject has to
be partly undressed and that there is physical contact
between the researcher and the subject, which may limit
its practical application in certain populations. As
increasing fatness results in increasing weight, weight
corrected for height methods can also be used as indicators for body fatness.
An appropriate weight/height index has to have a
high correlation with body fat, but also a low correlation with body height, as otherwise body fat percent
would be systematically over- or underestimated in
short people. The most popular of all indices is the
body mass index (BMI) or Quetelet Index. The WHO
(29,30) recommends the BMI as an indicator of overweight and obesity. The correlation between BMI and
body fat percent body fat percent (BF%) is high
(depending on the age group ranging from 0.6 to
0.8), and the correlation found with body height is
generally low and not signicant.
The BMI can also be used as a predictor for BF%.
Several studies have demonstrated a good relationship
between the BMI and the amount of body fat if age
and sex are accounted for (19,3133). When using such
age- and sex-specic equations percent body fat can
be predicted with an error of 35%, an error comparable with the prediction error of skinfold thickness or
impedance measurements.
In some subjects or groups of subjects, BMI cannot
be used to predict body fat, as for example in pregnancy and in body builders. It has to be kept in mind,
however, that the BMI also correlates with the fat-free
mass. The BMI is in fact not more than a weight index,
and as a measure of body fatness it assumes that a
xed part of the index consists of fat-free mass,
whereas all exceeding mass is body fat. The situation
is not so simple, however, as with increasing body
fatness the amount of fat-free mass also tends to
increase (more muscle needed to carry excess body
fat and more bone mass to support the heavier weight).
86
Moreover, the index assumes that the weight distribution over the body length is homogeneous. However, weight per unit length is higher in the trunk than
in the legs. This means that subjects with relatively
longer legs will generally have a lower BMI, and thus
in those subjects body fat tends to be underestimated
with a BMI-based formula. It has been discussed in
the literature (34) that the long-leggedness in the
Australian Aboriginal accounts for about 2 kg/m2 of
their low BMI. There are considerable dierences in
relative leg lengths among ethnic groups (27), with
blacks generally having longer legs than Caucasians
and some Asians groups having shorter legs than
Caucasians. It is clear that this has an impact on the
validity of the BMI as predictor of BF%. However, it
has to be kept in mind that dierences in relative leg
length also exist among various African groups (e.g.,
Ethiopians vs. West African groups) and Asian groups
(e.g., Chinese vs. Indians). Also, there is generally a
wide variation in relative leg length within a given
(homogeneous) ethnic group.
In addition, body build has been shown to have an
impact on the BMI/BF% relationship. Although the
eect of body build is often not found to be strong in
homogeneous populations (35,36), comparisons between dierent (ethnic) population groups have shown
that body build is a contributing factor (3739).
Figure 2 demonstrates how body build and leg
length aect relationship between BMI and body fatness, and Figure 3 shows the impact of relative leg
Figure 3 BF%: body fat percent. Bias: measured BF% minus predicted BF% (19). A: without correction; B: corrected
for relative leg lengths; C: corrected for frame size; D: corrected for relative leg lengths and frame size. (From Ref. 38.)
IV
87
Figure 4 Adjustments to be made in BMI to reect equal levels of body fat percent compared to Caucasians of the same age and
sex. (From Refs. 39, 40.)
88
89
that ethnicity per se contributed only little to the variation in lipid prole between blacks and whites after
controlling for dierences in other variables (among
them body mass index and body fat distribution).
In a recent study in Singapore we found that the
relative risk for having at least one cardiovascular
risk factor (e.g., elevated cholesterol, hypertension,
diabetes mellitus) is elevated at levels of WC or
WHR far below the WHO cuto points (50). Using
WHO cuto points for classication of abdominal
obesity (30) would miss a large part of the population
at risk. This elevated risk could be due to a higher
amount of visceral fat at low WC or to other factors,
e.g., genetic factors. Further studies in Singapore are
needed to determine the relationship between anthropometric measurements (WC and WHR) and the
amount of visceral fat by CT or MRI.
Generally, more studies among ethnic groups have to
be done to establish the relation between anthropometric indices of body fat distribution and visceral fat.
These studies should be complementary to epidemiological studies on the relationship between indices of
body fat distribution and disease risks. Results of both
laboratory studies and epidemiological studies will provide necessary information to accept existing universal
WC and WHR cuto points or to redene ethnicspecic cuto points. As in the case of the relation
between BMI and BF%, the use of standardized methodology is of utmost importance to avoid biased outcomes of studies. This standardization would include
landmarks for waist and hip circumference and measurements of CT/MRI.
VI
SUMMARY
90
REFERENCES
1.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
Techniques in Health and Disease. Cambridge: Cambridge University Press, 1995: 240254.
Wagner DR, Heyward VH. Measures of body composition in blacks and whites: a comparative review. Am J
Clin Nutr 200;71:13921402.
Deck-Cote K, Adams WC. Eects of bone density on
body composition estimates in young black and white
women. Med Sci Sports Exerc 1993;25:290296.
Ortiz O, Russell M, Daley TL, Baumgartner RN, Waki
M, Lichtman S, Wang J, Pierson RN Jr, Heymseld SB.
Dierences in skeletal muscle and bone mineral mass
between black and white females and their relevance to
estimate body composition. Am J Clin Nutr 1992;55:
813.
Deurenberg P, Weststrate JA, Seidell JC. Body mass
index as a measure of body fatness: age and sex specic
prediction formulas. Br J Nutr 1991;65:105114.
Deurenberg P, Tagliabue A, Schouten FJM. Multifrequency impedance for the prediction of extra-cellular
water and total body water. Brit J Nutr 1995;73:349
358.
Durnin JVGA, Womersley J. Body fat assessed from
total body density and its estimation from skinfold
thickness: measurements on 481 men and women aged
from 17 to 72 years. Br J Nutr 1974;32:7797.
Guricci S, Hartriyanti Y, Hautvast JGAJ, Deurenberg
P. Relationship between body fat and body mass index:
dierences between Indonesians and Dutch Caucasians.
Eur J Clin Nutr 1998;52:779783.
Deurenberg P, Deurenberg-Yap M, Wang JJ, Lin FP,
Schmidt G. Prediction of body fat percent from
anthropometry and impedance in Singapore and Beijing
Chinese. Asia Pacic J Clin Nutr 2000;9:9398.
Norgan NG. The assessment of the body composition of populations. In: Davies PSW, Cole TJ, eds.
Body Composition Techniques in Health and Disease. Cambridge: Cambridge University Press,
1995:195221.
Zillikens MC, Conway JM. Anthropometry in blacks:
applicability of generalized skinfold equations and
dierences in fat patterning between blacks and whites.
Am J Clin Nutr 1990;52:4551.
Guricci S, Hartriyanti Y, Hautvast JGAJ, Deurenberg
P. The prediction of extracellular water and total body
water by multi-frequency bio-electrical impedance in a
South East Asian population. Asia Pacic J Clin Nutr
1999;8:155159.
Eveleth PB, Tanner JM. World-wide Variation in
Human Growth. Cambridge: Cambridge University
Press, 1976.
Bioelectrical impedance analysis in body composition
measurement. NIH Technology Assessment Statement
1994, Dec 1214, pp 135.
WHO. Physical Status: The Use and Interpretation of
Anthropometry. Technical Report Series 854. Geneva:
WHO, 1995.
91
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
92
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
4
Prevalence of Obesity in Adults: The Global Epidemic
Jacob C. Seidell
Free University of Amsterdam and Free University Medical Center, Amsterdam,
The Netherlands
Aila M. Rissanen
Helsinki University Hospital, Helsinki, Finland
CLASSIFICATION OF OBESITY
AND FAT DISTRIBUTION
BMI (kg/m2)
Underweight
<18.5
Normal range
Overweight
Preobese
Obese class I
18.524.9
25.0 or higher
25.029.9
30.034.9
Obese class II
Obese class III
35.039.9
40 or higher
Associated health
risks
Low (but risk
of other clinical
problems
increased)
Average
Increased
Moderately
increased
Severely increased
Very severely
increased
93
94
II
PREVALENCE OF OBESITY
BY WHO REGION
Africa
The Americas
Table 1 Overweight (BMI 2529.9 kg/m2) and Obesity (BM1 z 30 kg/m2) Levels in
Women Aged 1549 Years in Sub-Saharan Africa
Country
Benin
Burkina Faso
Central African Republic
Comoros
Cote dIvoire
Ghana
Kenya
Malawi
Mali
Namibia
Niger
Senegal
Tanzania
Tanzania
Uganda
Zambia
Zambia
Zimbabwe
Source: Ref. 4.
Year of survey
Sample size
% Overweight
% Obese
1996
1992/1993
1994/1995
1996
1994
1993
1993
1992
1996
1992
1992
1992/1993
1991/1992
1996
1995
1992
1996/1997
1994
2266
3161
2025
773
3108
1773
3294
2323
4327
2205
3292
2895
4597
3721
3199
3239
3838
1968
6.9
5.9
5.5
15.9
11.0
9.3
11.4
8.1
7.2
13.8
6.2
12.0
9.3
10.8
7.3
11.8
10.5
17.4
2.1
1.0
1.1
4.4
3.0
3.4
2.4
1.1
1.2
7.1
1.2
3.7
1.9
2.6
1.2
2.4
2.3
5.7
95
Year
Area
Ethnic group
Men %
Women %
1982
1990
1990
1990
1990
1990
Coloured
African
White
African
African
Indian
7.2
13.9
17.6
12.7
12.9
3.5
31.4
48.6
20.4
40.2
43.9
17.6
Source: Ref. 5.
There are important ethnic dierences in the prevalence of obesity, particularly in women (Table 3). The
women/men prevalence ratio is highest among nonHispanic blacks (ratio f1.8), lower in MexicanAmericans (ratio f1.5) and lowest in non-Hispanic
whites (ratios f1.1).
The prevalence of obesity in Canada is less than in
the United States although the most recent estimates are
already a decade old. Canada has experienced also an
increase in the prevalence of overweight and obesity,
particularly in men (Fig. 2, top). The most recent estimates of the prevalence of obesity are 13.4 percent in
men and 15.4 in women (9).
Figure 1 Time trends of the prevalence of obesity (BMI z 30 kg/m2) in the United States based on the behavioral risk factor
surveillance system (self-reported height and weight). The NHANES III (National Health and Nutrition Examination Survey
III) was conducted between 1998 and 1994 (depicted here as the midpoint of the survey in 1991) in a nationally representative
sample based on measured weight and height. (From Refs. 7 and 8.)
96
Men
Women
Sex ratio
Non-Hispanic white
Non-Hispanic black
Mexican-American
20.0
21.3
23.1
22.4
37.4
34.2
1.12
1.76
1.48
Source: Ref. 8.
Figure 2 Time trends in the prevalence of overweight (BMI 2529.9 kg/m2) and obesity (BMI z 30 kg/m2) in Canadian men
(top) and women (bottom). (From Ref. 9.)
97
Table 4 Overweight (BMI 2529.9 kg/m2 and Obesity (BMI z 30 kg/m2) in Adults in
Latin American Countries
% Overweight
Country
Argentina
Brazil
Chile
Mexicoa
Mexicob
Paraguay
Peru
% Obese
Year of survey
Men
Women
Men
Women
1997
1997
1992
1992/1993
1995
1991/1992
1996
41
39
36
35
28.4
6.9
15.7
14.9
11
22.9
7.2
25.4
12.5
23.0
25.1
23
35.7
16.4
Southeast Asia
Table 5 Overweight (BMI 2529.9 kg/m2) and Obesity (BMI z 30 kg/m2) Levels in
Women Aged 1549 Years in Latin America
Country
Bolivia
Brazil
Brazil
Colombia
Dominican Republic
Dominican Republic
Guatamela
Haiti
Honduras
Mexico
Peru
Peru
Source: Ref. 4.
Year of survey
Sample size
% Overweight
% Obese
1994
1989
1996
1995
1991
1996
1995
1994/1995
1996
1987
1992
1996
2347
10189
3158
3319
2163
7356
4978
1896
885
3681
5200
10747
26.2
25.0
25.0
31.4
18.6
26.0
26.2
8.9
23.8
23.1
31.1
35.5
7.6
9.2
9.7
9.2
7.3
12.1
8.0
2.6
7.8
10.4
8.8
9.4
98
Figure 3 Time trends in the prevalence of obesity (BMI z 30 kg/m2) in Brazil by income (highest and lowest quartile of income)
and degree of urbanization, in (top) men and (bottom) women. (From Ref. 11.)
Europe
99
Figure 4 Time trends in the prevalence of obesity (BMI z 30 kg/m2) in Havana, Cuba (before and after the collapse of the
Soviet Union). (From Ref. 14.)
country. In countries with established market economies, obesity is usually more frequent among those with
relative low socioeconomic status, and the prevalence
increases with age until f6070 years of age after which
the prevalence declines (18). In most of these established
market economies it has been shown that the prevalence
is increasing over time (8,16). Tables 7 and 8 show the
increases in the prevalence of obesity in men and women
aged 3564 years in several centers participating in the
WHO MONICA project (19). It is clear that there is a
rapid increase in the prevalence of obesity in most
centers from countries in the European Union, particularly in men. The prevalence of obesity in men and
women in European countries in the EU region (Table 7)
Study
Age
India
Malaysia
Thailand
19881990
1990
National Health
Examination Survey
1991, n=13,300
Adults
1864
20+
a
Men and women combined.
Source: Ref. 1.
Men
Women
0.5a
7.9
4.0
6.1
5.6
100
Figure 5 Current and predicted worldwide prevalence of type 2 diabetes mellitus. (From Ref. 17.)
Table 7 Prevalence of Obesity (age-standardized % with BMI z 30) of Centers in EU Countries Participating in the First
Round of the MONICA Study (May 1979 to February 1989) and the Third Round (June 1989 to November 1996)
Men
Country (center)
Belgium (Ghent)
Denmark (Glostrup)
Finland (north Karelia)
Finland (Kuopio)
Finland (Turku/Loimaa)
France (Toulouse)
France (Lille)
Germany (Augsburg, urban)
Germany (Augsburg, rural)
Iceland (Iceland)
Italy (area Brianza)
Italy (Friuli)
Spain (Catalonia)
Sweden (North)
Switzerland (Vaud/Fribourg)
Switzerland (Ticino)
United Kingdom (Belfast)
United Kingdom (Glasgow)
Mean
Source: Ref. 19.
Women
1st
3rd
1st
3rd
Women/men
(sex ratio) 3rd
9
11
17
18
19
9
13
18
20
12
11
15
10
11
12
19
11
11
13.7
10
13
22
24
22
13
17
18
24
17
14
17
16
14
16
13
13
23
17.0
11
10
23
20
17
11
17
15
22
14
15
18
23
14
12
14
14
16
16.4
11
12
24
25
19
10
22
21
23
18
18
19
25
14
9
16
16
23
18.8
1.10
0.92
1.09
1.04
0.86
0.77
1.29
1.17
0.96
1.06
1.29
1.12
1.56
1.00
0.56
1.23
1.23
1.00
1.07
101
Table 8 Prevalence of Obesity (age-standardized % with BMI z 30 kg/m2) in Centers of Countries in Central and Eastern
Europe Participating in the First Round of the MONICA Study (May 1979 to February 1989) and the Third Round (June 1989
to November 1996)
Men
Country (center)
Women
st
rd
st
3rd
Women/men
(sex ratio) 3rd
Poland (Warsaw
Poland (Tarnobrzeg)
Russia (Moscow)
Russia (Novosibirsk)
Czech Republic (rural CZE)
Yugoslavia (Novi Sad)
18
13
14
13
22
18
22
15
8
15
22
17
26
32
33
43
32
30
28
37
21
43
29
27
1.27
2.47
2.63
2.87
1.32
1.59
Mean
16.3
16.5
32.7
30.8
2.03
Eastern Mediterranean
Figure 6 Time trends in the prevalence of obesity (BMI z 30 kg/m2) in the United Kingdom (Health Survey for England) and
the Netherlands (data from the National Institute of Public Health in Bilthoven). (From Ref. 17.)
102
Figure 7 The gender ratio (women/men) of the prevalence of obesity (BMI z 30 kg/m2) by age in the Health Survey for England
(ages 16+), 1997. (From Refs. 17 and 18.)
Africa and the Middle East. The results show that the
prevalence of obesity is higher in women than in men
(particularly in the Middle East and the Gulf states).
F
Table 9 Overweight (BMI 2529.9 kg/m2) and Obesity (BMI z 30 kg/m2) Levels in the Baltic States
% Overweight
Country
Estonia
Latvia
Lithuania
Lithuaniaa
Kazakstanb
Uzbekistanb
a
Year of survey
Sample size
Men
Women
Men
Women
1997
1997
1997
2000
1995
1996
1154
2292
2096
2195
3538
4077
32.0
41.0
41.9
45.6
23.9
33.0
32.7
31.6
21.8
16.3
9.9
9.5
11.4
16.9
6.0
17.4
18.3
23.4
16.7
5.4
Finbalt study based on self-reported height and weight (Janina Petkeviciene, personal communication).
Adapted from Martorell et al. (4).
Source: Ref. 20 except where noted.
b
% Obese
103
Table 10 Overweight (BMI 2529.9 kg/m2) and Obesity (BMI z 30 kg/m2) Levels in Women Aged 1549 Years in North Africa
and the Middle East
% Overweight
Country
Bahrain
Kuwait
Saudi Arabia
Jordan
Morocco
Moroccob
Moroccoc
Tunisiac
Egyptb
Turkeyb
% Obese
Year of survey
Sample size
Men
Women
Men
Women
1991/1992
1993/1994
1996
1994/1996
1984/1985
1992
1998/1999
1997
1995/1996
1993
290
3435
13177
2836
41921
2850
17320
2760
6769
2401
16.0
35.2
29.0
31.3
32.3
27.0
26.3
32.3
16.0
32.7
29.4
40.6
24.0
59.8
18.7a
28.0
23.3
5.2a
22.3
33.0
28.2
31.7
31.7
5.7
6.7
10.5
18.3
22.7
20.1
18.6
III
Table 11 Sex-Specic Prevalence Data of Obesity (BMI z 30 kg/m2) and Sex Ratio in Selected Studies in the Western Pacic
Region
Country
China
Japan
Philippines
Study
Chinese National
Nutrition Survey, 1992
National Nutrition Survey,
19901994 n=12,926
Food and Nutrition Research
Institute, 1993 n=9585
Age
(years)
Men
Women
Ratio
women/men
3564
1.0 (urban)
0.5 (rural)
1.9
1.7 (urban)
0.7 (rural)
2.9
1.70
1.40
1.53
20+
1.7
3.4
2.00
2045
104
Figure 8 Time trends in the prevalence of overweight (BMI z 25 kg/m2) in China. (From Ref. 21.)
Figure 9 Hypothetical calculations of the magnitude of a positive energy balance to gain 10 kg over 10 years. It is estimated that
an excess of 20 kcal/day over a 1-year period leads to a weight gain of about one 1 kg. One kilogram of weight gain is estimated to
lead to about a 15 kcal/day increase in 24-hr energy expenditure. (From Ref. 24.)
105
2.
3.
Biological inuences and unalterable factors (e.g., age, sex, hormonal factors, and
genetics).
Behavioural inuences (which are the result of
complex psychological factors, including habits, emotions, attitudes, beliefs, and cognitions developed through a background of
learning history).
Environmental inuences (physical, economic, and sociocultural environment).
106
IV
CONCLUSIONS
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
107
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
5
Fetal Origins of Obesity
David J. P. Barker
University of Southampton, Southampton, England
INTRODUCTION
110
Barker
Hertfordshire
(men aged 64)
0.70 (0.540.86)
0.83 (0.750.91)
Adult body mass
index (kg/m2)
Birth weight (lbs) 0.83 (1.50 to 0.15) 0.29 (0.52 to 0.05)
Placental
1.76 (0.73 to 4.24)
weight (lbs)
III
Undernutrition
Famine began abruptly in western Holland in November 1944 and ended with the liberation by the Allied
armies in May 1945. In the early months of 1945
ocial rations varied between 400 and 800 calories
per day. A study of f300,000 young military conscripts who were born around that time showed that
those who were conceived during the famine had higher
rates of obesity than those who were either in utero or
born when the famine began, or those who were never
exposed to famine (26). By the time the men and
women exposed to famine in utero reached 50 years
of age, the picture had changed (27). The men conceived in famine were no longer more obese than other
men, but the women conceived in famine were on
average 7.9 kg heavier than women not exposed to
famine; their body mass indices were 7.4% higher, and
their waist circumference was 7.4 cm greater. These
associations did not depend on their body size at
birth: indeed, their birth weights were similar to those
of unexposed childrenpresumably because their
mothers became well nourished in the second half
of pregnancy.
These fascinating observations suggest that high
body mass index and high abdominal fat, for which
waist circumference is a validated indicator (28), can
originate through fetal undernutrition. The sex dierences in response to undernutrition suggest that the
processes underlying its association with later obesity
are more likely to involve alterations in central hormonal regulatory mechanisms rather than changes at the
level of the fat cell.
B
Overnutrition
111
IV
112
Barker
Figure 2
Growth of 357 boys who later developed coronary heart disease in a cohort of 4630 boys born in Helsinki.
113
Table 2 Hazard Ratios for Deaths from Coronary Heart Disease According to Ponderal Index at Birth (birth weight/length3)
and Body Mass Index at 12 Years
Body mass index at 12 years (kg/m2)
Ponderal index
at birth (kg/m3)
V25
27
29
>29
V25
27
29
>29
a
b
16
a
547
618
458
225
2.0 (0.94.4)b
1.3 (0.62.9)
1.3 (0.63.0)
1.0
17
426
692
614
317
2.1
2.5
1.5
1.1
18
(1.04.7)
(1.25.2)
(0.73.2)
(0.42.6)
288
507
475
317
2.8
2.5
1.6
1.9
(1.26.2)
(1.15.3)
(0.73.6)
(0.84.4)
>18
233
424
436
279
4.3
2.2
2.1
1.5
(1.99.5)
(1.04.8)
(0.94.6)
(0.63.5)
No. of men.
95% condence intervals in parentheses.
between the diseases and between the two sexes (43), but
the overall picture is the same. Disease is related to the
rate of increase in body mass index as well as to body
mass index attained at any particular age (38,39). The
diseases are therefore related to the tempo of weight
gain in childhood as well as to the state of being obese or
overweight in adult life. The data from Helsinki can be
used to estimate the number of cases of disease that are
statistically attributable to fetal, infant, and childhood
growth. If, for example, each man and woman in the
cohort had had (1) a birth weight above the median for
the cohort, 3.4 kg, (2) weight at 1 year above the median,
10.0 kg, and (3) an increase in body mass index between
3 and 12 years below the median increase, 0.5 kg/m2,
there would have been a 44% (95% CI 2759) reduction
in hospital admissions and deaths from coronary heart
disease, a 62% (95% CI 4379) reduction in the incidence of type 2 diabetes, and a 31% (95% CI 1943)
reduction in the incidence of hypertension.
There are a number of possible processes by which, in
humans, undernutrition and small size at birth followed
by rapid childhood weight gain could lead to cardio-
VI
Table 3 Slope of Relation of Systolic Pressure (mmHg) at Age 50 per Kilogram Increase in Birth Weight by Thirds of
Distribution of Body Mass Index Among 1333 Men in Uppsala, Sweden
Body mass index (kg/m2)
Men
All
Born at term
(3841 weeks gestation)
Height >176 cm
114
Barker
(127)
(98)
(145)
(370)
30
147
151
154
150
(152)
(105)
(110)
(367)
>30
152
157
166
158
(42)
(31)
(35)
(108)
All
148
150
153
150
(321)
(234)
(290)
(845)
VII
CONCLUSIONS
Around the world the transition from chronic malnutrition to adequate nutrition, the so-called nutritional transition (52), is characterized by accelerated
childhood weight gain and the emergence of adult
obesity in people who were undernourished in utero
and during infancy. This is the path of growth that
leads to cardiovascular disease and type 2 diabetes.
The WHO study of the global burden of disease
found that, contrary to the preconception that these
diseases are diseases of auence, the probability
of death from them and other noncommunicable
diseases is higher in low-income regions than in
high-income regions such as established marked
economies (53). One resolution of this apparent
paradox is that the high rates of maternal and
perinatal disorders, nutritional deciencies and infective disease which characterize low-income regions
lead to poor fetal and infant growth and therefore
enhanced susceptibility to the eects of rapid weight
gain and obesity.
Although the epidemic of obesity in Western countries is linked to the epidemics of type 2 diabetes and
coronary heart disease, the paths of childhood growth
that lead to obesity and to these diseases dier. In the
Helsinki studies, children who became obese in later life
tended to be born with above average birthweight and
to continue to have above-average weight in childhood
(4). Children who developed obesity-related disorders
had below-average body size at birth and at 1 year, and
thereafter had accelerated weight gain so that their body
mass index reached the average at some point in childhood and thereafter exceeded it (38,39,54). This dissociation in the paths of growth that lead to them may help
to explain why despite an increasing prevalence of
obesity in Western countries (55) coronary heart disease
is declining (56).
To understand the origins of obesity and the disorders to which it is related, we may need to direct our
attention away from the lifestyles of adults, however
important these may be, to growth and development in
utero, and during infancy and childhood. We need to
understand how nutrition in early life establishes metabolic and endocrine pathways that lead to obesity and
premature death (14). Strategies to prevent obesityrelated disorders should include improvements of fetal
growth and the prevention of obesity in childhood.
115
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
116
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
Barker
Knowler WC. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity. A study of
discordant sibships. Diabetes 2000; 49:22082211.
Gillman MW, Rifas-Shiman SL, Camargo CA, Berkey
CS, Frazier AL, Rockett HRH, Field AE, Colditz GA.
Risk of overweight among adolescents who were
breastfed as infants. JAMA 2001; 285:24612467.
Ravelli ACJ, Van der Meulen JHP, Osmond C, Barker
DJP, Bleker OP. Infant feeding and adult glucose
tolerance, lipid prole, blood pressure and obesity.
Arch Dis Child 2000; 82:248252.
Barker DJP. Fetal origins of coronary heart disease.
BMJ 1995; 311:171174.
Barker DJP, Osmond C, Winter PD, Margetts B,
Simmonds SJ. Weight in infancy and death from
ischaemic heart disease. Lancet 1989; 2:577580.
Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner
B, Hankinson SE, Colditz GA, Willett WC, Hennekens
CH. Birth weight and risk of cardiovascular disease in a
cohort of women followed up since 1976. BMJ 1997;
315:396400.
Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen
R, Berglund L, Lithell UB, McKeigue PM. Reduced
fetal growth rate and increased risk of death from
ischaemic heart disease: cohort study of 15 000 Swedish
men and women born 191529. BMJ 1998; 317:2415.
Huxley RR, Shiell AW, Law CM. The role of size at
birth and postnatal catch-up growth in determining
systolic blood pressure: a systematic review of the
literature. J Hypertens 2000; 18:815831.
Forsen T, Eriksson J, Tuomilehto J, Reunanen A,
Osmond C, Barker D. The fetal and childhood growth
of persons who develop type 2 diabetes. Ann Intern
Med 2000; 133:176182.
Eriksson J, Forsen T, Tuomilehto J, Osmond C, Barker
D. Fetal and childhood growth and hypertension in
adult life. Hypertension 2000; 36:790794.
Eriksson JG, Forsen T, Tuomilehto J, Osmond C,
Barker DJP. Early growth and coronary heart disease
in later life: longitudinal study. BMJ 2001; 322:949953.
Willett WC, Dietz WH, Colditz GA. Guidelines for
healthy weight. N Engl J Med 1999;341:427434.
Morgan IJ, Metcalfe NB. Deferred costs of compensatory growth after autumnal food shortage in juvenile
salmon. Proc R Soc Lond B 2001; 268:295301.
Forsen T, Eriksson JG, Tuomilehto J, Osmond C,
Barker DJP. Growth in utero and during childhood
among women who develop coronary heart disease:
longitudinal study. BMJ 1999; 319:14031407.
6
Pediatric Overweight: An Overview
Bettylou Sherry and William H. Dietz
Centers for Disease Control and Prevention, Atlanta, Georgia, U.S.A.
INTRODUCTION
118
Obesity was dened as a BMI greater than the 95th centile for
women of the same age studied in NHANES I. The data represent
the dierences in the outcomes and the condence intervals of the
dierences between obese and nonobese women. Results controlled
for baseline income, parental education, chronic health condition,
height, self-esteem, age, and ethnicity.
Source: Ref. 13.
119
sensitive (24) because of the great concern of psychosocial dysfunction associated with the diagnosis of overweight and the high prevalence of eating disorders
among certain subsets of the pediatric population, such
as adolescent girls. Thus, clinicians are likely to favor a
measure that minimizes false positives, even if it does
not detect all children who are overweight.
Pediatricians commonly used an indirect measure of
adiposity, a weight-for-height index, to screen for overweight in children. Previously, weight-for-height was
used. However, the new Centers for Disease Control
and Prevention (CDC) growth charts provide weightfor-height2, or BMI, percentiles for children ages 220
years, allowing a single screening tool to be used (and
compared) throughout the life span after 2 years of age
(25). For children <2 years of age, weight-for-height is
still the screening tool of choice to assess weight status
(25). With the exception of 3- to 5-year-olds, BMI is
more correlated with body fat than is weight-for-height.
Among children and adolescents ages 319 years, the
correlation coecients between BMI and percentage of
body fatness dened by pooled dual-energy x-ray
absorptiometry (DXA), a direct measure of adipostiy,
range from 0.78 to 0.88, which are higher than those
found between DXA and weight-for-height (26). This
indicates that BMI-for-age is better than weight-forheight for predicting both underweight and overweight,
except among 2- to 5-year-olds, for whom the two
approaches are equivalent (26). Thus, for indirectly
assessing overweight, BMI can be used for all children
ages 2 years and above, although weight-for-height
might be substituted for those aged 25 years.
More direct assessment of adiposity is possible by
several methods including DXA (27,28), underwater
weighing, bioelectrical impedance analyses, total body
water, and measurement of triceps skinfold thickness.
With the exception of triceps skinfold thickness, these
methods are still primarily used for research, because
they are more complex to obtain and require expensive
equipment. Each of these measurement techniques has
dierent assumptions and limitations, yet the percent fat
values derived from the methods are highly correlated
(2830). Unfortunately, measurement of triceps skinfold
thickness requires calipers, which are not commonly
available in pediatricians oces. More importantly,
reproducible skinfold measurements may be a problem.
Obtaining reliable triceps skinfold measurements
requires practice, and between-observer measurements
are not as reproducible as measurements of height and
weight. Furthermore, skinfold measurement may
become less reliable as body fatness increases. Because
skinfold measurements are currently the only practical
120
III
PREVALENCE
Prevalence estimates based on BMI and on triceps skinfolds have shown substantial increases in the prevalence
of obesity in the United States since the 1960s (21,21a).
The prevalence estimates of overweight summarized
in Table 2 were based on the new CDC growth chart
reference, using the gender- and age-specic 95th
weight-for-length and BMI percentile cutos to dene
overweight. In 19992000 approximately 12% of 623
month olds, 10% of 25 yr olds, and 15% of 619 yr olds
were overweight. For the 219 yr olds, there were no
signicant dierences by gender in 19992000. Available data indicate that the greatest increases occurred
between 19761980 and 19881994 except for 623
month old girls, 25 yr old boys, and 1219 yr old girls,
all of whom had greater increases between 19881994
and 19992000 (21a). Signicant increases in the prevalence of overweight between 19881994 and 19992000
were found for non-Hispanic blacks and Mexican
Figure 1 Recommendations for weight goals. Patients with acute complications, such as pseudotumor cerebri, sleep apnea,
obesity hypoventilation syndrome, or orthopedic problems, should be referred to a pediatric obesity center. *Children younger
than 2 years should be referred to a pediatric obesity center for treatment. **Complications such as mild hypertension,
dyslipidemias, and insulin resistance. (From Ref. 37.)
121
Table 2 Prevalence of Overweight (BMI z95th percentile for age and gender) Between 1963 and 2000 in the United States:
Children Aged 6 Months to 19 Yearsa
Prevalence of overweight (percent)
Age
Gender
623 moh
Boys
Girls
Boys
Girls
Boys
Girls
Boys
Girls
25 yr
611 yr
1219 yr
19631965b
19661970c
4.0
4.5
4.5
4.7
19711974d
19761980e
19881994f
19992000g
5.0
4.9
4.3
3.6
6.1
6.2
8.2
6.1
4.7
5.3
6.6
6.4
4.8
5.3
9.9
7.9
6.1
8.2
11.6
11.0
11.3
9.7
9.8
14.3
9.9
11.0
16.0
14.5
15.5
15.5
122
In Africa and Asia, the prevalence of wasting (weightfor-height <2 SD below the NCHS/WHO reference
median) was 2.53.5 times higher than that of overweight (44). Other country reports found that mean
BMI appeared to be increasing rapidly among children
and adolescents in Denmark (45), Italy (46), Bahrain
(47), and Brazil (48).
In the 94-country study cited above, the prevalence of
overweight increased in 16 of 38 countries for which
trend data were available (44). In Latin American and
Caribbean countries, however, no increased trend in the
prevalence of overweight among preschool children was
Table 3 International Secular Trends in the Prevalence Overweight and at Risk for Overweight Among Children and
Adolescents
Country
Canada (national)
Reference
50
Age
713 yr
Samples
1981: 4176
1996: 7847
Indices
BMI >85th
>95th
51
2 yr 11 mo
to 4 yr
1989: 2728
1998: 2633
BMI >85th
>95th
52
519 yr
1980: NA
1991: NA
BMI >85th
53
714 yr
1985: 1536
1995: 1901
54
67 yr
1314 yr
1985 to 1996
67 yr = 90997
1314 yr=106284
Chile (national)
55
58 yr
Bolivia (national)
56
15 yr
1987:
1996:
1989:
1997:
Dominican Republic
(national)
56
Guatemala (national)
56
Peru (national)
United States
(national)
NA = Not available.
56
56
15 yr
15 yr
15 yr
15 yr
NA
NA
NA
4860
1986: NA
1996: 2984
1981: NA
1996: 6477
1992: NA
1996: 11796
1975: NA
19881994: 4112
BMI>85th
Weight-for-height
(WHO)>2 SD
Weight-for-height
>85th
>95th
Weight-for-height
>85th
>95th
Weight-for-height
>85th
>95th
Weight-for-height
>85th
>95th
Weight-for-height
>85th
>95th
Change in prevalence
Boys: 15 to 28.8%
Girls: 15 to 23.6%
Boys: 5 to 13.5%
Girls: 5 to 11.8%
Children: 14.7 to 23.6%
Children: 5.4 to 9.2%
1980: children 15%
1991: boys 18%,
girls, 20%
Boys: 11.8 to 16.3%
Girls: 13.0 to 20.7%
Boys: 6.1 to 8.2%
Girls: 5.3 to 9.9%
Boys 67: f6 to f14%
Girls 67: f10 to f18%
1314 Boys: f3 to f6%
1314 Girls: f1 to f1.5%
Boys: 6.5 to 13.1%
Girls: 7.7 to 14.7%
Children: 15.9 to 22.7%
Children: 2.1 to 4.6%
Children: 12.3 to 15.3%
Children: 2.6 to 4.6%
Children: 4.9 to 10.0%
Children: 0.5 to 2.0%
Children: 20.6 to 23.9%
Children: 3.9 to 4.7%
Children: 12.5 to 15.3%
Children: 2.8 to 3.1%
IV
Adiposity changes dramatically in childhood and adolescence. In an early and important series of studies of
the body composition of children and adolescents,
Cheek described their changes in body fat, determined
by measuring body composition with deuterium oxide
(57). Based on Cheeks data, body fat as a percentage of
body weight in boys increases in the prepubertal phase
of growth, then declines coincident with the growth
spurt. In contrast, fat as a percentage of body weight
remains relatively constant in girls prior to adolescence
but increases during the adolescent growth spurt.
Between the ages of 10 and 15 years, Cheek estimated
that body fat as a percentage of body weight declined
from 17.8% to 11.2% in boys but rose from 16.6% to
23.5% in girls. Similar changes were subsequently
described by other investigators (58).
Studies of adipocyte size and number in infancy and
childhood demonstrate substantial age-dependent variations in their contribution to body fat mass (59,60).
Cross-sectional and longitudinal studies of adipocyte
numbers indicate that adipocyte numbers increase modestly throughout infancy and childhood in nonoverweight children, but that a pronounced and signicant
increase occurs after age 10 years. In contrast, the size of
fat cells increases to adult levels in late infancy, after
which it decreases to the level observed in early infancy
in nonoverweight children (59), then remains constant
until adolescence. Fat cell size in overweight children
continues to increase to adult levels coincident with the
development of overweight, after which the cells do not
increase in size again until adolescence. In addition,
overweight children have more adipocytes than do nonoverweight children, regardless of the age at which they
are studied. These data indicate that in late infancy,
increases in body fat in nonoverweight children may be
primarily attributable to increases in adipocyte size,
whereas after age 10 years, increases in body fat in these
children reect an increase in both adipocyte size and
number. Among overweight children, both adipocyte
size and number are increased from the time they
become overweight, irrespective of their age. Weight
loss reduces adipocyte size, but does not aect adipocyte
number (61).
Changes in the thickness of triceps skinfold parallel
the changes in body fat described by Cheek (62).
Beginning at age 45 years, the triceps skinfold begins
123
124
infant (74). In turn, children who were large for gestational age at birth have greater and progressively
increasing adiposity through 36 years of age than do
their normal-size counterparts (75).
The argument that fetal life represents a critical
period for adiposity has not been totally resolved, the
evidence from the infants of mothers with diabetes
notwithstanding. Several large studies have shown an
association between high birth weight and child adiposity (7578) or adult adiposity after controlling for gestational age (77,78), but most did not adjust for
confounding variables such as parental fatness, maternal smoking, gestational diabetes, or socioeconomic
status (79). Conversely, low birth weight may be associated with an increase in intra-abdominal fat deposition that may in turn account for an increased likelihood
of risk factors for cardiovascular disease, including
hypertension, diabetes, and hyperlipidemia (80). However, the association between lower birth weight and the
development of overweight has not been clearly demonstrated. Although babies with lower birth weight
have been shown to have an increased risk of syndrome
X and of heart and pulmonary disease in adulthood
(81), it is not clear that these consequences are mediated
by excess adiposity.
The second period of apparent increased risk for later
obesity, adiposity rebound, involves early acceleration of the BMI after its nadir at 47 years of age. This
phenomenon appears to be associated with an increased
risk of later obesity (82,83). That infants of mothers
with gestational or insulin-dependent diabetes during
pregnancy also appear to have onset of overweight
during this period (74) raises questions as to whether
early acceleration of the BMI after its nadir is a risk for
later obesity. Other research shows that parental obesity
is also associated with early adiposity rebound (84) and
that early rebound may reect overweight associated
with maternal diabetes. Thus, whether there exists a true
period of risk for the development of overweight at this
time, independent of maternal diabetes and/or parental
overweight, remains unclear.
Although adiposity rebound has been associated
with adult adiposity, this may only be an epiphenomenon (85). Increased BMI at rebound has not yet been
associated with higher body fat, nor do we know
whether the increased BMI observed in adults who
have had early rebound is attributable to greater body
fat. In addition, whether age at rebound or the size of
the BMI at rebound has the greater inuence on adult
BMI remains unclear. New evidence shows that the
BMI at age 7 years and age at rebound both predict
adult BMI (86), and a positive association has been
VI
ENVIRONMENTAL ASSOCIATIONS
125
Dietary intake and the energy spent on activity represent the only discretionary components of energy intake
and expenditure. Over the past 30 years, important
changes have occurred in family eating patterns, including greater consumption of fast food, carbonated beverages, and preprepared meals. At the same time, some
children are less physically active because of increased
use of cars, concern for neighborhood safety, and
decreased opportunity for physical activity at school
or on the way to school. Childrens time spent watching
television and playing video games has increased. Both
the food intake and physical activity of young children
are strongly inuenced by their parents. Although the
literature that examines the eect of the potential risk
factors for overweight in children is growing, as yet
there are few longitudinal studies of adequate duration
and rigor that have identied causal factors.
1
Breastfeeding
Breastfeeding may protect against subsequent overweight in childhood. Two review papers on this topic
published in 1999 and in 2001 both failed to nd
conclusive evidence of a signicant positive eect
of breastfeeding (79,94). Nonetheless, well-designed
studies with large samples that controlled for potential
confounders have demonstrated a protective eect
of breastfeeding against overweight in childhood.
Von Kries et al. (95) found that infants who were
ever breastfed were 0.75 (95% Condence Interval
[CI] = 0.570.98) times as likely to be overweight
(BMI >90th centile German schoolchildren) at 56
years of age. Gillman et al. (96) found that infants who
were exclusively or mostly breastfed were 0.78 (95%
CI = 0.660.81) times as likely to be overweight (BMI
>95th centile NCHS/CDC reference) at 914 years of
age. Both studies found a dose-response eect: breastfeeding of at least 6 or 7 months was more protective
than <3 months. Although the Hediger et al. study
(NHANES III) found an insignicant protective eect
(odds ratio for mostly breastfeeding was 0.84, 95%
CI = 0.621.13) (97), the small sample size of overweight children in this study may have inuenced their
ability to document a protective eect. Only f300
of f2700 children were overweight by 35 years of
age (97).
126
Dietary Practice
The behavior and practices of parents strongly inuences the dietary intake of their children. During
childhood, parental intake of carbohydrate, fat, and
energy appears to account for 2397% of the variance
in childrens intakes of these nutrients (98). However,
family resemblances in nutrient intake may reect
familial resemblances only in body size, since we do
not know from this study whether actual BMIs were
comparable. This possibility is strengthened by the
observation that the relationship between the preferences of parents and children for specic sets of foods
does not dier substantially from the relationship
between the preferences of children and unrelated
adults (99). Resemblances in nutrient intake, when
they occur, appear to reect a common environment
rather than a genetically mediated preference for
macronutrients (100).
The family environment has the potential to promote
healthy eating. For example, children who eat meals
with their family consume more fruits and vegetables,
have a more nutritionally dense diet with less of their
energy intake derived from fat, and drink fewer carbonated and sugared beverages than do children who do
not eat with their families (101). A recent summary of
the intakes of youth ages 219 years, based on the U.S.
Department of Agricultures 19891991 Continuing
Surveys of Food Intakes by Individuals, documented
that American children have a widespread need for
improvement in their diets (102). Indeed, the authors
found that only 1% of youth met their recommended
intake of nutrients, and membership in this small group
was associated with excess intake, especially of fat (102).
Daily consumption of three meals of approximately
equal energy content may be another potential strategy
to reduce adiposity in children (103). Further evidence
that food patterns may contribute to overweight is the
association between incident overweight and the consumption of sugar-sweetened drinks in school children
(104). Interestingly, the available trend data on energy
intake among children suggest that it has not changed
over f20 years: total energy intake did not change
between 1973 and 1994 among 10-year-old children in
the Bogalusa Heart Study (105).
3
127
Males
Infants (116)
5 years (117)
912 years (118)
1218 years (119)
1.36 (.13)
1.61 (.23)
1.79 (.20)
Combinedb
Females
1.35 (.29)
1.40 (.17)
1.53 (.28)
1.69 (.28)
imately two-thirds of youths in grades 712 participated in three or more episodes of vigorous activity
each week, and minority females other than Asians
had lower levels (123,124). One objective for Healthy
Peop1e 2010 is to increase vigorous physical activity
episodes of 20 minutes or more to at least 3 days per
week for 85% of adolescents (125). The survey data
above demonstrate that non-Hispanic black and Hispanic (or Mexican-American) females are not meeting
this objective.
A recent review of studies (126) conducted between
1970 and 1998 found consistent positive correlations of
physical activity in children (412 years old) with gender
(male), having overweight parents, healthy diet, previous physical activity, intention to be physically active,
preference for physical activity, access to facilities, and
time spent outdoors. The only consistent negative correlate in this review was perceived barriers to physical
activity (126). No associations were found between
physical activity and socioeconomic status, race/ethnicity, body image, self-esteem, perceived benets, attitudes toward sweating, other after-school activity,
alcohol use, smoking, caloric intake, neighborhood
safety, or parents providing transportation (126). In
the same review, among adolescents 13l8 years old,
physical activity correlated with gender (male), race/
ethnicity (white), perceived competence in the activity,
intentions to be physically active, previous physical
activity, community sports, sensation seeking, parental
support, support from others, sibling physical activity,
direct help from parents, and opportunities to exercise.
The only consistently negative correlates were depression and sedentary activities after school and on weekends (126). In 1996, the Surgeon Generals Report
(Physical Activity and Health), which reviewed the
literature through 1995, found slightly dierent associations (127). To verify that the potential determinants
listed are causally related to physical activities, they
need to be examined prospectively and in concert with
other potentially associated variables.
Evidence is now available from cross-sectional studies that strongly suggest that television watching is a risk
factor for overweight (128,129). In their recent examination of the association among television watching,
energy intake, and overweight in U.S. children based on
the nationally representative NHANES III, Crespo et
al. found that the prevalence of overweight (BMI >95th
centile in NHANES II and III data) was lowest among
children who watched V1 hr of television per day and
highest among those who watched z4 hr daily (128).
Further analyses of the NHANES III data showed that
among the 26% of children who watched z4 hr of
128
television per day, body fat and BMI were higher than
among those who watched <2 hr (122). Data from the
Framingham Childrens Study showed that when age,
television viewing, energy intake, baseline triceps, and
parents BMI were controlled, inactive children were 3.8
times as likely to have increasing triceps skinfold measurements between age 4 years and entry into the rst
grade than were active children (130).
Activity levels seem to have a strong familial component. The higher familial correlations for activity within
than across generations suggest that the environment is
more important than genetics (131). Intensive analyses
of a large cohort representing almost 400 families conrmed the observation that stronger correlations of
physical activity occurred within the same generation
(132), but they also demonstrated a heritability of 29%
for level of habitual physical activity. No genetic eect
was found for exercise participation (132). In recent
studies in which we compared parent and child patterns
of activity (personal communication, William H. Dietz,
May 25, 2001), measures of vigorous activity were better
correlated between spouses than between motherdaughter or father-daughter pairs. In contrast, time
watching television was better correlated within families. These results suggest that patterns of inactivity, but
not patterns of activity, are correlated within families.
C
Social Environment
Socioeconomic status has not been consistently associated with overweight in childhood, but two studies that
controlled for parental fatness found negative associations between parental education and childhood BMI
(133,134). In contrast, there is a strong consistent,
positive relationship between low socioeconomic status
in childhood and fatness in adulthood (79). If women
change social class as adults, they are likely to reect the
prevalence of obesity in the social class they join
(32,135).
VII
SCREENING OVERWEIGHT
and extended duration of breastfeeding, and the elimination of the barriers that lead to early termination of
breastfeeding, must become high priorities. Work site
facilities and policies that allow mothers who must
return to work to continue to provide breast milk for
their infants may represent one of the policy shifts
necessary to help address the overweight epidemic (137).
In the public health sector, states are developing
state obesity plans that include targeting their high-risk
populations and testing intervention programs in these
groups. Fresh new ideas for increasing physical activity
need to be included at the community level. For
example, community planners need to consider opportunities for family physical activity, such as sidewalks,
neighborhoods with stores and schools within walking
distance, and community parks. Eorts must be directed toward the identication of children who are overweight or at risk for overweight in childhood and
toward the propagation of successful treatment and
prevention strategies.
129
10.
11.
12.
13.
14.
15.
REFERENCES
Strauss RS. Childhood obesity and self-esteem.
Pediatrics 2000; 105(1). URL: http://www.pediatrics.
org/cgi/content/full/full/105/1/e15.
2. Davison KK, Birch LL. Weight status, parent
reaction, and self-concept in ve-year-old girls. Pediatrics 2001; 107:4653.
3. Freedman DS, Dietz WH, Srinivasan SR, Berenson
GS. The relation of overweight to cardiovascular risk
factors among children and adolescents: the Bogalusa
Heart Study. Pediatrics 1999; 103:11751182.
4. Ford ES, Galuska DA, Gillespie C, Will JC, Giles
WH, Dietz WH. C-reactive protein and body mass
index: ndings from the Third National Health and
Nutrition Examination Survey, 19881994. J Pediatr
2001; 138:486492.
5. American Diabetes Association. Type 2 diabetes in
children and adolescents. Pediatrics 2000; 105:671680.
6. Garn SM, Clark DC. Nutrition, growth, development,
and maturation: ndings from the ten-state nutrition
survey of 19681970. Pediatrics 1975; 56:306319.
7. Kinugasa A, Tsunamoto K, Furukawa N, et al. Fatty
liver and its brous changes found in a simple obesity
of children. J Pediatr Gastroenterol Nutr 1984; 3:408
414.
8. Crichlow RW, Seltzer MH, Jannetta PJ. Cholecystitis
in adolescents. Dig Dis 1972; 17:6872.
9. Dietz WH. Health consequences of obesity in youth:
childhood predictors of adult disease. Pediatrics 1998;
101(suppl 3):518S525S.
16.
1.
17.
18.
19.
20.
21.
21a.
22.
130
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
Martorell R, Khan LK, Hughes ML, GrummerStrawn LM. Obesity in Latin American women and
children. J Nutr 1998;128:14641473.
Tremblay MS, Willms JD. Secular trends in the body
mass index of Canadian children. CMAJ 2000;163:
14291433.
Bundred P, Kitchiner D, Buchan I. Prevalence of
overweight and obese children between 1989 and 1998:
population based series of cross sectional studies. BMJ
2001;322:326328.
Charles MA. Update on the epidemiology of obesity
and type 2 diabetes in France. (in French) Diabetes
Metab 2000; 26(suppl 3):1720.
Kromeyer-Hauschild K, Zellner K, Jaeger U, Hoyer
H. Prevalence of overweight and obesity among school
children in Jena (Germany). Int J Obes Relat Metab
Disord 1999;23:11431150.
Moreno LA, Sarr a A, Fleta J, Rodr guez G, Bueno
M. Trends in body mass index and overweight
prevalence among children and adolescents in the
region of Aragon (Spain) from 1985 to 1995. Int J
Obes Relat Metab Disord 2000;24:925931.
Kain J, Uauy R, Diaz M. Increasing prevalence of
obesity among school children in Chile, 19871996. Int
J Obes Relat Metab Disord 1998;22(suppl 4): Abstract
7.
Martorell R, Khan LK, Hughes ML, GrummerStrawn LM. Overweight and obesity in preschool
children from developing countries. Int J Obes Relat
Metab Disord 2000;24:959967.
Cheek DB. Human Growth. Philadelphia: Lea &
Febiger, 1968.
Malina RM, Bouchard C. Models and methods for
studying body composition. In: Malina RM, Bouchard C, eds. Growth, Maturation, and Physical
Activity. Champaign IL: Human Kinetics, 1991.
Knittle JL, Timmers K, Ginsberg-Fellner F, Brown
RE, Katz DP. The growth of adipose tissue in children
and adolescents. Cross-sectional and longitudinal
studies of adipose tissue cell number and size. J Clin
Invest 1979;63:239246.
Poissonnet CM, LaVelle M, Burdi AR. Growth and
development of adipose tissue. J Pediatr 1988;113:19.
Knittle JL, Ginsberg-Fellner F. Eect of weight
reduction on in vitro adipose tissue lipolysis and
cellularity in obese adolescents and adults. Diabetes
1972;21:754761.
Garn SM, Clark DC. Trends in fatness and the origins
of obesity. Ad Hoc Committee to Review the TenState Nutrition Survey. Pediatrics 1976;57:443456.
Rolland-Cachera MF, Deheeger M, Guilloud-Bataille
M, Avons P, Patois E, Sempe M. Tracking the
development of adiposity from one month of age to
adulthood. Ann Hum Biol 1987;14:219229.
Malina RM, Bouchard C. Subcutaneous fat distribution during growth. In: Bouchard C, Johnston FE,
131
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
132
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
ciated with childhood obesity? Results from a population-based sample of third graders. Obes Res 2001;
9:306312.
Lissau I, Breum L, Sorensen TI. Maternal attitude to
sweet eating habits and risk of overweight in ospring:
a ten-year prospective population study. Int J Obes
Relat Metab Disord 1993;17:125129.
Lissau I, Sorensen TI. Parental neglect during childhood and increased risk of obesity in young adulthood. Lancet 1994;343:324327.
Mellbin T, Vuille JC. Rapidly developing overweight
in school children as an indicator of psychosocial
stress. Acta Paediatr Scand 1989; 78:568575.
Mellbin T, Vuille JC. Further evidence of an association between psychosocial problems and increase in
relative weight between 7 and 10 years of age. Acta
Paediatr Scand 1989;78:576580.
Davies PS, Gregory J, White A. Physical activity and
body fatness in pre-school children. Int J Obes Relat
Metab Disord 1995;9:610.
Davies PS, Wells JC, Fieldhouse CA, Day JM, Lucas
A. Parental body composition and infant energy
expenditure. Am J Clin Nutr 1995;61:10261029.
Fontvieille AM, Harper IT, Ferraro RT, Spraul M,
Ravussin E. Daily energy expenditure by ve-year-old
children, measured by doubly labeled water. J Pediatr
1993;123:200207.
Livingstone MB, Coward WA, Prentice AM, et al.
Daily energy expenditure in free-living children:
comparison of heart rate monitoring with the doubly
labeled water (2H218O) method. Am J Clin Nutr 1992;
56:343352.
Bandini LG, Schoeller DA, Dietz WH. Energy
expenditure in obese and nonobese adolescents.
Pediatr Res 1990;27:198203.
Schoeld WN. Predicting basal metabolic rate, new
standards and review of previous work. Hum Nutr
Clin Nutr 1985;39c(suppl):541.
DiGuiseppi C, Roberts I, Li L. Inuence of changing
travel patterns on child death rates from injury: trend
analysis. BMJ 1997;314:710713 [published erratum
appears in BMJ 1997;314:1385].
Anderson RE, Crespo CJ, Bartlett SJ, Cheskin KJ,
Pratt M. Relationship of physical activity and television watching with body weight and level of fatness
among children: results from the Third National
Health and Nutrition Examination Survey. JAMA
1998;279:938942.
Centers for Disease Control and Prevention. CDC
Surveillance Summaries, June 9, 2000. MMWR 2000;
49(No. SS-5).
Gordon-Larsen P, McMurray RG, Popkin BM.
Adolescent physical activity and inactivity vary by
133
ethnicity: the National Longitudinal Study of Adolescent Health. J Pediatr 1999; 35:301306.
125. U.S. Department of Health and Human Services.
Healthy People 2010, 2nd ed. With Understanding and
Improving Health and Objectives for Improving
Health. Vol 2. Washington: Government Printing
Oce, 2000, chap 22, p 19.
126. Sallis JF, Prochaska JJ, Taylor WC. A review of
correlates of physical activity of children and adolescents. Med Sci Sports Exerc 2000;32:963975.
127. U.S. Department of Health and Human Services.
Physical Activity and Health: A Resport of the
Surgeon General. Atlanta: Centers for Disease Control and Prevention, National Center for Chronic
Disease Prevention and Health Promotion, 1996:234
236.
128. Crespo CJ, Smit E, Troiano RP, Bartlett SJ, Macera
CA, Anderson RE. Television watching, energy
intake, and obesity in US children: results from the
third National Health and Nutrition Examination
Survey, 19881994. Arch Pediatr Adolesc Med 2001;
155:360365.
129. Dietz WH, Gortmaker SL. Do we fatten our children
at the television set? Obesity and television
viewing in children and adolescents. Pediatrics 1985;75:
807812.
130. Moore LL, Nguyen US, Rothman KJ, Cupples LA,
Ellison RC. Preschool physical activity level and
change in body fatness in young children: the
Framingham Childrens Study. Am J Epidemiol
1995;142:982988.
131. Perusse L, LeBlanc C, Bouchard C. Familial resemblance in lifestyle components: results from the
Canada Fitness Survey. Can J Public Health 1988;
79:201205.
132. Perusse L, Tremblay A, LeBlanc C, Bouchard C.
Genetic and environmental inuences on level of
habitual physical activity and exercise participation.
Am J Epidemiol 1989;129:10121022.
133. Agras WS, Kraemer HC, Berkowitz RI, Hammer LD.
Inuence of early feeding style on adiposity at 6 years
of age. J Pediatr 1990;116:805809.
134. Kramer MS, Barr RG, Pless IB, et al. Determinants of
weight and adiposity in early childhood. Can J Public
V Health 1986;77(suppl 1):98103.
135. Goldblatt PB, Moore ME, Stunkard AJ. Social factors
in obesity. JAMA 1965;192:97101.
136. Epstein LH, Valoski A, Wing RR, McCurley J.
Ten-year follow-up of behavioral, family-based
treatment for obese children. JAMA 1990;264:
25192523.
137. Dietz WH. Breastfeeding may help prevent childhood
overweight. JAMA 2001;285:25062507.
7
Obesity in the Elderly: Prevalence, Consequences, and Treatment
Robert S. Schwartz
University of Colorado Health Sciences Center, Denver, Colorado, U.S.A.
INTRODUCTION
136
Schwartz
137
138
Schwartz
Inactivity
Fat Oxidation
IV
A
CONSEQUENCES OF OBESITY
IN OLDER PERSONS
Metabolic
Many of the common obesity-related metabolic abnormalities found in young and middle-aged individuals
appear to be related to insulin resistance and hyperinsulinemia, what has come to be called the insulin
resistance or metabolic syndrome (84). While the
exact components of this syndrome vary among different populations (85,86), in general it is made up of
central obesity (39,87); insulin resistance and hyperinsulinemia (88); abnormal glucose metabolism (89);
dyslipidemias (41,90) such as high triglycerides, low
high-density lipoprotein (HDL) cholesterol and small,
dense, low-density lipoprotein (LDL) particles (91),
hypertension (84), and atherosclerosis (92).
These same metabolic disorders are extremely
prevalent in older populations. For example, it is well
known that glucose tolerance worsens with age, with
a 12 mg/dL increase in fasting glucose and a 1020
mg/dL increase in postprandial glucose for each
decade after age 30 (93). NIDDM is the fth most
common chronic disease in the elderly, aecting
>20% of individuals over age 65, with approximately
half of these being undiagnosed (94). Diabetes has
profound eects on health care utilization and costs,
with up to one-seventh of all health care dollars being
spent caring for diabetics (95). While in the past this
139
Functional
140
Schwartz
141
142
Schwartz
Numerous studies strongly indicate that both endurance and resistance exercise are benecial in the elderly.
While the amount of weight loss associated with training is small, it may preferentially come from the most
critical intra-abdominal depots and thus be associated
with substantial metabolic improvement. In addition,
exercise is associated with the maintenance or an increment in lean body mass and may be required to maintain
dietary weight loss long term.
D
143
8.
9.
10.
11.
12.
13.
ACKNOWLEDGMENTS
Dr. Schwartz is supported in part by NIH grant RO-1
AG 10943, NIH grant RO-1 DK 48152, NIH grant
UO-1 DK 48413, and NIH grant P-30 DK 35816.
14.
15.
REFERENCES
1.
16.
17.
18.
19.
20.
21.
22.
Gallagher D, Ruts E, Visser M, Heshka S, Baumgartner, RN, Wang J, Pierson RN, Pi-Sunyer FX,
Heymseld SB. Weight stability masks sarcopenia in
elderly men and women. Am J Physiol Endocrinol
Metab 2000; 279:E366E375.
Evans WJ, Campbell WW. Sarcopenia and age-related
changes in body composition and functional capacity.
J Nutr 1993; 123:465468.
Baumgartner RN, Koehler KM, Gallagher D, Romero
L, Heymseld SB, Ross RR, Garry PJ, Lindeman RD.
Epidemiology of sarcopenia among the elders in New
Mexico. Am J Epidemiol 1998; 147:755763.
Frontera WR, Meredith CN, OReilly KP, Knuttgen
HG, Evans WJ. Strength conditioning in older men:
skeletal muscle hypertrophy and improved function.
J Appl Physiol 1988; 64:10381044.
Fiatarone MA, Marks EC, Ryan ND, Meredith CN,
Lipsitz LA, Evans WJ. High-intensity strength training in nonagenarians. Eects on skeletal muscle.
JAMA 1990; 263:30293034.
Buchner DM, Beresford SA, Larson EB, LaCroix AZ,
Wagner EH. Eects of physical activity on health
status in older adults. II. Intervention studies. Annu
Rev Public Health 1992; 13:469488.
Buchner DM, Cress ME, Wagner EH, De Lateur BJ,
Price R, Abrass IB. The Seattle FICSIT/MoveIt study:
the eect of exercise on gait and balance in older
adults. J Am Geriatr Soc 1993; 41:321325.
Baumgartner RN, Stauber PM, McHugh D, Koehler
KM, Garry PJ. Cross-sectional age dierences in body
composition in persons 60+ years of age. J Gerontol
1995; 50A:M307M316.
Evans WJ. What is sarcopenia? J Gerontol 1995;
50A:58.
Flynn MA, Nolph GB, Baker AS, Martin WM,
Krause G. Total body potassium in aging humans: a
longitudinal study. Am J Clin Nutr 1989; 50:713
717.
Novak LP. Aging, total body potassium, fat-free mass,
and cell mass in males and females between ages 18
and 85 years. J Gerontol 1972; 27:438443.
Tzanko SP, Norris AH. Longitudinal changes in
basal metabolism in man. J Appl Physiol 1978;
45:536539.
Cohn SH, Vartsky D, Yasumura S, Savitsky A, Zanzi
I, Vaswani A, Ellis KJ. Compartmental body composition based on total-body potassium and calcium. Am
J Physiol 1980; 239:E524E530.
Baumgartner RN, Heymseld SB, Roche AF. Human
body composition and the epidemiology of chronic
disease. Obes Res 1995; 3:7395.
Chumlea WC, Guo SS, Steinbaugh ML. Prediction of
stature from knee height for black and white adults
and children with application to mobility-impaired or
handicapped persons. J Am Diet Assoc 1994; 94:1385
1388.
144
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
Schwartz
Chumlea WC, Roche AF, Webb P. Body size,
subcutaneous fatness and total body fat in older
adults. Int J Obes 1984; 8:311317.
Baumgartner RN, Stauber PM, McHugh D, Wayne S,
Garry PJ, Heymseld SB. Body composition in the
elderly using multicompartmental methods. Basic Life
Sci 1993; 60:251254.
Baumgartner RN, Heymseld SB, Lichtman S, Wang
J, Pierson RN, Jr. Body composition in elderly people:
eect of criterion estimates on predictive equations.
Am J Clin Nutr 1991; 53:13451353.
Mazariegos M, Wang ZM, Gallagher D, Baumgartner
RN, Allison DB, Wang J, Pierson RN Jr, Heymseld
SB. Dierences between young and old females in the
ve levels of body composition and their relevance to
the two-compartment chemical model. J Gerontol
1994; 49:M201M208.
Hewitt MJ, Going SB, Williams DP, Lohman TG.
Hydration of the fat-free body mass in children and
adults: implications for body composition assessment.
Am J Physiol 1993; 265:E88E95.
Chumlea WC, Guo SS. Bioelectrical impedance and
body composition: present status and future directions
[see comments]. Nutr Rev 1994; 52:123131.
Lapidus L, Bengtsson C, Hallstrom T, Bjorntorp P.
Obesity, adipose tissue distribution and health in
womenresults from a population study in Gothenburg, Sweden. Appetite 1989; 13:2535.
Larsson B, Seidell J, Svardsudd K, Welin L, Tibblin
G, Wilhelmsen L, Bjorntorp P. Obesity, adipose tissue
distribution and health in menthe study of men born
in 1913. Appetite 1989; 13:3744.
Ohlson LO, Larsson B, Svardsudd K, Welin L,
Eriksson H, Wilhelmsen L, Bjorntorp P, Tibblin G.
The inuence of body fat distribution on the incidence
of diabetes mellitus. 13.5 years of follow-up of the
participants in the study of men born in 1913.
Diabetes 1985; 34:10551058.
Larsson B, Svardsudd K, Welin L, Wilhelmsen L,
Bjorntorp P, Tibblin G. Abdominal adipose tissue
distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the
study of men born in 1913. Br Med J Clin Res Ed
1984; 288:14011404.
Krotkiewski M, Bjorntorp P, Sjostrom L, Smith U.
Impact of obesity on metabolism in men and women.
Importance of regional adipose tissue distribution.
J Clin Invest 1983; 72:11501162.
Kissebah AH, Vydelingum N, Murray R, Evans DJ,
Hartz AJ, Kalkho RK, Adams PW. Relation of body
fat distribution to metabolic complications of obesity.
J Clin Endocrinol Metab 1982; 54:254260.
Stevens J, Knapp RG, Keil JE, Verdugo RR. Changes
in body weight and girths in black and white adults
studied over a 25 year interval. Int J Obes 1991; 15:
803808.
36.
Carmelli D, McElroy MR, Rosenman RH. Longitudinal changes in fat distribution in the Western
Collaborative Group Study: a 23-year follow-up. Int
J Obes 1991; 15:6774.
37. Shimokata H, Tobin JD, Muller DC, Elahi D, Coon
PJ, Andres R. Studies in the distribution of body fat. I.
Eects of age, sex, and obesity. J Gerontol 1989;
44:M66M73.
38. Vague J. The degree of masculine dierentiation of
obesities: a factor determining predisposition to
diabetes, atherosclerosis, gout and uric calculous
disease. Am J Clin Nutr 1956; 4:2034.
39. Despres JP. Abdominal obesity as important component of insulin-resistance syndrome. Nutrition 1993;
9:452459.
40. Bouchard C, Despres JP, Mauriege P. Genetic and
nongenetic determinants of regional fat distribution.
Endocr Rev 1993; 14:7293.
41. Pouliot MC, Despres JP, Nadeau A, Moorjani S,
PrudHomme D, Lupien PJ, Tremblay A, Bouchard
C. Visceral obesity in men. Associations with glucose
tolerance, plasma insulin, and lipoprotein levels.
Diabetes 1992; 41:826834.
42. Matsuzawa Y, Shimomura I, Nakamura T, Keno Y,
Tokunaga K. Pathophysiology and pathogenesis of
visceral fat obesity. Ann NY Acad Sci 1995; 748:399
406.
43. Boyko EJ, Leonetti DL, Bergstrom RW, Newell
Morris L, Fujimoto WY. Visceral adiposity, fasting
plasma insulin, and blood pressure in JapaneseAmericans. Diabetes Care 1995; 18:174181.
44. Fujimoto WY, Bergstrom RW, Leonetti DL, Newell
Morris LL, Shuman WP, Wahl PW. Metabolic and
adipose risk factors for NIDDM and coronary disease
in third-generation Japanese-American men and women with impaired glucose tolerance. Diabetologia 1994;
37:524532.
45. Cefalu WT, Wang ZQ, Werbel S, Bell Farrow A,
Crouse JRr, Hinson WH, Terry JG, Anderson R.
Contribution of visceral fat mass to the insulin
resistance of aging. Metabolism 1995; 44:954959.
46. Schwartz RS, Shuman WP, Bradbury VL, Cain KC,
Fellingham GW, Beard JC, Kahn SE, Stratton JR,
Cerqueira MD, Abrass IB. Body fat distribution in
healthy young and older men. J Gerontol 1990;
45:M181M185.
47. Borkan GA, Hults DE, Gerzof SG, Robbins AH,
Silbert CK. Age changes in body composition revealed
by computed tomography. J Gerontol 1983; 38:673
677.
48. Lemieux S, PrudHomme D, Bouchard C, Tremblay
A, Despres JP. Sex dierences in the relation of
visceral adipose tissue accumulation to total body
fatness. Am J Clin Nutr 1993; 58:463467.
49. Baumgartner RN, Rhyne RL, Garry PJ, Chumlea
WC. Body composition in the elderly from magnetic
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
145
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
146
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
Schwartz
Kahn HS, Byers T. Recreational physical activity and
ten-year weight change in a US national cohort. Int J
Obes Relat Metab Disord 1993; 17:279286.
Goran MI, Calles-Escandon J, Poehlman ET, OConnell M, Danforth E Jr. Eects of increased energy
intake and/or physical activity on energy expenditure
in young healthy men. J Appl Physiol 1994; 77:
366372.
Rising R, Harper IT, Fontvielle AM, Ferraro RT,
Spraul M, Ravussin E. Determinants of total daily
energy expenditure: variability in physical activity. Am
J Clin Nutr 1994; 59:800804.
Calles-Escandon J, Poehlman ET. Aging fat oxidation
and exercise. Aging (Milano) 1997; 9:5763.
DeFronzo RA, Ferrannini E. Insulin resistance. A
multifaceted syndrome responsible for NIDDM,
obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14:
173194.
Chaiken RL, Banerji MA, Huey H, Lebovitz HE. Do
blacks with NIDDM have an insulin-resistance
syndrome? Diabetes 1993; 42:444449.
Morales PA, Mitchell BD, Valdez RA, Hazuda HP,
Stern MP, Haner SM. Incidence of NIDDM and
impaired glucose tolerance in hypertensive subjects. The
San Antonio Heart Study. Diabetes 1993; 42:154161.
Bjorntorp P. Abdominal obesity and the metabolic
syndrome. Ann Med 1992; 24:465468.
Ferrannini E. The insulin resistance syndrome. Curr
Opin Nephrol Hypertens 1992; 1:291298.
Lemieux S, Despres JP. Metabolic complications of
visceral obesity: contribution to the aetiology of type 2
diabetes and implications for prevention and treatment. Diabete Metab 1994; 20:375393.
Mitchell BD, Haner SM, Hazuda HP, Valdez R,
Stern MP. The relation between serum insulin levels
and 8-year changes in lipid, lipoprotein, and blood
pressure levels. Am J Epidemiol 1992; 136:1222.
Austin MA, Mykkanen L, Kuusisto J, Edwards KL,
Nelson C, Haner SM, Pyorala K, Laakso M.
Prospective study of small LDLs as a risk factor for
non-insulin-dependent diabetes mellitus in elderly men
and women. Circulation 1995; 92:17701778.
Despres JP, Marette A. Relation of components of
insulin resistance syndrome to coronary disease risk.
Curr Opin Lipidol 1994; 5:274289.
Kahn SE, Schwartz RS, Porte DJ, Abrass IB. The
glucose intolerance of aging: implications for intervention. Hosp Prac 1991; 26:2938.
Harris MI. Epidemiology of diabetes mellitus among
the elderly in the United States. Clin Geriatr Med
1990; 6:703719.
Rubin RJ, Altman WM, Mendelson DN. Health care
expenditures for people with diabetes mellitus. J Clin
Endocrinol Metab 1992; 78:809A809F.
Meyers DA, Goldberg AP, Bleecker ML, Coon PJ,
147
124. Iribarren C, Sharp DS, Burchel CM, Petrovitch H.
Association of weight loss and weight uctuation with
mortality among Japanese American men [see comments]. N Engl J Med 1995; 333:686692.
125. Reynolds MW, Fredman L, Langenberg P, Magaziner
J. Weight, weight change and mortality in a random
sample of older community-dwelling women. J Am
Geriatr Soc 1999; 47:14091414.
126. French SA, Folsom AR, Jeery RW, Zheng W, Mink
PJ, Baxter JE. Weight variability and incident disease
in older women: the Iowa Womens Health Study. Int
J Obes 1997; 21:217223.
127. Williamson DF, Pamuk ER. The association between
weight loss and increased longevity. A review of the
evidence. Ann Intern Med 1993; 119:731736.
128. Pamuk ER, Willianmson DF, Serdula MK, Madans J,
Byers TE. Weight loss and subsequent death in a cohort of U.S. adults. Ann Intern Med 1993; 119:744
748.
129. Williamson DF, Pamuk E, Thun M, Flanders D,
Byers T, Heath C. Prospective study of intentional
weight loss and mortality in never-smoking overweight
US white women aged 4064 years [published erratum
appears in Am J Epidemiol 1995; 142(3):369]. Am J
Epidemiol 1995; 141:11281141.
130. Verdery RB. Clinical evaluation of failure to thrive in
older people. Clin Geriatr Med 1997; 13:769-778.
131. Newman, AB, Yanez D, Harris T, Duxbury A,
Enright PL, Fried LP. Weight change in old age and
its association with mortality. J Am Geriatr Soc 2001;
49:13091318.
132. Dey DK, Rothenberg E, Sundh V, Bosaeus I, Steen B.
Body mass index, weight change and mortality in the
elderly. A 15 y longitudinal population study of 70 y
olds. Eur J Clin Nutr 2001; 55:482492.
133. Allison DB, Zannolli R, Faith MS. Weight loss
increases and fat loss decreases all-cause mortality
rate: results from two independent cohort studies. Int J
Obes Relat Metab Disord 1999; 23:603611.
134. Dengel DR, Hagberg JM, Coon PJ, Drinkwater DT,
Goldberg AP. Eects of weight loss by diet alone or
combined with aerobic exercise on body composition
in older obese men. Metabolism 1994; 43:867871.
135. Purnell JQ, Kahn SE, Albers JJ, Nevin DN, Brunzell
JD, Schwartz RS. Eect of weight loss with reduction
of intra-abdominal fat on lipid metabolism in older
men. J Clin Endocrinol Metab 2000; 85:977982.
136. Colman E, Katzel LI, Rogus E, Coon P, Muller D,
Goldberg AP. Weight loss reduces abdominal fat and
improves insulin action in middle-aged and older men
with impaired glucose tolerance. Metabolism 1995;
44:15021508.
137. Dengel DR, Hagberg JM, Coon PJ, Drinkwater DT,
Goldberg AP. Comparable eects of diet and exercise
on body composition and lipoproteins in older men.
Med Sci Sports Exerc 1994; 26:13071315.
148
138. Barzilai N, Bupta G. Revisiting the role of fat mass in
the life extension induced by caloric restriction.
J Gerontol 1999; 54:B89B96.
139. Schwartz RS, Buchner DM. Exercise in the elderly:
physiologic and functional eects. In: Hazzard WR,
Bierman EL, Blass JP, Ettinger WHJ, Halter JB, eds.
Principles of Geriatric Medicine and Gerontology, Vol
3. New York: McGraw-Hill, 1994:91105.
140. Wilmore JH. Variations in physical activity habits and
body composition. Int J Obes Relat Metab Disord
1995; 19:S107S112.
141. Barlow CE, Kohl HW, Gibbons LW, Blair SN.
Physical tness, mortality and obesity. Int J Obes
Relat Metab Disord 1995; 19:S41S44.
142. Schwartz RS, Hirth VA. The eects of endurance and
resistance training on blood pressure. Int J Obes Relat
Metab Disord 1995; 19:S52S57.
143. Helmrich SP, Ragland DR, Leung RW, Paenbarger
RS, Jr. Physical activity and reduced occurrence of
non-insulin-dependent diabetes mellitus [see comments]. N Engl J Med 1991; 325:147152.
144. Despres JP, Lamarche B, Bouchard C, Tremblay A,
PrudHomme D. Exercise and the prevention of
dyslipidemia and coronary heart disease. Int J Obes
Relat Metab Disord 1995; 19:S45S51.
145. Pavlou KN, Krey S, Stefee WP. Exercise as an
adjunct to weight loss and maintainence in moderately
obese subjects. Am J Clin Nutr 1989; 49:11151123.
146. Ewbank PP, Darga LL, Lucas CP. Physical activity as
a predictor of weight maintenance in previously obese
subjects. Obes Res 1995; 3:257263.
147. Schwartz RS, Shuman WP, Larson V, Cain KC,
Fellingham GW, Beard JC, Kahn SE, Stratton JR,
Cerqueira MD, Abrass IB. The eect of intensive
endurance exercise training on body fat distribution in
young and older men. Metabolism 1991; 40:545551.
148. Kohrt WM, Obert KA, Holloszy JO. Exercise training
improves fat distribution patterns in 60- to 70-year-old
men and women. J Gerontol 1992; 47:M99M105.
149. Schwartz RS, Cain KC, Shuman WP, Larson V,
Stratton JR, Beard JC, Kahn SE, Cerqueira MD,
Abrass IB. Eect of intensive endurance training on
lipoprotein proles in young and older men. Metabolism 1992; 41:649654.
150. Kirwan JP, Kohrt WM, Wojta DM, Bourey RE,
Holloszy JO. Endurance exercise training reduces
glucose-stimulated insulin levels in 60- to 70-year-old
men and women. J Gerontol 1993; 48:M84M90.
151. Katzel LI, Bleecker ER, Colman EG, Rogus EMS,
Goldberg AP. Eects of weight loss vs. aerobic
exercise training on risk factors for coronary disease
in healthy, obese, middle-aged and older men. JAMA
1995; 274:19151921.
152. Goran MI, Poehlman ET. Endurance training does
not enhance total energy expenditure in healthy elderly
persons. Am J Physiol 1992; 263:E950E957.
Schwartz
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
8
Economic Costs of Obesity
Ian D. Caterson
University of Sydney, Sydney, New South Wales, Australia
Janet Franklin
Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
Graham A. Colditz
Harvard Medical School and Brigham & Womens Hospital, Boston, Massachusetts, U.S.A.
INTRODUCTION
149
150
II
Caterson et al.
TYPES OF COSTS
Direct Costs
Indirect Costs
These are the social and personal costs or losses associated with obesity. While some of these may be relatively easy to estimate, for example, the amount spent
on commercial weight loss programs, other aspects are
more dicult, variable, and subject to the whim of the
individual health economist. An example of the latter
would be an estimation of the monetary value of the
III
151
Year (Ref.)
United States
1995 (4)
1995 (5)
1990 (6)
Canada
The Netherlands
France
1993 (7)
1997 (8)
198189 (9)
1992 (10)
United Kingdom
Australia
1992 (11)
199091 (12)
198990 (13)
New Zealand
1991 (14)
Type of cost
Direct
Direct
Indirect
Direct
Indirect
Direct
Direct
Direct
Direct
Indirect
Direct
Direct & Indirect
Direct
Indirect
Direct
Amount
US$ 70 billion
US$51.6 billion
US$47.6 billion
US$45.8 billion
US$23 billion
2.4
4
2
0.71.5
>2
These studies used a variety of BMI cut points for obesity and methods for obtaining costs. These are all prevalence studies.
152
IV
Caterson et al.
4.
5.
The use of dierent BMI cut points for overweight and obesity
Dierent obesity-associated diseases used in the
analysis
Lack of reliable data sets which enable relative
risks for obesity related diseases, in the specic
community, to be calculated
Which cost centers are available (or used) for
cost analysis
Great dierences in the cost of the health care
system in dierent countries (in the United
States treatment costs far more than in other
countries)
United States
(25)
Canada
(8)
France
(10)
United Kingdom
(12)
New Zealand
(14)
Australia
(13)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
153
Table 3 Relative Risk Values for the Obese Population Used in Recent Studies (see Tables 1, 2)
Disease
U.S.
Canada
France
New Zealand
Australia
Type II diabetes
Coronary heart disease
Endometrical Ca
Hypertension
Gallstones/gallbladder disease
PM breast cancer
Colon cancer
Myocardial infarction
Stroke
Venous thrombosis
Hyperlipidemia
Gout
Osteoarthritis
Pulmonary embolism
27.6
3.5
2
3.9
3.2
1.3
1.5
4.37
1.72
2.19
2.51
1.85
1.31
1.16
1.14
1.41
2.39
2.9
2
2.9
2
1.2
1.3
1.9
3.1
1.5
1.5
2.5
1.8
16.7
3.3
2
4.3
10
1.3
1.3
16.7
3.3
2
4.3
10
1.3
154
Caterson et al.
155
VI
CONCLUSION
The obesity epidemic is continuing to increase in magnitude globally. Estimates of the costs of obesity provide one measure that integrates the public health
burden of this preventable condition and its health
consequences. Two factors drive the economic burden
of obesitythe prevalence of obesity, and the range of
conditions that arise as a consequence of obesity. Uniform classication of obesity will lead to more consistent estimation of the costs of obesity. The prevalence
of obesity is, however, expected to rise in many countries given the recent global trends. While published
estimates may considerably underestimate the true
burden of obesity, the substantial proportion of health
expenditures consumed by conditions that arise as a
consequence of obesity indicates that perhaps greater
priority should be placed on prevention of excess
weight gain and the development of obesity. Future
studies of the costs of obesity should strive to adhere to
the methodologic points summarized in this chapter.
However, as new conditions become clearly linked to
obesity as our understanding of the health consequences of obesity continue to broaden, the costs of disease
will likely also increase purely as a consequence of these
new insights, regardless of the proportion of the population who are obese.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
156
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Caterson et al.
services use and health care costs among members of a
health maintenance organisation. Arch Intern Med
1998; 158:466472.
Birmingham CL, Muller JL, Palepu A, Spinelli JJ, Anis
AH. The cost of obesity in Canada. Can Med Assoc J
1999; 160:503506.
Seidell JC. The impact of obesity on health status: some
implications for health care costs. Int J Obes 1995;
19:S13S16.
Levy E, Levy P, LePen C, Basdevant A. The economic
cost of obesity: the French situation. Int J Obes 1995;
19:788792.
Detourmay B, Fagnani F, Phillippo M, Pribil C, Charles
MA, Sermet C, Basdevant A, Eschwege E. Obesity
morbidity and health care costs in France: an analysis of
the 19911992 Medical Care Household Survey. Int J
Obes 2000; 24:151155.
West, R. Obesity. In: Oce of Health Economics
Monographs on Current Health Issues. London: Oce
of Health Economics, 1994:3842.
Segal L, Carter R, Zimmet P. The cost of obesity: the
Australian perspective. Pharmacoeconomics 1994; 5:45
52.
Swinburn, B, Ashton T, Gillespie J, Cox B, Menon A,
Simmons D, Birbeck J. Health care costs of obesity in
New Zealand. Int J Obes 1997; 21:891896.
Colditz G, Mariani A. The cost of obesity and sedentarism in the United States. In: Bouchard C, ed.
Physical Activity and Obesity. Champaign, IL: Human
Kinetics, 2000:5566.
Seidell JC. Societal and personal costs of obesity. Exp
Clin Endocrinol Diabetes 1998; 106:79.
Hauner, H, Koster I, Von Ferber L. Frequency of
obesity in medical records and utilisation of outpatient health care by obese subjects in Germany. An
analysis of health insurance data. Int J Obes 1996;
20:820824.
Burton WN, Chen CY, Schultz AB, Edington DW. The
economic costs associated with body mass idex in a
workplace. J Occup Environ Med 1998; 40:786792.
Tucker LA, Friedman GM. Obesity and absenteeism:
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
9
Genetics of Human Obesity
Claude Bouchard
Pennington Biomedical Research Center, Baton Rouge, Louisiana, U.S.A.
Louis Perusse
Laval University, Sa`nte-Foy, Quebec, Canada
INTRODUCTION
II
THE PHENOTYPES
158
Bouchard et al.
Figure 1 Diagram of the determinants of positive energy balance and fat deposition with indication about the sites of action of a
genetic predisposition.
159
Figure 2 Common variance between three body fat phenotypes. Percent fat estimated from underwater weighing: truncalabdominal fat assessed from skinfolds or CT scans; abdominal visceral fat estimated by CT scan at the L4/L5 vertebrae. (From
Ref. 219.)
entirely satisfactory as genetic studies deal with individual dierences in the phenotype of interest and, for
them to be successful, the phenotype of a complex
multifactorial trait must be measured with a reasonable degree of precision.
That percent body fat remains quite heterogeneous at
any level of BMI is further illustrated in Table 2, based
on data from middle-aged adult males. For instance, in
27 men with a BMI of 2830, the mean percent body fat
was 28, but the range varied from 15% to 41%. We
have observed the same phenomenon and with as
much heterogeneity in women at all levels of BMI.
The same point can be made for regional fat distribution phenotypes. Thus the correlation between the
waist-to-hip circumferences ratio (WHR) and abdominal visceral fat is positive and generally signicant
in various populations, but the association is charac-
Percent fat
Fat-free mass
Sum 6 skinfolds
TER
41
37
58
10
40
25
67
8
Percent fat and fat-free mass were derived from underwater weighing
assessment of body density. TER = ratio of trunk to extremity
skinfolds. Trunk skinfolds are the sum of subscapular, suprailiac, and
abdominal skinfolds. Extremity skinfolds are the sum of triceps,
biceps, and medial calf skinfolds.
Source: Ref. 219.
BMI
Mean
Min.
Max.
27
76
46
27
2022
2325
2627
2830
17
22
26
28
8
11
16
15
32
35
40
41
160
Bouchard et al.
BMI
% Fat (range)
Mean
Min.
Max.
15
19
18
16
2122
2425
2728
3031
1418
1924
2529
3033
58
89
133
153
31
50
63
77
84
140
199
261
GENETIC EPIDEMIOLOGY
OF HUMAN OBESITY
There are several considerations in genetic epidemiological studies of obesity (5). First, obesity is not a
simple Mendelian trait. For example, expression of
genetic propensities may depend on appropriate environmental stimulation (i.e., gene-by-environment interaction), or developmental stage (i.e., age dependency),
or sex (i.e., sex limited). Second, obesity is not a
homogeneous trait stemming from a unique gene or
set of genes. Third, the trait measured may index other
traits such as bone and muscle mass, which also may
have separate genetic determinants.
Genetic epidemiological methods are useful for
addressing specic questions in human obesity, such
as determining if there are genetic factors underlying an
obesity phenotype, characterizing the sources of the
genetic inuence through maternal vs. paternal trans-
Review of Methods
Multifactorial
variance (e.g., spouse resemblance and additional sibship resemblance) can be investigated. Twin studies
(1416) allow for separation of the G component since
monozygotic (MZ) twins share 100% of their genes
while dizygotic (DZ) twins share half on the average.
Major concerns with twin data are that MZ twins
may share more common environmental eects (and
they do share more dominance deviations) than do DZ
twins that can inate the genetic component (see 6).
The correlation between MZ twins reared apart is
a relatively unbiased estimate of the broad-sense
heritability (additive + dominance), although one must
assume that the twins were reared in uncorrelated
environments. Full adoption studies (see 17) are useful
in separating common environmental eects since
adoptive parents and their adopted ospring (and
adopted sibling pairs) share only environmental sources
of variance while the adoptees and their biological
parents share only genetic sources of variance. Assumptions underlying adoption designs include no
selective (or late) placement into the adoptive home
and that adoptive families are representative of the
general population.
Longitudinal assessment (i.e., repeated measures
across time) can be applied to any of the family, twin,
or adoption designs (see 1820). Longitudinal study
designs are particularly important in obesity research
since it is generally recognized that fat accumulates with
time, and trends in the familial eect may arise through
secular environmental eects, or through age-limited
developmental eects of genes as for example the
growth spurt at puberty (21). Even more importantly,
with body fat accretion up to a new body mass level
(e.g., a given obesity level), the causes of the positive
energy balance leading to obesity may be progressively
masked over time. For instance, an apparent decit in
resting energy expenditure is compensated by an
increase in the metabolic mass associated with weight
gain (22), similarly for an apparent decit in lipid
oxidation rate which is eliminated when the gain in fat
mass has been large enough to ensure a greater reliance
on lipid oxidation (23). It adds a dimension to the
complex task of understanding the causes of obesity
and dening the role of genes. To unmask the true
susceptibilities to be in positive energy balance, one
has to rely on longitudinal data that will make it possible
to dene the relevant predictors of obesity and to specify
their genetic and molecular basis.
Multivariate assessment is another important design
issue in the study of obesity since there are likely to be
multiple relevant predictors, each having unique determinants. Multivariate genetic epidemiology studies
161
Major Gene
Combined Models
Complex traits such as obesity involve multiple intercorrelated phenotypes, and it is highly unlikely that
we will discover anything close to the gene which
explains most of the variation for the phenotype.
Instead, we expect genetic eects in the oligogenic
(few genes) to polygenic (many genes) range, with an
elaborate interplay between many factors, including
gene-gene and gene-environmental interactions. While
a lot of analytic progress has been made using the
strategies discussed so far, a combined approach (see
30) is potentially much more powerful and holds great
promise for these traits. Combined approaches
describe models that include multiple sources of var-
162
Bouchard et al.
Review of Findings
Maternal/
patenal
Familial
environment
3050
No
Minor
1030
Minor
5080
Mixed
results
No
2540
No
Minor
No
163
(861)
(60)
(284)
(629)
(301)
(301)
(618)
335 (71)
607 (201)
493 (134)
Kirghizian
Turkmenian
Chuvashian
11204 (2580)
(74)
(197)
(135)
(165)
(87)
(541)
Ginsburg (115)
Rice (72)
Borecki (84)
397
558
516
672
1742
2461
Kirghizian
Turkmenian
Chuvashian
Israeli
Mexican
NHLBI-FHS
random
SOS
(403)
(29)
616 (42)
3925
231
1302
2534
1223
1223
2625
1167 (123)
(179)
2935 (961)
9226 (3281)
Individuals
(families)
Ginsburg (74)
Hasstedt (82)
Price (75)
LRC white
LRC black
Utah
LRC white
LRC black
Muscatine
French
QFS
QFS
PIMA Indians
Ness (68)
Moll (71)
Tiret (76)
Rice (79)
Borecki (73)
Price (78)
LRC
Italian
LRC
Tecumseh
Sample
Karlin (81)
Zonta (77)
Price (69)
Province (70)
Source
44%
40%
37%
PC2 (fBMI)
0
9%
1724% (age)
834% (age)l
BMI
BMI
66%
53%
34%
41%
20%
34%
50%
42%
3540%
42%
30%
% Variance for
multi-factor
No
No
No
No
19%
30%
12%
34%
33%
35%
14%
No
35%
No
No
Yesf
Yesg
No
No
14%
20%
% Variance for
major gene
17%
40%
40%
30%
14%
44%
BMI
BMI
BMI
BMI
BMIe
BMI
BMI
BMI
BMI
BMI
BMI
BMIc
BMI
Phenotype
Genetic heterogeneityi
Genotype-dependent
Recessive (combined cohorts)
vs. codominant (separately
by cohorts)
Ascertainedd
Ascertaineda
Ascertainedb
Ascertaineda
Ospring
Parents
Notes
164
Bouchard et al.
Am. black
Nigerian
QFS
Mexican-Am.
HERITAGE
white
French
QFS
HERITAGE white
Colilla (220)
Comuzzie (85)
Rice (99)
Rice (120)
607 (201)
493 (134)
Utah
Tecumseh
QFS
India
Kirghizian
Turkmenian
Chuvasnian
Kirghizian
Turkmenian
Chuvasnian
Kirghizian
Turkmenian
Chuvasnian
Hasstedt (35)
Province (70)
Borecki (54)
Feitosa (114)
Ginsburg (115)
Ginsburg (115)
Ginsburg (115)
335 (71)
607 (201)
493 (134)
335 (71)
607 (201)
493 (134)
335 (71)
Italian
Zonta (77)
1691 (432)
744 (59)
(3281)
1223 (301)
(179)
S-leut
784 (89)
440 (98)
913 (220)
1630 (300)
543 (26)
438 (86)
315 (95)
1159 (400)
619 (175)
1691 (432)
Paganini-Hill (222)
Lecomte (221)
Borecki (83)
Rice (86)
India
Feitosa (88)
PC4 (fsubcutaneous
upper vs. lower)
PC3 (finternal
upper vs. lower)
Triceps SF
Subscapular
Discriminant
scorem
RFPI
TER
TER-fm
SF6-fm
Trunk SF-fm
TER
TER-ee,ei
TER-sf
PC1
(fSF)
FM-ht
BMI
FM
FM
%BF
FM
FM
FM
BMI
BMI-ee, eik
BMI
30%
30%
42%
No
37%
34%
No
34%
34%
3551%l
55%
50%
44%
57%
33%
35%
60%
83%
26%
Yes
No
64%
47%
31%
37%
No
52%
42%l
45%
45%
3542%
64%
No
No
39%
36%
%
25%
25%
6117%
9%
No
No
4%
No
No
No
10%
No
47%
538%
80%14%
0
0
22%
26%
2035%
0
Principal components of
anthropometrics
Principal components of
anthropometrics
Principal components of
anthropometrics
Parent-ospring
Ascertainedn
Ascertainedb dominant
Sex-dependent
2 Pleiotropic/oligogenic
loci78% of covariance
Training response dominant
Males-females
Baseline
Ospring-parents
Ospring-parents
Codominant
NHLBI-FHS random
Feitosa (106)
HERITAGE white
HERITAGE white
Rice (99)
Rice (120)
440 (98)
438 (86)
382 (100)
2713 (1038)
482 (99)
Individuals
(families)
AVF
AVF-fm
AVF
AVF-fm
AVF
AVF-fm
SF6
TER
TER-sf
WHR
WHR-sf
WHR
WHR-BMI
Phenotype
51%
No
54%
No
18%
26%
47%
54%
56%
48%
No
35%
No
% Variance for
major gene
21%
44%
17%
42%
No
No
30%
17%
18%
No
50%
No
35%
% Variance for
multi-factor
Training responses
Baseline
Random + obese
Additive
Additive
Additive
Additive
Notes
QFS phase 2
Bouchard (118)
HERITAGE
Sample
An (105)
Source
Table 5 (continued )
166
Bouchard et al.
167
168
Bouchard et al.
the variance with an additional 29% due to a multifactorial component. These ndings are consistent
with the hypothesis that there is more than one genetic
factor underlying fat distribution, and that removal
of the gene for total fat allows for a second locus
specic to fat distribution to be detected. However, in
the HERITAGE study (105), an additive major gene
accounting for >50% of the variance was found, but
total fat adjustment had no eect on the major gene
inference. This was in contrast to results for WHR in
the same study (previously discussed), in which total fat
adjustment reduced the major gene inference. Together,
these studies support the previous multifactorial studies
suggesting that both pleiotropic and oligogenic loci
underlie body composition. A putative major locus
was also reported in Utah pedigrees (35) for a relative
fat pattern index [RFPI = subscapular/(subscapular +
suprailiac)], and two recent studies also support major
gene eects for fat distribution in other ethnic groups
from India (114) and Eastern Europe (115).
3
abdominal visceral fat. In other words, genetic pleiotropy was inferred, where the same major gene aected
both fat mass and the abdominal visceral fat traits. A
cross-trait study conducted between fat mass and
abdominal visceral fat (119) supported the pleiotropy
hypothesis. The bivariate (cross-trait) familiality was
2950% (with sex dierences), indicating genetic pleiotropy. Moreover, since the univariate familiality for
each trait was even higher (5577% for fat mass and
5565% for abdominal visceral fat), each trait was
assumed to be inuenced by additional familial factors that were specic to each (i.e., oligogenic). Given
the signicant spouse cross-trait correlations, at least
some of the bivariate familial eect may be environmental in origin. Finally, the visceral fat response
to exercise training was also a function of a recessive
major gene accounting for 2025% of the variance
(120). However, in this case, adjusting for total fat
did not change the major gene inference. This suggests
that the genes for visceral fat response to exercise
training may be independent from those aecting total
level of fatness.
4
IV
A
This section focuses on association studies with candidate genes and on the results of genomic scans
designed to identify genomic regions that harbor genes
of importance for obesity. The molecular dissection of
complex phenotypes such as obesity is based on two
strategies: linkage and association studies. Both rely
169
on the same principle, i.e., the coinheritance of adjacent DNA markers, with the dierence that linkage
focuses only on recent and usually observable generations, while association relies on the fact that particular DNA markers can remain together on ancestral
haplotypes for several generations, leading to a phenomenon known as linkage disequilibrium (122,123).
Reviews of methods and strategies to identify genes
underlying complex phenotypes can be found elsewhere (123126). The number of genes and DNA
sequence variations that have been shown to be associated and/or linked with obesity has increased considerably since the rst edition of this volume. The
yearly updates of the obesity gene map published since
1996 (127134) provide a good indication of the
progress accomplished in the past several years in the
search for genes determining human obesity. Other
topics of relevance for the understanding of the molecular basis of human obesities can be found in Chapter
10 by Chua et al. All the gene symbols, names, and
chromosomal locations of the genes listed in this
section are given in the Appendix found at the end
of this chapter.
Review of Findings
Association Studies
170
Bouchard et al.
Table 6 Evidence for the Presence of an Association Between Markers of Candidate Genes with BMI, Body Fat, and Other
Obesity-Related Phenotypes
Gene
Location
Phenotype
TNFRSF1B
LEPR
1p36.3-p36.2
1p31
HSD3B1
LMNA
ATP1A2
AGT
ACP1
APOB
POMC
ADRA2B
IRS1
PPARG
1p13.1
1q21.2-q21.3
1q21-q23
1q42-q43
2p25
2p24-p23
2p23.3
2p13-q13
2q36
3p25
APOD
CCKAR
FABP2
UCP1
NPY5R
CART
GRL
ADRB2
3q26.2-qter
4p15.2-p15.1
4q28-q31
4q28-q31
4q31-q32
5q
5q31-q32
5q31-q32
TNFA
ESR1
GCK
NPY
PON2
LEP
6p21.3
6q25.1
7p15.3-p15.1
7p15.1
7q21.3
7q31.3
LPL
ADRB3
8p22
8p12-p11.2
CBFA2T1
ADRA2A
SUR1
IGF2
INS
UCP2
8q22
10q24-q26
11p15.1
11p15.5
11p15.5
11q13
UCP3
11q13
APOA4
DRD2
11q23
11q23
GNB3
12p13
P value
Ref.
<.05
.003<P<.05
(223,224)
(225231)
.04
.0001<P<.05
.0001<P<.05
.007<P<.02
.002<P<.02
.005<P<.05
<.01
.01
.03<P<.05
.001<P<.05
(232)
(233235)
(236,237)
(238,239)
(240,241)
(242,243)
(170,244)
(245)
(246248)
(249258)
.006
.003.041
.008<P<.01
.001<P<.05
<.05
.0021
.001<P<.039
.001<P<.05
(259)
(260)
(261263)
(264266)
(267)
(268)
(269271)
(154,254,272279)
.004<P<.035
.0001
.002
.03<P<.04
<.05
.005<P <.05
(224,280284)
(285)
(286)
(287,288)
(289)
(290297)
.05
.002<P<.05
(298)
(136156)
.0002<P<.02
.002<P<.012
.02
.02
.0002<P<.009
.001<P<.05
(299)
(154,300)
(301)
(302)
(302304)
(305311)
.0037<P<.04
(312316)
.004<P<.023
.002<P<.05
(317,318)
(319321)
.001<P<.05
(322326)
171
Table 6 (continued)
Gene
Location
IGF1
12q22-q23
CD36L1
HTR2A
12q24.1-q24.3
13q14-q21
HSPA2
NMB
MC5R
MC4R
14q21
15q22-qter
18p11.2
18q22
INSR
LDLR
19p13.3-p.13.2
19p13.3
LIPE
GYS1
ADA
HTR2C
19q13.1-q13.2
19q13.3
20q12-q13.11
Xq24
Phenotype
P value
Ref.
<.05
(327)
.004.03
.028.047
(328)
(329)
<106
.03
.003
.0022<P<.004
(330)
(331)
(332)
(332)
.05
.001<P<.04
(333)
(197,334337)
.002
.03
.0004.01
.0009.02
(338)
(339)
(340)
(341)
gene, the LEP gene, the UCP2 and UCP3 genes, the
GNB3 gene, and the LDLR gene. Other genes that were
found to be associated with obesity phenotypes include
the TNFRSF1B, HSD3B1, LMNA, ATP1A2, AGT,
ACP1, APOB, POMC, ADRA2B, IRS1, APOD,
CCKAR, FABP2, UCP1, NPY5R, CART, GRL,
ESR1, GCK, NPY, PON2, LPL, CBFA2T1, SUR1,
IGF2, INS, APOA4, DRD2, IGF1, CD36L1, HTR2A,
HSPA2, NMB, MC5R, MC4R, INSR, LIPE, GYS1,
ADA, and HTR2C genes.
2
172
Bouchard et al.
Linkage Studies
Pima Indians
173
Trait
Markers
LOD score
Candidate gene
D1S550
D6S271
D11S200D11S2366
D11S976
D11S4464D11S912
D16S265
D18S877
D20S601
2.8
2.1
2.8
2.0
3.6
2.0
2.3
3.0
D2S1788
D2S1788
D6S1008
D8S1121
D8S1110
D17S1293
2.8
4.97.5
1.5
3.2
2.2
2.3
D2S165D2S367
D5S426
D10S197
2.42.7
2.9
4.9
POMC
1.53.2
ASIP, GNAS1,
MC3R
D1S534
D4S2417
D4S2397
D7S1808
D7S1875
D9S1122,257
IGF1
D12S2078, 1045
D13S285
IGF1R
D17S2180, 1290, 1302
2.3
1.8
2.3
2.7
2.0
2.12.3
1.9
1.52.9
1.9
3.6
1.52.2
NHLH2, HSDB3
NPY2R
PPARGC1
NPY, GHRHR
LEP, CAV2
HSD17B3
IGF1
TCF1
NA
IGF1R
HSD17B1, PYY,
PYY
FFM
D18S535
3.6
D18S1155
DX6799DX6804
2.4
3.5
MC4R
HTR2C
18q12
Finnish Families (179)
18q21
Xq24
LEPR
TNFA
DRD2
MC4R
ASIP
POMC
ADRB3
D3S2427
2.43.3
SLC2A2, APM1
D17S947
5.0
SLC2A4
D2S441
D2S1334, D2S1399
D2S434, IRS1
1.88
1.972.33
1.872.49
IRS1
174
Bouchard et al.
Table 7 (continued)
Location
Trait
Markers
LOD score
3p26.3
3q29
4q31.22
5q31.2-q31.3
7q36.2-q36.3
8q23.3
9q34.3
10p15.3-p15.1
11p15.2-p14.1
ASF
ASF
ASF
ASF, ATF
ASF, ATF
BMI
BMI
BMI, FM
ASF
D3S2387
D3S1311
D4S2431
D5S658, D5S1480
D7S3070, NOS3, D7S559
D8S556
D9S158
D10S1435, 189
C11P15_3, GATA34E08
2.16
2.45
2.34
1.842.06
1.742.53
2.0
2.3
2.12.7
1.751.85
12p12.1
14q24.1
14q11-q11.2
19p13
22q11.23
BMI, FM
ASF
BMI, FM, FFM
Leptin
ASF
D12S1042
D14S588
D14S283, 742, 1280
LDLR
D22S264
2.12.2
2.38
1.72.4
P = .0009
1.96
D3S3608
D7S640, 636
D10S220
D14S276
D14S74, 280
D16S510
D16S407
1.6
1.8
2.7
1.8
2.5
1.7
1.7
Candidate gene
CPE
NOS3
SUR, CCKBR,
TUB
ANG
LDLR
PPARG
LEP
ASF, abdominal subcutaneous fat; AVF, abdominal visceral fat; FFM, fat-free mass; RQ, 24-hr respiratory quotient.
Finnish Families
Another genome scan performed in 367 obese individuals from 166 Finnish families revealed evidence of 2
QTLs inuencing obesity, dened as a BMI z 30 kg/m2
(179). The strongest evidence of linkage was uncovered
on chromosome Xq24 between markers DX6799 and
DX6804 (LOD = 3.5) in a region where the serotonin
2C receptor (HTR2C) gene is located. Evidence of
linkage with obesity was also observed in a region of
chromosome 18q21 (LOD = 2.4 with D18S1155) anking the MC4R gene.
7
175
176
Bouchard et al.
7q31
8q11-23
9q22-34
10p12-15
14q11-31
17q11-21
18q12-21
20q11-13
Studies
Ref.
(165,166)
(177,178)
(173)
(169171)
(183)
V
(177,178)
(181,182)
(169171)
(181,182)
(177,178)
(181,182)
(183)
(173)
(181,182)
(183)
(177,178)
(169171)
(179)
(165168)
(177,178)
(165168)
(176)
GENE-ENVIRONMENT AND
GENE-GENE INTERACTIONS
177
Markers
PGD
D1S193, 200, 476
LEPR
ATP1B1
ATP1A2
ACP1
POMC
IGKC
GYPA
ISL1
GRL
ADRB2
BF
TNFA
D2S2337
TNFir24,
D6S273,291
Location
1p36.2-p36.13
1p35-p31
1p31
1q22-q25
1q21-q23
2p25
2p23.3
2p12
4q28.2-q31.1
5q22.3
5q31-q32
5q31-q32
6p21.3
6p21.3
GLO1
6p21.3-p21.1
NPY
7p15.1
LEP
D7S680,514, 530,
504, 1875, 495
KEL
ADRB3
ORM1
AK1
SUR1
CCKBR
UCP2/UCP3
IGFI
ESD
MC5R
MC4R
ADA
7q31.3
7q33
D8S1121
D10S204,193,178
1 and TCF8
D11S419
D20S17,120
8p12-p11.2
9q31-q32
9q34.1
10p11.22
11p15.1
11p15.4
11q13
12q22-q23
13q14.1-q14.2
18p11.2
18q22
20q12-q13.11
MC3R
20q13.2-q13.3
P1
22q11.2-qter
Phenotypes
P or LOD value
Ref.
Subcutaneous fat
BMI, subcutaneous fat,
fat mass
BMI, subcutaneous fat,
fat mass, fat free mass
Respiratory quotient
Respiratory quotient
BMI, subcutaneous fat
Leptin
Subcutaneous fat
TER
Obesity, BMI, leptin
BMI > 27
TER
Subcutaneous fat
%Fat
.03
.009<P<.02
(341)
(157)
.005<P<.05
(225)
.04
.02
.004<P<.02
LOD = 2.0
.03
.02
.0004<P<.03
.009
.02
.01<P<.03
.002<P<.05
(236)
(343)
(341,344)
(244)
(342)
(345)
(346)
(347)
(300)
(342)
(283)
Subcutaneous fat,
relative weight
Principal component
of height, weight, skinfolds,
abdominal and hip
circumferences, obesity
Obesity, fat mass, BMI,
subcutaneous fat, waist
circumference, WHR
BMI, subcutaneous fat,
trunk to extremity
skinfolds ratio
BMI
Subcutaneous fat
Subcutaneous fat
Obesity
.004<P<.05
(342)
.04<P<.05
(348)
.0001<P<.04
(343,348353)
.0001<P<.04
(345)
LOD = 3.2
.03
.01
1.1<LOD<2.5
(171)
(342)
(342)
(174)
.003
.01
.000002
.02
<.04
.001<P<.02
(301)
(346)
(354)
(327)
(345)
(332)
.001<P<.04
.004<P<.02
(332)
(345,355)
.008<P<.02
(355)
.03
(342)
BMI
Leptin
Resting metabolic rate
Visceral fat
Subcutaneous fat, % fat
BMI, subcutaneous fat,
fat mass, %fat,
fat-free mass, resting
metabolic rate
Respiratory quotient, obesity
BMI, subcutaneous fat,
fat mass, %fat
BMI, subcutaneous fat,
fat mass
Relative weight
a
The absence of gene symbol indicates that the linkage study involved a targeted chromosomal region.
See Table 5 legend for denitions.
178
Bouchard et al.
Review of Methods
Figure 3 Five hypothetical relationships between genetic susceptibility to disease and risk factors for disease. The genetic
susceptibility may be either polygenic or due to a dominant, recessive, or X-linked major locus. The risk factor may be only one
of many factors associated with disease risk, and may itself have either genetic or nongenetic origins. (From Ref. 186.)
179
180
Bouchard et al.
Review of Findings
Figure 4 Intrapair resemblance in the response of identical twins to long-term changes in energy balance. Left panel: 12 pairs of
identical twins were submitted to an 84,000-kcal energy intake surplus over 100 days. Right panel: 7 pairs were subjected to a
negative energy balance protocol caused by exercise. The energy decit was 58,000 kcal over 93 days. (From Refs. 201 and 204.)
short-term overfeeding, demonstrate that some individuals are more at risk than others to gain fat when
energy intake surplus is clamped at the same level for
everyone and when all subjects are conned to a
sedentary lifestyle. The within-identical-twin-pair
response to the standardized caloric surplus suggests
that the amount of fat stored is likely inuenced by
the genotype. Similar results were essentially obtained
in a shorter (22 days) overfeeding experiment (200).
The long-term overfeeding study also revealed that
there was six times more variance between pairs than
within pairs for the changes in upper body fat and in
CT-determined abdominal visceral fat when both
were adjusted for the gain in total fat mass. These
observations indicate that some individuals are storing fat predominantly in selected fat depots primarily
as a result of undetermined genetic characteristics. It
also suggests that variations in regional fat distribution are more closely related to the genotype of the
individuals than variations in body mass and in overall body composition.
At the beginning of the overfeeding treatment,
almost all the daily caloric surplus was recovered as
body energy gain, but the proportion decreased to
60% at the end of the 100-day protocol (205). The
weight gain pattern followed an exponential with a
half-duration of f86 days. We have estimated that
the weight gain attained in the experiment would have
reach about 55% of the anticipated maximal weight
gain had the overfeeding protocol been continued
indenitely (205). The mean body mass gain for the
24 subjects of the 100-day overfeeding experiment was
8.1 kg, of which 5.4 kg was fat mass and 2.7 kg was
fat-free mass. Assuming that the energy content of
body fat is f22 MJ/kg (9300 kcal/kg, assuming a
100% triglyceride content) and that of fat-free tissue is
2.42 MJ/kg (1020 kcal/kg), then about 63% of the
excess energy intake was recovered on the average as
body mass changes. This proportion is of the same
order as that reported by other investigators (206,207),
i.e., between 60% and 75% of total excess energy
intake. There were, however, individual dierences
among the 24 subjects with respect to the amount of
fat and fat free tissue gained.
Resting metabolic rate in absolute terms increased by
f10% with overfeeding. However, the increase was
only marginal when expressed by unit of fat-free mass
(208,209). The intrapair resemblance for the changes in
resting metabolic rate brought about by overfeeding
was signicant but became nonsignicant when the
changes in body mass or body composition were taken
into account. The thermic response to food, as assessed
181
Seven pairs of young adult male identical twins completed a negative energy balance protocol during which
they exercised on cycle ergometers twice a day, 9 out of
10 days, over a period of 93 days while being kept on a
constant daily energy and nutrient intake (204). The
mean total energy decit caused by exercise above the
estimated energy cost of body weight maintenance
reached 244 MJ. Baseline energy intake was estimated
over a period of 17 days preceding the negative energy
balance protocol. Mean body weight loss was 5.0 kg and
was entirely accounted for by the loss of fat mass. Fatfree mass was unchanged. Body energy losses reached
191 MJ, which represented f78% of the estimated
energy decit. Decreases in metabolic rates and in the
182
Bouchard et al.
VI
RECOMMENDATIONS
Genomewide Explorations
183
184
Bouchard et al.
Gene or
locus
AK1
ANG
APM1
APOA4
APOB
APOD
ASIP
ATP1A2
ATP1B1
ATRN
B, C
BBS2
BBS4
BF
BSCL2
CART
APPENDIX Symbols, Full Names, and Cytogenetic
Gene or
locus
A
ACP1
ADA
ADRB2
ADRA2A
ADRA2B
ADRB3
AGT
Name
Acid phosphatase 1,
soluble
Adenosine deaminase
Adrenergic, beta-2-,
receptor, surface
Adrenergic, alpha-2A-,
receptor
Adrenergic, alpha-2B-,
receptor
Adrenergic, beta-3-,
receptor
Angiotensinogen
Location
CAV2
CBFA2T1
CCKAR
2p25
CCKBR
20q12-q13.11
5q31-q32
CD36L1
10q24-q26
2p13-q13
8p12-p11.2
1q42-q43
CPE
DF
DRD2
ESD
Name
Adenylate kinase 1
Angiogenin, ribonuclease, RNase A
family, 5
Adipose most
abundant
gene transcript 1,
adiponectin
Apolipoprotein A-IV
Apolipoprotein B
(including Ag (x)
antigen)
Apolipoprotein D
Agouti (mouse)
signaling protein
ATPase, Na+ K+
transporting, alpha 2
(+) polypeptide
ATPase, Na+ K+
transporting, beta 1
polypeptide
Attractin (with dipeptidylpeptidase IV activity)
Bardet-Biedl
syndrome 2 gene
Bardet-Biedl
syndrome 4 gene
B-factor, properdin
Berardinelli-Siep
congenital lipodystrophy 2 gene
Cocaine- and amphetamine-regulated transcript
Caveolin 2
Core-binding factor,
runt domain, alpha
subunit 2; translocated to, 1;
cyclin D-related
Cholecystokinin A
receptor
Cholecystokinin B
receptor
(or gastrin receptor)
CD36 antigen (collagen
type I receptor,
thrombospondin
receptor)-like 1
Carboxypeptidase E
Dopamine receptor D2
Esterase D/formylglutathione hydrolase
Location
9q34.1
14q11.1-q11.2
3q27
11q23
2p24-p23
3q26.2-qter
20q11.2-q12
1q21-q23
1q22-q25
20p13
16q21
15q22.3-q23
6p21.3
11q13
5q
7q31.1
8q22
4p15.2-p15.1
11p15.4
12q24.1-q24.3
4q32
11q23
13q14.1-q14.2
FGF13
GI, K
GCK
GHRH
GHRHR
GLO1
GNAS1
GNB3
GPC3
GPC4
GRL
GYPA
GYS1
HSD3B1
HSD17B1
HSD17B3
HSPA2
Name
185
Location
Gene or
locus
Estrogen receptor 1
Fatty acid binding
protein 2, intestinal
Fanconi-Bickel
syndrome
Fibroblast growth
factor receptor 3
(achondroplasia,
thanatophoric
dwarfism)
Fibroblast Growth
Factor 13
6q25.1
4q28-q31
HTR2A
3q26.1-q26.3
HTR2C
Glucokinase
(hexokinase 4,
maturity onset
diabetes of the
young 2
Growth hormone
releasing hormone
Growth hormone
releasing hormone
receptor
Glyoxalase I
Guanine nucleotide
binding protein
(G protein), alpha
stimulating activity
polypeptide 1
Guanine nucleotide
binding protein
(G protein),
beta polypeptide 3
Glypican 3
Glypican 4
Glucocorticoid
receptor
Glycophorin A
(includes MN
blood group)
Glycogen synthase
1 (muscle)
Hydroxy-delta-5-steroid
dehydrogenase,
3 beta- and steroid
delta-isomerase 1
11-Hydroxysteroid
(17-beta)
dehydrogenase 1
11-Hydroxysteroid
(17-beta)
dehydrogenase 3
Heat shock 70kD
protein 2
7p15.3-p15.1
4p16.3
IGF1
IGF1R
Xq26
IGF2
IGKC
20q11.2
INS
INSR
IRS
7p14
IRS1
ISL1
6p21.3-p21.1
20q13.2-q13.3
KEL
L
LDLR
12p13
LEPR
LEP
Xq26.1
Xq26.1
5q31-q32
4q28.2-q31.1
19q13.3
LIPE
LMNA
LPL
MO
MC3R
MC4R
MC5R
MKKS
1p13.1
NDN
NHLH2
17q11-q21
NMB
NOS3
9q22
14q21
NPY
NPY2R
Name
5-hydroxytryptamine
(serotonin)
receptor 2A
5-hydroxytryptamine
(serotonin)
receptor 2C
Insulin-like growth
factor 1
(somatomedin C)
Insulin-like growth
factor 1 receptor
Insulin-like growth
factor 2
(somatomedin A)
Immunoglobulin
kappa constant
Insulin
Insulin receptor
Insulin Resistance
syndromes
Insulin receptor
substrate 1
ISL1 transcription
factor, LIM/homeodomain (islet-1)
Kell blood group
Low-density lipoprotein
receptor (familial
hypercholesterolemia)
Leptin receptor
Leptin (murine
obesity homolog)
Lipase, hormone
sensitive
Lamin A/C
Lipoprotein lipase
Melanocortin 3 receptor
Melanocortin 4 receptor
Melanocortin 5 receptor
McKusick-Kaufman
syndrome
Necdin(mouse)
homolog
Nescient helix loop
helix 2
Neuromedin B
Nitric oxide
synthase 3
(endothelial cell)
Neuropeptide Y
Neuropeptide Y
receptor Y2
Location
13q14-q21
Xq24
12q22-q23
15q25-q26
11p15.5
2p12
11p15.5
19p13.3-p13.2
19p13.3
2q36
5q22.3
7q33
19p13.3
1p31
7q31.3
19q13.1-q13.2
1q21.2-q21.3
8p22
20q13.2-q13.3
18q22
18p11.2
20p12
15q11.2-q12
1p12-p11
15q22-qter
7q36.2
7p15.1
4q31
186
Gene or
locus
NPY5R
ORM1
P, S
P1
PCSK1
PGD
PMM2
POMC
PON2
PPARG
PPARGC1
PPCD
PPY
PROP1
PYY
SIM1
SLC2A2
SLC2A4
SNRPN
SUR1
T, U, W
TBX3
TCF1
TCF8
Bouchard et al.
Name
Neuropeptide Y
receptor Y5
Orosomucoid 1
P blood group (P one
antigen)
Proprotein convertase
subtilisin/kexin
type 1
Phosphogluconate
dehydrogenase
Phosphomannomutase 2
Proopiomelanocortin
Paraoxonase 2
Peroxisome proliferative
activated receptor,
gamma
Peroxisome proliferative
activated receptor,
gamma, coactivator 1
Posterior Polymorphous
Corneal dystrophy
Pancreatic polypeptide
Prophet of Pit 1,
paired-like
homeodomain
transcription factor
Peptide YY
Single-minded
(Drosophila)
homolog 1
Solute carrier family 2
(facilitated glucose
transporter),
member 2
Solute carrier family 2
(facilitated glucose
transporter),
member 4
Small nuclear ribonucleoprotein
polypeptide N
Sulfonylurea receptor 1
T-box3 (ulnar mammary
syndrome)
Transcription factor 1,
hepatic; hepatic
nuclear factor (HNF1)
Transcription factor 8
(represses interleukin 2 expression)
Location
Gene or
locus
4q31-q32
THRB
9q31-q32
TNFA
TNFRSF1B
22q11.2-qter
5q15-q21
TUB
UCP1
1p36.2-p36.13
16p13.3-p13.2
UCP2
2p23.3
7q21.3
3p25
UCP3
4p15.1
Name
Thyroid hormone
receptor, beta
Tumor necrosis factor
Tumor necrosis factor
receptor superfamily
member 1B
Tubby (mouse)
homolog
Uncoupling protein 1
(mitochondrial,
proton carrier)
Uncoupling protein 2
(mitochondrial,
proton carrier)
Uncoupling protein 3
(mitochondrial,
proton carrier)
Location
3p24.3
6p21.3
1p36.3-p36.2
11p15.5
4q28-q31
11q13
11q13
* The gene symbols, names and cytogenetic locations are from the
Locus Link Web site (http//www.ncbi.nlm.nih.gov/LocusLink) available from the National Center for Biotechnology Information
20q11
17q21
5q
REFERENCES
1.
17q21.1
6q16.3-q21
2.
3q26.1-q26.2
3.
17p13
4.
15q12
5.
11p15.1
12q24.1
12q24.2
6.
7.
10p11.2
8.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
187
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
188
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
Bouchard et al.
household environments: the Princeton School District
Family Study. Metabolism 1983; 32:8289.
Longini IM Jr, Higgins MW, Hinton PC, Moll PP,
Keller JB. Genetic and environmental sources of
familial aggregation of body mass in Tecumseh,
Michigan. Hum Biol 1984; 56:733757.
Biron P, Mongeau J-G, Bertrand D. Familial resemblance of body weight and weight/height in 374 homes
with adopted children. J Pediatr 1977; 91:555558.
Heller R, Garrison RJ, Havlik RJ, Feinleib M,
Padgett S. Family resemblances in height and relative
weight in the Framingham Heart Study. Int J Obes
1984; 8:399405.
Price RA, Cadoret RJ, Stunkard AJ, Troughton E.
Genetic contributions to human fatness: an adoption
study. Am J Psychiatry 1987; 144:10031008.
Price RA, Gottesman II. Body fat in identical twins
reared apart: roles for genes and environment. Behav
Genet 1991; 21:17.
Srensen TIA, Price RA, Stunkard AJ, Schulsinger F.
Genetics of obesity in adult adoptees and their
biological siblings. BMJ 1989; 298:8790.
Stunkard AJ, Foch TT, Hrubec Z. A twin study of
human obesity. JAMA 1986; 256:5154.
Stunkard AJ, Srensen TIA, Hanis C, Teasdale TW,
Chakraborty R, Schull WJ, Schulsinger F. An
adoption study of human obesity. N Engl J Med
1986; 314:193198.
Stunkard AJ, Harris JR. Pedersen NL, McClearn GE.
The body-mass index of twins who have been reared
apart. N Engl J Med 1990; 322:14831487.
Vogler GP, Srensen TIA, Stunkard AJ, Srinivasan
MR, Rao DC. Inuences of genes and shared family
environment on adult body mass index assessed in an
adoption study by a comprehensive path model. Int J
Obes 1995; 19:4045.
MacDonald A, Stunkard J. Body mass indexes of
British separated twins. N Engl J Med 1990; 322:1530.
Tambs K, Moum T, Eaves L, Neale M, Midthjell K,
Lund-Larsen PG, Ness S, Holmen J. Genetic and environmental contributions to the variance of the body
mass index in Norwegian sample of rst- and seconddegree relatives. Am J Hum Biol 1991; 3:257267.
McLaughlin JA. The inheritance of body-mass index
in the Virginia 30,000. Behav Genet 1991; 21:581
(abstract).
Bouchard C. Genetics of obesity: overview and research directions. In: Bouchard C. ed. The Genetics of
Obesity, Boca Raton, FL: CRC Press, 1994:223233.
Borecki IB, Rice T, Perusse L, Boulard C, Rao DC.
Major gene inuence on the propensity to store fat in
trunk versus extremity depots: evidence from the
Quebec Family Study. Obes Res 1995; 3:18.
Cardon LR. Developmental analysis of the body mass
index in the Colorado Adoption Project. Behav Genet
1991; 21:563564 (abstract).
56.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
189
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
190
100. Perusse L, Leblanc C, Bouchard C. Inter-generation
transmission of physical tness in the Canadian
population. Can J Sport Sci 1988; 13:814.
101. Donahue RP, Prineas RJ, Gomez O, Hong CP.
Familial resemblance of body fat distribution: the
Minneapolis Childrens Blood Pressure Study. Int J
Obes 1992; 16:161167.
102. Sellers TA, Drinkard C, Rich SS, Potter JD, Jeery
RW, Hong C-P, Folsom AR. Familial aggregation
and heritability of waist-to-hip ratio in adult women:
The Iowa Womens Health Study. Int J Obes 1994;
18:607613.
103. Towne B, Roche AF, Chumlea WC, Guo S, Siervogel
RM. No evidence of pleiotropy for either body mass
index or waist/hip circumference ratio and plasma
cholesterol concentration. Obes Res 1993; 1:1105
(abstract).
104. Esposito-Del Puente A, Scal L, De Filippo E, Peri
MR, Caldara A, Caso G, Contaldo F, Valerio G,
Franzese A, Di Maio S, Rubino A. Familial and
environmental inuences on body composition and
body fat distribution in childhood in southern Italy.
Int J Obes 1994; 18:596601.
105. An P, Rice T, Borecki IB, Perusse L, Gagnon J, Leon
AS, Skinner JS, Wilmore JH, Bouchard C, Rao DC.
Major gene eect on subcutaneous fat distribution in a
sedentary population and its response to exercise
training: the HERITAGE Family Study. Am J Hum
Biol 2000; 12:600609.
106. Feitosa MF, Borecki I, Hunt SC, Arnett DK, Rao
DC, Province M. Inheritance of the waist-to-hip ratio
in the National Heart, Lung, and Blood Institute
Family Heart Study. Obes Res 2000; 8:294301.
107. Mueller WH, Reid RM. A multivariate analysis of
fatness and relative fat patterning. Am J Phys Anthrop
1979; 50:199208.
108. Li Z, Rice T, Perusse L, Bouchard C, Rao DC.
Familial aggregation of subcutaneous fat patterning:
principal components of skinfolds in the Quebec
Family Study. Am J Hum Biol 1996; 8:535542.
109. Bouchard C. Inheritance of human fat distribution. In:
Bouchard C, Johnston FE, eds. Fat Distribution
During Growth and Later Health Outcomes. Current
Topics in Nutrition and Disease, Vol 17. New York:
Alan R. Liss, 1988:103125.
110. Bouchard C. Genetic and environmental inuences on
regional fat distribution. In: Oomura Y, Tarui S,
Inoue S, Shimazu T, eds. Progress in Obesity Research
1990. London: Libbey, 1991:303308.
111. Comuzzie AG, Blangero J, Mahaney MC, Mitchell
BD, Stern MP, MacCluer JW. Genetic and environmental correlations among skinfold measures. Int J
Obes 1994; 18:413418.
112. Rice T, Bouchard C, Perusse L, Rao DC. Familial
clustering of multiple measures of adiposity and fat
distribution in the Quebec Family Study: a trivariate
Bouchard et al.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
191
128.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
192
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
Bouchard et al.
morphism: a genetic marker for visceral fat obesity
and the insulin resistance syndrome. Diabetologia
1997; 40:200204.
Shima Y, Tsukada T, Nakanishi K, Ohta H. Association of the Trp64Arg mutation of the beta3adrenergic receptor with fatty liver and mild glucose
intolerance in Japanese subjects. Clin Chim Acta 1998;
274:167176.
Thomas GN, Tomlinson B, Chan JC, Young RP,
Critchley JA. The Trp64Arg polymorphism of the
beta3-adrenergic receptor gene and obesity in Chinese subjects with components of the metabolic
syndrome. Int J Obes Relat Metab Disord 2000;
24:545551.
Ukkola O, Rankinen T, Weisnagel SJ, Sun G, Perusse
L, Chagnon YC, Despres JP, Bouchard C. Interactions among the alpha2-, beta2-, and beta3-adrenergic
receptor genes and obesity-related phenotypes in
the Quebec Family Study. Metabolism 2000; 49:
10631070.
Urhammer SA, Clausen JO, Hansen T, Pedersen O.
Insulin sensitivity and body weight changes in young
white carriers of the codon 64 amino acid polymorphism of the beta3-adrenergic receptor gene.
Diabetes 1996; 45:11151120.
Strazzullo P, Iacone R, Siani A, Cappuccio F, Russo
O, Barba G, Barbato A, DElia L, Trevisan M,
Farinaro E. Relationship of the Trp64Arg polymorphism of the beta3-adrenoceptor gene to central
adiposity and high blood pressure: interaction with
age. Cross-sectional and longitudinal ndings of the
Olivetti Prospective Heart Study. J Hypertens 2001;
19:399406.
Chagnon YC, Perusse L, Bouchard C. Familial
aggregation of obesity, candidate genes and quantitative trait loci. Curr Opin Lipidol 1997; 8:205211.
Maurie`ge P, Bouchard C. Trp64Arg mutation in
beta 3-adrenoceptor gene of doubtful signicance
for obesity and insulin resistance. Lancet 1996; 348:
698699.
Allison DB, Heo M, Faith MS, Pietrobelli A. Metaanalysis of the association of the Trp64Arg polymorphism in the beta3 adrenergic receptor with body
mass index. Int J Obes 1998; 22:559566.
Fujisawa T, Ikegami H, Kawaguchi Y, Ogihara T.
Meta-analysis of the association of Trp64Arg polymorphism of beta 3-adrenergic receptor gene with
body mass index. J Clin Endocrinol Metab 1998; 83:
24412444.
Kurokawa N, Nakai K, Kameo S, Liu ZM, Satoh H.
Association of BMI with the beta3-adrenergic receptor
gene polymorphism in Japanese: meta-analysis. Obes
Res 2001; 12:741745.
Lynch M, Walsh B. Genetics and Analysis of
Quantitative Traits. Sunderland, MA: Sinauer Associate, 1998.
163.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
193
185. Sims EA, Goldman RF, Gluck CM, Horton ES,
Kelleher PC, Rowe DW. Experimental obesity in man.
Trans Assoc Am Phys 1968; 81:153170.
186. Ottman R. An epidemiologic approach to geneenvironment interaction. Genet Epidemiol 1990; 7:
177185.
187. Ottman R. Epidemiologic analysis of gene-environment interaction in twins. Genet Epidemiol 1994; 11:
7586.
188. Khoury MJ, Wagener DK. Epidemiological evaluation of the use of genetics to improve the predictive
value of disease risk factors. Am J Hum Genet 1995;
56:835844.
189. Ottman R, Susser E, Meisner M. Control for environmental risk factors in assessing genetic eects on
disease familial aggregation. Am J Epidemiol 1991;
134:298309.
190. Blangero J. Statistical genetic approaches to human
adaptability. Hum Biol 1993; 65:941966.
191. Eaves LJ. The resolution of genotype environment
interaction in segregation analysis of nuclear families.
Genet Epidemiol 1984; 1:215228.
192. Eaves LJ. Including the environment in models for
genetic segregation. J Psychiatr Res 1987; 21:639647.
193. Plomin R, DeFries JC, Loehlin JC. Genotype-environment interaction and correlation in the analysis of
human behavior. Psychol Bull 1977; 84:309322.
194. Tiret L, Abel L, Rakotovao R. Eect of ignoring
genotype-environment interaction on segregation
analysis of quantitative traits. Genet Epidemiol 1993;
10:581586.
195. Bouchard C, Perusse L, Leblanc C. Using MZ twins in
experimental research to test for the presence of
genotype-environment interaction eect. Acta Genet
Med Gemellol 1990; 39:8589.
196. Hallman DM, Boerwinkle E, Saha N, Sandholzer C,
Menzel HJ, Csazar A, Utermann G. The apolipoprotein E polymorphism: a comparison of allele frequencies and eects in nine populations. Am J Hum Genet
1991; 49:338349.
197. Zee RYL, Griths LR, Morris BJ. Marked association of a RFLP for the low density lipoprotein receptor gene with obesity in essential hypertensives.
Biochem Biophys Res Commun 1992; 189: 965971.
198. Berg K. Twin studies of coronary heart disease and
its risk factors. Acta Genet Med Gemellol 1984; 33:
349361.
199. Berg K, Borresen AL, Nance WE. Apparent inuence of marker genotypes on variation in serum
cholesterol in monozygotic twins. Clin Genet 1981;
19:6770.
200. Poehlman ET, Tremblay A, Despres JP, Fontaine E,
Perusse L, Theriault G, Bouchard C. Genotypecontrolled changes in body composition and fat
morphology following overfeeding in twins. Am J
Clin Nutr 1986; 43:723731.
194
201. Bouchard C, Tremblay A, Despres JP, Nadeau A,
Lupien PJ, Theriault G, Dussault J, Moorjani S,
Pinault S, Fournier G. The response to long-term
overfeeding in identical twins. N Engl J Med 1990;
322:14771482.
202. Poehlman ET, Tremblay A, Nadeau A, Dussault J,
Theriault G, Bouchard C. Heredity and changes in
hormones and metabolic rates with short-term training. Am J Physiol 1986; 250:E711E717.
203. Poehlman ET, Tremblay A, Marcotte M, Perusse L,
Theriault G, Bouchard C. Heredity and changes in
body composition and adipose tissue metabolism after
short-term exercise training. Eur J Appl Physiol 1987;
56:398402.
204. Bouchard C, Tremblay A, Despres JP, Theriault G,
Nadeau A, Lupien PJ, Moorjani S, Prudhomme D,
Fournier G. The response to exercise with constant
energy intake in identical twins. Obes Res 1994; 2:
400410.
205. Deriaz O, Tremblay A, Bouchard C. Nonlinear weight
gain with long term overfeeding in man. Obes Res
1993; 1:179185.
206. Norgan NG, Durnin JVGA. The eect of 6 weeks of
overfeeding on the body weight, body composition,
and energy metabolism of young men. Am J Clin Nutr
1980; 33:978988.
207. Ravussin E, Schutz Y, Acheson KJ, Dusmet M,
Bourquin L, Jequier E. Short-term, mixed-diet overfeeding in man: no evidence for Luxuskonsumption.
Am J Physiol 1985; 249:E470E477.
208. Tremblay A, Despres JP, Theriault G, Fournier G,
Bouchard C. Overfeeding and energy expenditure in
humans. Am J Clin Nutr 1992; 56:857862.
209. Deriaz O, Fournier G, Tremblay A, Despres JP,
Bouchard C. Lean-body-mass composition and resting
energy expenditure before and after long-term overfeeding. Am J Clin Nutr 1992: 56:840847.
210. Levine JA, Eberhardt NL, Jensen MD. Role of
nonexercise activity thermogenesis in resistance to fat
gain in humans. Science 1999; 283:212214.
211. Ukkola O, Tremblay A, Sun G, Chagnon YC,
Bouchard C. Genetic variation at the uncoupling
protein 1, 2 and 3 loci and the response to long-term
overfeeding. Eur J Clin Nutr. 2001; 55:10081015.
212. Ukkola O, Tremblay A, Despres JP, Chagnon YC,
Campeld LA, Bouchard C. Leptin receptor
Gln223Arg variant is associated with a cluster of
metabolic abnormalities in response to long-term
overfeeding. J Intern Med 2000; 248:435439.
213. Ukkola O, Tremblay A, Bouchard C. Beta-2 adrenergic receptor variants are associated with subcutaneous fat accumulation in response to long-term
overfeeding. Int J Obes Relat Metab Disord 2001;
25:16041608.
214. Ukkola O, Sun G, Bouchard C. Insulin-like growth
factor 2 (IGF2) and IGF-binding protein 1 (IGFBP1)
Bouchard et al.
gene variants are associated with overfeeding-induced
metabolic changes. Diabetologia 2001; 44:22312236.
215. Dizier MH, Bona ti-Pellie C, Clerget-Darpoux F.
Conclusions of segregation analysis for family data
generated under two-locus models. Am J Hum Genet
1993; 53:13381346.
216. Cardon LR, Fulker DW. The power of interval
mapping of quantitative trait loci, using selected sib
pairs. Am J Hum Genet 1994; 55:825833.
217. Almasy L, Blangero J. Multipoint quantitative-trait
linkage analysis in general pedigrees. Am J Hum
Genet 1998; 62:11981211.
218. Province MA, Rice T, Borecki IB, Gu C, Rao DC. A
multivariate and multilocus variance components
approach using structural relationships to assess
quantitative linkage via SEGPATH. Genet Epidemiol
2003; 24(2):128138.
219. Bouchard C. Genetics of human obesities: introductory notes. In: Bouchard C, ed. The Genetics of
Obesity. Boca Raton, FL: CRC Press, 1994:115.
220. Colilla S, Rotimi C, Cooper R, Goldberg J, Cox N.
Genetic inheritance of body mass index in AfricanAmerican and African families. Genet Epidemiol
2000; 18:360376.
221. Lecomte E, Herbeth B, Nicaud V, Rakotovao R,
Artur Y, Tiret L. Segregation analysis of fat mass and
fat-free mass with age- and sex-dependent eects: The
Stanislas Family Study. Genet Epidemiol 1997; 14:
5162.
222. Paganini-Hill A, Martin AO, Spence MA. The S-leut
anthropometric traits: Genetic analysis. Am J Phys
Anthrop 1981; 55:5567.
223. Benjaeld AV, Wang XL, Morris BJ. Tumor necrosis
factor receptor 2 gene (TNFRSF1B) in genetic basis
of coronary artery disease. J Mol Med 2001; 79:
109115.
224. Fernandez-Real JM, Gutierrez C, Ricart W, Casamitjana R, Fernandez-Castaner M, Vendrell J, Richart C,
Soler J. The TNF-alpha gene Nco I polymorphism
inuences the relationship among insulin resistance,
percent body fat, and increased serum leptin levels.
Diabetes 1997; 46:14681472.
225. Chagnon YC, Chung WK, Perusse L, Chagnon M,
Leibel RL, Bouchard C. Linkages and associations
between the leptin receptor (LEPR) gene and human
body composition in the Quebec Family Study. Int J
Obes Relat Metab Disord 1999; 23:278286.
226. Chagnon YC, Wilmore JH, Borecki IB, Gagnon J,
Perusse L, Chagnon M, Collier GR, Leon AS, Skinner
JS, Rao DC, Bouchard C. Associations between the
leptin receptor gene and adiposity in middle-aged
Caucasian males from the HERITAGE family study. J
Clin Endocrinol Metab 2000; 85:2934.
227. Mammes O, Aubert R, Betoulle D, Pean F, Herbeth
B, Visvikis S, Siest G, Fumeron F. LEPR gene
polymorphisms: associations with overweight, fat
228.
229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
195
239. Rankinen T, Gagnon J, Perusse L, Rice T, Leon AS,
Skinner JS, Wilmore JH, Rao DC, Bouchard C. Body
fat, resting and exercise blood pressure and the
angiotensinogen M235T polymorphism: the HERITAGE family study. Obes Res 1999; 7:423430.
240. Lucarini N, Finocchi G, Gloria-Bottini F, Macioce M,
Borgiani P, Amante A, Bottini E. A possible genetic
component of obesity in childhood. Observations on
acid phosphatase polymorphism. Experientia 1990;
46:9091.
241. Lucarini N, Antonacci E, Bottini N, Gloria-Bottini F.
Low-molecular-weight acid phosphatase (ACP1), obesity, and blood lipid levels in subjects with non-insulindependent diabetes mellitus. Hum Biol 1997; 69:
509515.
242. Rajput-Williams J, Knott TJ, Wallis SC, Sweetnam P,
Yarnell J, Cox N, Bell GI, Miller NE, Scott J.
Variation of apolipoprotein-B gene is associated with
obesity, high blood cholesterol levels, and increased
risk of coronary heart disease. Lancet 1988; 2:
14421446.
243. Saha N, Tay JSH, Heng CK, Humphries SE. DNA
polymorphisms of the apolipoprotein B gene are
associated with obesity and serum lipids in healthy
Indians in Singapore. Clin Genet 1993; 44:113120.
244. Miraglia del Guidice E, Cirillo G, Santoro N, DUrso
L, Carbone MT, Di Toro R, Perrone L. Molecular
screening of the proopiomelanocortin (POMC) gene in
Italian obese children: report of three new mutations.
Int J Obes Relat Metab Disord 2001; 25:6167.
245. Heinonen P, Koulu M, Pesonen U, Karvonen MK,
Rissanen A, Laakso M, Valve R, Uusitupa M,
Scheinin M. Identication of a three-amino acid
deletion in the alpha2B-adrenergic receptor that is
associated with reduced basal metabolic rate in obese
subjects. J Clin Endocrinol Metab 1999; 84:24292433.
246. Celi FS, Negri C, Tanner K, Raben N, De Pablo F,
Rovira A, Pallardo LF, Martin-Vaquero P, Stern MP,
Mitchell BD, Shuldiner AR. Molecular scanning for
mutations in the insulin receptor substrate-1 (IRS-1)
gene in Mexican Americans with type 2 diabetes
mellitus. Diabetes Metab Res Rev 2000; 16:370377.
247. Krempler F, Hell E, Winkler C, Breban D, Patsch W.
Plasma leptin levels: interaction of obesity with a
common variant of insulin receptor substrate-1.
Arterioscler Thromb Vasc Biol 1998; 18:16861690.
248. Lei HH, Coresh J, Shuldiner AR, Boerwinkle E,
Brancati FL. Variants of the insulin receptor substrate-1 and fatty acid binding protein 2 genes and the
risk of type 2 diabetes, obesity, and hyperinsulinemia
in African-Americans: the Atherosclerosis Risk in
Communities Study. Diabetes 1999; 48:18681872.
249. Cole SA, Mitchell BD, Hsueh WC, Pineda P,
Beamer BA, Shuldiner AR, Comuzzie AG, Blangero J, Hixson JE. The Pro12Ala variant of
peroxisome proliferator-activated receptor-gamma2
196
250.
251.
252.
253.
254.
255.
256.
257.
258.
259.
Bouchard et al.
(PPAR-gamma2) is associated with measures of
obesity in Mexican Americans. Int J Obes Relat
Metab Disord 2000; 24:522524.
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J,
Mykkanen L, Kuusisto J, Laakso M, Fujimoto W,
Auwerx J. A Pro12Ala substitution in PPARgamma2
associated with decreased receptor activity, lower
body mass index and improved insulin sensitivity.
Nat Genet 1998; 20:284287.
Ek J, Urhammer SA, Sorensen TI, Andersen T,
Auwerx J, Pedersen O. Homozygosity of the Pro12Ala
variant of the peroxisome proliferation-activated
receptor-gamma2 (PPAR-gamma2): divergent modulating eects on body mass index in obese and lean
Caucasian men. Diabetologia 1999; 42:892895.
Hsueh WC, Cole SA, Shuldiner AR, Beamer BA,
Blangero J, Hixson JE, MacCluer JW, Mitchell BD.
Interactions between variants in the beta 3-adrenergic
receptor and peroxisome proliferator-activated receptor-gamma 2 genes and obesity. Diabetes Care 2001;
24:672677.
Lei HH, Chen MH, Yang WS, Chiu MC, Chen MC,
Tai TY, Chuang LM. Peroxisome proliferator-activated receptor gamma 2 Pro12Ala gene variant is
strongly associated with larger body mass in the
Taiwanese. Metabolism 2000; 49:12671270.
Meirhaeghe A, Fajas L, Helbecque N, Cottel D,
Auwerx J, Deeb SS, Amouyel P. Impact of the
peroxisome proliferator activated receptor gamma2
Pro12Ala polymorphism on adiposity, lipids and noninsulin-dependent diabetes mellitus. Int J Obes Relat
Metab Disord 2000; 24:195199.
Meirhaeghe A, Fajas L, Helbecque N, Cottel D, Lebel
P, Dallongeville J, Deeb S, Auwerx J, Amouyel P. A
genetic polymorphism of the peroxisome proliferatoractivated receptor gamma gene inuences plasma
leptin levels in obese humans. Hum Mol Genet 1998;
7:435440.
Ristow M, Muller-Wieland D, Pfeier A, Krone W,
Kahn CR. Obesity associated with a mutation in a
genetic regulator of adipocyte dierentiation. N Engl J
Med 1998; 339:953959.
Vaccaro O, Mancini FP, Rua G, Sabatino L,
Colantuoni V, Riccardi G. Pro12Ala mutation in the
peroxisome proliferator-activated receptor gamma2
(PPARgamma2) and severe obesity: a case-control
study. Int J Obes Relat Metab Disord 2000; 24:1195
1199.
Valve R, Sivenius K, Miettinen R, Pihlajamaki J,
Rissanen A, Deeb SS, Auwerx J, Uusitupa M, Laakso
M. Two polymorphisms in the peroxisome proliferator-activated receptor-gamma gene are associated
with severe overweight among obese women. J Clin
Endocrinol Metab 1999; 84:37083712.
Vijayaraghavan S, Hitman GA, Kopelman PG.
Apolipoprotein-D polymorphism: a genetic marker
197
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
198
292. Le Stun C, Le Bihan C, Schork NJ, Bougneres P. A
common promoter variant of the leptin gene is
associated with changes in the relationship between
serum leptin and fat mass in obese girls. Diabetes
2000; 49:21962200.
293. Li WD, Reed DR, Lee JH, Xu W, Kilker RL, Sodam
BR, Price RA. Sequence variants in the 5V anking
region of the leptin gene are associated with obesity in
women. Ann Hum Genet 1999; 63:227234.
294. Mammes O, Betoulle D, Aubert R, Giraud V, Tuzet S,
Petiet A, Colas-Linhart N, Fumeron F. Novel polymorphisms in the 5V region of the LEP gene: Association
with leptin levels and response to low-calorie diet in
human obesity. Diabetes 1998; 47:487489.
295. Mammes O, Betoulle D, Aubert R, Herbeth B, Siest
G, Fumeron F. Association of the G-2548A polymorphism in the 5V region of the LEP gene with
overweight. Ann Hum Genet 2000; 64:391394.
296. Oksanen L, Ohman M, Heiman M, Kainulainen K,
Kaprio J, Mustajoki P, Koivisto V, Koskenvuo M,
Janne OA, Peltonen L, Kontula K. Markers for the
gene ob and serum leptin levels in human morbid
obesity. Hum Genet 1997; 99:559564.
297. Shintani M, Ikegami H, Yamato E, Kawaguchi Y,
Fujisawa T, Nakagawa Y, Hamada Y, Ueda H, Miki
T, Ogihara T. A novel microsatellite polymorphism in
the human OB gene: a highly polymorphic marker for
linkage analysis. Diabetologia 1996; 39:13981401.
298. Jemaa R, Tuzet S, Portos C, Betoulle D, Apfelbaum
M, Fumeron F. Lipoprotein lipase gene polymorphisms: associations with hypertriglyceridemia and
body mass index in obese people. Int J Obes 1995;
19:270274.
299. Wolford JK, Bogardus C, Prochazka M. Polymorphism in the 3V untranslated region of MTG8 is
associated with obesity in Pima Indian males. Biochem
Biophys Res Commun 1998; 246:624626.
300. Oppert JM, Tourville J, Chagnon M, Maurie`ge P,
Dionne FT, Perusse L, Bouchard C. DNA polymorphisms in the a2 and h2 adrenoceptor genes and
regional fat distribution in humans: association and
linkage studies. Obes Res 1995; 3:249255.
301. Hani EH, Clement K, Velho G, Vionnet N, Hager J,
Philippi A, Dina C, Inoue H, Permutt MA, Basdevant
A, North M, Demenais F, Guy-Grand B, Froguel P.
Genetic studies of the sulfonylurea receptor gene locus
in NIDDM and in morbid obesity among French
Caucasians. Diabetes 1997; 46:688694.
302. ODell SD, Bujac SR, Miller GJ, Day IN. Associations
of IGF2 ApaI RFLP and INS VNTR class I allele size
with obesity. Eur J Hum Genet 1999; 7:821827.
303. Dunger DB, Ong KKL, Huxtable SJ, Sherri A,
Woods KA, Ahmed ML, Golding J, Pembrey ME,
Ring S, Bennett ST, Todd JA. Association of the
INS VNTR with size at birth. Nat Genet 1998; 19:
98100.
Bouchard et al.
304.
199
324.
325.
326.
327.
328.
329.
330.
331.
332.
333.
200
334. Griths LR, Nyholt DR, Curtain RP, Ganey PT,
Morris BJ. Cross-sectional study of a microsatellite
marker in the low density lipoprotein receptor gene in
obese normotensives. Clin Exp Pharmacol Physiol
1995; 22:496498.
335. Mattevi VS, Coimbra CE Jr, Santos RV, Salzano FM,
Hutz MH. Association of the low-density lipoprotein
receptor gene with obesity in Native American
populations. Hum Genet 2000; 106:546552.
336. Rutherford S, Nyholt D, Curtain RP, Quinlan SR,
Ganey PT, Morris BJ, Griths LR. Association of a
low density lipoprotein receptor microsatellite variant
with obesity. Int J Obes Relat Metab Disord 1997;
21:10321037.
337. Zee RYL, Schrader AP, Robinson BG, Griths LR,
Morris BJ. Association of HincII RFLP of low density
lipoprotein receptor gene with obesity in essential
hypertensives. Clin Genet 1995; 47:118121.
338. Magre J, Laurell H, Fizames C, Antoine PJ, Dib C,
Vigouroux C, Bourut C, Capeau J, Weissenback J,
Langin D. Human hormone-sensitive lipase. Genetic
mapping, identication of a new dinucleotide repeat,
and association with obesity and NIDDM. Diabetes
1998; 47:284286.
339. Orho-Melander M, Almgren P, Kanninen T, Forsblom C. Groop L. A paired-sibling analysis of the
XbaI polymorphism in the muscle glycogen synthase
gene. Diabetologia 1999; 42:11381145.
340. Bottini E, Gloria-Bottini F. Adenosine deaminase and
body mass index in non-insulin-dependent diabetes
mellitus. Metabolism 1999; 48:949951.
341. Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama
W, Nonaka K. Identication of polymorphic loci in
the promoter region of the serotonin 5-HT2C receptor
gene and their association with obesity and type II
diabetes. Diabetologia 2000; 43:373376.
342. Wilson AF, Elston RC, Tran LD, Siervogel RM. Use
of the robust sib-pair method to screen for singlelocus, multiple-locus, and pleiotropic eects: application to traits related to hypertension. Am J Hum
Genet 1991; 48:862872.
343. Onions KL, Hunt SS, Rutkowski MP, Klanke CA, Su
YR, Reif M, Menon AG. Genetic markers at the
leptin (OB) locus are not signicantly linked to
hypertension in African Americans. Hypertension
1998; 31:12301234.
344. Bailey-Wilson JE, Wilson AF, Bamba V. Linkage
analysis in a large pedigree ascertained due to essential
familial hypercholesterolemia. Genet Epidemiol 1993;
10:665669.
345. Borecki IB, Rice T, Perusse L, Bouchard C, Rao DC.
An exploratory investigation of genetic linkage with
body composition and fatness phenotypes: the Quebec
Family Study. Obes Res 1994; 2:213219.
Bouchard et al.
346.
347.
348.
349.
350.
351.
352.
353.
354.
355.
10
Molecular Genetics of Rodent and Human Single Gene Mutations
Affecting Body Composition
Streamson Chua, Jr., Kathleen Graham Lomax, and Rudolph L. Leibel
Columbia University College of Physicians and Surgeons, New York, New York, U.S.A.
INTRODUCTION
201
202
Chua et al.
II
203
Cholecystokinin
receptor
CCKAR
Carboxy peptidase E
CEBP (alpha,
beta, gamma)
CPE
Mouse: X; human:
Xq26-q28
Bombesinlike receptor 3
BRS3
Callipyge locus
Location/mouse
and human
Gene
product
ASIP (mouse:
Agouti, Ay
Gene
Nature of
mutation
Deletion
Spontaneous mutation in
sheep associated with increased muscle mass in
hindquarters of sheep
Spontaneously mutant
OLETF rat with adultonset obesity, hyperphagia,
males with impaired glucose tolerance.
Knockout model,
rodent phenotype
Refs.
(49,149,278)
(277)
(276)
(274,275)
(273)
None reported
(11,49)
None reported
Human
phenotype
204
Chua et al.
Targeted disruption
16 Mutations described in
AHO patients; some
create premature stop
codons, others increase
GDP (guanosine diphosphate) release
Glypican 3
Glypican 4
GNAS1
GPC3
GPC4
1. 13 bp del NT391
2. exon 2 del
3. Trp296Arg
4. IVS5, G-T, +1
(premature stop)
5. Arg199Ter
Deletion of last 2 exons
GPC3 and entire
GPC4 gene
FGF13
Dopamine beta
hydroxylase
DBH
Dopamine
DGAT
None reported.
Homozygous deciency is
lethal in embryonic period.
Evidence for imprinting as
heterozygotes with maternal null allele have dierent
phenotypes from heterozygotes with paternal null
allele.
None reported.
None reported
Simpson-Golabi-Behmel 1:
obesity, X-linked overgrowth syndrome with
associated visceral and
skeletal abnormalities
(283)
(253)
(282)
(232)
(280)
Similar phenotype in
subjects with bilateral
lesions of lat
hypothalamus
(279)
None reported
Insulin-like growth
factor 2
Leptin
HMGIC
IGF2
LEP
Location/mouse
and human
Growth hormone
releasing hormone
receptor
Gene
product
GHRHR
Gene
Table 1 (continued)
1. guanine deletion,
codon 133 (G398)
2. C!T, codon
105, exon 3; R105W
Transactivation in mouse
model of Sun; targeted
disruption in mouse
model of DeChiara
Spontaneous mutation in
lit mice; inactivating
mutation
Nature of
mutation
Human
phenotype
Knockout model,
rodent phenotype
(49,166,170,278,
293,294)
(291,292)
(288290)
(284287)
Refs.
206
Chua et al.
Leptin receptor
Melanocortin 4 receptor
McKusick-Kaufman
syndrome gene
Myosin IX A
LEPR
MC4R
MCH
MKKS
MYO9A
Targeted deletion
27 Dierent mutations in
humans published; most
are missense (for example Ser30Phe) with 2
frameshift (GATT insertion in codon 244; CTCT
deletion codon 211), 1
nonsense (Tyr35 STOP),
1 loss of function (deletion of 18q)
None reported.
(300)
(223,224,228,296
299)
BBS6: mental retardation,
obesity, postaxial polydactyly, retinopathy, renal malformations
MKKS: developmental
anomalies include hydrometrocolpos postaxial polydactyly,
congenital heart disease
Bardet-Biedl syndrome
type 4 (BBS4): mental
retardation, obesity,
postaxial polydactyly,
retinopathy, renal
disease
(295)
(13,49,189,190,192,
278,293,294)
(49,180,278,293,
294)
None reported
Mouse: Chr. 6;
human: 7p15.1
Nescient helix-loop-helix
2; also known as
HEN2 and NSCL2
Neuropeptide
Y/receptors
NPY
Targeted deletion
KO
Nature of
mutation
Mouse: 1 at 27.8;
human: 2q32.1
Location/mouse
and human
Gene
product
Nhlh2
GDF8/ aka
MSTN
MYOD1
Gene
Table 1 (continued)
Knockout model,
rodent phenotype
Refs.
(306)
(307)
None reported
(303305)
(301,302)
None reported
None reported
None reported
Human
phenotype
208
Chua et al.
16 Published mutations in
humans; half are silent
Mouse: Chr. 12 at 4;
human: 2p23.3
Phosphomannomutase 2
Pro-opiomelanocortin
Peroxisome proliferator
activated receptor
gamma 2
PMM2
POMC
PPAR gamma 2
Targeted disruption; KO
Perilipin
PLIN
Compound heterozygote:
Gly483Arg, A!C+4,
exon 5 donor splice site
Proprotein convertase
subtilisin/kexin type 1;
also known as PC1
PCSKI
None reported.
None reported.
(278,293,312)
(40,194)
(311)
(309,310)
(293,308)
SRY-BOX 3
SIM1 (dimerizes
with ARNT2)
SOX3
STAT5A
Location/mouse
and human
Mouse: P: 7 at 28 Ipw: Chr.
7 at 28; Snrpn: Chr. 7 at
29; Ndn: Chr. 7 at 28;
human: 15q11.2-q12
Gene
product
Gene
Table 1 (continued)
KO
Deletion
Nature of
mutation
Knockout model,
rodent phenotype
Human
phenotype
(319)
(233)
(218220)
(313318)
Refs.
210
Chua et al.
TUB
TULP1
None reported.
Recessive retinitis
pigmentosa
(155,322)
(153,157,158,
321)
(165,320)
(256)
Single-gene mutations that produce obesity in humans are well documented: e.g., Bardet-Biedl, and more recently, genes that are components of the leptin axis. Intensive screening of human populations for
mutations in orthologs of the spontaneous rodent obesity mutations have shown that such mutations (LEP, LEPR) exist, thereby conrming the role(s) of these genes in the control of human body weight.
However, such mutations are extremely rare in humans. Other genes, known by virtue of physiology or the phenotypes of knockout animals to participate in energy homeostasis, have been implicated in human
obesity: pro-opiomelanocortin (POMC), melanocortin-4 receptor (MC4R), and prohormone convertase 1 (PCSK1). Of these, MC4R mutations are highly prevalent, and are found in 35% of patients with
BMI > 40. However, not all individuals with these mutations are obese, suggesting that obesity is contingent on the presence of genetic variation in other genes in these individuals and/or on specic
developmental or environmental factors. For rare types of syndromic human obesity (e.g., Prader-Willi, Bardet-Biedl, Alstrom, Biemond, Cohen), specic regions of the genome have been implicated.
THRB
T-box 3
TBX3
212
Chua et al.
Figure 1 Structure of Agouti locus. (A) Gene structure of Raly and Agouti in normal mice, including resulting transcripts and
appearance of mice with normal brown coat color. (B) Structure of Agouti locus in Ay mice, with altered transcript and obese
mice with yellow coat color. (C) Structure of Agouti locus, transcripts, and mouse appearance for Avy, Aiy, Ahvy mice. (D)
Structure of Agouti locus, transcripts, and mouse appearance (normal weight, black coat color) for a mice. (E) Photographs of
wild-type mice (a/a), agouti mice (A/A), heterozygous mouse for yellow mutation (Ay/a), and double homozygous mouse for
agouti and mahoganoid (A/A, md/md).
and 4 kb, correspond to proteins that encode membrane-bound and soluble forms of attractin. The
membrane-bound form is found in the brain, skin,
heart, kidney, liver, and lung, while the soluble form is
specic to hematopoietic tissues. The protein has several
putative motifs: serine protease, EGF-like regions, a
CUB domain, c-type lectin domain, and a ligandbinding domain for gamma chain cytokines. Mahogany
mouse mutants are hyperphagic but remain lean,
perhaps owing to increased energy expenditure. The
mahogany mutation was also able to prevent the obesity
and the yellow pigmentation caused by the dominant
Yellow mutation. Surprisingly, mahogany is unable to
prevent the obesity resulting from transgenic overexpression of AGRP, a peptide clearly related to ASP
(see below). However, the identication of an Attractin
mutation in the rat neurological mutation zitter suggests
that a reassessment of the mahogany phenotype may be
necessary (20,22,23). Transgenic complementation with
the membrane bound form of attractin corrected the
neurological defect as well as the abnormal pigmentation of zitter rats, whereas the soluble attractin did not
aect either phenotype. All of the rodent Attractin
mutations cause spongiform encephalopathy and hypomyelination. Thus, the lean phenotype of Attractin
mutants might be due to a wasting syndrome caused by
encephalopathy and/or the movement disorder caused
by hypomyelination rather than being due to a specic
eect on Agouti (ASP) or AGRP action.
The mahoganoid mutation was recently cloned and
identied as a 54 kDa RING-containing protein with
E3 ubiquitin ligase activity. The gene has been named
Mahogunin (gene symbol, Mgrn1). The allelic series is
due mostly to spontaneous IAP (intracisternal particle)
insertions; the Mgrn1nc (nonagouti curly), a chemicallyinduced mutation, may be due to a T!A mutation in
intron 9. Based on the failure of overexpression of Attractin (Atrn) to rescue the phenotype of md animals,
Atrn is placed proximal to Mgrn1 in a pathway that operates at or proximal to the melanocortin receptor 1 and
possibly 3/4. Levels of Mgrn1 expression are not aected
by Atrn, and vice versa. Like Atrn, Mgrn1 is widely expressed in adult tissues, with similar expression patterns
throughout the brain. The patterns of spongiform degeneration in brain (hippocampus, thalamus, stem and
cerebellum) are similar in md and mg aecteds, and are
proportionate to the apparent degree of inactivation
of gene expression. For example, both Atrnmg-L and
Mgrn1md mutants (apparent hypomorphic alleles) show
no evidence of brain degeneration up to 8 and 12
months, respectively, whereas the Mgrn1md-nc, Atrnmg,
213
and Atrnmg3J (putative nulls) do (23a; 23b). The mechanisms by which mg and md rescue the obesity phenotype
of Ay, may be related to anatomic eects within the
hypothalamus and/or to eects on increased energy
expenditure due to tremor. However, neither mg (23c)
or md (unpublished data) appears to rescue the obese
phenotype of the Lepob mouse, creating the possibility
that, as implied by the coat color eects conveyed via
MC1R, that the mg and md mutations are quite specic
to the melanocortin pathway with regard to eects on
energy homeostasis, and/or that the magnitude of the
aberration in the Lepob overwhelms any compensation
provided by md or mg.
5
214
sal phenomenon, however, since leptin receptordecient rats do not show the elevated hypothalamic AGRP
mRNA levels seen in mice. Since nonmutant rats do
show fasting-induced increases in AGRP mRNA, it is
possible that other factors inuence AGRP expression.
Since AGRP/NPY neurons bearing MC3R are responsive to melanocortins, it is probable that Agrp expression is regulated by melanocortin agonists, such as
MSH peptides, and antagonists, such as AGRP itself.
In Ay mice, hypothalamic AGRP mRNA is considerably suppressed, presumably due to the inhibitory eect
of high levels of ASP on melanocortin receptors. It is
quite possible that there exists an ultrashort feedback
autoregulatory loop for Agrp expression. For example,
AGRP, upon its release and inhibition of melanocortin
Chua et al.
Figure 2 Genes regulating body fat. This gure includes only some of the genes known to participate in regulating body fat. The
genes in boldface have been shown by mutation and pedigree analysis to be capable of causing human obesity. See Table 1 for other
candidate genes (272): ARCuate, ParaVentricular Nucleus, Lateral HypothAlamus. The receptors for the various peptides are not
shown, but are also candidate genes in the context of this proposal. For example, POMC is processed to aMSH, ACTH, and
various opioid peptides. aMSH is a ligand for the MC4 receptor (MC4R) that it engages to reduce food intake and energy
expenditure. AGRP interferes with the action of aMSH at this receptor, and hence has the eect of increasing food intake and
energy expenditure. PCSK1 is a processing enzyme for many of these peptides, and PPARg is a transcription factor that aects
adipocyte dierentiation. Genes such as the ADRB3 and members of the UCP family may play roles in energy expenditure.
Symbols: aMSH (a melanocyte stimulating hormone); ADRB3 (h 3 adrenergic receptor), AGRP (agouti-related peptide); ARC
(arcuate nucleus); BBB (blood-brainbarrier); CART (cocaine-amphetamine related transcript); CRH (corticotropin releasing
hormone); HCRT/orexin (hypocretin); LEP (leptin); LEPR (leptin receptor); LHA (lateral hypothalamus); MC4R (melanocortin
4 receptor); MCH (melanocyte-concentrating hormone); NPY (neuropeptide Y); PCSK1 (pro-protein convertase); POMC (proopiomelanocortin); PPARg (peroxisome proliferator activated receptor gamma); PVN (paraventricular nucleus); TRH
(thyrotropin-releasing hormone); UCP (uncoupling protein).
215
medulla and vasa vasorum, unlike the discrete neuroanatomical localization of Agrp expression in the
medial arcuate hypothalamus.
9
Proopiomelanocortin (POMC)
216
Chua et al.
Figure 3 POMC posttranslational processing. POMC is a 267amino acid length precursor molecule which is processed in the
pituitary to several peptides, the major peptides being ACTH (39 amino acids), a-MSH (13 amino acids), and h-endorphin (30
amino acids). The POMC precursor has basic residue cleavage sites listed above the diagram showing sites at which processing of
the prohormone occurs. PC1 cleaves POMC into ACTH and h-lipotropin, whereas PC2 cleaves POMC into h-endorphin and aMSH. Carboxypeptidase E (CPE) is a proprotein processing exopeptidase, cleaving at C-terminal basic residues, and may
function as a regulated secretory pathway sorting receptor, using a sorting signal sequence in the N-terminal region of the POMC
precursor molecule. JP, joining peptide.
Melanocortin ReceptorsMC4R
and MC3R
III
217
Leptin-decient mice (Lepob) exhibit early-onset hyperphagia and obesity, being obese to inspection at the time
of weaning at postnatal day 21 or up to a week later.
After weaning, the mutant mice ingest up to twice the
calories of lean littermates and rapidly gain weight and
adipose tissue. On the C57BL/6J strain, mutant mice
of both sexes are twice the weight of lean siblings at 8
weeks. The mutants maintain this extreme adiposity as
long as circulating insulin concentrations are suciently
elevated above physiological concentrations. In some
strains of mice (such as C57BLKS/J), leptin deciency
leads to insulinopenia and severe hyperglycemia with
persistent insulin resistance (53). In this state of absolute
and relative insulin deciency, the mutant mice rapidly
lose weight and adipose tissue. The importance of hyperphagia in the development of the obese state is shown
by pair-feeding studies in which obese mice are fed the
amount of food taken spontaneously by genetically lean
mice. In such studies, the obese animals still gain slightly
more weight than the lean animals, but a much higher
fraction of the additional weight is adipose tissue (54).
Thus, the increased body fat of the obese mice reects
the conuence of leptins eects on energy intake, expenditure and partitioning.
LEPTIN (OBESE )
Glucose Intolerance
218
Chua et al.
Cold Intolerance
Caloric Partitioning
in the regulation of growth of various tissue compartments, such as preferential expansion of white adipose
tissue, to lead to obesity. Body composition analyses in
mice consistently show that leptin deciency causes an
excessive absolute and relative accumulation of white
adipose tissue, with a reduction in skeletal muscle,
diminished linear growth, and reduced brain weights.
There are several candidate mechanisms for this eect,
each of which has been observed in leptin decient mice:
(1) defective growth hormone axis; (2) defective thyroid
hormone axis; (3) hypothalamic hypogonadism; and (4)
reduced physical activity. The caloric partitioning eect
is dramatically demonstrated during pair-feeding studies in which the ingested calories of mutant mice are
yoked to genetically lean control mice (60). After a
period of such restricted feeding, the mutant mice attain
slightly greater body weights than lean mice. However
body composition analysis shows that the mutant mice
have increased absolute fat content (about twofold)
(55). Therefore, the obesity of leptin deciency is due
to both hyperphagia and to preferential deposition of
stored calories as fat.
5
It is well known that hypogonadism alters body composition and increases fat accumulation in both sexes.
Leptin deciency, in most of the strains tested (C57BL/
6J, C57BLKS/J, DBA/2V, and V), causes hypothalamic
hypogonadism and infertility (53). The low sex hormone
levels probably contribute to the adiposity of the
mutant mice. However, the original strain of leptin
receptor decient rats (Zucker fatty strain) can be
selected for fertility in mutant males. Recently, the Lepob
mutation has been transferred to the BALB/cJ strain
(61). Both male and female mutants of this strain are
obese, yet fertile and produce normal pups. This striking
strain dierence between C57BL/6J, the standard obese
inbred strain host, and BALB/cJ could be utilized to
identify allelic variants of genes that modify leptin
eects on the integrity of the gonadal axis.
B
Leptin secretion and blood levels are regulated by nutritional factors, in addition to their correlation to fat
mass. Leptin is secreted via the constitutive synthetic
and secretory pathway that is highly sensitive to adipocyte volume (68). The mechanism for this sensitivity to
adipocyte volume is not known, but provides an explanation for the correlation of circulating leptin concentrations with adipose tissue mass. Insulin has a
stimulatory eect on leptin gene transcription and
translation, and causes release of a leptin from a pool
of stored leptin (69). Glucocorticoids have a similar
219
stimulatory eect on leptin gene transcription and synthesis of leptin, although glucocorticoids do not stimulate the release of stored leptin.
The insulin-mediated stimulation of leptin transcription could be mediated directly, via stimulation of the
phosphorylation cascades initiated by the insulin receptor, or indirectly, via metabolites produced during
glucose metabolism, such as UDP-glucosamine (70).
Initial characterization of the leptin promoters from
man and mouse indicated the presence of a CCAAT
enhancer-binding protein (C/EBP) site (71) that could
stimulate transcription in preadipocytes and that C/
EBP alpha could stimulate leptin transcription (72).
Subsequent studies have indicated that C/EBP alpha is
downregulated during insulin treatment of fully dierentiated adipocytes, suggesting that stimulation of C/
EBP alpha activity is not the mechanism for insulinmediated stimulation of leptin transcription (73). These
results need to be more fully explored in order to
reconcile the discrepancies (see Fig. 4).
Treatment of rodents and adipocytes with a class
of drugs called thiazolidinediones (TZDs; used as insulin-sensitizing agents in type 2 diabetes mellitus) have
been found to suppress leptin gene expression. In addition, TZDs can increase fat accumulation, probably
by stimulating adipocyte proliferation and dierentiation. TZDs activate PPAR gamma, a transcription factor that positively regulates adipocyte dierentiation.
Figure 4 Regulation of leptin synthesis. Insulin and glucocorticoids stimulate leptin gene transcription and synthesis, whereas
fatty acids that activate PPARg are inhibitory to leptin synthesis.
220
Chua et al.
Leptin circulates in a bound form in most lean individuals. The leptin binding protein in humans is probably a
proteolytically shed form of membrane bound leptin
receptor since the 3V terminal exon for the soluble leptin
receptor isoform is nonfunctional in humans, due to
absence of a polyadenylation signal (79). In rodents, a
transcript (LEPR-E) directly encodes a soluble leptin
receptor. In obese individuals, circulating leptin concentrations are higher and the ratio of bound leptin to
free leptin is altered in favor of free leptin, presumably
due to independent mechanisms that modulate leptin
and soluble leptin receptor (51,80).
Leptin is cleared primarily by the kidneys. In end
stage renal disease, leptin concentrations are elevated,
owing to diminished leptin clearance (81). These elevated leptin levels could be partially responsible for the
221
Figure 5 Genetic structure of the Lepob and Lepob2J loci. Lepob contains a point mutation in the second exon, R105X, that leads
to premature chain termination. Lepob2J has a transposon element inserted into the promoter. This transposon element is from
the ETn family of transposons and contains multiple splice-acceptor sites that interfere with normal splicing.
222
Chua et al.
increase leptin concentrations at the high end of physiological concentrations (10 ng/mL) do not appear to
cause alterations in NPY mRNA, but other neuropeptides remain to be studied. It is remarkable that
the lack of adipose tissue in these leptin-treated animals
does not lead to insulin resistance and diabetes usually
associated with lipodystrophy, a syndrome characterized by diminished adipose depots. In fact, leptin transgenic mice are exceptionally lean and have increased
glucose tolerance, implying that high leptin concentrations in normal lean organisms cause enhanced glucose
metabolism. The paradox remains as to the lack of
ecacy of leptin in correcting obesity and insulin
resistance in diet-induced obesity.
IV
223
224
Chua et al.
Figure 6 Genomic structure of Lepr and alternative transcripts. (A) Genomic structure of Lepr. Coding exons are in blocks and
numbered. Terminal exons are denoted by numbers under the exons while coding exons are numbered above the exons (exon 16
bears a transmembrane domain). Colored blocks within exons represent sequence motifs: yellow represents a JAK box, white
represents a STAT box, while a black block represents the single transmembrane domain. (B) Alternative transcripts of Lepr.
Four isoforms of LEPR are represented. LEPR-E is a soluble receptor, terminating at exon 14V and excluding the transmembrane
domain (black) in exon 16. All of the membrane bound receptors (LEPR-A, LEPR-B, LEPR-C) include exon 17, which has a
JAK box. The LEPR-B isoform is the sole receptor that contains the STAT box.
tion in cells transfected with two dierent membranebound LEPR isoformsLEPR-A and LEPR-B.
LEPR appears to form homodimers prior to ligand
binding (116), and one can postulate that the cytoplasmic tails of the isoforms dictate preferential
self-dimerization or dierential sorting to various subcellular compartments.
db
db3J
225
dbNCSU
LeprTg(Mth11)1Aig
dbPas
fatty
226
Chua et al.
fatty f
227
CARBOXYPEPTIDASE E ( fat)
228
Chua et al.
As would be expected, the brains of fat mice show numerous abnormalities in neuropeptide content. Almost
all neuropeptides are processed via the regulated secretory pathway and require CPE function, both for proteolytic cleavage and for sorting (149). Chief among
these defects are deciencies in the processing of POMC
and CCK (150) that might be predicted to lead to a loss
of inhibition of food intake. Orexigenic peptides such as
MCH are also improperly processed in fat mice, perhaps muting somewhat the increase in food intake that
might occur if only anorexiant peptides were aected.
However, the action of the extremely potent orexiant,
AGRP, may actually be enhanced by CPE deciency. In
the AGRP transgenic mouse, constitutive expression of
unprocessed AGRP is sucient to promote hyperphagia and obesity. Thus, the net eect of CPE deciency
on anorexigenic and orexigenic peptides and neurons
could result in obesity.
VI
TUBBY
The tubby protein is expressed in neural tissues, primarily in the hypothalamus (arcuate, PVN, and VMN) and
other regions of the brain, as well as the retina and
cochlea. Within neuronal cells, the tubby protein is
localized to the nucleolus (155). While increased apoptosis has been implicated as a causal mechanism for the
loss of hearing and vision, this is unlikely to be the case
for the obesity and hypothalamic neurons. Expression
studies show that tubby mRNA is increased in the
hypothalamus of mutant mice. This would be unlikely
to be the case if neurons were being eliminated via
apoptosis. A selective reduction of a subpopulation of
neurons is possible since there is a small reduction of
229
230
Chua et al.
In outcross progeny, Tubby homozygotes are not uniformly deaf. A modier gene, moth1, for modier of
tubby hearing, was localized to chromosome 2 (155).
Analysis of the mode of inheritance indicated that the
B6 allele was recessive suggesting that a loss-of-function
mutation is present in the C57BL/6J strain that is only
manifest in the absence of tubby protein. Because no
other phenotypes were analyzed, it is not known
whether the modier aects the degree of obesity and
the retinal degeneration. However, since retinal degeneration due to TULP1 mutations (humans and mice) is
the only phenotype, and the mutations do not produce
obesity or deafness, it is quite possible that tissuespecic expression of moth1 would only manifest as an
eect on hearing.
VII
a. LEP G398!Del
Montague et al. (166) reported a consanguineous
Pakistani family with two children who were homozygous for an inactivating G398!Del leptin mutation.
The children (8-year-old girl, BMI 45.8; 2-year-old boy,
BMI 36.6) were identied because of their extreme
obesity and hyperphagia; both had heights at the 75th
centile for their ages. The mutation creates a frameshift
resulting from the deletion of a guanine nucleotide at
position 398, codon 133. Fourteen amino acids are
introduced into the reading frame of the mutant protein,
followed by a premature stop codon. Transient transfection experiments of CHO cells with the mutant
protein demonstrated the presence of mutant leptin in
the cell lysates but none was secreted, suggesting abnormal protein transport within the cell. Western blot
analysis of the sera of the aected children showed no
serum leptin, supporting the prediction that the mutation prevented protein secretion. In this sense, the functional eect of this human mutation closely resembles
that of Lepob.
Similar to ob/ob mice with inactivating leptin mutations, these children developed early-onset, severe
hyperphagia and obesity. These children had few associated endocrine abnormalities, mainly mild euglycemic
231
Clement et al. (180) described three sisters from a consanguineous Algerian family (Berbers) who were homozygous for an inactivating LEPR mutation: IVS16,
G!A, +1. The mutation is in the 3V donor splice site
232
Chua et al.
Refs.
Yes
Yes
Variable association
Eects on BMI in response to diet;
polymorphism more frequent in
obese population
Eects on BMI in response to diet
Eects on BMI in response to diet
Eects on BMI in response to diet
Eects on BMI in response to diet
Eects on BMI in response to diet
Eects on BMI in response to diet
None
Decreased leptin concentration in 2 subjects
Decreased leptin concentration in 2 subjects
None; silent mutation
(166)
(170)
(323325)
(323,326)
(323)
(323)
(323)
(323)
(323)
(323,327)
(328)
(324)
(324)
(324)
Melanocortin 4 Receptor.
MC4R (18q21.3-q22)
233
Ref.
Variable
No association with obesity
Variable
No association with BMI
Variable
Found in 2 subjects
Variable
Associated with BMI among lean subjects
Found in 3 subjects
(183,185,187,329,330)
(187,331)
(183,185187,329,330,332335)
(185)
(183,185187,330)
(331)
(185,332)
(185)
(180)
Pro-opiomelanocortin. POMC(2p23.2)
POMC is synthesized as a large precursor molecule, prePOMC, that is processed in the pituitary into several
transcripts, including ACTH, aMSH, h-lipotropin, and
h-endorphin (see Fig. 3). PC1 cleaves POMC into
ACTH and h-lipotropin, whereas PC2 cleaves POMC
into h-endorphin and aMSH (see Fig. 3). Krude et al.
(194) described two unrelated children with inactivating
POMC mutations. Both had severe, early-onset obesity,
adrenal insuciency, and red hair. The phenotypes are
consistent with absence of the pre-POMC cleavage
products: ACTH and aMSH. The functional consequences of absence of ACTH and aMSH ligand/receptor activity are discussed with regard to the relevant
mouse mutations above. The light skin and hair of the
children with these mutations are due to reduced MSH
activity at MC1R.
One patient was a 3-year-old girl who weighed 32 kg
and was a compound heterozygote for mutations in
exon 3: G7013T and C7133Del (194). Both mutations in
the 3-year-old led to premature termination of POMC,
at codons 79 and 131, respectively, and absence of
ACTH, a MSH, and h-endorphin. She had no detectable circulating ACTH or cortisol after CRH stimula-
PC1 (5q15-q21)
234
Chua et al.
Mechanism (Ref.)
Interference with appropriate
synthesis of ACTH and aMSH (194)
Abolishes POMC translation
(194)
Silent (336)
Nucleotide 51 (promoter)
G!C
Nucleotide 670 (5VUTR)
G!A
Nucleotide 4512
(codon 6) C!T, Cys/Cys
Nucleotide 7726 (codon
116) C!T, Leu/Leu
Nucleotide 8246
(3VUTR) C!T
Nucleotide 8086 (codon
Seen in only 1 subject (336)
236) G!C, Arg/Gln
In-frame 9-bp insertion
Insertion of either
and 18-bp insertion
Ser-Ser-Gly or
between codons 73, 74
Ser-Ser-Gly-Ser-Ser-Gly (337)
Out-of-frame 6-bp inser- Insertion of Arg-Ala (337)
tion within codon 176,
GGG CCC
Glu188Gly
Missense (337)
G7016A, Asp80Asn
Missense (337)
C6982T, C7285T
Silent (337)
C3832T
Silent (337)
C7111G
Silent (337)
G7316T, Glu180Stop
Premature stop codon within
g-LPH sequence (337)
concentration, nearly undetectable insulin, hypocortisolism, and hypogonadotropic hypogonadism, all consistent with impaired processing of the respective
prohormones. Interestingly, the Cpefat mice display
hyperproinsulinemia, consistent with their more distal
enzymatic defect in carboxypeptidase E.
6
PPARg (3p25)
235
Barroso et al. (217) described two mutations, Val290Met and Pro467Leu, which destabilize helix 12 in the
ligand-binding domain and lead to transcriptional
impairment by apparent dominant negative eects on
the nonmutant transcripts. A mother and her son were
identied who were heterozygous for Pro476Leu. Both
subjects had type 2 diabetes and hypertension, but were
not obese (55-year-old woman, BMI 24.9; 3l-year-old
male, BMI 25.9). A 15-year-old girl was identied who
was heterozygous for Val290Met. She also had type 2
diabetes and hypertension, and was not obese (BMI
25.6) (Table 5).
7
SIM1 (6q16.3-q21)
Val290Met
Pro476Leu
His478His, C1431T, exon 6
Mechanism (reference)
Missense C!G; expression study (204) showed mutant with
decreased ability to mediate transcriptional activation and
adipogenesis induced by TZDs; Ala allele has decreased
binding anity to cognate promoter elements and decreased
ability to transactivate responsive promoters (206); less
active PPARg: decreased BMI, improved insulin sensitivity
(208,211).
Ligand-binding domain (213).
Overexpression in broblasts produces a protein with defective
serine phosphorylation at position 114, accelerated adipocyte dierentiation greater triglyceride accumulation than
wildtype. More active PPARg may result in increased BMI
and increased insulin resistance (214,215).
Mutations destabilized helix 12 in the ligand-binding domain
leading to transcriptional impairment by dominant negative
eects on non-mutant transcripts (217).
Silent; association between this SNP, RFLP, and bone mineral
density in postmenopausal Japanese women (216).
236
Chua et al.
margins, coast of Maine), hyperthyroidism, and precocious puberty (due to constitutively activated gonadal
LH and FSH receptors) (222).
IX
two rings, each with eight dissimilar units, in a cylindrical assembly. Inactivating mutations of MKKS lead
to BBS6, whereas less severe mutations (missense,
frameshift) result in the McKusick-Kaufman syndrome
(hydrometrocolpos, postaxial polydactyly, and congenital heart disease). It is possible that inactivation of
MKKS leads to misfolding of target proteins whose
resulting malfunction results in BBS. Alternatively,
MKKS may be part of an oligomeric protein whose
function is disrupted by the absence or aberrant
sequence of MKKS.
Heterozygosity eects have been described for BBS.
Croft found that heterozygous BBS subjects (type
unspecied) had increased frequency of obesity,
hypertension, diabetes mellitus, and renal disease
(229). In a study of 34 heterozygotes, again without
specifying BBS types (230), the proportion of overweight (dened as BMI>31.1) male heterozygotes
(26.7%) was signicantly higher than age-matched
U.S. white males (8.9%).
3
Borjeson-Forssman-Lehmann Syndrome
(BFLS) (Xq26.3)
237
SOX3 deletion who had hemophilia and mental retardation, and partial primary testicular failure, recapitulating several features of BFLS (mild mental
retardation, small testes) (233).
4
The CDG1a syndrome, also known as Jaeken syndrome, is a severe, multisystemic, autosomal-recessive
disorder that usually presents in the neonatal period
and is characterized by the defective glycosylation of
glycoconjugates (especially asparagine-N-linked oligosaccharides in the ER) (234). The syndrome includes
severe encephalopathy, axial hypotonia, abnormal eye
movement, pronounced psychomotor retardation,
peripheral neuropathy, and serum glycoprotein abnormalities. Patients have a peculiar distribution of subcutaneous fat (fat pads above buttocks, lipodystrophy),
moderate obesity, and hypogonadism. PMM2, phosphomannomutase 2, has been implicated as the responsible gene, which is required for the synthesis of GDPmannose (converts mannose 6-phosphate to mannose
1-phosphate). Nearly 60 mutations have been described,
mostly in exons 5 and 8, with 90% accounted for by
two mutations: F119L and R141H (not seen in homozygous state, mutant protein with zero activity in in
vitro assay).
5
238
Chua et al.
Dittrich et al. described a model involving an imprinting center mapping to 15q11-q13 (246). Their
model proposed that the imprinting center (IC) contained an imprintor and an imprint switch initiation site
(involving exon 1 of SNRPN), and that the imprintor is
transcribed only from the paternal chromosome. There
are numerous transcripts encoded in the IC that are
alternatively spliced and that are only expressed from
the paternal chromosome. Since some subjects with
PWS (and Angelmans) have mutations aecting the
IC, the transcripts are not expressed. Thus, the IC may
be critical in regulating alternative RNA splicing in the
SNRPN transcripts. Lyko et al. studied this region in
Drosophila and showed that a 215-bp region containing
the SNRPN promoter region has a silencer of maternal
SNRPN (247). Lyko suggested that this silencer element
may play a role in the imprinting of 15q11-13 and may
repress SNRPN expression from the maternal allele.
Bressler et al., however, showed that a deletion of
exon 1 of mouse Snrpn (f1 kb) did not elicit any
obvious phenotypic change, while a 4.8-kb deletion
including the same region led to a partial imprinting
defect and perinatal lethality when paternally inherited
(248). Also, Schulze et al. reported a PWS patient with a
balanced 9:15 translocation whose breakpoint was
between SNRPN and an adjacent gene, PAR1, with
SNRPN unaected by the translocation (249). This
patient met formal criteria for PWS, including obesity
(moderate), hypopigmented in relation to his family,
PWS facies, and delayed puberty, but he displayed no
hyperphagia (250). These data suggest that SNRPN
may play a role in regulation of food intake, but not
in the other somatic and endocrine phenotypes associated with PWS.
It is unlikely a single gene will be implicated as the
cause of the diverse range of PWS phenotypic features
given the sizeable deletion in most PWS patients and the
number of genes (at least two) in that interval (251).
Drosophila or mice harboring Snprn deletions and contiguous gene interruptions may help to clarify the
molecular pathogenesis of the PWS.
6
UMS is an autosomal-dominant syndrome characterized by obesity; delayed growth and puberty; and complex malformations of the ulnar ray, teeth, axillary
apocrine glands, and urogenital system. The TBX3 gene
(12q24.1) has been implicated as causative by Bamshad
et al. (255). TBX3 encodes a transcription factor that
seems to be critical to the morphogenesis of several organs. Mutations in a related gene, TBX5, are associated
with anterior limb malformations in the Holt-Oram
syndrome; TBX3 appears to be associated with the posterior limb malformations of UMS. The aected subjects were doubly heterozygous for mutations predicted
to alter DNA binding: 1 bp del 227T leading to a premature stop codon; IVS 2ds, G!C, +1. Further study
by Bamshad found additional novel TBX3 mutations in
families with UMS, but identied no obvious phenotypic dierences between those with missense mutations, frameshifts, or deletions (256). The molecular
mechanism for the obesity in this syndrome is unknown.
8
239
Lipodystrophy Syndromes
with Single-Gene Basis
240
Chua et al.
SUMMARY
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
241
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
242
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
Chua et al.
peptide yy and pancreatic polypeptide. Nature 1982;
296:659660.
Clark JT, Kalra PS, Kalra SP. Neuropeptide Y
stimulates feeding but inhibits sexual behavior in rats.
Endocrinology 1985; 117:24352442.
Chua SC Jr, Leibel RL, Hirsch J. Food deprivation
and age modulate neuropeptide gene expression in the
murine hypothalamus and adrenal gland. Brain Res
Mol Brain Res 1991; 9:95101.
White JD, Olchovsky D, Kershaw M, Berelowitz M.
Increased hypothalamic content of preproneuropeptide-Y messenger ribonucleic acid in streptozotocindiabetic rats. Endocrinology 1990; 126:765772.
Wilding JP, Ajala MO, Lambert PD, Bloom SR.
Additive eects of lactation and food restriction to
increase hypothalamic neuropeptide Y mRNA in rats.
J Endocrinol 1997; 152:365369.
McCarthy HD, Kilpatrick AP, Trayhurn P, Williams
G. Widespread increases in regional hypothalamic
neuropeptide Y levels in acute cold-exposed rats.
Neuroscience 1993; 54:127132.
Jhanwar-Uniyal M, Chua SC Jr. Critical eects of
aging and nutritional state on hypothalamic neuropeptide Y and galanin gene expression in lean and
genetically obese Zucker rats. Brain Res Mol Brain
Res 1993; 19:195202.
Chua SC Jr, Brown AW, Kim J, Hennessey KL, Leibel
RL, Hirsch J. Food deprivation and hypothalamic
neuropeptide gene expression: eects of strain background and the diabetes mutation. Brain Res Mol
Brain Res 1991; 11:291299.
Korner J, Wardlaw SL, Liu SM, Conwell IM, Leibel
RL, Chua SC Jr. Eects of leptin receptor mutation on
agrp gene expression in fed and fasted lean and obese
(LA/N fa f ) rats. Endocrinology 2000; 141:24652471.
Castro MG, Morrison E. Post-translational processing
of proopiomelanocortin in the pituitary and in the
brain. Crit Rev Neurobiol 1997; 11:3557.
Yaswen L, Diehl N, Brennan MB, Hochgeschwender
U. Obesity in the mouse model of pro-opiomelanocortin deciency responds to peripheral melanocortin.
Nat Med 1999; 5:10661070.
Cone RD, Lu D, Koppula S, Vage DI, Klungland H,
Boston B, Chen W, Orth DN, Pouton C, Kesterson
RA. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation.
Recent Prog Horm Res 1996; 51:287317.
Cone RD. The central melanocortin system and its
role in energy homeostasis. Ann Endocrinol (Paris) (in
French) 1999; 60:39.
Chen AS, Marsh DJ, Trumbauer ME, Frazier EG,
Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y,
Cao L, Metzger JM, Strack AM, Camacho RE, Mellin
TN, Nunes CN, Min W, Fisher J, Gopal-Truter S,
MacIntyre DE, Chen HY, Van der Ploeg LH.
Inactivation of the mouse melanocortin-3 receptor
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
243
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
244
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
Chua et al.
source of leptin production in pregnant rat: gestational
prole of leptin in plasma and adipose tissues.
Biochem Biophys Res Commun 1997; 240:798802.
Schubring C, Kiess W, Englaro P, Rascher W, Dotsch
J, Hanitsch S, Attanasio A, Blum WF. Levels of leptin
in maternal serum, amniotic uid, and arterial and
venous cord blood: relation to neonatal and placental
weight. J Clin Endocrinol Metab 1997; 82:14801483.
Chen SC, Cunningham JJ, Smeyne RJ. Expression of
ob receptor splice variants during prenatal development of the mouse. J Recept Signal Transduct Res
2000; 20:87103.
Ducy P, Amling M, Takeda S, Priemel M, Schilling
AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty
G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell
2000; 100:197207.
Steppan CM, Crawford DT, Chidsey-Frink KL, Ke
H, Swick AG. Leptin is a potent stimulator of bone
growth in ob/ob mice. Regul Pept 2000; 92:7378.
Ghilardi N, Ziegler S, Wiestner A, Stoel R, Heim
MH, Skoda RC. Defective stat signaling by the leptin
receptor in diabetic mice. Proc Natl Acad Sci USA
1996; 93:62316235.
Lord GM, Matarese G, Howard JK, Baker RJ, Bloom
SR, Lechler RI. Leptin modulates the t-cell immune
response and reverses starvation-induced immunosuppression. Nature 1998; 394:897901.
Sierra-Honigmann MR, Nath AK, Murakami C,
Garcia-Cardena G, Papapetropoulos A, Sessa WC,
Madge LA, Schechner JS, Schwabb MB, Polverini PJ,
Flores-Riveros JR. Biological action of leptin as an
angiogenic factor. Science 1998; 281:16831686.
Moon BC, Friedman JM. The molecular basis of the
obese mutation in ob2j mice. Genomics 1997; 42:152
156.
Spiegelman BM, Flier JS. Obesity and the regulation
of energy balance. Cell 2001; 104:531543.
Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL,
Foster D, Lasser G, Prunkard DE, Porte D Jr, Woods
SC, Seeley RJ, Weigle DS. Specicity of leptin action on
elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 1996;
45:531535.
Vaisse C, Halaas JL, Horvath CM, Darnell JE, Jr.,
Stoel M, Friedman JM. Leptin activation of STAT3
in the hypothalamus of wild-type and ob/ob mice but
not db/db mice. Nat Genet 1996; 14:9597.
Banks AS, Davis SM, Bates SH, Myers MG Jr.
Activation of downstream signals by the long form of
the leptin receptor. J Biol Chem 2000; 275:14563
14572.
Spanswick D, Smith MA, Groppi VE, Logan SD,
Ashford ML. Leptin inhibits hypothalamic neurons by
activation of atp-sensitive potassium channels. Nature
1997; 390:521525.
245
126. Turkenkopf IJ, Kava RA, Feldweg A, Horowitz C,
Greenwood MR, Johnson PR. Zucker and Wistar
diabetic fatty rats show dierent response to adrenalectomy. Am J Physiol 1991; 261:R912R919.
127. Kava RA, West DB, Lukasik VA, Wypijewski C,
Wojnar Z, Johnson PR, Greenwood MR. The eects
of gonadectomy on glucose tolerance of genetically
obese (fa/fa) rats: Inuence of sex and genetic background. Int J Obes Relat Metab Disord 1992; 16:103
111.
128. Leiter EH, Chapman HD. Obesity-induced diabetes
(diabesity) in C57BL/KsJ mice produces aberrant
trans-regulation of sex steroid sulfotransferase genes.
J Clin Invest 1994; 93:20072013.
129. Chua SC Jr, White DW, Wu-Peng XS, Liu SM, Okada
N, Kershaw EE, Chung WK, Power-Kehoe L, Chua
M, Tartaglia LA, Leibel RL. Phenotype of fatty due to
GLN269PRO mutation in the leptin receptor (Lepr).
Diabetes 1996; 45:11411143.
130. Takaya K, Ogawa Y, Isse N, Okazaki T, Satoh N,
Masuzaki H, Mori K, Tamura N, Hosoda K, Nakao
K. Molecular cloning of rat leptin receptor isoform
complementary dnasidentication of a missense
mutation in Zucker fatty (fa/fa) rats. Biochem Biophys
Res Commun 1996; 225:7583.
131. Ellwood KC, Michaelis OEt, Emberland JJ, Bhathena
SJ. Hormonal and lipogenic and gluconeogenic enzymatic responses in LA/N-corpulent rats. Proc Soc Exp
Biol Med 1985; 179:163167.
132. Michaelis OEt, Ellwood KC, Judge JM, Schoene NW,
Hansen CT. Eect of dietary sucrose on the SHR/Ncorpulent rat: a new model for insulin-independent
diabetes. Am J Clin Nutr 1984; 39:612618.
133. Wu-Peng XS, Chua SC Jr, Okada N, Liu SM,
Nicolson M, Leibel RL. Phenotype of the obese
Koletsky ( f) rat due to TYR763STOP mutation in the
extracellular domain of the leptin receptor (Lepr):
evidence for decient plasma-to-CSF transport of
leptin in both the Zucker and Koletsky obese rat.
Diabetes 1997; 46:513518.
134. Takaya K, Ogawa Y, Hiraoka J, Hosoda K, Yamori
Y, Nakao K, Koletsky RJ. Nonsense mutation of
leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat Genet 1996; 14:130131.
135. Kowalski TJ, Liu SM, Leibel RL, Chua SC Jr.
Transgenic complementation of leptin-receptor deciency. I. Rescue of the obesity/diabetes phenotype of
Lepr-null mice expressing a Lepr-b transgene. Diabetes
2001; 50:425435.
136. Ahima RS, Kelly J, Elmquist JK, Flier JS. Distinct
physiologic and neuronal responses to decreased leptin
and mild hyperleptinemia. Endocrinology 1999;
140:49234931.
137. Xu B, Dube MG, Kalra PS, Farmerie WG,
Kaibara A, Moldawer LL, Martin D, Kalra SP.
Anorectic eects of the cytokine, ciliary neurotropic
246
factor, are mediated by hypothalamic neuropeptide Y:
comparison with leptin. Endocrinology 1998; 139:466
473.
138. Leiter EH, Coleman DL, Eisenstein AB, Strack I.
Dietary control of pathogenesis in C57BL/KsJ db/db
diabetes mice. Metabolism 1981; 30:554562.
139. Leiter EH, Prochazka M, Shultz LD. Eect of immunodeciency on diabetogenesis in genetically diabetic
(db/db) mice. J Immunol 1987; 138:32243229.
140. Solomon J, Mayer J. The eect of adrenalectomy on
the development of the obese-hyperglycemic syndrome in ob/ob mice. Endocrinology 1973; 93:510
512.
141. Makimura H, Mizuno TM, Roberts J, Silverstein J,
Beasley J, Mobbs CV. Adrenalectomy reverses obese
phenotype and restores hypothalamic melanocortin
tone in leptin-decient ob/ob mice. Diabetes 2000;
49:19171923.
142. Chen HL, Romsos DR. Dexamethasone rapidly
increases hypothalamic neuropeptide y secretion in
adrenalectomized ob/ob mice. Am J Physiol 1996;
271:E151E158.
143. Coleman DL, Eicher EM. Fat ( fat) and tubby (tub):
two autosomal recessive mutations causing obesity
syndromes in the mouse. J Hered 1990; 81:424427.
144. Naggert JK, Fricker LD, Varlamov O, Nishina PM,
Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter
EH. Hyperproinsulinaemia in obese fat/fat mice
associated with a carboxypeptidase E mutation which
reduces enzyme activity. Nat Genet 1995; 10:135142.
145. Fricker LD. Carboxypeptidase E. Annu Rev Physiol
1988; 50:309321.
146. Blazquez M, Shennan KI. Basic mechanisms of
secretion: sorting into the regulated secretory pathway. Biochem Cell Biol 2000; 78:181191.
147. Shen FS, Aguilera G, Loh YP. Altered biosynthesis
and secretion of pro-opiomelanocortin in the intermediate and anterior pituitary of carboxypeptidase edecient, Cpe fat/Cpe fat mice. Neuropeptides 1999;
33:276280.
148. Zhang CF, Snell CR, Loh YP. Identication of a novel
prohormone sorting signal-binding site on carboxypeptidase E, a regulated secretory pathway-sorting
receptor. Mol Endocrinol 1999; 13:527536.
149. Cool DR, Normant E, Shen F, Chen HC, Pannell L,
Zhang Y, Loh YP. Carboxypeptidase e is a regulated
secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe fat mice. Cell
1997; 88:7383.
150. Beinfeld MC. CCK biosynthesis and processing: recent
progress and future challenges. Life Sci 1997; 61:2359
2366.
151. Ohlemiller KK, Hughes RM, Mosinger-Ogilvie J,
Speck JD, Grosof DH, Silverman MS. Cochlear and
retinal degeneration in the tubby mouse. Neuroreport
1995; 6:845849.
Chua et al.
152. Noben-Trauth K, Naggert JK, North MA, Nishina
PM. A candidate gene for the mouse mutation tubby.
Nature 1996; 380:534538.
153. Kleyn PW, Fan W, Kovats SG, Lee JJ, Pulido JC, Wu
Y, Berkemeier LR, Misumi DJ, Holmgren L, Charlat
O, Woolf EA, Tayber O, Brody T, Shu P, Hawkins F,
Kennedy B, Baldini L, Ebeling C, Alperin GD, Deeds
J, Lakey ND, Culpepper J, Chen H, GlucksmannKuis MA, Moore KI. Identication and characterization of the mouse obesity gene Tubby: a member of
a novel gene family. Cell 1996; 85:281290.
154. Lewis CA, Batlle IR, Batlle KG, Banerjee P, Cideciyan
AV, Huang J, Aleman TS, Huang Y, Ott J, Gilliam
TC, Knowles JA, Jacobson SG. Tubby-like protein 1
homozygous splice-site mutation causes early-onset
severe retinal degeneration. Invest Ophthalmol Vis Sci
1999; 40:21062114.
155. Ikeda A, Zheng QY, Rosenstiel P, Maddatu T, Zuberi
AR, Roopenian DC, North MA, Naggert JK,
Johnson KR, Nishina PM. Genetic modication of
hearing in tubby mice: evidence for the existence of a
major gene (Moth1) which protects tubby mice from
hearing loss. Hum Mol Genet 1999; 8:17611767.
156. Guan XM, Yu H, Van der Ploeg LH. Evidence of
altered hypothalamic pro-opiomelanocortin/neuropeptide Y MRNA expression in tubby mice. Brain
Res Mol Brain Res 1998; 59:273279.
157. Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao
J, Shan WS, Myszka DG, Shapiro L. G-protein
signaling through tubby proteins. Science 2001;
292:20412050.
158. Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro
L. Implication of tubby proteins as transcription
factors by structure-based functional analysis. Science
1999; 286:21192125.
159. Smith GP, Gibbs J. Satiating eect of cholecystokinin.
Ann NY Acad Sci 1994; 713:236241.
160. Miyasaka K, Kanai S, Ohta M, Kawanami T, Kono
A, Funakoshi A. Lack of satiety eect of cholecystokinin (CCK) in a new rat model not expressing the
Cck-a receptor gene. Neurosci Lett 1994; 180:143146.
161. Moran TH, Katz LF, Plata-Salaman CR, Schwartz
GJ. Disordered food intake and obesity in rats lacking
cholecystokinin A receptors. Am J Physiol 1998;
274:R618R625.
162. Moran TH. Cholecystokinin and satiety: current
perspectives. Nutrition 2000; 16:858865.
163. Lacourse KA, Swanberg LJ, Gillespie PJ, Rehfeld JF,
Saunders TL, Samuelson LC. Pancreatic function in
Cck-decient mice: adaptation to dietary protein does
not require CCK. Am J Physiol 1999; 276:G1302
G1309.
164. Miyasaka K, Shinozaki H, Suzuki S, Sato Y, Kanai S,
Masuda M, Jimi A, Nagata A, Matsui T, Noda T,
Kono A, Funakoshi A. Disruption of cholecystokinin
Cckb receptor gene did not modify bile or pancreatic
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
247
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
248
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
Chua et al.
Dononoue PA, Burns TL, Shuldiner AR, Silver K,
Andersen RE, Pedersen O, Echwald S, Sorensen TIA,
Behn P, Permutt MA, Jacobs KB, Elston RC, Homan DJ, Allison DB. Brief report: a meta-analytic
investigation of linkage and association of common
leptin receptor polymorphisms with body mass index
and waist. Submitted.
Heo M, Leibel RL, Fontaine KR, et al. A metaanalytic investigation of linkage and association of
common leptin receptor (LEPR) polymorphisms with
body mass index and waist circumference. Intl Jnl of
Obesity 2002; 26:640646.
Vaisse C, Clement K, Guy-Grand B, Froguel P. A
frameshift mutation in human MC4R is associated with
a dominant form of obesity. Nat Genet 1998; 20:113
114.
Cody JD, Reveles XT, Hale DE, Lehman D, Coon H,
Leach RJ. Haplosuciency of the melancortin-4
receptor gene in individuals with deletions of 18q.
Hum Genet 1999; 105:424427.
Hinney A, Schmidt A, Nottebom K, Heibult O, Becker
I, Ziegler A, Gerber G, Sina M, Gorg T, Mayer H,
Siegfried W, Fichter M, Remschmidt H, Hebebrand J.
Several mutations in the melanocortin-4 receptor gene
including a nonsense and a frameshift mutation
associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab 1999; 84:14831486.
Wardlaw SL. Clinical review 127: obesity as a neuroendocrine disease: Lessons to be learned from proopiomelanocortin and melanocortin receptor mutations in
mice and men. J Clin Endocrinol Metab 2001; 86:1442
1446.
Krude H, Biebermann H, Luck W, Horn R, Brabant
G, Gruters A. Severe early-onset obesity, adrenal
insuciency and red hair pigmentation caused by
pomc mutations in humans. Nat Genet 1998; 19:155
157.
Comuzzie AG, Hixson JE, Almasy L, Mitchell BD,
Mahaney MC, Dyer TD, Stern MP, MacCluer JW,
Blangero J. A major quantitative trait locus determining serum leptin levels and fat mass is located
on human chromosome 2. Nat Genet 1997; 15:273
276.
Hixson JE, Almasy L, Cole S, Birnbaum S, Mitchell
BD, Mahaney MC, Stern MP, MacCluer JW, Blangero J, Comuzzie AG. Normal variation in leptin
levels in associated with polymorphisms in the
proopiomelanocortin gene, POMC. J Clin Endocrinol
Metab 1999; 84:31873191.
Davidson HW, Peshavaria M, Hutton JC. Proteolytic
conversion of proinsulin into insulin. Identication of
a Ca2+-dependent acidic endopeptidase in isolated
insulin-secretory granules. Biochem J 1987; 246:279
286.
Normant E, Loh YP. Depletion of carboxypeptidase e,
a regulated secretory pathway sorting receptor, causes
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
249
219. Michaud JL, DeRossi C, May NR, Holdener BC, Fan
CM. Arnt2 acts as the dimerization partner of Sim1 for
the development of the hypothalamus. Mech Dev
2000; 90:253261.
220. Holder JL, Butte NF, Zinn AR. Profound obesity
associated with a balanced translocation that disrupts
the Sim1 gene. Hum Mol Genet 2000; 9:101108.
221. Aldred MA, Trembath RC. Activating and inactivating mutations in the human Gnas1 gene. Hum Mutat
2000; 16:183189.
222. de Sanctis C, Lala R, Matarazzo P, et al. McCuneAlbright syndrome: a longitudinal clinical study of 32
patients. J Pediat Endocr Metab 1999; 12:817826.
223. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis
RA, Hoskins BE, Scambler PJ, Davidson WS, Beales
PL, Lupski JR. Triallelic inheritance in Bardet-Biedl
syndrome, a Mendelian recessive disorder. Science
2001; 293:22562259.
224. Burghes AH, Vaessin HE, De La Chapelle A.
Genetics: the land between Mendelian and multifactorial inheritance. Science 2001; 293:22132214.
225. Kwitek-Black AE, Carmi R, Duyk GM, Buetow KH,
Elbedour K, Parvari R, Yandava CN, Stone EM,
Sheeld VC. Linkage of Bardet-Biedl syndrome to
chromosome 16q and evidence for non-allelic genetic
heterogeneity. Nat Genet 1993; 5:392396.
226. Elbedour K, Zucker N, Zalzstein E, Barki Y, Carmi
R. Cardiac abnormalities in the Bardet-Biedl syndrome: echocardiographic studies of 22 patients. Am J
Med Genet 1994; 52:164169.
227. Green JS, Parfrey PS, Harnett JD, Farid NR, Cramer
BC, Johnson G, Heath O, McManamon PJ, OLeary
E, Pryse-Phillips W. The cardinal manifestations of
Bardet-Biedl syndrome, a form of Laurence-MoonBiedl syndrome. N Engl J Med 1989; 321:10021009.
228. Slavotinek AM, Biesecker LG. Unfolding the role of
chaperones and chaperonins in human disease. Trends
Genet 2001; 17:528535.
229. Croft JB, Swift M. Obesity, hypertension, and renal
disease in relatives of Bardet-Biedl syndrome sibs. Am
J Med Genet 1990; 36:3742.
230. Croft JB, Morrell D, Chase CL, Swift M. Obesity in
heterozygous carriers of the gene for the Bardet-Biedl
syndrome. Am J Med Genet 1995; 55:1215.
231. Kubota T, Oga S, Ohashi H, Iwamoto Y, Fukushima
Y. Borjeson-Forssman Lehmann syndrome in a
woman with skewed X-chromosome inactivation.
Am J Med Genet 1999; 87:258261.
232. Gecz J, Baker E, Donnelly A, Ming JE, McDonaldMcGinn DM, Spinner NB, Zackai EH, Sutherland
GR, Mulley JC. Fibroblast growth factor homologous
factor 2 (fhf2): gene structure, expression and mapping
to the Borjeson-Forssman-Lehmann syndrome region
in xq26 delineated by a duplication breakpoint in a
bs-like patient. Hum Genet 1999; 104:5663.
233. Rousseau F, Vincent A, Rivella S, Heitz D, Triboli C,
250
Maestrini E, Warren ST, Suthers GK, Goodfellow P,
Mandel JL. Four chromosomal breakpoints and four
new probes mark out a 10-cm region encompassing the
fragile-X locus ( fraxa). Am J Hum Genet 1991;
48:108116.
234. Matthijs G, Schollen E, Van Schaftingen E, Cassiman
JJ, Jaeken J. Lack of homozygotes for the most
frequent disease allele in carbohydrate-decient glycoprotein syndrome type 1a. Am J Hum Genet 1998;
62:542550.
235. Nicholls RD, Saitoh S, Horsthemke B. Imprinting in
Prader-Willi and Angelman syndromes. Trends Genet
1998; 14:194200.
236. Kishino T, Lalande M, Wagsta J. UBE3A/E6-AP
mutations cause Angelman syndrome. Nat Genet
1997; 15:7073.
237. Eiholzer U, Blum WF, Molinari L. Body fat
determined by skinfold measurements is elevated
despite underweight in infants with Prader-LabhartWilli syndrome. J Pediatr 1999; 134:222225.
238. Cassidy SB, Schwartz S. Prader-Willi and Angelman
syndromes. Disorders of genomic imprinting. Medicine (Baltimore) 1998; 77:140151.
239. Robinson WP, Bernasconi F, Mutirangura A, Ledbetter DH, Langlois S, Malcolm S, Morris MA,
Schinzel AA. Nondisjunction of chromosome 15:
origin and recombination. Am J Hum Genet 1993;
53:740751.
240. Robinson WP, Bottani A, Xie YG, Balakrishman J,
Binkert F, Machler M, Prader A, Schinzel A.
Molecular, cytogenetic, and clinical investigations of
Prader-Willi syndrome patients. Am J Hum Genet
1991; 49:12191234.
241. Mitchell J, Schinzel A, Langlois S, Gillessen-Kaesbach
G, Schuenhauer S, Michaelis R, Abeliovich D, Lerer
I, Christian S, Guitart M, McFadden DE, Robinson
WP. Comparison of phenotype in uniparental disomy
and deletion prader-willi syndrome: sex specic dierences. Am J Med Genet 1996; 65:133136.
242. Reed ML, Le SE. Maternal imprinting of human
snrpn, a gene deleted in Prader-Willi syndrome. Nat
Genet 1994; 6:163167.
243. Ishikawa T, Kibe T, Wada Y. Deletion of small
nuclear ribonucleoprotein polypeptide n (snrpn) in
Prader-Willi syndrome detected by uorescence in situ
hybridization: two sibs with the typical phenotype
without a cytogenetic deletion in chromosome 15q.
Am J Med Genet 1996; 62:350352.
244. Sun Y, Nicholls RD, Butler MG, Saitoh S, Hainline
BE, Palmer CG. Breakage in the SNRPN locus in a
balanced 46,XY,t(15;19) Prader-Willi syndrome patient. Hum Mol Genet 1996; 5:517524.
245. Kuslich CD, Kobori JA, Mohapatra G, GregorioKing C, Donlon TA. Prader-Willi syndrome is caused
by disruption of the SNRPN gene. Am J Hum Genet
1999; 64:7076.
Chua et al.
246. Dittrich B, Buiting K, Korn B, Rickard S, Buxton J,
Saitoh S, Nicholls RD, Poustka A, Winterpacht A,
Zabel B, Horsthemke B. Imprint switching on human
chromosome 15 may involve alternative transcripts of
the SNRPN gene. Nat Genet 1996; 14:163170.
247. Lyko F, Buiting K, Horsthemke B, Paro R. Identication of a silencing element in the human 15q1l-q13
imprinting center by using transgenic Drosophila.
Proc Natl Acad Sci USA 1998; 95:16981702.
248. Bressler J, Tsai TF, Wu MY, Tsai SF, Ramirez MA,
Armstrong D, Beaudet AL. The SNRPN promoter is
not required for genomic imprinting of the PraderWilli/Angelman domain in mice. Nat Genet 2001;
28:232240.
249. Schulze A, Hansen C, Skakkebaek NE, BrondumNielsen K, Ledbetter DH, Tommerup N. Exclusion of
snrpn as a major determinant of Prader-Willi syndrome by a translocation breakpoint. Nat Genet 1996;
12:452454.
250. Holm VA, Cassidy SB, Butler MG, Hanchett JM,
Greenswag LR, Whitman BY, Greenberg F. PraderWilli syndrome: consensus diagnostic criteria. Pediatrics 1993; 91:398402.
251. De los Santos T, Schweizer J, Rees CA, Francke U.
Small evolutionarily conserved RNA, resembling C/D
box small nucleolar RNA, is transcribed from PWCRL,
a novel imprinted gene in the Prader-Willi deletion
region, which is highly expressed in brain. Am J Hum
Genet 2000; 67:10671082.
252. Pilia G, Hughes-Benzie RM, MacKenzie A, Baybayan
P, Chen EY, Huber R, Neri G, Cao A, Forabosco A,
Schlessinger D. Mutations in GPC3, a glypican gene,
cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat Genet 1996; 12:241247.
253. Veugelers M, Cat BD, Muyldermans SY, Reekmans
G, Delande N, Frints S, Legius E, Fryns JP,
Schrander-Stumpel C, Weidle B, Magdalena N, David
G. Mutational analysis of the GPC3/GPC4 glypican
gene cluster on Xq26 in patients with Simpson-GolabiBehmel syndrome: identication of loss-of-function
mutations in the GPC3 gene. Hum Mol Genet 2000;
9:13211328.
254. Weksberg R, Shen DR, Fei YL, Song QL, Squire J.
Disruption of insulin-like growth factor 2 imprinting
in Beckwith-Wiedemann syndrome. Nat Genet 1993;
5:143150.
255. Bamshad M, Lin RC, Law DJ, Watkins WC,
Krakowiak PA, Moore ME, Franceschini P, Lala R,
Holmes LB, Gebuhr TC, Bruneau BG, Schinzel A,
Seidman JG, Seidman CE, Jorde LB. Mutations in
human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 1997;
16:311315.
256. Bamshad M, Le T, Watkins WS, Dixon ME, Kramer
BE, Roeder AD, Carey JC, Root S, Schinzel A, Van
Maldergem L, Gardner RJ, Lin RC, Seidman CE,
257.
258.
259.
260.
261.
262.
263.
264.
251
265. Brown AM, Willi SM, Argyropoulos G, Garvey WT.
A novel missense mutation, R70W, in the human
uncoupling protein 3 gene in a family with type 2
diabetes. Hum Mutat 1999; 13:508.
266. Brown AM, Dolan JW, Willi SM, Garvey WT,
Argyropoulos G. Endogenous mutations in human
uncoupling protein 3 alter its functional properties.
FEBS Lett 1999; 464:189193.
267. Garg A, Wilson R, Barnes R, Arioglu E, Zaidi Z,
Gurakan F, Kocak N, ORahilly S, Taylor SI, Patel
SB, Bowcock AM. A gene for congenital generalized
lipodystrophy maps to human chromosome 9q34. J
Clin Endocrinol Metab 1999; 84:33903394.
268. Wan YJ, An D, Cai Y, Repa JJ, Hung-Po Chen T,
Flores M, Postic C, Magnuson MA, Chen J, Chien
KR, French S, Mangelsdorf DJ, Sucov HM. Hepatocyte-specic mutation establishes retinoid X receptor alpha as a heterodimeric integrator of multiple
physiological processes in the liver. Mol Cell Biol
2000; 20:44364444.
269. Cao H, Hegele RA. Nuclear lamin A/C R482Q
mutation in Canadian kindreds with Dunnigan-type
familial partial lipodystrophy. Hum Mol Genet 2000;
9:109112.
270. Raaele Di Barletta M, Ricci E, Galluzzi G, Tonali P,
Mora M, Morandi L, Romorini A, Voit T, Orstavik
KH, Merlini L, Trevisan C, Biancalana V, Housmanowa-Petrusewicz I, Bione S, Ricotti R, Schwartz K,
Bonne G, Toniolo D. Dierent mutations in the lmna
gene cause autosomal dominant and autosomal
recessive Emery-Dreifuss muscular dystrophy. Am J
Hum Genet 2000; 66:14071412.
271. Speckman RA, Garg A, Du F, Bennett L, Veile R,
Arioglu E, Taylor SI, Lovett M, Bowcock AM.
Mutational and haplotype analyses of families with
familial partial lipodystrophy (Dunnigan variety)
reveal recurrent missense mutations in the globular
C-terminal domain of lamin a/c. Am J Hum Genet
2000; 66:11921198.
272. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin
DG. Central nervous system control of food intake.
Nature 2000; 404:661671.
273. Ohki-Hamazaki H, Watase K, Yamamoto K, Ogura
H, Yamano M, Yamada K, Maeno H, Imaki J,
Kikuyama S, Wada E, Wada K. Mice lacking bombesin receptor subtype-3 develop metabolic defects and
obesity. Nature 1997; 390:165169.
274. Inoue H, Iannotti CA, Welling CM, Veile R, DonisKeller H, Permutt MA. Human cholecystokinin type
a receptor gene: cytogenetic localization, physical
mapping, and identication of two missense variants
in patients with obesity and non-insulin-dependent
diabetes mellitus (NIDDM). Genomics 1997; 42:331
335.
275. Miller LJ, Holicky EL, Ulrich CD, Wieben ED.
Abnormal processing of the human cholecystokinin
252
receptor gene in association with gallstones and
obesity. Gastroenterology 1995; 109:13751380.
276. Duckett SK, Snowder GD, Cockett NE. Eect of the
callipyge gene on muscle growth, calpastatin activity,
and tenderness of three muscles across the growth
curve. J Anim Sci 2000; 78:28362841.
277. Wang ND, Finegold MJ, Bradley A, Ou CN,
Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR,
Darlington GJ. Impaired energy homeostasis in c/ebp
alpha knockout mice. Science 1995; 269:11081112.
278. Comuzzie AG, Allison DB. The search for human
obesity genes. Science 1998; 280:13741377.
279. Smith SJ, Cases S, Jensen DR, Chen HC, Sande E,
Tow B, Sanan DA, Raber J, Eckel RH, Farese RV Jr.
Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet 2000;
25:8790.
280. Thomas SA, Matsumoto AM, Palmiter RD. Noradrenaline is essential for mouse fetal development.
Nature 1995; 374:643646.
281. Thomas SA, Palmiter RD. Thermoregulatory and
metabolic phenotypes of mice lacking noradrenaline
and adrenaline. Nature 1997; 387:9497.
282. Yu S, Yu D, Lee E, Eckhaus M, Lee R, Corria Z,
Accili D, Westphal H, Weinstein LS. Variable and
tissue-specic hormone resistance in heterotrimeric GS
protein alpha-subunit (GS alpha) knockout mice is
due to tissue-specic imprinting of the GS alpha gene.
Proc Natl Acad Sci USA 1998; 95:87158720.
283. Veugelers M, Vermeesch J, Watanabe K, Yamaguchi
Y, Marynen P, David G. GPC4, the gene for human
K-Glypican, anks GPC3 on Xg26: Deletion of the
GPc3-GPc4 gene cluster in one family with, SimpsonGolabi-Behmel syndrome. Genomics 1998; 53:111.
284. Lin SC, Lin CR, Gukovsky I, Lusis AJ, Sawchenko
PE, Rosenfeld MG. Molecular basis of the little mouse
phenotype and implications for cell typespecic
growth. Nature 1993; 364:208213.
285. Wajnrajch MP, Gertner JM, Harbison MD, Chua SC,
Leibel RL. Nonsense mutation in the human growth
hormone-releasing hormone receptor causes growth
failure analogous to the little (lit) mouse. Nat Genet
1996; 12:8890.
286. Netchine I, Talon P, Dastot F, Vitaux F, Goossens M,
Amselem S. Extensive phenotypic analysis of a family
with growth hormone (GH) deciency caused by a
mutation in the GH-releasing hormone receptor gene.
J Clin Endocrinol Metab 1998; 83:432436.
287. Maheshwari HG, Silverman BL, Dupuis J, Baumann
G. Phenotype and genetic analysis of a syndrome
caused by an inactivating mutation in the growth
hormonereleasing hormone receptor: dwarsm of
SINDH. J Clin Endocrinol Metab 1998; 83:40654074.
288. Anand A, Chada K. In vivo modulation of hmgic
reduces obesity. Nat Genet 2000; 24:377380.
289. Arlotta P, Tai AK, Manoletti G, Cliord C, Jay G,
Chua et al.
290.
291.
292.
293.
294.
295.
296.
297.
298.
299.
300.
301.
302.
253
316. Buiting K, Dittrich B, Gross S, Greger V, Lalande M,
Robinson W, Mutirangura A, Ledbetter D, Horsthemke B. Molecular denition of the Prader-Willi
syndrome chromosome region and orientation of the
snrpn gene. Hum Mol Genet 1993; 2:19911994.
317. Muscatelli F, Abrous DN, Massacrier A, Boccaccio I,
Le Moal M, Cau P, Cremer H. Disruption of the
mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human PraderWilli syndrome. Hum Mol Genet 2000; 9:31013110.
318. Yang T, Adamson TE, Resnick JL, Le S, Wevrick R,
Francke U, Jenkins NA, Copeland NG, Brannan CI.
A mouse model for Prader-Willi syndrome imprintingcentre mutations. Nat Genet 1998; 19:2531.
319. Socolovsky M, Fallon AE, Wang S, Brugnara C,
Lodish HE. Fetal anemia and apoptosis of red cell
progenitors in Stat5a-/-5b-/- mice: a direct role for
Stat5 in Bcl-x(1) induction. Cell 1999; 98:181191.
320. Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L,
Carter TA, Kazlauskaite R, Pankratz DG, WynshawBoris A, Refeto S, Weintraub B, Willingham MC,
Barlow C, Cheng S. Mice with a targeted mutation in
the thyroid hormone beta receptor gene exhibit
impaired growth and resistance to thyroid hormone.
Proc Natl Acad Sci USA 2000; 97:1320913214.
321. Stubdal H, Lynch CA, Moriarty A, Fang Q, Chickering T, Deeds JD, Fairchild-Huntress V, Charlat O,
Dunmore JH, Kleyn P, Huszar D, Kapeller R.
Targeted deletion of the tub mouse obesity gene
reveals that tubby is a loss-of-function mutation. Mol
Cell Biol 2000; 20:878882.
322. Hagstrom SA, North MA, Nishina PL, Berson EL,
Dryja TP. Recessive mutations in the gene encoding
the tubby-like protein Tulpl in patients with retinitis
pigmentosa. Nat Genet 1998; 18:174176.
323. Mammes O, Betoulle D, Aubert R, Giraud V, Tuzet S,
Petiet A, Colas-Linhart N, Fumeron F. Novel polymorphisms in the 5V region of the Lep gene: association
with leptin levels and response to low-calorie diet in
human obesity. Diabetes 1998; 47:487489.
324. Hager J, Clement K, Francke S, Dina C, Raison J,
Lahlo N, Rich N, Pelloux V, Basdevant A, GuyGrand B, North M, Froguel P. A polymorphism in the
5V untranslated region of the human ob gene is
associated with low leptin levels. Int J Obes Relat
Metab Disord 1998; 22:200205.
325. Lucantoni R, Ponti E, Berselli ME, Savia G, Minocci
A, Calo G, de Medici C, Liuzzi A, Di Blasio AM. The
a19g polymorphism in the 5V untranslated region of
the human Obese gene does not aect leptin levels in
severely obese patients. J Clin Endocrinol Metab 2000;
85:35893591.
326. Mammes O, Betoulle D, Aubert R, Herbeth B, Siest
G, Fumeron F. Association of the G-2548A polymorphism in the 5V region of the LEP gene with
overweight. Ann Hum Genet 2000; 64:391394.
254
327.
328.
329.
330.
331.
332.
Chua et al.
Oksanen L, Kainulainen K, Heiman M, Mustajoki P,
Kauppinen-Makelin R, Kontula K. Novel polymorphism of the human OB gene promoter in lean and
morbidly obese subjects. Int J Obes Relat Metab
Disord 1997; 21:489494.
Shigemoto M, Nishi S, Ogawa Y, Isse N, Matsuoka
N, Tanaka T, Azuma N, Masuzaki H, Nishimura H,
Yoshimasa Y, Hosoda K, Nakao K. Molecular
screening of both the promoter and the protein coding
regions in the human OB gene in japanese obese
subjects with non-insulin-dependent diabetes mellitus.
Eur J Endocrinol 1997; 137:511513.
Thompson DB, Ravussin E, Bennett PH, Bogardus C.
Structure and sequence variation at the human leptin
receptor gene in lean and obese Pima Indians. Hum
Mol Genet 1997; 6:675679.
Wauters M, Mertens I, Chagnon M, Rankinen T,
Considine RV, Chagnon YC, Van Gaal LF, Bouchard
C. Polymorphisms in the leptin receptor gene, body
composition and fat distribution in overweight and
obese women. Int J Obes Relat Metab Disord
2001;25:714720.
Roth H, Korn T, Rosenkranz K, Hinney A, Ziegler A,
Kunz J, Siegfried W, Mayer H, Hebebrand J,
Grzeschik KH. Transmission disequilibrium and
sequence variants at the leptin receptor gene in
extremely obese German children and adolescents.
Hum Genet 1998; 103:540546.
De Silva AM, Walder KR, Aitman TJ, Gotoda T,
Goldstone AP, Hodge AM, De Courten MP, Zimmet
PZ, Collier GR. Combination of polymorphisms in
OB-R and the OB gene associated with insulin
333.
334.
335.
336.
337.
11
Rodent Models of Obesity
David A. York
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
I INTRODUCTION
Gabt1
GABA transporter I
MCH
Pmch
a
Agrp
Pomc
Atrn
Md
Pomc41
Htr1b
Drd1a
Drd2
Drd3
Adrb3
5HT1B
Dopamine D1
Dopamine D2
Dopamine D3R
h3-adrenergic
II. Hormones/peptides
Agouti
AgRP
POMC
Mahogany (mg)
Mahogonoid (Md)
h-endorphin
18, 20
8, 1
5, 34
4, 75.5
6, 60.55
X
10, 12
unknown
13, 7.0
6, 49
X, 66.15
Nr3c1
Insr
Cckar
Tnfrsf1b
Tnfrsf1a
Brs3
Esr1
Fshr
Chrm3
H1r
Htr2c
10, 47
2, 89
8
12, 4
2, 73.9
16, 2
12, 4
3, 50.4
9,46
13, 32
9, 28
16, 23.3
8, 10
15, 12.4
8, 33
3, 36
8, 32.5
Sdc3
Npy1r
Npy2r
Npy5r
12, 1
Sdc1
Syndecan 3
NPY Y1
NPY Y2
NPY Y5
GRII antisense
GRII
Insulin receptor
CCKA
TNF2P75
TNF2P55
Bombesin BRS-3
Estrogen Ra
FSH-R
Muscarinic M3R
Histamine H1
5HT2C
2,100
unknown
Mc3r
Mc4r
Name
Position
(Chr, cM)
TG & KO
Tg
Tg
KO
KO
KO
KO
Tg
KO
KO
KO
KO
KO
KO
KO
KO
KO
Tg
KO
KO
KO
KO
KO
KO
KO
KO
KO
KO
KO
KO
KO
KO
Tg
Transgenic (Tg) or
knockout (KO)
Several mutations
Single mutation
POMC knockout/hendorphin-deleted knockin
h-Actin promoter
h-Actin promoter
Target to brain
Neuron-specic knockout
Double-knockout
Comment
Eect
Transgenic (Tg) and Gene Knockout (KO) Models That Aect Energy Balance and/or Body Composition
I. Receptors/transporters
MC3
MC4
MC3/MC4
Syndecan 1
Gene
Table 1
256
York
6, 35.5
Unknown
9, 1
Gfptl
Cyp19
Casp1
Sgne1
Gapd
Glutamine:fructose-6phosphate amino
transferase
Aromatase
IL1h converting E.
7B2
G3PDH
6, 56
2, 64
6, 56
15, 46.9
11, 40
11, 40
Fabp4
Dgat
Slc2a4
Slc2a4
aP2
DGAT
Glut4
Glut4
7, 5.5
Lipe
unknown
unknown
HSL
Acc2
Plin
Iapp
Il6
Tnf
Tnfrsf1b
Tnfrsf1a
I11rn
Tgfb1
Amylin
IL6
TNFa
TNF receptor P75
TNF receptor P55
IL 1 receptor antagonist
TGF1h
III. Metabolic
Acetyl CoA carboxylase 2
Perilipin
11, 65
11, 65
11,65
2, 89
3, 8
13, 52
13, 52
11, syntenic
Gh
Gh
Gh
Ghrh
Crh
Crhbp
Crhpb
Ppy
6, 62
5, 17
17, 19.1
4,75.5
6,60.55
2, 10
7, 6.5
6, 10.5
11, 1.3
Lep
Igfbp1
Leptin
Insulin-like growth
factor 1 binding protein
Growth hormone
Growth hormone
Growth hormone
GHRH
CRH
CHR binding protein
CRH binding protein
Pancreatic polypeptide
11, 61
7, 69.2
Hcrt
Th
Orexin (hypocretin)
Tyrosine hydroxylase
Tg
KO
KO
KO
Tg
KO
KO
KO
Tg
KO
KO
KO
KO
KO
KO
KO
KO
Tg
Tg
Tg
KO
Tg
Tg
Tg
Tg
KO
Tg
Tg
Tg
KO
KO
PEPCK promoter
cmv-hactin promoter
Metallothionin promoter
Metallothionin promoter
On metallothionin promoter
Lethal unless NE
synthesis restored
Ptprb
Stat5
PTP1B
STAT5
Hmga2
Icam1
VI. Structural
Hmgic
ICAM-1
Gnas
Pkar2b
Gsa
9,7
10, 67.5
3, syntenic
7, 12/14, 20.5
12, 1
15, 48.8
8, 33/15, 48.5
11, 60.5
5, 58
2, 104
unknown
8, 38/7, 50
8, 45
17, 34.3
KO
KO
KO
KO
KO
KO
Tg
Tg
KO
KO
KO
KO
KO
KO
KO
KO
Ucp1/Ucp3
Mt
C3
KO
KO
KO/Tg
UCP1/UCP3
Metallothionein I & II
ASP
8, 38
7, 50
7/50
Tg
KO
Tg
KO
Transgenic (Tg) or
knockout (KO)
KO
Ucp1
Ucp2
Ucp3
UCP1
UCP2
UCP3
6, 56
6, 56
8, 38
2, 64
Position
(Chr, cM)
UCP1-Dta
Gapd
Gapd
Ucpl
G3PDH
G3PDH
UCP1
Name
Sgne1
(continued )
7B2
Gene
Table 1
Cushingoid-type of obesity
Eect
Homozygous lethal
Comment
258
York
259
Single-Gene Obesities
260
York
residues from the B-chain of insulin during its processing from proinsulin. The impairment in enzyme
activity in Cpefat/Cpefat mice explains their 10-fold
increased proinsulin to insulin ratios in the pancreas
and the very high level of proinsulin rather than
insulin in the circulation. The obesity, however, results
from the role of carboxypeptidase E in the posttranslational processing of numerous neuropeptides including pro-opiomelanocortin to a-MSH, h-endorphin
and h-lipotropin, proenkephalins, preproNPY, vasopressin, oxytocin, gastrin, and CCK. While Naggert et
al. (2) suggest that the obesity of Cpefat/Cpefat mouse
is likely to result from a complex pattern of alterations
in neuropeptide activity and secretion within the
hypothalamic-pituitary system rather than the hyperproinsulinemia, it is not surprising that it has many
similarities to the obesity of the MC4 receptor knockout mouse (29). The mutation also appears to have
dierential eects on postranslational processing in
the CNS and the periphery. The processing of procholecystokinin provides an example of this. In Cpefat/
Cpefat mice bioactive CCK was reduced in neural
tissue but not in gastrointestinal endocrine cells,
although the level of the enzyme substrate glycylarginine-extended CCK was greatly elevated in both
tissues (30).
3 Tubby (tub/tub) Mouse
This mutation was rst reported by Coleman and Eicher
in 1990 (27). It is an autosomal-recessive mutation on
chromosome 7 in the gene coding for the tubby protein,
one of a family of four proteins that also includes
TULPs 13. A characteristic of these proteins is the
f260amino acid domain at the carboxyl terminus that
forms a helix barrel structure that binds avidly to DNA.
The tubby mutation introduces a splice site at the
junction of the 3V-coding sequence that leads to the loss
of this carboxyl terminus domain (31). Knockout of tub
conrmed that the tubby gene mutation is a loss of
function mutation (32).
The wild-type tub protein is expressed in the hypothalamus and other brain regions, where it is localized to
plasma membranes, released by activation of Gaq
protein, and translocated into the nucleus (33). This
process may be activated by 5HT2c receptor activity.
Studies of CHO cells expressing the human insulin
receptor have shown an insulin-dependent phosphorylation of tyrosine residues on the tub protein. This has
led to the suggestion that tub acts as an adapter protein
linking the insulin receptor to protein tyrosine kinases
and may function as part of a neural insulin signaling
mechanism (34).
261
262
York
KK Mice
a.
263
thought to act upstream of the MC4 and MC1 receptors. However, mg can suppress diet-induced obesity (63).
b.
The Syndecans
264
d.
York
In addition to a role in regulation of pituitary-adrenal function, CRH and Urocortin inhibit food intake
and promote energy expenditure, particularly the sympathetically mediated BAT thermogenesis. Numerous
models, targeting specic components of this system,
have identied the ability to alter homeostasis. These
models generally produce a cushingoid-type of central
adiposity. The models include the transgenic overexpression of antisense cDNA to the brain type II
glucocorticoid receptor (GR) (68,69), knockout of
the brain type II GR, and transgenic expression of
CRH (70,71). The concentration of free CRH in the
CNS is aected by the levels of the CRH-binding
protein. Knockout of this gene results in a hypophagic
small mouse whereas overexpression regulated by the
metallothionin promoter caused obesity (72,73).
Despite these eects, knockout of CRH1 and CRH2
receptors does not have any major phenotypic eects
on body weight or food intake although the response
to exogenous urocortin or CRH may be absent or
diminished (7477).
e.
Orexin
Like leptin, insulin has been proposed as a longterm signal to the brain on the status of the energy
Cholecystokinin (CCK)
Bombesin
tension, and impaired glucose tolerance (91). BRS-3decient mice also show changes in sensitivity to nutrient stimuli, showing an enhanced preference for
saccharin solutions but also a stronger aversive response to LiCl (92).
j.
With the recognition of adipose tissue as an endocrine organ and the suggestion that TNFa secretion was
linked to insulin resistance (98), attention has focused
on the possibility that TNFa and other cytokines may
have an important role in the physiological control of
energy balance as well as their pathological role in
cancer cachexia. Divergent results have been reported.
TNFa-null mice either may be of normal weight or even
gain weight normally when fed a high-fat diet (99) or
they may be characterized by a signicant reduction in
body weight (100). To date, two receptor subtypes (P55
and P75) have been identied. Mice that are P75/
have lower body weight than wild type mice (101) when
fed a high fat diet whereas P55/ mice exhibit an
attenuated cachectic response to tumors (102). Similarly, mice lacking the IL6 gene do not exhibit the tumor
related reduction in food intake (103). Genetic studies in
which the expression of IL1 receptor antagonist (Il1ra)
is manipulated also suggest a role for IL1 in energy
regulation and cancer cachexia. Transgenic overexpression of IL1ra, which blocks the binding of IL1 to its
receptor, promotes weight reduction as would be
anticipated (104).
265
l.
Neurotransmitters
266
York
Metabolic Genes
a.
Lipid Metabolism
Carbohydrate Metabolism
1 Glucose transporters Glut4 is an insulin-regulated glucose transporter expressed in adipose tissue and
muscle. In adipose tissue glucose carbon is required for glyceride synthesis and for fatty acid synthesis. Overexpression of the Glut4 gene (Slc2a4) in
adipose tissue using the aP2 promoter results in an
obese mouse with enhanced glucose clearance that is
not further exaggerated by feeding a high-fat diet
(129). Expressing Glut4 in muscle with the myosin
light chain promoter has no eects on body weight or
body composition, but does again improve insulinstimulated glucose disposal (130,131). In contrast,
Glut4 (Slc2a4)-null mice have little white adipose
Converting Enzymes
267
268
e.
York
Other
Signaling Proteins
a.
PKARIIh
Transcription Factors
a.
Lipin (d)
PPARa
SREBP-1c
269
Vgf
d. A-ZIP/F-1
Structural Genes
a.
Hmgic
e.
C/EBP
Nh1h2
270
York
Hypothalamic Obesity
Endocrine Obesity
271
III
SUMMARY
272
York
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
273
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
274
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
York
correlation in dierent phenotypes of viable yellow
mice. Science 1965; 147:11451147.
Gill AM, Leiter EH, Powell JG, Chapman HD, Yen
TT. Dexamethasone-induced hyperglycemia in obese
Avy/a (viable yellow) female mice entails preferential
induction of hepatic estrogen sulfotransferase. Diabetes 1994; 43:9991004.
Wol GL, Flack JD. Genetic regulation of plasma
corticosterone concentration and its response to
castration and allogenic tumor growth in the mouse.
Nat New Biol 1971; 232:181182.
Bultman SJ, Michaud EJ, Woychik RP. Molecular
characterization of the mouse agouti locus. Cell 1992;
71:11951204.
Perry W, Hustad C, Swing D, Jenkins N, Copeland N.
A transgenic mouse assay for agouti protein activity.
Genetics 1995; 140:267274.
Klebig ML, Wilkinson JE, Geisler, JG, Woychik RP.
Ectopic expression of the agouti gene in transgenic
mice causes obesity, features of type II diabetes, and
yellow fur. Proc Natl Acad Sci USA 1995; 92:4728
4732.
Wilson BD Ollman MM Kany L, Stoer M, Bell GI,
Barsch GS. Structure and function of ASP, the human
homolog of the mouse agouti gene. Hum Mol Genet
1995; 4:223230.
Zemel MB, Kim JH, Woychik RP, et al. Agouti
regulation of intracellular calcium: role in the insulin
resistance of viable yellow mice. Proc Natl Acad Sci
USA 1995; 92:47334737.
Lu D, Willard D, Patel IR, Kadwell S, Overton L,
Kost T, Luther M, Chen W, Woychik RP, Wilkison
WO, Cone RD. Agouti protein is an antagonist of the
melanocyte-stimulating hormone receptor. Nature
(Lond) 1994; 371:799802.
Ollman MM, Wilson BD, Yang Y-K, Kerns JA, Chen
Y, Gantz I, Barsh GS. Antagonism of central
melanocortin receptors in vitro and in vivo by
agouti-related protein. Science 1997; 278:135138.
Nakamura M, Yamada K. Studies on a diabetic (KK)
strain in the mouse. Diabetologia 1967; 3:212221.
Shimizu H, Shargill NS, Bray GA, Yen FT, Geselchen
PD. Eects of MSH on food intake, body weight and
coat color of the yellow obese mouse. Life Sci 1989;
45:543552.
Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone
RD. Role of melanocortinergic neurons in feeding and
the agouti obesity syndrome. Nature 1997; 385:165
168.
Fan W, Dinulescu DM, Butler AA, Zhou J, Marks
DL, Cone RD. The central melanocortin system can
directly regulate serum insulin levels. Endocrinology
2000; 141:30723079.
Flier JS, Harris M, Hollenberg AN. Leptin, nutrition,
and the thyroid: the why, the wherefore, and the
wiring. J Clin Invest 2000; 105:859861.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
275
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
tor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 2000; 24:410414.
Bradbury MJ, McBurnie MI, Denton DA, Lee KF,
Vale WW. Modulation of urocortin-induced hypophagia and weight loss by corticotropin-releasing
factor receptor I deciency in mice. Endocrinology
2000; 141:27152724.
Kishimoto T, Radulovic J, Radulovic M, Lin CR,
Schrick C, Hooshmand F, Hermanson O, Rosenfeld
MG, Spiess J. Deletion of crhr2 reveals an anxiolytic
role for corticotropin-releasing hormone receptor-2.
Nat Genet 2000; 24:415419.
Shimada M, Tritos NA, Lowell BB, Flier JS,
Maratos-Flier E. Mice lacking melanin-concentrating
hormone are hypophagic and lean. Nature 1998;
396:670674.
Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R,
Kokkotou E, Elmquist J, Lowell B, Flier JS,
Maratos-Flier E. Melanin-concentrating hormone
overexpression in transgenic mice leads to obesity
and insulin resistance. J Clin Investigation 2001; 107:
379386.
Chemelli RM, Willie JT, Sinton CM, Elmquist JK,
Scammell T, Lee C, Richardson JA, Williams SC,
Xiong Y, Kisanuki Y, Fitch TE, Nakazato M,
Hammer RE, Saper CB, Yanagisawa M. Narcolepsy
in orexin knockout mice: molecular genetics of sleep
regulation. Cell 1999; 98:437451.
Hara J, Beuckmann CT, Nambu T, Willie JT,
Chemelli RM, Sinton CM, Sugiyama F, Yagami K,
Goto K, Yanagisawa M, Sakurai T. Genetic ablation
of orexin neurons in mice results in narcolepsy,
hypophagia, and obesity. Neuron 2001; 30:345354.
Bruning JC, Gautam D, Burks DJ, Gillette J,
Schubert M, Orban PC, Klein R, Krone W, MullerWieland D, Kahn CR. Role of brain insulin receptor
in control of body weight and reproduction. Science
2000; 289:21222125.
Moller DE, Change PY, Yaspelkis BB 3rd, Flier JS,
Wallberg-Henriksson H, Ivy JL. Transgenic mice with
muscle-specic insulin resistance develop increased
adiposity, impaired glucose tolerance, and dyslipidemia. Endocrinology 1996; 137:23972405.
Devine E, Young AA. Weight gain in male and female
mice with amylin gene knockout. Diabetes 1998;
47:A317 (abstract).
Rajkumar K, Modric T, Murphy LJ. Impaired
adipogenesis in insulin-like growth factor binding
protein-1 transgenic mice. J Endocrinol 1999;
162:457465.
Baldwin BA, Parrott RF, Ebenezer IS. Food for
thought: a critique on the hypothesis that endogenous
cholecystokinin acts as a physiological satiety factor.
Prog Neurobiol 1998; 55:477507.
Fumakoshi A, Miyassaka K, Shinozaki H, Masada
M, Kawanami T, Takata Y, Komo A. An animal
276
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
York
model of congenital defect of gene expression of
cholecystokinin (CCK)-A receptor. Biochem Biophys
Res Commun 1993; 210:787796.
Schwartz GJ, Whitney A, Skoglund C, Castonguay
TW, Moran TH. Decreased responsiveness to dietary
fat in Otsuka Long-Evans Tokushima fatty rats lacking
CCK-A receptors. Am J Physiol 1999; 277:R1144
R1151.
Kopin AS, Mathes WF, McBride EW, Nguyen M, AlHaider, Schmitz F, Bonner-Weir S, Kanarak S,
Beinbom M. The cholecystokinin-A receptor mediates
inhibition of food intake yet is not essential for the
maintenance of body weight. J Clin Invest 1999;
103:383391.
Lacourse KA, Swanbert LJ, Gillespie PJ, Rehfeld JF,
Saunders TL, Samuelson LC. Pancreatic function in
CCK-decient mice: adaptation to dietary protein
does not require CCK. Am J Physiol 1999;
276:G1302G1309.
Ohki-Hamazaki H, Watase K, Yamamoto K, Ogura
H, Yamano M, Yamada K, Maeno H, Imaki J,
Kikuyama S, Wada E, Wada K. Mice lacking
bombesin receptor subtype-3 develop metabolic defects and obesity. Nature 1997; 390:165169.
Yamada K, Wada E, Imaki J, Ohki-Hamazaki H,
Wada K. Hyperresponsiveness to palatable and
aversive taste stimuli in genetically obese (bombesin
receptor subtype-3-decient) mice. Physiol Behav
1999; 66:863867.
Donahue LR, Beamer WG. Growth hormone deciency in little mice results in aberrant body
composition, reduced insulin-like growth factor-I
and insulin-like grown factorbinding protein-3
(IGFBP-3), but does not aect IGFBP-2, -1 or -4. J
Endocrinol 1993; 136:91104.
Searle TW, Murray JD, Baker PJ. Eect of increased
production of growth hormone on body composition
in mice: transgenic versus control. J. Endocrinol 1992;
132:285291.
Chen XL, Lee K, Hartzell DL, Dean RG, Hausman
GJ, McGraw RA, Della-Ferra MA, Baile CA.
Adipocyte insensitivity to insulin in growth hormone-transgenic mice. Biochem Biophys Res Commun 2001; 283:933937.
Oberbauer AM, Runstadler JA, Murray JD, Havel
PJ. Obesity and elevated plasma leptin concentration
in oMT1A-o growth hormone transgenic mice. Obes
Res 2001; 9:5158.
Cai A, Hyde JF. The human growth hormonereleasing hormone transgenic mouse as a model of
modest obesity: dierential changes in leptin receptor
(OBR) gene expression in the anterior pituitary and
hypothalamus after fasting and OBR localization in
somatotrophs. Endocrinology 1999; 140: 36093614.
Hotamisligil GS, Shargill NS, Spiegelman BM.
Adipose expression of tumor necrosis factor-alpha:
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
277
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to dietinduced obesity. Proc Natl Acad Sci USA 2001;
64946499.
Cummings DE, Brandon EP, Planas JV, Motamed K,
Idzerda RL, McKnight GS. Genetically lean mice
result from targeted disruption of the RII beta subunit
of protein kinase A. Nature 1996; 382:622626.
Osuga J, Ishibashi S, Oka T, Yaguy H, Tozawa R,
Fujimoto A, Shionoiri F, Yahagi N, Kraemer FB,
Tsutsumi O, Yamada N. Targeted disruption of
hormone-sensitive lipase results in male sterility and
adipocyte hypertrophy, but not in obesity. Proc Natl
Acad Sci USA 2000; 97:787792.
Hotamisligil GS, Johnson RS, Distel RJ, Ellis R,
Papaioannou VE, Spiegelman BM. Uncoupling of
obesity from insulin resistance through a targeted
mutation in aP2, the adipocyte fatty acid binding
protein. Science 1996; 274:13771379.
Uysal KT, Scheja L, Wiesbrock SM, Bonner-Weir S,
Hotamisligil GS. Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinology 2000; 141:33883396.
Smith SJ, Cases S, Jensen DR, Chen HC, Sande E,
Tow B, Sanan DA, Raber J, Eckel RH, Farese RV Jr.
Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat. Nat Genet 2000;
25:8790.
Shepherd PR, Gnudi L, Tozzo E, Yang H, Leach F,
Kahn BB. Adipose cell hyperplasia and enhanced
glucose disposal in transgenic mice overexpressing
GLUT4 selectively in adipose tissue. J Biol Chem
1993; 268:2224322246.
Ikemoto S, Thompson KS, Takahashi M, Itakura H,
Lane MD, Ezaki O. High fat dietinduced hyperglycemia: prevention by low level expression of a
glucose transporter (GLUT4) minigene in transgenic
mice. Proc Natl Acad Sci USA 1995; 92:30963099.
Tsao TS, Burcelin R, Katz EB, Huang L, Charron
MJ. Enhanced insulin action due to targeted GLUT4
overexpression exclusively in muscle. Diabetes 1996;
45:2836.
Stenbit AE, Tsao TS, Li J, Burcelin R, Geenen DL,
Factor SM, Houseknecht K, Katz EB, Charron MJ.
GLUT4 heterozygous knockout mice develop muscle
insulin resistance and diabetes. Nat Med 1997;
3:10801081.
Veerababu G, Tang J, Homan RT, Daniels MC,
Hebert LF Jr, Crook ED, Cooksey RC, McClain DA.
Overexpression of gluatamine: fructose-6-phosphate
amidotransferase in the liver of transgenic mice results
in enhanced glycogen storage, hyperlipidemia, obesity,
and impaired glucose tolerance. Diabetes 2000;
49:20702078.
Jones MEE, Thorburn AW, Britt KL, Hewitt KN,
Wreford NG, Proietto J, Oz OK, Leury BJ, Robertson
278
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
York
KM, Yao S, Simpson ER. Aromatase-decient
(ArKO) mice have a phenotype of increased adiposity.
Proc Natl Acad Sci USA 2000; 97:1273512740.
Yao JH, Ye SM, Burgess W, Zachary JF, Kelley KW,
Johnson RW. Mice decient in interleukin-1beta
converting enzyme resist anorexia induced by central
lipopolysaccharide. Am J Physiol 1999; 277:R1435
R1443.
Kozak LP, Kozak UC, Clarke GT. Abnormal brown
and white fat development in transgenic mice overexpressing glycerol 3-phosphate dehydrogenase.
Genes 1991; 5:22562264.
Ookuma K, Bray GA, York DA. The eect of
goldthioglucose on the feeding response to CL
316,243 in transgenic mice overexpressing glycerophosphate dehydrogenase or uncoupling protein. Int J
Obes 1998; 22(suppl 3):S16 (abstract).
Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T,
Kishimoto T, Takahashi N, Yamauchi N, Kubota N,
Murayama S, Aizawa T, Akanuma Y, Kasai H, Yazaki
Y, Kadowaki T. Role of NADH shuttle system
in glucose-induced activation of mitochondrial metabolism and insulin secretion. Science 1999; 283:981
985.
Lowell BB, S-Susulic V, Hamann A, Lawitts JA,
Himms-Hagen J, Boyers BB, Kozak LP, Flier JS.
Development of obesity in transgenic mice after
genetic ablation of brown adipose tissue. Nature
(Lond) 1993; 366:740742.
Bray GA. Reciprocal relation between the sympathetic nervous system and food intake. Brain Res Bull
1991; 27:517520.
Himms-Hagen J. Role of brown adipose tissue
termogenesis in control of thermoregulatory feeding
in rats. A new hypothesis that links thermostatic and
glucostatic hypotheses for control of food intake. Proc
Soc Exp Biol Med 1995; 208:159169.
Ross SR, Graves RA, Spiegelman BM. Targeted
expression of a toxin gene to adipose tissue: transgenic
mice resistant to obesity. Genes Dev 1993; 7:1318
1324.
Enerback S, Jacobsson A, Simpson EM, Guerra C,
Yamashita H, Harper M-E, Kozak LE. Mice lacking
mitochondrial uncoupling protein are cold-sensitive
but not obese. Nature 1997; 387:9094.
Kopecky J, Hodny Z, Rossmeisl M, Syrovy I, Kozak
LP. Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution.
Am J Physiol 1996; 270(5 Pt 1):E768E775.
Li B, Nolte LA, Ju JS, Han DH, Coleman T,
Holloszy JO, Semenkovich CF. Skeletal muscle
respiratory uncoupling prevents diet-induced obesity
and insulin resistance in mice. Nat Med 2000; 6(10):
11151120.
Arsenijevic D, Onuma H, Pecqueur C, Raimbault S,
Manning BS, Mirous B, Couplan E, Alves-Guerra
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
279
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
280
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
York
chromosomal loci determining obesity in a multifactorial mouse model. J Clin Invest 1995; 95:1545
1552.
Warden CH, Fisler JS, Pace MJ, Svenson L, Lusis AJ.
Coincidence of genetic loci for plasma cholesterol
levels and obesity in a multifactorial mouse model.
J Clin Invest 1993; 92:773779.
Taylor BA, Phillips SA. Detection of of obesity QTLs
on mouse chromosomes 1 and 7 by selective DNA
pooling. Genomics 1996; 34:389398.
West DB, Boozer CN, Moody DC, Atkinson RL.
Dietary obesity in nine inbred mouse strains. Am J
Physiol 1992; 262:R1025R1032.
Fisler JS, Bray GA. Dietary obesity: eects of drugs
on food intake in S5B/Pl and Osborne-Mendel rats.
Physiol Behav 1985; 34:225231.
West DB, Waguespack J, York B, Goudey-Lefevre J,
Price RA. Genetics of dietary obesity in AKR/J
SWR/J mice: segregation of the trait and identication
of a linked locus on chromosome 4. Mamm Genome
1994; 5:546552.
West DB, Goudey-Lefevre J, York B, Truett GE.
Dietary obesity linked to genetic loci on chromosomes
9 and 15 in a polygenic mouse model. J Clin Invest
1994; 94:14101416.
York B, Truett AA, Monteiro MP, Barry SJ, Warden
CH, Naggert JK, Maddatu TP, West DB. Geneenvironment interaction: a signicant diet-dependent
obesity locus demonstrated in a congenic segment on
mouse chromosome 7. Mamm Genome 1999; 10:457
462.
Dhar M, Webb LS, Smith L, Hauser L, Johnson D,
West D. A novel ATPase on mouse chromosome 7 is a
candidate gene for increased body fat. Physiol
Genomics 2000; 4:93100.
Lyons MJ, Faust IM, Hemmes RB, Buskirk DR,
Hirsch J, Zabriskie JB. A virally induced obesity
syndrome in mice. Science 1982; 216:8285.
Carter JK, Ow CL, Smith RE. Rous-associated virus
type 7 induces a syndrome in chickens characterized by
stunting and obesity. Infect Immun 1983; 39:410422.
Carter JK, Garlich JD, Donaldson WE, Smith RE.
Inuence of diet on a retrovirus-induced obesity and
stunting syndrome. Avian Dis 1983; 27:317322.
Gosztonyi G, Ludwig H. Borna diseaseneuropathology and pathogenesis. Curr Top Microbiol
Immunol 1995; 190:3973.
Dhurandhar NV, Kulkarni P, Ajinkya SM, Sherikar
A. Eect of adenovirus infection on adiposity in
chicken. Vet Microbiol 1992; 31:101107.
Dhurandhar NV, Israel BA, Kolear JM, Mayhew GF,
Cook ME, Atkinson RL. Increased adiposity in
animals due to a human virus. Int J Obes 2000;
24:989996.
Dhurandhar NV, Atkinson RL. Viruses and obesity.
Curr Opin Endocrinol Diabetes 2000; 7:247251.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
211.
212.
213.
214.
215.
216.
281
217.
218.
219.
220.
221.
222.
223.
12
Primates in the Study of Aging-Associated Obesity
Barbara C. Hansen
University of Maryland, Baltimore, Maryland, U.S.A.
AGING-ASSOCIATED NATURALLY
OCCURRING SPONTANEOUS
OBESITY IN NONHUMAN PRIMATES
284
Hansen
II
calories neither increased nor decreased physical activity relative to similar-weight animals (15). Energy
expenditure per kg lean body mass was signicantly
reduced by a degree of calorie restriction sucient only
to prevent the development of obesity (15).
Although several studies have involved dietary
manipulations thought to facilitate the development of
obesity, where these dietary regimens have been tested
in young animals, obesity has not developed (18). Some
very high fat diets, for example, 60% fat, have been
found to produce weight gain in young monkeys. Highfat diets have been used to alter lipoprotein composition
(19). The usual dietary regimen of laboratory monkeys,
primate chow, would be expected to be optimal in the
prevention of obesity, as it is high in ber, low in fat
(17%), and relatively low in caloric density (4 kcal/g). In
colonies where the calorie allocation to each monkey is
strictly controlled, that is, restricted below ad libitum
levels, obesity does not develop. Under conditions of ad
libitum feeding (food continuously available for 824
hr/d), obesity will eventually develop in perhaps 50%
or more of the laboratory-maintained animals, despite
the presumed optimal diet composition. As discussed
below, long-term experimental limitation of calories,
adjusted on an individual basis to prevent body weight
increase, can prevent the development of this middleage-onset obesity (20).
III
MEASUREMENT OF ADIPOSITY
IN MONKEYS
IV
285
286
Hansen
VI
GENETICS OF OBESITY
IN PRIMATES
Gene-Environment Interactions
287
Figure 1 Relationship between fasting plasma leptin levels and percent body fat in rhesus monkeys varying in degree of
adiposity. (From Ref. 56.)
288
Hansen
Figure 2 Longitudinal changes in plasma leptin levels compared to changes in plasma insulin, plasma glucose, and body weight
in two monkeys. Panel A shows a monkey in which leptin and body weight changes are highly related, while panel B shows a
monkey that is equally obese but shows no elevation in plasma leptin levels.
289
290
Hansen
Figure 3 Comparison of fat weight, plasma leptin levels, and plasma adiponectin levels in three groups of monkeyslean, obese
with insulin resistance, and obese with type 2 diabetes. *P<.05, **P<.01, ***P<.001. (From Ref. 74.)
Figure 4 Longitudinal changes in plasma adiponectin levels (left panel) and insulin sensitivity as measured by a euglycemic
hyperinsulinemic clamp (M rate, glucose uptake rate) as monkeys progress from normal/lean (phase 1) to obese with increasing
insulin resistance (phases 36), to impaired glucose tolerance (phase 7), to overt type 2 diabetes mellitus (phase 8).
reduce markers of the metabolic syndrome and potentially mitigate the risk of cardiovascular disease
and diabetes.
VII
VIII
291
PPARa
a Receptor and Agonists
The PPARa receptor gene has been mapped to chromosome 22q12-q13.1, and its tissue distribution shows
increased expression in metabolically active tissues such
as heart, liver, kidney, and muscle. No single highanity natural ligand for the PPARa receptor has been
found, but this receptor may sense the ux of free fatty
acids in the tissues where it is expressed. Among the
known activators of this receptor are the brates.
Although compounds that activate these receptors in
rodents induce peroxisome proliferation and hepatomegaly in man following years of extensive use of the
brates, PPARa ligands are not believed to have these
292
Hansen
eects. Thus, there appear to be functional and physiological dierences that are species specic. In humans
and nonhuman primates, the PPARa ligands generally
function in lipid and fatty acid homeostasis. In addition
to pharmaceutical agents, these receptors are probably
activated by fatty acids and their metabolites. Monkeys share with humans 97% cDNA identity, and 99%
identity with the putative protein of the PPARa
receptor (81).
The brates were developed before the receptor was
known, based on their lipid-lowering properties, and
include such agents as fenobrate, clobrate, and bezabrate. Fenobrate, for example, is a dual activator of
both PPARa and PPARg, but has 10-fold higher
selectivity for PPARa, while bezabrate acts at all three
receptor types. Fenobrate has been shown to lower
triglycerides (50%), to lower LDL cholesterol (27%),
and to increase HDL cholesterol (35%). Apoproteins B100 and CIII were also lowered (70% and 29%, respectively). Elevated plasma insulin levels were reduced by
40% in monkeys, supporting a role as an insulin sensitizer (81). Thus, this PPARa agent improved features of
the metabolic syndrome including reducing the insulin
resistance of obesity, but did not produce weight loss.
We have termed another PPARa activator, BM
17.0744, a calorie restriction mimetic agent as, in obese
insulin-resistant monkeys, it appears to exert many of
the positive features associated with-long-term calorie
restriction (see below). This agent is not in the brate
class [it is 2,2-dichlorophenyl dodecanoic acid, and its
general features have been described (82)]; however, it
seems to carry signicant PPARa activity, acting as
both an antidyslipidemic and antidiabetic agent. In
overweight insulin-resistant male rhesus monkeys, body
weight was signicantly reduced in a dose-related manner across six of six subjects, an eect not observed with
other PPARa agents. Hyperinsulinemia declined,
although it was not normalized, and insulin sensitivity
was greatly improved. Triglycerides were substantially
reduced, particularly the VLDL triglycerides. While
total cholesterol and LDL cholesterol were not signicantly aected, HDL cholesterol was nearly doubled,
suggesting improvement in the lipid prole of these
monkeys (83).
PPARg
g Receptor and Agonists
PPARyy
293
IX
GALECTIN-12
294
Hansen
XI
Other specic candidate genes, including adiposespecic genes (101), are being identied and studied in
nonhuman primates (102), and their ongoing study in
spontaneously obese primates should oer insights into
their roles in obesity.
In addition, the development of new antiobesity
compounds directed toward new target genes or their
receptors suggests further possibilities for the mitigation
of obesity. The GLP-1 receptor is one such target, with
at least two new long-acting agents having been examined in monkeys (103,104). We had previously shown
the ability of GLP-1 to raise insulin levels; however,
GLP-1 itself is too short-acting to be considered an
attractive therapeutic agent (79).
Figure 5 Expression of Galectin-12 in the subcutaneous and omental adipose tissue of four groups of rhesus monkeys: lean,
obese, type 2 diabetic, and long-time calorie restricted. (From Ref. 100.)
XII
PREVENTION OF OBESITY IN
NONHUMAN PRIMATES HAVING
A HIGH PROPENSITY TO
DEVELOP OBESITY
REFERENCES
1.
2.
3.
295
G, eds. Regulation of Body Weight: Biological and
Behavioral Mechanisms. Chichester: John Wiley &
Sons, 1996:4560.
4. Hansen BC. Obesity and diabetes in monkeys. In:
Bjorntorp P, Brodo BN, eds. Obesity. New York:
J.B. Lippincott, 1992:256265.
5. Kemnitz JW, Goy RW, Flitsch TJ, Lohmiller JJ,
Robinson JA. Obesity in male and female rhesus
monkeys: fat distribution, glucoregulation, and serum
androgen levels. J Clin Endocrinol Metab 1989; 69:
287293.
6. Hamilton CL, Kuo PT, Feng L. The eects of high
carbohydrate diets on hyperinsulinemic monkeys
(Macaca mulatta). J Med Primatol 1974; 3:276284.
7. Hansen BC. Induction of obesity in nonhuman
primate models of human obesity. In: Hayes KC, ed.
Primates in Nutritional Research. New York: Academic Press, 1979:291314.
8. Jen K-LC, Hansen BC. Feeding behavior during
experimentally induced obesity in monkeys. Physiol
Behav 1984; 33:863869.
9. Walike BC, Goodner CJ, Koerker DJ. Assessment
of obesity in pigtailed monkeys (Macaca nemestrina).
J Med Primatol 1977; 6:151162.
10. Wilson ME, Gordon TP, Blank MS, Collins DC.
Timing of sexual maturity in female rhesus monkeys
(Macaca mulatta) housed outdoors. J Reprod Fertil
1984; 70:625633.
11. Wolfe L. Age and sexual behavior of Japanese macaques (Macaca fuscata). Arch Sex Behav 1978; 7:55
68.
12. Howard CF, Kessler MJ, Schwartz S. Carbohydrate
impairment and insulin secretory abnormalities among
Macaca mulatta from Cayo Santiago. J Med Primatol
1986; 11:147146.
13. Schwartz SM, Kemnitz JW. Age- and gender-related
changes in body size, adiposity, and endocrine and
metabolic parameters in free-ranging rhesus macaques. Am J Phys Anthropol 1992; 89:109121.
14. Kemnitz JW, Sladky KK, Flitsch TJ, Pomerantz SM,
Goy RW. Androgenic inuences on body size and
composition of adult rhesus monkeys. Am J Physiol
1988; 255:E857864.
15. DeLany JP, Hansen BC, Bodkin NL, Hannah J, Bray
GA. Long-term calorie restriction reduces energy
expenditure in aging monkeys. J Gerontol A Biol Sci
Med Sci 1999; 54:B5B11.
16. Kemnitz J, Francken G. Characteristics of spontaneous obesity in male rhesus monkeys. Physiol Behav
1986; 38:477483.
17. Ramsey JJ, Colman RJ, Swick AG, Kemnitz J. Energy
expenditure, body composition, and glucose metabolism in lean and obese rhesus monkeys treated with
ephedrine and caeine. Am J Clin Nutr 1998; 68:42
51.
18. Jen K-LC, Bodkin N, Metzger BL, Hansen BC.
296
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Hansen
Nutrient composition: eects on appetite in monkeys
with oral factors held constant. Physiol Behav 1985;
34:655659.
Gray DS, Sharma RC, Chin HP, Jiao Q, Kramsch
DM. Body fat and fat distribution by anthropometry and the response to high-fat cholesterolcontaining diet in monkeys. Exp Mol Pathol 1993;
58:5360.
Hansen BC. Primate animal models of non-insulin
dependent diabetes mellitus. In: LeRoith D, Taylor SI,
Olesfky JM, eds. Diabetes Mellitus: A Fundamental
and Clinical Text. Philadelphia: Lippincott-Raven,
1996:595603.
Jen K-LC, Hansen BC, Metzger BL. Adiposity,
anthropometric measures, and plasma insulin levels
of rhesus monkeys. Int J Obes 1985; 9:213224.
Laber-Laird K, Shively CA, Karstaedt N, Bullock
BC. Assessment of abdominal fat deposition in female cynomolgus monkeys. Int J Obes 1991; 15:213
220.
Sharma RC, Kramsch DM, Lee PL, Colletti P, Jiao Q.
Quantitation and localization of regional body fat
distribution-a comparison between magnetic resonance imaging and somatometry. Obes Res 1996;
4:167178.
Narita H, Ohkubo F, Yoshida T, Cho F, Yoshikawa
Y. Measuring bone mineral content and soft tissue
mass in living the cynomolgus monkey. Jikken
Dobutsu (Exp Anim) 1994; 43:261265.
Metzger BL, Hansen BC, Speegle LM, Jen K-LC.
Characterization of glucose intolerance in obese
monkeys. J Obes Weight Regul 1985; 4:153167.
Wagner JD, Cline JM, Shadoan MK, Bullock BC,
Rankin SE, Cefalu WT. Naturally occurring and
experimental diabetes in cynomolgus monkeys: a
comparison of carbohydrate and lipid metabolism
and islet pathology. Toxicol Pathol 2001; 29:142148.
OBrien TD, Wagner JD, Litwak KN, Carlson CS,
Cefalu WT, Jordan K, Johnson KH, Butler PC. Islet
amyloid and islet amyloid polypeptide in cynomolgus
macaques (Macaca fascicularis): an animal model of
human non-insulin-dependent diabetes mellitus. Vet
Pathol 1996; 33:479485.
Wagner JD, Carlson CS, OBrien TD, Anthony MS,
Bullock BC, Cefalu WT. Diabetes mellitus and islet
amyloidosis in cynomolgus monkeys. Lab Anim Sci
1996; 46:3641.
Cefalu WT, Wagner JD, Bell-Farrow AD. Role of
glycated proteins in detecting and monitoring diabetes
in cynomolgus monkeys. Am Assoc Lab Anim Sci
1993; 43:7377.
Hansen BC, Bodkin NL. h-Cell hyperresponsiveness:
earliest event in development of diabetes in monkeys.
Am J Physiol 1990; 259:R612R617.
deKoning EJP, Bodkin NL, Hansen BC, Clark A.
Diabetes mellitus in Macaca mulatta monkeys is
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
44a.
45.
46.
297
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
298
72.
73.
74.
75.
76.
77.
78.
79.
80.
Hansen
Funahashi T, Matsuzawa Y. Genomic structure and
mutations in adipose-specic gene, adiponectin. Int J
Obes Relat Metab Disord 2000; 24:861868.
Yokota T, Oritani K, Takahashi I, Ishikawa J,
Matsuyama A, Ouchi N, Kihara S, Funahashi T,
Tenner AJ, Tomiyama Y, Matsuzawa Y. Adiponectin,
a new member of the family of soluble defense
collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 2000; 96:17231732.
Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama
A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K,
Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y,
Yamashita S, Funahashi T, Matsuzawa Y. Adipocytederived plasma protein, adiponectin, suppresses lipid
accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001; 103:10571063.
Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK,
Arita Y, Hansen BC, Matsuzawa Y. Circulating
concentrations of the adipocyte protein adiponectin
are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in
rhesus monkeys. Diabetes 2001; 50:11261133.
Zoccali C, Mallamaci F, Tripepi G, Benedetto FA,
Cutrupi S, Parlongo S, Malatino LS, Bonanno G,
Seminara G, Rapisarda F, Fatuzzo P, Buemi M,
Nicocia G, Tanaka S, Ouchi N, Kihara S, Funahashi
T, Matsuzawa Y. Adiponectin, metabolic risk factors,
and cardiovascular events among patients with endstage renal disease. J Am Soc Nephrol 2002; 13:134
141.
Hotta K, Funahashi T, Arita Y, Takahashi M,
Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H,
Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N,
Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y,
Nakamura T, Yamashita S, Hanafusa T, Matsuzawa
Y. Plasma concentrations of a novel, adipose-specic
protein, adiponectin, in type 2 diabetic patients.
Arterioscler Thromb Vasc Biol 2000; 20:15951599.
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes; close association
with insulin resistance and hyperinsulinemia. J Clin
Endocrinol Metab 2001; 86:19301935.
Walston J, Lowe A, Silver K, Yang Y, Bodkin NL,
Hansen BC, Shuldiner AR. The h3-adrenergic receptor in the obesity and diabetes prone rhesus monkey is
very similar to human and contains arginine at codon
64. Gene 1997; 188:207213.
Hansen BC. Primates in the experimental pharmacology of obesity. In: Lockwood D, Hener TG, eds.
Handbook of Experimental Pharmacology: Obesity
Pathology and Therapy. Heidelberg: Springer-Verlag,
2000:416489.
Oliver WR Jr, Shenk JL, Snaith MR, Russell CS,
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
Horikoshi H, Hansen BC. A thiazolidinedione improves in vivo insulin action on skeletal muscle
glycogen synthase in insulin-resistant monkeys. Int J
Exp Diabetes Res 2000; 1:195202.
Hansen BC, Bodkin NL, Shashkin PN, Smith SA,
Ortmeyer HK. Rosiglitazone alters insulin secretion,
glycogen metabolism and triglycerides in prediabetic
monkeys. Diabetes Res 2000; 50:S391.
Hansen BC, Oliver WR. The PPARg agonist,
GI262570, improves the prediabetic features of the
metabolic syndrome X in insulin resistance primates.
Diabetologia 2000; 43:269.
Willson TM, Brown PJ, Sternbach DD, Henke BR.
The PPARs: from orphan receptors to drug discovery.
J Med Chem 2000; 43:527550.
Naithani VK, Steens GJ, Tager HS. Isolation and
amino-acid sequence determination of monkey insulin
and proinsulin. Hoppe-Seylers Z Physiol Chem 1984;
365:571575.
Huang Z, Bodkin NL, Ortmeyer HK, Hansen BC,
Shuldiner AR. Hyperinsulinemia is associated with
altered insulin receptor mRNA splicing in muscle
of the spontaneously obese diabetic rhesus monkey.
J Clin Invest 1994; 94:12891296.
Fan Z, Kole H, Bernier M, Huang Z, Accilli D, et al.
Molecular mechanism of insulin resistance in the
spontaneously obese and diabetic rhesus monkey: site
directed mutagenesis of the insulin receptor. Endocrinology 1995; 77:180.
Barondes SH, Castronovo V, Cooper DN, Cummings
RD, Drickamer K, Feizi T, Gitt MA, Hirabayashi J,
Hughes C, Kasai K. Galectins: a family of animal betagalactoside-binding lectins. Cell 1994; 76:597598.
Hadari YR, Arbel-Goren R, Levy Y, Amsterdam A,
Alon R, Zakut R, Zick Y. Galectin-8 binding to
integrins inhibits cell adhesion and induces apoptosis.
J Cell Sci 2000; 113(pt 13):23852397.
Hotta K, Funahashi T, Matsukawa Y, Takahashi M,
Nishizawa H, Kishida K, Matsuda M, Kuriyama H,
299
101.
102.
103.
104.
105.
106.
107.
108.
13
Behavioral Neuroscience and Obesity
Sarah F. Leibowitz
The Rockefeller University, New York, New York, U.S.A.
Bartley G. Hoebel
Princeton University, Princeton, New Jersey, U.S.A.
INTRODUCTION
Hormones
302
Table 1 Abbreviations of Hormones and Neurochemicals
Reviewed in This Chapter
Hormones involved in eating and body weight regulation
ACTH, adrenocorticotropic hormone
CORT, corticosterone
E2, estradiol
GH, growth hormone
Glucose
HPA, hypothalamo-pituitary-adrenal
Insulin
Leptin
Lipids
P, progesterone
Peptides that increase eating and body weight
AGRP, agouti-related protein
Amandamide
Beacon
DYN, dynorphin
GAL, galanin
GALP, galaninlike peptide
Ghrelin
GHRH, growth hormonereleasing hormone
GHRP, growth hormonereleasing peptide
GnRH, gonadotrophin-releasing hormone
MCH, melanin-concentrating hormone
NPY, nueropeptide Y
Opioid peptides
ORX, orexin
PRL, prolactin
PYY, peptide YY
VGF (nonacronym)
Peptides that reduce eating and body weight
a-MSH, alpha-melanocyte-stimulating hormone
aFGF, acidic broblast growth factor
Amylin
apo A-1V, apolipoprotein A-IV
apo D, apolipoprotein D
AVP, arginine vasopressin
BBS, bombesin
Calcitonin
CART, cocaine- and amphetamine-regulated transcript
CCK, cholecystokinin
CGRP, calcitonin gene-related peptide
CNTF, ciliary neurotropic factor
CRH, corticotropin-releasing hormone
Cyclo(his-Pro)
Cytokines
ENT, enterostatin
GLP-1, glucagon-like peptide 1
Glucagon
IL, interleukin
Melanocortins
MSH, melanocyte-stimulating hormone
NMU, neuromedin U
NT, neurotensin
OT, oxytocin
POMC, pro-opiomelanocortin
PrRP, prolactin-releasing peptide
TNFa, tumor necrosis factor-alpha
TRH, thyrotropin-releasing hormone
Neurochemicals
303
are shown in Figure 1 as inhibiting a lateral hypothalamic feeding system that uses the feeding-stimulatory
peptides, orexin and DYN. Also listed in Figure 1 are
additional satiety peptides. The classic example is cholecystokinin (CCK), which inhibits feeding through its
actions in the gut as well as the brain. Recent research
links both the feeding and satiety peptide systems to the
powerful endocrine inuences mentioned above: insulin, leptin, CORT, and the gonadal steroids, E2 and P.
The interactions of these hormones with brain neurotransmitters and neuromodulators are critical in determining specic states of nutrient balance and weight
gain. This is illustrated in Figure 1, by insulin and
leptin inhibiting the production of the feeding-stimulatory peptides, NPY and AGRP, while stimulating the
feeding-inhibitory peptides, a-MSH and CART. These
and other neuropeptide systems are reviewed in detail
304
systems as a function of states of sleep, arousal, selective attention, and stress. This is followed by Section
VI, which reviews evidence supporting two dierent
roles for acetylcholine (ACh) in the reinforcement of
feeding (Fig. 2). Specically, the release of ACh is
necessary to arouse a DA motivation system in the
midbrain, whereas ACh interneurons inhibit eating by
counteracting DA when it is released in the forebrain.
The amino acid neurotransmitters, glutamate and
gamma-amino butyric acid (GABA) also have interest-
Figure 2 Schematic side view of the brain with emphasis on the hypothalamic area (in the expanded cross section) and the two
neural circuits (shown with bold arrows). The expanded view of the hypothalamus indicates some of the local feeding and satiety
neurons and their inputs (see Fig. 1). The hypothalamus is part of a much larger feeding circuit. Starting in the lower right corner,
signals from the tongue and gut enter the brainstem. The hypothalamus also senses chemical information and sends it to the
brainstem. The NTS output goes to the PBN and from there, via the thalamus, projects to the areas labeled, sensory cortex,
amygdala, and hippocampus. Here chemosensory information is combined with other sense modalities, such as sights, sounds,
locations, and codes for safe nutrition vs. toxic foods. The arrows from the hippocampus (place memory), amygdala (emotion
memory), and prefrontal cortex (complex choice memory) sweep into the nucleus accumbens (NAc) and hypothalamus on
GLUT neurons (input to NAc is shown). The NAc is a sensorimotor interface in the cognitive/limbic loop drawn in bold lines
from PFC to NAc then GP and back to the PFC via the thalamus, with commands branching o to motor output circuits. The
ACh interneurons in the NAc may act as gates that counteract DA input from the VTA. Other monoamines and opioid peptides
that act in this circuit are discussed in the text (Secs. VVII). The medial and lateral hypothalamus help control the NAc via the
pathways shown descending from the hypothalamus to the brainstem, including an ORX/DYN output for feeding and a CRH
pathway for satiation. The circuit ascends via cholinergic cell groups 5 and 6, to the VTA where DA cells project to the NAc and
to the rest of the limbic system. The NAc projects back to the hypothalamus. By this route, feeding and satiety signals generated
in the hypothalamus can inuence DA/ACh balance in the NAc to reinforce or inhibit instrumental behavior and motivation.
Brain Areas
305
306
II
Insulin
Leptin
long-form receptor isoform, which contains intracellular motifs required for activation of the JAK-STAT
signal transduction pathway (see Table 1). Whereas a
primary defect in leptin expression may lead to human
disease, as shown in studies of consanguineous kindreds
with extreme obesity, mutations of the genes that produce leptin or its receptor are rare in humans (22,24).
Leptin expression is inuenced by the status of
energy stores in body fat, with adipocyte size an important determinant of leptin synthesis (25). Whereas leptin
levels in blood correlate strongly with total body fat
stores, it is unknown whether leptin expression is inuence by triglyceride levels, lipid metabolites, or mechanical factors associated with increased adipocyte size
(22,23). Since changes in leptin expression after fasting
and feeding do not necessarily correspond with changes
in body fat, leptin may serve as a mediator of energy
balance, as well as an indicator of energy stores. Regulation of leptin expression by nutrition may be mediated, in part, by insulin, which is positively related to
leptin levels, and also to glucocorticoids, which are
negatively related (22,23,26). Cytokines also stimulate
the synthesis of leptin, which may contribute to the
anorexia and weight loss in response to inammation.
Anatomical and functional studies suggest that
leptin exerts its eects on energy balance primarily
by acting in the brain. This protein is secreted into the
circulation and enters the brain through a saturable
transport mechanism (9,22,27,28). Peripheral leptin
injection activates neurons in hypothalamic feedingregulatory areas that have dense concentrations of
leptin receptors. Peripheral as well as central injection
of leptin reduces food intake, insulin secretion and
adiposity (28), with centrally administered leptin producing more potent eects. Leptin also increases
energy expenditure and normalizes blood glucose
concentrations in obese mice (29). Hyperleptinemia,
produced in normal-weight rats through adenovirus
gene transfer of the ob gene, causes loss of virtually all
body fat, an eect that is absent in rats with MH
lesions (30).
Leptin-sensitive neurons in the hypothalamic nuclei
express neuropeptides and neurotransmitters that are
implicated in the central regulation of energy balance
and, thus, may mediate leptins actions (1,22,31). The
long-form leptin receptor in the ARC is coexpressed
with peptides that stimulate feeding, as well as with
those that inhibit feeding. In general, the expression
or synthesis of neurochemicals that potentiate feeding
behavior is inhibited by leptin injection and elevated
in leptin-decient or food-deprived rodents. Diametrically opposite changes, in contrast, are seen with
307
neurochemicals that suppress food intake. By modulating these peptides in the ARC, leptin may also
inuence feeding by controlling the expression of
orexigenic peptides in other hypothalamic sites, such
as the PVN and LH, which are possibly controlled by
projections from the ARC. To understand the physiological signicance of these ndings obtained with
leptin injections or gene mutations, further studies
of this hormone performed under natural feeding
conditions are needed. A fall in leptin levels during
fasting, accompanied by a rise in feeding-stimulatory
peptides, has been suggested to signal starvation (1).
However, a reevaluation of leptins physiological
functions and its relationship to specic peptides has
been encouraged by specic evidence, for example,
that leptin corrects the neuroendocrine abnormalities
of ob/ob mice at considerably lower doses than those
required to reverse the overeating and obesity (32).
Moreover, its eects in intact mice may not be altered
by targeted mutations of the feeding-regulatory peptide gene (33).
The evidence that leptin injection produces feeding
suppression and weight loss restricted to adipose tissue,
while increasing energy expenditure and lipid oxidation
(22,3436), supports a role for this hormone as an
antiobesity hormone. However, this is inconsistent with
the nding that circulating leptin concentrations rise in
direct proportion to the amount of adipose tissue (31).
This rise in leptin with obesity has been interpreted as an
indication of leptin resistance (22), possibly resulting
from a dysregulation of leptin synthesis and secretion or
from abnormalities of brain leptin transport, leptin
receptors, and/or postreceptor signaling. Potential molecular mediators of leptin resistance may include
SOCS-3, a member of the suppressors of cytokine signaling family, as well as SH2-containing tyrosine phosphatase, SHP-2, and molecules downstream from the
initial step of receptor interaction (see Table 1 for
abbreviations). Evolutionarily, it is extremely important to be ecient in the storage of energy when food is
available.
Thus, the common occurrence of leptin-resistant
obesity suggests that the predominant function of this
hormone in energy balance is not to reduce body fat but
is to mediate physiological processes of adaptation
during fasting and promotion of energy conservation
(22,37). Starvation triggers complex neural, metabolic,
hormonal, and behavioral adaptations to maintain
energy substrates, protect lean mass, and promote
survival. This is accomplished by switching from a
carbohydrate- to fat-based metabolism, mediated by a
decline in insulin and rise in counterregulatory hor-
308
Studies of the natural light/dark cycle in normalweight animals have led to the proposal that distinct
functions are performed by the dierent steroid receptors (42). The type I receptor is activated under conditions of low levels of circulating CORT (0.52.0 Ag/
dL), and it functions tonically throughout the daily
cycle to sustain feeding, particularly fat intake, and
enhance fat deposition. Fat intake occurs at a fairly
constant level across the feeding cycle in almost every
meal, although it rises toward the second half of the
active phase. This stable behavioral pattern provides a
continuous supply of a high-caloric nutrient, which can
be readily stored in the gastrointestinal tract or adipose
tissue for short- or long-term use, respectively. This
tonic control of fat intake, possibly mediated through
hypothalamic type I receptors, may be analogous to
their function in the basal forebrain for maintaining
salt balance (47) and in lower brainstem for monitoring
blood pressure (48).
The type II receptor, in contrast, is activated under
conditions of somewhat higher or moderate levels of
CORT. This receptor may function phasically during
the early hours of the active cycle when CORT normally rises to levels of 310 Ag/dL, and it also comes
into play also during periods of stress when even higher
levels are achieved (42). A primary function of the type
II receptor at the onset of the feeding cycle is to
replenish and defend the bodys carbohydrate stores
through both ingestion and storage. This immediate
defense is required to prevent the hypoglycemia that
may develop after periods of little eating and continued
utilization of carbohydrate stores. This defense provides adequate supplies to the brain to stabilize neuronal processes (49,50). The phasic, anabolic eect of
moderate levels of CORT may be contrasted with the
type II receptor actions of high CORT levels, such as
after severe stress or starvation. In addition to stimulating nutrient ingestion, unusually high CORT concentrations actually have catabolic actions on the
bodys fat and protein stores to provide additional
substrates for maintaining normal carbohydrate balance. Under stable conditions, however, the type II
receptor subtype is very likely inactive at times of the
circadian cycle or in physiological states when glycogen
stores are plentiful, cellular glucose uptake is normal,
and circulating CORT levels are low.
Receptors mediating these actions of the adrenal steroids across the circadian cycle are located in the brain
(42). As described below, they are particularly responsive in the hypothalamic PVN, which plays a primary
role in controlling CORT release as well as nutrient
balance. Neurons in the ARC are similarly responsive to
CORT. In maintaining carbohydrate stores, the type II
receptors act in part through central neurochemical
systems that synthesize NPY in the ARC and NE in
the brainstem. Circulating CORT enhances gene
expression, transport, and receptor activity, ultimately
potentiating the action of NPY and NE released in the
medial PVN, and it very likely determines the circadian
rhythm of endogenous NPY and noradrenergic activity
detected in the hypothalamus. Natural rhythms of
circulating steroids and their receptor subtypes are
critical in maintaining normal control of physiological
processes (53,54). These rhythms allow for necessary
shifts in phases of priming, activation and rest. Without
these rhythms, a chronic state of activation, which
constitutes a stress to the organism, will eventually
result in pathology. In the control of nutrient balance,
the dual-control receptor systems involving type I and
type II receptors provide a mechanism that responds to
shifts in circulating CORT and assists in coordinating
metabolic processes appropriate for specic circadian
309
310
Glucose
ATP-sensitive K+ channel (74). The mechanisms underlying the response of glucose-sensitive neurons,
which are more concentrated in the LH, remain to
be characterized (75).
Both obesity and diabetes are associated with alterations in brain glucose sensing (76). Rats with dietinduced obesity, hyperinsulinemia, or insulin-dependent diabetes have abnormalities in glucose-responsive
neurons. These include disturbances in neurotransmitter systems, specic peptides, monoamines, and amino
acids that are involved in glucose sensing. A functional
relationship between circulating glucose and central
neurochemical systems is suggested by the nding that
glucose-responsive neurons in the ARC are hyperpolarized by the actions of both leptin and insulin on the
K-ATP channel (76). Further, the expression and
production of brain peptides, such as NPY in the
ARC, or ligand binding to specic a2-noradrenergic
receptors in the PVN, for example, are stimulated by
the injection or ingestion of glucose (77,78), suggesting
the involvement of glucose-responsive neurons.
F
Lipids
311
III
Neuropeptide Y
312
receptors of the Y1 and Y5 subtype that are concentrated in these areas (31,91).
The eects produced by hypothalamic NPY injections support the proposed role of this peptide in
maintaining carbohydrate balance. These actions of
exogenous NPY, summarized in greater detail in various reviews (69,89,90,92), include a stimulatory eect
on feeding behavior, with a preferential eect on carbohydrate intake. The endocrine eects of NPY (56,93,94)
involve enhanced release of CORT, which favors the
availability and utilization of glucose, and increased
pancreatic secretion of insulin, which functions together
with CORT to promote lipogenesis (95). These behavioral and endocrine eects of NPY are accompanied by
metabolic changes eecting enhanced parasympathetic
nervous system activity and reduced sympathetic activity (93,96). The eects include a reduction in energy
expenditure and thermogenesis, decreased glucose
uptake in muscle, and a diversion of excess energy and
glucose towards fat synthesis in white adipose tissue.
Pharmacological and anatomical studies (31,91) suggest that these eects of NPY, involving the neurocircuit from the ARC to the PVN, may be mediated, in
part, through connections with other neural systems
involved in energy homeostasis (Fig. 1). These include
reciprocal connections with systems that inhibit feeding, such as CRH in the PVN, melanocortin neurons in
the ARC, and 5HT in the midbrain. They also involve
peptides that stimulate feeding, including MCH and
orexin in the PFLH. The demonstration that NPY
neurons in the ARC also express the peptide AGRP,
an endogenous antagonist of the feeding-inhibitory
melanocortin system, provides evidence for another
avenue of communication between NPY and other
neuropeptides modulating feeding (91,9799).
Endogenous NPY has a role in mediating natural
feeding. With acute administration, injections of NPY
antisera, receptor antagonists, and antisense oligodeoxynucleotides to NPY mRNA invariably reduce
food intake (100102). Moreover, with repeated injections, NPY produces overeating, obesity, and related
endocrine and metabolic disturbances (56,87). Antisense oligodeoxynucleotides to NPY mRNA reduce
endogenous NPY levels in the ARC and suppress
body weight gain (102). In light of these ndings, it
was surprising that NPY knockout mice and NPY
overexpressing mice showed little change in eating or
body weight (33,88). The ability of NPY-decient
mice to maintain normal eating patterns may be
attributed, in part, to a compensatory increase in the
production of other peptides, such as AGRP and
GAL, which also enhance food intake and weight
gain (103). There is evidence, however, that a knockout of the NPY gene can reduce weight gain in mice
that have a mutation of the leptin gene or diabetes,
indicating a role for endogenous NPY in mediating
some eects of leptin or insulin deciency (104).
Moreover, a recent genetic study demonstrates that,
in homozygous mice, NPY overexpression in the brain
leads to an obese phenotype on a sucrose-loaded diet,
accompanied by overeating, hyperglycemia, and
hyperinsulinemia (105).
A variety of endocrine signals feed back to regulate
NPY synthesis in the ARC-PVN neural projection. This
is reected in measures of gene expression or translation, in addition to peptide synthesis, transport,
release, and receptor activity. In these hypothalamic
areas, the adrenal steroid CORT acts through glucocorticoid type II receptors to stimulate NPY gene
expression, synthesis, and receptor activity (42,106
109). Moreover, the behavioral action of NPY is similarly enhanced by CORT, while antagonized by a
glucocorticoid receptor blocker. These eects of CORT
on NPY may be direct as well as indirect via the CRH
system (109). This suggests that NPY helps to integrate
the activities of the hypothalamic feeding systems and
the HPA axis, which are important for the circadian
rhythmicity of physiological processes (109). A dierent
pattern becomes evident with the gonadal steroids, E2
and P. Administration of E2 inhibits NPY gene expression in the ARC and its release in the PVN, and E2
deciency increases NPY in the PVN. This suggests a
role for this peptide in the anorexic action of E2 (31). In
contrast, administration of P has a stimulatory eect on
NPY in E2-primed animals (60,110112). This evidence
obtained with P, similar to CORT, suggests that both
steroids promote weight gain and body fat accrual
through their stimulatory eect on NPY in the ARC
(108,113).
In contrast to these steroids are the hormones insulin
and leptin, which are released in relation to the amount
of body fat. These hormones have a potent, inhibitory
eect on NPY gene expression in the ARC, NPY
peptide levels in the PVN, and feeding induced by
NPY injection (1,114). These suppressive eects may
explain the enhanced expression of NPY after food
deprivation, which reduces levels of insulin and leptin
and, conversely, the satiety-producing eects seen with
injections of these hormones (11). Further support for
this close relationship between NPY neurons and the
circulating hormones is obtained from the ndings that
leptin and insulin receptors are densely expressed in the
ARC. A subpopulation of NPY neurons coexpresses
the leptin receptor. The expression of NPY in these
neurons is invariably elevated in rats decient in insulin, leptin, or the leptin receptor (31,91,97).
Studies of physiological or pathological states reveal
associations between dietary macronutrients, circulating hormones, metabolic processes, and hypothalamic
NPY (10,115118). For example, the relationships
among carbohydrate intake, circulating CORT levels,
lipogenic processes, and NPY levels are evident in adult
rats given a choice of macronutrient diets. They exhibit
strong, positive correlations among NPY, CORT levels,
and spontaneous intake of carbohydrate, as opposed to
fat or protein (42,51,108,119,120). These relationships
are seen at the start of the active feeding period.
Carbohydrate is the preferred dietary nutrient at this
time, when CORT levels and NPY gene expression
naturally peak, and both gluconeogenesis and glycogenolysis are elevated to support the utilization of carbohydrate. Dietary and pharmacological manipulations
also reveal enhanced NPY expression and CORT under
conditions of diet-induced insulin resistance or after
2-deoxy-D-glucose blockade of glucose utilization
(121123). In fact, in weanling animals, both the
NPY system and the HPA axis reach peak development at an age when carbohydrate accounts by choice
for >65% of the animals diet and lipogenesis is
elevated (70,71,124,125).
Similar to CORT, a possible stimulatory eect of P
on NPY is evident across the 4-day female cycle.
Proestrus reveals peak levels of NPY in the MPO, as
well as the ARC and PVN. This occurs with a rise in
circulating levels of P, subsequent to E2 priming, and
an increase in lipogenesis (112,126,127). The inhibitory
relationship between NPY and both leptin and insulin
is clearly evident in studies of obesity-prone rats (128
130). In a preobese state, when leptin and insulin levels
are relatively low, NPY mRNA is elevated in the
obesity-prone subjects, sugesting a role for this peptide
in the early stages of weight gain. This is in contrast to
a reduction in NPY detected in the postobese state,
when leptin and insulin levels rise signicantly with
body fat accrual in the obesity-prone subjects. A
strong, inverse relationship between NPY and circulating leptin or insulin is underscored by the ndings
that NPY is reduced in a variety of obese states, such
as those produced by a high-fat or high-energy diet,
VMH lesions, neurotoxins, or a mutation of the tubby
gene (131134). These ndings lead one to question the
function of NPY in the maintenance of obesity and
contrast with those obtained for other feeding-stimulatory peptides, such as GAL and the endorphins.
These latter peptides are elevated in dierent states
of obesity and are less responsive or even stimulated
313
314
Agouti-Related Protein
Agouti-related protein (AGRP) is a naturally occurring antagonist that binds to a receptor to prevent its
response to another molecule (178). This protein
inhibits the activity of melanocortins, small peptides
derived from a large precursor, pro-opiomelanocortin
(POMC), which also gives rise to h-endorphin. As
described in Section IV, the melanocortins have an
inhibitory eect on feeding and body weight, and
AGRP, while having little intrinsic signaling activity,
binds directly to melanocortin receptors primarily to
inhibit melanocortin binding.
A variety of evidence suggests a close relationship
between AGRP and the NPY neurocircuit. AGRP
colocalizes almost 100% with NPY in neurons of the
ARC (98,179). As with NPY, AGRP is a very potent
stimulant of feeding behavior, and it promotes body fat
accrual. In fact, this peptide is even more potent than
NPY over the long term, because its actions outlast the
drug itself and increase eating for days (180). The
endocrine prole for AGRP is similar to that for
NPY, including an increase in insulin levels (181,182).
There is evidence that AGRP and NPY send similar
types of signals that reinforce one another, possibly
through the inhibition of a Gs-coupled receptor by
AGRP and the activation of Gi-coupled receptor by
NPY (183). The possibility that these two peptides
represent redundant components of a parallel circuit
may help to explain why NPY-decient animals show
only minor defects in eating behavior and leptin signaling (33). However, some dierences between the AGRP
and NPY neurocircuits appear to exist. The stimulatory
eect of AGRP on food intake is longer-lasting than,
and additive with, that of NPY, and it is accompanied
by a somewhat dierent pattern of c-Fos immunoreactivity in extrahypothalamic areas (184,185).
That the endogenous peptides function in a similar
manner is supported by evidence revealing similar
changes in endogenous AGRP and NPY expression
under physiological conditions (186,187). For example,
both peptides in the ARC are stimulated by conditions
of negative energy balance and reduced leptin levels.
This is evident in leptin-decient or streptozotocininduced diabetic mice, after food deprivation or on a
carbohydrate-rich diet, and in response to glucopenia
induced by 2-deoxy-D-glucose (122,181,188,189). Further, these peptides are both suppressed under conditions of positive energy balance or enhanced leptin
levels. This is evident in obese or leptin-injected rodents
(187,188), in adrenalectomized rats with reduced glucocorticosteroid levels (190,191), or after insulin injection
in streptozotocin-induced diabetes (189). As described
in sections below, these patterns observed with endogenous NPY and AGRP expression are opposite to those
seen with measurements of POMC and a-MSH. This
supports the idea that the NPY/AGRP and melanocortin systems interact antagonistically in the control of
eating and body weight.
D Orexins
The orexins are a recently identied class of neuropeptides, also described as hypocretins (192,193). Orexin A
and orexin B, sharing 46% identity, are coded by the
same gene, and are localized in neurons of the PFLH.
Administration of orexin A stimulates feeding behavior
more eectively than orexin B, possibly through activation of orexin-1 and orexin-2 receptors (192). This
eect, localized to the PFLH and PVN (31), is considerably smaller and of shorter duration than that pro-
315
duced by NPY or AGRP. In addition to this feedingstimulatory eect, orexin A injection increases energy
metabolism and vagal nervedependent gastric acid
acid secretion (194,195). The importance of the orexins
in feeding behavior is suggested by evidence from
genetic studies, revealing an increase in food intake in
orexin-overexpressing mice and a decrease in orexindecient mice (196).
Neuroanatomical studies demonstrate reciprocal
synaptic contacts between orexin cells in the PFLH
and leptin-responsive neurons in the ARC that express
NPY, AGRP, POMC (197199). This suggests that
orexin may function as a downstream eector molecule of these peptide systems. Orexin-containing axons
also contact other orexin cells that express leptin
receptors, indicating possible autoregulation of orexin
function (199). These orexin-expressing neurons in the
PFLH lie adjacent to, but do not overlap, another cell
population, described below, that produces a dierent
feeding-stimulatory peptide, melanin-concentrating
hormone (197,198,200).
Despite their close anatomical relationship, it is clear
that the orexins in the PFLH function dierently from
other feeding-stimulatory systems in the ARC, suggesting that the regulatory mechanisms of these peptides
dier (201). Whereas the PFLH and ARC systems may
be upregulated by food deprivation (192,202,203), diametrically opposite results are obtained in genetically
obese mice, which show a decrease in hypothalamic
orexin mRNA (204,205) but an increase in NPY and
AGRP (204,205). Further, in contrast to the ARC
peptides that are inhibited by leptin and invariably
elevated when leptin is low (see above), functional
evidence for a direct interaction between leptin and
orexin neurons in the PFLH is lacking, despite the
presence of leptin receptors (199,201). Orexin mRNA
or peptide level is reduced both when leptin is decient
and when it is injected (204,206). Moreover, the orexins
remain stable in conditions or states with markedly
altered leptin levels, including overfeeding, dietary
obesity, or food restriction with leptin treatment (203,
205207).
Whereas leptin may not be a key regulator of the
orexins, there is evidence suggesting that the orexin
neurons are controlled by changes in circulating glucose
and may stimulate feeding specically under conditions
of hypoglycemia. Prepro-orexin mRNA in the PFLH is
elevated when plasma glucose falls and food is withheld
(203,208), and it is reduced by food ingestion (209),
suggesting a role in short-term feeding behavior. Some
neurons in the LH are known to be glucose sensitive,
that is, stimulated by a decline in glucose (75). These
316
Melanin-Concentrating Hormone
Opioid Peptides
Opioid Subsystems
317
The next question is whether the LH-PBN opioidrelated path is involved in self-stimulation and feeding
reinforcement, as well as in the prolongation of a meal.
In support of this proposal electrodes in the LH that
318
Amandamide
The endogenous cannabinoid, amandamide, can induce eating and may interact with opioid systems
(286). Tetrahydrocannabinol (THC) induces accumbens DA release that can be blocked by an opioid
antagonist in the VTA. Thus, marijuana reinforces
behavior, in part, by releasing DA via an opioid system.
This may also be the mechanism through which marijuana induces appetite for food (287). A cannabinoid
receptor antagonist reduces food intake in rats (288).
The same drug causes a small but signicant decrease in
body weight in people (289).
H
the active cycle (292294). This proposal receives support from experiments with antiserum raised against
GHRH, which suppresses spontaneous feeding. Injections of GHRH stimulate intake of protein, having
little impact on carbohydrate or fat intake. Moreover,
an antiserum against GHRH preferentially inhibits
protein consumption at the onset of the natural feeding
cycle. This may reect a role for endogenous GHRH, in
the MPO/SCN area, in stimulating both growth and
the ingestion of the nutrients important for growth.
There is evidence that growth hormonereleasing
peptides (GHRP), acting within the brain, mimic an
unidentied native GH-releasing hormone-amplifying
hormone. Systemic administration of GHRP-6 induces
c-Fos protein in the ARC (295). Further, intracerebroventricular administration of low doses of the GHRP,
KP-102, stimulates feeding in rats, while having no
eect after systemic administration, and it amplies
the feeding-stimulatory eect of GHRH through a
specic GHRP receptor, possibly in the hypothalamus
(296). There is also evidence that GHRH may interact
with other neurochemical systems in the brain to control
eating and body weight. For example, the GHRH
system is closely associated with, and may depend on,
the opioid system in the PVN. Opiate agonists stimulate
the ingestion of protein as well as fat, an eect blocked
by GHRH antiserum, and the action of GHRH is antagonized by PVN injections of opioid receptor antagonists (291,297). Also, GHRH-expressing neurons in
the ARC coexpress GAL, which stimulates feeding and
increases adiposity after chronic administration (see
above). Studies demonstrate that, in these ARC neurons, GAL expression is induced by GH and reduced in
the absence of GH, suggesting that the pattern of
GHRH and GH release may, in turn, be shaped by
GAL (172). In a recent study, double-labeling immunohistochemistry indicates that orexin-containing, but
not MCH-containing, neurons in the LH are activated
by central administration of GHRP-6 (298).
In obesity, GH secretion is impaired, secondary to
the rise in body fat and circulating lipids, and treatment
with GH decreases adiposity, reduces triglyceride accumulation, and enhances lipolysis (290,299). A role for
GH in body fat accumulation is conrmed by the
observation that mice overexpressing GH have
increased abdominal fat (300). They are larger and
exhibit hyperphagia and increased levels of insulin and
leptin, in association with reduced responsiveness of the
leptin receptor to fasting. Whereas the physiological
mechanisms underlying this obese state remain to be
dened, this mouse model points to the importance of
GHRH in the regulation of body composition.
319
Ghrelin
320
Beacon
VGF
Prolactin
IV
Many peptides have been discovered that have inhibitory eects on feeding and weight gain (Table 1). An
important question addressed in the investigation of
these substances is whether their behavioral or physiological eects are both specic and meaningful in the
overall control of energy balance. Discussed below are
most of the satiety peptides that have sucient evidence
to support their role in the control of feeding and
metabolism. In most cases, the peptides are synthesized
in the brain to act through local neurocircuits. In others,
these substances are synthesized in peripheral organs
and send signals to the brain via the circulation, vagus
nerve, or sympathetic aerents.
A
Melanocortins
321
322
Cytokines
Cytokines are protein molecules released by lymphocytes and/or monocyte macrophages during various
disease states, such as infection and cancer. Several
proinammatory cytokines, most notably tumor
necrosis factor-alpha (TNFa), interleukin (IL)-1, IL-6,
and ciliary neurotropic factor (CNTF), induce anorexia
and body weight loss (88,350,351). Evidence suggests
that the anorexia is mediated by central neural mechanisms, most notably in the hypothalamus where the
receptors for most cytokines are particularly dense
(352). Peripherally administered TNFa and IL-1B produce anorexia in rats at doses estimated to yield pathophysiological concentrations in the cerebrospinal uid
of animal models or patients with wasting disorders
(353). These peripheral cytokines are released into the
circulation and, through the blood brain barrier and
circumventricular organs, are transported into the
brain, where they exert their eects via the vagus nerve
or second messengers, such as nitric oxide and prostanoids in the brain vasculature. Cytokines are also
produced by neurons and glia within the brain, including the hypothalamus, in response to microbial and
inammatory products or peripheral cytokines.
Whereas the absence of TNFa does not prevent the
development of obesity, targeted mutation of the TNFa
gene or its type 1 and 2 receptor subtypes improves
insulin sensitivity, supporting a role for TNFa as a
mediator of insulin resistance in obesity-diabetes models (88,354). Furthermore, IL-1B and IL-6 mutant mice
resist anorexia, body weight loss, and fever caused by
inammatory-inducing agents, and IL-1 receptor
antagonistnull mice have reduced body weight (88).
The idea that circulating signals generated in proportion to body fat mass inuence appetite and energy
expenditure through central mechanisms has been
clearly demonstrated with the cloning of the leptin gene
(20) and the nding that leptin, which is positively
related to body fat mass, reduces food intake through
leptin receptors in the hypothalamus (22). Leptin is a
member of the IL-6 superfamily of proteins, with many
biochemical features of a cytokine molecule (20),
and the leptin receptor is most closely related to glycoprotein 130, a common signal transducer among receptors for members of the IL-6 superfamily (355,356).
Evidence suggests that leptin increases hypothalamic
production of cytokines (357) and activates cytokinelike
signal transduction pathways, by stimulating JAKSTAT via the leptin receptor (358360) (see Table 1
for abbreviations). Leptin also activates SOCS-3,
which reduces intracellular signaling by inhibiting
JAK activity, a potential mechanism underlying leptin
resistance (360). Thus, excessive leptin or leptinlike
signaling, resulting from increased inammatory cytokines in overlapping and redundant cytokine networks,
may contribute to the anorexia and weight loss in
wasting illnesses (361), although it is not essential to
this response (362).
In light of the inhibitory eect of leptin on NPY
expression in the ARC described above, it is not surprising to nd a similar relationship between circulating
cytokines and the NPY feeding system in the development of anorexia (361). Cytokines such as IL-1 and
CNTF antagonize NPY gene expression in the ARC
and reduce NPY-induced feeding as well as Y1 receptor
abundance (363,364). Whereas this eect may occur
indirectly via stimulation of leptin secretion (361), a
direct action is supported by the nding that a CNTF
derivative corrects the obesity and metabolic disorders
of mice decient in leptin or its receptor and also of dietinduced obesity models unresponsive to leptin (358).
Further evidence supporting the involvement of NPY in
cytokine eects is obtained in anorexic, tumor-bearing
rats, which show a reduction in NPY levels or release,
NPY-induced feeding, and NPY receptor anity in
association with anorexia and weight loss (353,365).
Whereas cytokine-induced anorexia may also
involve other neurochemicals, such as CRH, CCK,
and 5HT, that suppress feeding and modulate NPY
(88,361,366), there is compelling evidence supporting a
key role for the melanocortin system that provides a
bidirectional tuning necessary to maintain energy
stability under dierent conditions (367,368). This
includes the nding that anorexia and weight loss
induced by sarcoma growth are both reversed and
prevented by administration of AGRP, the endogenous
melanocortin antagonist. Further, both genetic and
pharmacologic blockade of central melanocortin receptor signaling prevents the complex cytokine response
and the weight loss that accompanies lipopolysaccharide injection. Whereas a close relationship is known to
exist between leptin and the melanocortin system, the
eects of melanocortin blockade occur independently
of this hormone.
323
324
Corticotropin-Releasing Hormone
325
Enterostatin
Neurotensin
326
Apolipoproteins
Apolipoprotein A-IV (apo A-IV) is a glycoprotein produced by the small intestine and released into the blood
in response to a lipid meal (433436). The increased synthesis of apo A-IV in response to fat absorption, rather
than related to the uptake or reesterication of fatty
acids to triglycerides, is induced by the formation of
chylomicrons. It may also be responsive to a factor from
the ileum, probably peptide tyrosine-tyrosine (PYY).
The evidence that other apolipoproteins in the intestine
are unresponsive to fat consumption indicates a specic
role for apo A-IV in relation to dietary fat. After
systemic or central administration, apo A-IV causes a
signicant, dose-dependent suppression of feeding.
Since the secretion of apo A-IV is rapid, this protein
Glucagon
327
Glucagon-like Peptide 1
328
glucose levels (460). In addition, acute onset of anorexia occurs in animals receiving transplantable glucagonoma tumor lines, which produce highly elevated
levels of proglucagon mRNA and plasma GLP-1 and
glucagon (461).
A possible role for GLP-1 in obesity is suggested by
evidence that chronic administration of GLP-1 reduces
feeding and body weight, and a GLP-1 antagonist
produces the opposite eect (409,456,462). Also, obese
subjects exhibit lower levels of GLP-l in response to a
meal (463). However, the involvement of this peptide
in normal body weight regulation is not substantiated
by genetic studies (454,464). Targeted disruption of
the GLP-1 receptor gene has little eect on feeding
and weight gain in mice, even after several months on
a high-fat diet, despite fasting hyperglycemia and
reduced insulin secretion. Moreover, a combined disruption of leptin and GLP-1 action produces mice of
comparable body weight to those with leptin deciency alone. Also, transgenic mice with sustained
elevations in circulating exendin-4, a potent GLP-1
agonist, eat normally.
An alternative possibility is that GLP-1 acts on
neurons involved in the stress response (454,465). Central administration of GLP-1 produces conditioned
taste aversion and has aversive side eects. It induces
similar patterns of neuronal c-fos activation to that
caused by lithium chloride, which can be blocked by a
GLP-1 receptor antagonist. Further, deletion of the
GLP-1 receptor gene results in an exaggerated CORT
response to restraint stress. The available evidence
indicates that dierent central pathways mediate
GLP-1 induced satiety and taste aversion (465). This
peptide is a likely candidate in mediating cancerinduced anorexia (88).
J
Cholecystokinin
food intake without nausea (478,479). As further evidence for CCK satiety, CCK antagonists can increase
food intake when given peripherally or locally in
regions, such as the PVN-MH (480).
Functioning as a paracrine hormone, CCK is
released from secretory cells and nerve bers in the
upper intestine, where it works locally to stimulate
pancreatic secretion and gallbladder contraction. The
peptide also inhibits gastric emptying by constricting
the pyloric sphincter (470). Receptors for CCK involved in feeding suppression exist, for example, in
the pyloric sphincter, the sensory vagus nerve where
they are transported to vagal nerve terminals, and the
PBN and PVN. These sites may all be part of a CCK
pathway involved in the control of feeding. The
sequence of events after a meal to promote satiety
may include the release of peripheral CCK, which acts
on vagal nerve endings in the gut, followed by signals
to the hindbrain and hypothalamus through central
CCK neurons.
To suppress feeding, CCK in the PVN may act by
counteracting the a2-noradrenergic feeding response,
synergizing with 5HT (481,482) or leptin (14,471), and
interacting with E2 during the estrous period (439,483).
There is evidence that CCKs satiating action increases
during estrus in female rats (484) and is attenuated by
consumption of a high-fat diet (485). The hypothalamic
output under the inuence of CCK is presumably biased
to adjust the hindbrain centers to stop feeding reexes.
The PVN projects back to the vagal motor nucleus,
where there are cells excited by CCK. This may involve a
hindbrain DA-CCK interaction (486). The vagal output, in turn, projects back to the gastrointestinal tract.
Technical approaches used to demonstrate this circuit
include CCK suppression of sham eating, sphincter
extirpation, selective vagotomy, CCK receptor binding,
local CCK brain injections, receptor antagonists, c-Fos
immunoreactivity, and electrophysiological recording
(469,470,487490). Thus, CCK acts in both the body
and the brain, and it sends neural information from one
to the other but does not seem to cross the blood brain
barrier. The primary receptor for CCK satiety is the
CCKA subtype, which has the same sequence and overall function in the brain and body (491,492). Mice
lacking the CCKA receptor are hyperphagic, diabetic,
and obese (493). An antagonist of the CCKA receptor
can attenuate satiety without aecting preference conditioning, suggesting separate mechanisms (494).
Cholecystokinin can inhibit the learning of food
incentives (495). Rats perform fewer responses for food
if they have prior experience performing the response
under the inuence of CCK injections. Apparently,
Bombesin
Soon after bombesin (BBS) was found in the mammalian gut, the satiety properties of this peptide were
discovered (502). The evidence suggests that BBS-like
peptides t most of the criteria for an integrative peptide
with parallel functions in the body and brain (503).
Peripheral BBS shortens meals and lengthens the time to
the next meal, without behavioral or subjective signs of
illness (504). Central injection of BBS into dierent sites
of the hypothalamus and forebrain also reduces feeding
(505,506). There exist several BBS-like peptides, such as
gastrin-releasing peptide and forms of neuromedin,
which may act within the brain or body (507). Peripherally administered BBS can stimulate the release of
gastrin, CCK, insulin, and other gut peptides that
contribute to satiety. When given chronically on an
appropriate schedule, BBS can cause weight loss (508).
Evidence that BBS receptor knockout mice become
329
Neuromedin U
Neuromedin U (NMU) is a neuropeptide that is distributed throughout the gut and brain (510). Peripheral
activities of NMU include regulation of adrenocortical function and stimulation of smooth muscle. Two
NMU receptors have recently been identied. These
are G-protein-coupled receptors, with NMU1R expressed predominantly in peripheral tissues and
NMU2R in specic regions of the brain, including the
PVN and the ependymal layer of the third ventricle
(510). Neuromedin U is expressed in the VMH, and
fasting downregulates NMU mRNA. Moreover, intracerebroventricular injection of NMU markedly suppresses food intake and body weight in rats (510,511),
while anti-NMU antiserum increases feeding (512).
Central injection of NMU also stimulates activity level,
body temperature, and heat production (511). These
ndings suggest that NMU, a potent anorexic peptide,
is a catabolic signaling molecule in the brain, possibly
involving neural mechanisms in the ventromedial region
of the hypothalamus.
M
Amylin
330
Calcitonin
Prolactin-Releasing Peptide
Until recently, the hypothalamic peptide hormone regulating the secretion of PRL from the anterior pituitary was unknown. A new peptide, prolactin-releasing
peptide (PrRP), has been identied which is proposed
to perform this function (530). This peptide, however,
is not found in the external layer of the ME, precluding its role as a classical hypophysiotropic hormone.
Additional studies, however, suggest that this peptide
has other functions related to energy homeostasis. The
expression of PrRP is concentrated in the DMN and
brainstem, with PrRP receptor mRNA highest in the
DMN and PVN (531). A recent study shows that PrRP
and mRNA is reduced in obese Zucker rats (532) and
in situations of negative energy balance, including fasting and lactation (516), when leptin levels are low.
Moreover, central administration of PrRP reduces
food intake and weight gain, producing its strongest
eect after injection into the DMN (516,533). Further,
in vitro studies demonstrate a stimulatory eect of
PrRP on the release of a-MSH and NT, two feedinginhibitory peptides (533), suggesting possible mechanisms through which this peptide may act to control
feeding behavior.
P
underlying its feeding-suppressive eect (543). Conversely, brain GAL, which stimulates feeding, plays a
role in inhibiting pituitary OT release (544).
Q
Cyclo(His-Pro)
331
prime dierent systems at dierent times. For example, one major role is to impose a circadian rhythm on
the feeding systems. Biogenic amines may also selectively potentiate subsystems for selection of specic
macronutrients, which vary across the light-dark cycle.
Norepinephrine has another feature of particular interest. This monoamine can modulate opposing systems
depending on which noradrenergic pathway is active
and which receptors are upregulated at the time.
Remarkably, changes in receptor binding and gene
expression can occur in a matter of hours and perhaps
minutes. These and other mechanisms of action are
reviewed below.
A
Norepinephrine
332
Serotonin
333
Dopamine
334
Hypothalamic DA contributes to AMPH-induced anorexia (609611). This is of renewed interest due to the
recent upsurge in the use of phentermine, which is a
dopaminergic and noradrenergic drug (612). A variety
of DA-related eects may occur in the hypothalamus,
depending on the site of intervention and experimental technique used. Hypothalamic DA is released, in
part, from an incertohypothalamic cell group, also
MH neurons intimately involved in the control of
pituitary functions (613), and from one or more DA
cell groups (A8, A9, A10) with branches that ascend
from the midbrain. Injections of DA in the LH suppress food intake, an action blocked specically by
DA receptor antagonists (609,610). Anorexic doses of
AMPH injected in the LH increase extracellular DA,
although NE and 5HT are also increased (614). All
three monoamines may suppress feeding and mediate
the actions of AMPH under dierent conditions (559,
577,584,611,615).
As further evidence of a DA satiety function in the
LH, some compounds that block DA receptors stimulate eating behavior. This was demonstrated with the
nonspecic receptor antagonist chlorpromazine and
with the specic D 2 receptor antagonist sulpiride
(559,616). Chronic peripheral injections of sulpiride
cause hyperphagia and obesity in rats, analogous to
the eect sometimes seen in schizophrenic patients
undergoing antipsychotic treatment with D2 antagonists (610,616). This eect may be due, in part, to
dopaminergic control of pituitary functions, such as
E2 release (617), or to disinhibition of a behavior reinforcement system that leads to overeating. Sulpiride
in the LH has locomotor and reward eects. Remarkably, rats will even self-inject sulpiride into their own
LH (616). This suggests that DA agonists can act at
hypothalamic D2 receptors to inhibit instrumental
responses, including responses involved in the reinforcement of eating.
In studies using microdialysis, the release of DA in
the MH is positively correlated with eating behavior
(618). It is proposed that taste and smell may enhance
the release of hypothalamic DA at the start of a meal, to
behavior such as eating, mating, aggression, and associated stimuli. It appears from a teleological point of
view that animals perform voluntary behavior in order
to get the eects of DA release in the NAc and perhaps
in other forebrain sites such as the PFC (641). Recording from VTA cells in the awake monkey suggests that
neural activity signals a salient change in the environment (642). The debate as to whether DA creates a
simple error signal, a reward (pleasure and liking), or an
incentive (motivation and wanting) seems to hinge on
which component of the ascending DA system is being
addressed. Evidence is accumulating to indicate that
DA in the NAc shell region generates wanting, or
what in the feeding eld is usually referred to as appetite
(625,643).
Dopamine in the NAc is also involved in reinforcing behavior to escape an aversive stimulus. Extracellular DA increases during MH stimulation escape
behavior, but not during the same stimulation when
it is inescapable (622). Thus, DA may be a negative
reinforcer for active escape, as well as a positive
reinforcer for active approach in feeding situations.
Its role in these reinforcement processes could be incentive motivation.
3
335
336
VI
Histamine
Acetylcholine
Amino Acids
337
338
LH. Under natural conditions, this may initiate lifesaving ingestive behavior (7).
VII
Sensory Inputs
339
340
341
342
IX
CONCLUSION
ronment, food availability, and food taste. The neuralhormonal system of energy homeostasis evolved in an
environment of scarcity. It needs sociopolitical help in
coping with problems created by refugee migrations on
the one hand, and advertised superabundance on the
other. An understanding of the neuroscience of ingestive behavior and obesity must bring with it a sensible
food distribution and education system. Otherwise, it
will just be science for the sake of treatment, without all
the benets that could accrue from prevention of starvation and overeating.
ACKNOWLEDGMENTS
Some of the research described in this review has been
supported by U.S. Public Health Service grants MH
43422 (S.F.L.) and MH 30697 and DA 10608 (B.G.H.).
We thank Ms. Kate Sepiashvili, Henrietta EnninfulEghan, and Nicole Avena for their assistance in the
preparation of this review chapter.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
343
relevance to eating, addiction and depression. In:
Kahneman D, Diener E, Shwarz N, eds. Well Being:
The Psychological Foundations of Hedonism. New
York: Russel Sage Foundation 1999:560574.
9. Woods SC, Chavez M, Park CR, Riedy C, Kaiyala K,
Richardson RD, et al. The evaluation of insulin as a
metabolic signal inuencing behavior via the brain.
(Review) Neurosci Biobehav Rev 1996; 20:139144.
10. Schwartz MW, Sipols AJ, Marks JL, Sanacora G,
White JD, Scheurink A, et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin.
Endocrinology, 1992; 130:36083616.
11. Kaiyala KJ, Woods SC, Schwartz MW. New model
for the regulation of energy balance and adiposity by
the central nervous system. (Review) Am J Clin Nutr
1995; 62:1123S1134S.
12. McGowan MK, Andrews KM, Kelly J, Grossman SP.
Eects of chronic intrahypothalamic infusion of
insulin on food intake and diurnal meal patterning in
the rat. Behav Neurosci 1990; 104:373385.
13. Vanderweele DA. Insulin is a prandial satiety hormone. Physiol Behav 1994; 56:619622.
14. Woods SC, Schwartz MW, Baskin DG, Seeley RJ.
Food intake and the regulation of body weight. Annu
Rev Psychol 2000; 51:255277.
15. Baura GD, Foster DM, Porte D Jr, Kahn SE,
Bergman RN, Cobelli C, et al. Saturable transport
of insulin from plasma into the central nervous system
of dogs in vivo. A mechanism for regulated insulin
delivery to the brain. J Clin Invest 1993; 92:18241830.
16. Kapeller R, Moriarty A, Strauss A, Stubdal H,
Theriault K, Siebert E, et al. Tyrosine phosphorylation
of tub and its association with Src homology 2 domaincontaining proteins implicate tub in intracellular signaling by insulin. J Biol Chem 1999; 274:2498024986.
17. Schwartz MW, Figlewicz DP, Baskin DG, Woods SC,
Porte D Jr. Insulin in the brain: a hormonal regulator
of energy balance. (Review) Endocr Rev 1992; 13:387
414.
18. Tang C, Akabayashi A, Manitiu A, Leibowitz SF.
Hypothalamic galanin gene expression and peptide
levels in relation to circulating insulin: possible role
in energy balance. Neuroendocrinology 1997; 65:265
275.
19. Sahu A, Dube MG, Phelps CP, Sninsky CA, Kalra PS,
Kalra SP. Insulin and insulin-like growth factor II
suppress neuropeptide Y release from the nerve terminals in the paraventricular nucleus: a putative hypothalamic site for energy homeostasis. Endocrinology
1995; 136:57185724.
20. Zhang Y, Proenca R, Maei M, Barone M, Leopold
L, Friedman JM. Positional cloning of the mouse
obese gene and its human homologue. Nature 1994;
372:425432.
21. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identication and expression
344
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
345
in luteinizing hormonereleasing hormone neurons.
Proc Natl Acad Sci USA 1993; 90:1047910483.
69. Leibowitz SF. Brain peptides and obesity: pharmacologic treatment. (Review) Obes Res 1995; 3(suppl
4):573S589S.
70. Alexander JT, Akabayashi A, Gabriel SM, Thomas
BE, Leibowitz SF. Galanin and neuropeptide Y
immunoreactivity in brain nuclei of female and male
rats in relation to puberty. Soc Neurosci Abstr 1994;
20:99.
71. Leibowitz SF, Lucas DJ, Leibowitz KL, Jhanwar YS.
Developmental patterns of macronutrient intake in
female and male rats from weaning to maturity. Physiol Behav 1991; 50:11671174.
72. Ono T, Sasaki K, Shibata R. Feeding- and chemicalrelated activity of ventromedial hypothalamic neurones in freely behaving rats. J Physiol 1987; 394:221
237.
73. Mobbs CV, Kow LM, Yang XJ. Brain glucose-sensing
mechanisms: ubiquitous silencing by aglycemia vs.
hypothalamic neuroendocrine responses. Am J Physiol
Edocrinol Metab 2001; 281:E649-E654.
74. Lynch RM, Tompkins LS, Brooks HL, Dunn-Meynell
AA, Levin BE. Localization of glucokinase gene expression in the rat brain. Diabetes 2000; 49:693700.
75. Bernardis LL, Bellinger LL. The lateral hypothalamic
area revisited: ingestive behavior. Neurosci Biobehav
Rev 1996; 20:189287.
76. Levin BE, Dunn-Meynell AA, Routh VH. Brain glucose sensing and body energy homeostasis: role in
obesity and diabetes. Am J Physiol 1999; 276:R1223R1231.
77. Wang J, Dourmashkin JT, Yun R, Leibowitz SF.
Rapid changes in hypothalamic neuropeptide Y
produced by carbohydrate-rich meals that enhance
corticosterone and glucose levels. Brain Res 1999;
848:124136.
78. Jhanwar-Uniyal M, Papamichael MJ, Leibowitz SF.
Glucose-dependent changes in alpha 2-noradrenergic
receptors in hypothalamic nuclei. Physiol Behav 1988;
44:611617.
79. Watkins PA, Hamilton JA, Leaf A, Spector AA,
Moore SA, Anderson RE, et al. Brain uptake and
utilization of fatty acids: applications to peroxisomal
biogenesis diseases. J Mol Neurosci 2001; 16:8792.
80. Drew PA, Smith E, Thomas PD. Fat distribution and
changes in the blood brain barrier in a rat model of
cerebral arterial fat embolism. J Neurol Sci 1998; 156:
138143.
81. Brossard N, Croset M, Lecerf J, Pachiaudi C,
Normand S, Chirouze V, et al. Metabolic fate of an
oral tracer dose of [13C]docosahexaenoic acid triglycerides in the rat. Am J Physiol 1996; 270:R846-R854.
82. Volterra A, Trotti D, Cassutti P, Tromba C, Salvaggio
A, Melcangi RC, et al. High sensitivity of glutamate
uptake to extracellular free arachidonic acid levels in
346
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
347
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
348
regulation and role of hypothalamic galanin systems:
renewed interest in a pleiotropic peptide family. Clin
Exp Pharmacol Physiol 2001; 28:100105.
137. Tempel DL, Leibowitz SF. Diurnal variations in the
feeding responses to norepinephrine, neuropeptide Y
and galanin in the PVN. Brain Res Bull 1990; 25:821
825.
138. Chae HJ, Hoebel BG, Tempel DL, Paredes M,
Leibowitz SF. Neuropeptide-Y, galanin and opiate
agonists have dierential eects on nutrient ingestion.
Soc Neurosci Abstr 1995; 21:696.
139. Kyrkouli SE, Stanley BG, Hutchinson R, Seira RD,
Leibowitz SF. Peptide-amine interactions in the hypothalamic paraventricular nucleus: analysis of galanin
and neuropeptide Y in relation to feeding. Brain Res
1990; 521:185191.
140. Leibowitz SF. Macronutrient and brain peptides: what
they do and how they respond. In: Berthoud HR,
Seeley RJ, eds. Neural and Metabolic Control of
Macronutrient Intake. Boca Raton: CRC Press, 2000:
389406.
141. Bergonzelli GE, Pralong FP, Glauser M, Cavadas C,
Grouzmann E, Gaillard RC. Interplay between
galanin and leptin in the hypothalamic control of
feeding via corticotropin-releasing hormone and neuropeptide Y. Diabetes 2001; 50:26662672.
142. Leibowitz SF. Hypothalamic galanin, dietary fat, and
body fat. In: Bray G, Ryan D, eds. Nutrition, Genetics
and Obesity. Baton Rouge: Louisiana State University
Press, 1999: 338381.
143. Akabayashi A, Koenig JI, Watanabe Y, Alexander JT,
Leibowitz SF. Galanin-containing neurons in the
paraventricular nucleus: a neurochemical marker for
fat ingestion and body weight gain. Proc Natl Acad Sci
USA 1994; 91:1037510379.
144. Barton C, Lin L, York DA, Bray GA. Dierential
eects of enterostatin, galanin and opioids on high-fat
diet consumption. Brain Res 1995; 702(12):5560.
145. Lin L, Bray G, York DA. Enterostatin suppresses
food intake in rats after near-celiac and intracarotid
arterial injection. Am J Physiol Regul Integr Comp
Physiol 2000; 278:R1346R1351.
146. Corwin RL, Rowe PM, Crawley JN. Galanin and the
galanin antagonist M40 do not change fat intake in a
fat-chow choice paradigm in rats. Am J Physiol 1995;
269: R511R518.
147. Koegler FH, Ritter S. Feeding induced by pharmacological blockade of fatty acid metabolism is
selectively attenuated by hindbrain injections of the
galanin receptor antagonist, M40. Obes Res 1996;
4:329336.
148. Leibowitz SF, Kim T. Impact of a galanin antagonist
on exogenous galanin and natural patterns of fat
ingestion. Brain Res 1992; 599:148152.
149. Corwin RL, Robinson JK, Crawley JN. Galanin
antagonists block galanin-induced feeding in the
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
349
tide (GALP) as a potential regulator of pituitary
hormone secretion. 31st Annual Meeting of the Society
for Neurosciences, San Diego, CA, Nov 1015, 2001.
177. Jureus A, Cunningham MJ, Li D, Johnson LL,
Krasnow SM, Teklemichael DN, et al. Distribution
and regulation of galanin-like peptide (GALP) in
the hypothalamus of the mouse. Endocrinology 2001;
142: 51405144.
178. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen
Y, Gantz I, et al. Antagonism of central melanocortin
receptors in vitro and in vivo by agouti-related
protein. Science 1997; 278:135138.
179. Baskin DG, Hahn TM, Schwartz MW. Leptin sensitive neurons in the hypothalamus. Horm Metab Res
1999; 31:345350.
180. Hagan MM, Rushing PA, Pritchard LM, Schwartz
MW, Strack AM, Van der Ploeg LH, et al. Long-term
orexigenic eects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade. Am
J Physiol Regul Integr Comp Physiol 2000; 279:R47
R52.
181. Wortley KE, Davydova Z, Leibowitz SF. Agoutirelated peptide (AGRP), like NPY is stimulated in the
arcuate nucleus by a high-carbohydrate diet and, after
injection, increases levels of hormones that promote
lipogenesis. Obes Res 2002; 10(1):6567.
182. Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark
KL. Overexpression of Agrt leads to obesity in
transgenic mice. Nat Genet 1997; 17:273274.
183. Wilson BD, Bagnol D, Kaelin CB, Ollmann MM,
Gantz I, Watson SJ, et al. Pysiological and anatomical
circuitry between Agouti-related protein and leptin signaling. Endocrinology 1999; 140:23872397.
184. Hagan MM, Benoit SC, Rushing PA, Pritchard LM,
Woods SC, Seeley RJ. Immediate and prolonged
patterns of Agouti-related peptide-(83-132)-induced
c-Fos activation in hypothalamic and extrahypothalamic sites. Endocrinology 2001; 142:10501056.
185. Wirth MM, Giraudo SQ. Agouti-related protein in
the hypothalamic paraventricular nucleus: eect on
feeding [in process citation]. Peptides 2000; 21:1369
1375.
186. Mizuno TM, Mobbs CV. Hypothalamic agoutirelated protein messenger ribonucleic acid is inhibited
by leptin and stimulated by fasting. Endocrinology
1999; 140:814817.
187. Ziotopoulou M, Mantzoros CS, Hileman SM, Flier JS.
Dierential expression of hypothalamic neuropeptides
in the early phase of diet-induced obesity in mice. Am J
Physiol Endocrinol Metab 2000; 279:E838E845.
188. Ebihara K, Ogawa Y, Katsuura G, Numata Y,
Masuzaki H, Satoh N, et al. Involvement of agoutirelated protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action.
Diabetes 1999; 48:20282033.
189. Qu SY, Yang YK, Li JY, Zeng Q, Gantz I. Agouti-
350
related protein is a mediator of diabetic hyperphagia.
Regul Pept 2001; 98:6975.
190. Makimura H, Mizuno TM, Roberts J, Silverstein J,
Beasley J, Mobbs CV. Adrenalectomy reverses obese
phenotype and restores hypothalamic melanocortin
tone in leptin-decient ob/ob mice. Diabetes 2000;
49:19171923.
191. Arvaniti K, Huang Q, Richard D. Eects of leptin and
corticosterone on the expression of corticotropinreleasing hormone, agouti-related protein, and proopiomelanocortin in the brain of ob/ob mouse. Neuroendocrinology 2001; 73:227236.
192. Sakurai T, Amemiya A, Ishii M, Matsuzaki I,
Chemelli RM, Tanaka H, et al. Orexins and orexin
receptors: a family of hypothalamic neuropeptides and
G proteincoupled receptors that regulate feeding
behavior. Cell 1998; 92:573585.
193. De Lecea L, Kildu TS, Peyron C, Gao X, Foye PE,
Danielson PE, et al. The hypocretins: hypothalamusspecic peptides with neuroexcitatory activity. Proc
Natl Acad Sci USA 1998; 95:322327.
194. Lubkin M, Stricker-Krongrad A. Independent feeding
and metabolic actions of orexins in mice. Biochem
Biophys Res Commun 1998; 253:241245.
195. Takahashi N, Okumura T, Yamada H, Kohgo Y.
Stimulation of gastric acid secretion by centrally administered orexin-A in conscious rats. Biochem Biophys Res Commun 1999; 254:623627.
196. Hara J, Beuckmann CT, Nambu T, Willie JT,
Chemelli RM, Sinton CM, et al. Genetic ablation of
orexin neurons in mice results in narcolepsy, hypophagia, and obesity Neuron 2001; 30:345354.
197. Broberger C, De Lecea L, Sutclie JG, Hokfelt T.
Hypocretin/orexin-and melanin-concentrating hormone-expressing cells form distinct populations in
the rodent lateral hypothalamus: relationship to the
neuropeptide Y and agouti gene-related protein
systems. J Comp Neurol 1998; 402:460474.
198. Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee
C, Kelly J, et al. Chemically dened projections linking the mediobasal hypothalamus and the lateral
hypothalamic area. J Comp Neurol 1998; 402:442
459.
199. Horvath TL, Diano S, Van den Pol AN. Synaptic
interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and
endocrine regulations. J Neurosci 1999; 19:10721087.
200. Peyron C, Tighe DK, Van den Pol AN, De Lecea L,
Heller HC, Sutclie JG, et al. Neurons containing
hypocretin (orexin) project to multiple neuronal
systems. J Neurosci 1998; 18:999610015.
201. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M.
To eat or to sleep? Orexin in the regulation of feeding
and wakefulness. Annu Rev Neurosci 2001; 24:429
458.
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
351
229.
352
Hoebel BG, Novin D, eds. The Neural Basis of
Feeding and Reward. Brunswick, ME: Haer Inst.,
1982:507515.
242. Siviy SM, Calcagnetti DJ, Reid LD. A temporal
analysis of naloxones suppressant eect on drinking.
Pharmacol Biochem Behav 1982; 16:173175.
243. Rudski JM, Billington CJ, Levine AS. Naloxones
eects on operant responding depend upon level of
deprivation. Pharmacol Biochem Behav 1994; 49:377
383.
244. Cooper SJ. Sweetness, reward and analgesia. Trends
Pharmacol Sci 1984; 322323.
245. Kanarek RB, White ES, Biegen MT, Marks-Kaufman R. Dietary inuences on morphine-induced
analgesia in rats. Pharmacol Biochem Behav 1991;
38:681684.
246. Blass EM, Homeyer LB. Sucrose as an analgesic for
newborn infants. Pediatrics 1991; 87:215218.
247. Bodnar RJ. Opioid receptor substype antagonists and
ingestion. In: Cooper SJ, Clifton PG, eds. Drug
Receptor Subtypes and Ingestive Behaviour. San
Diego: Academic Press, 1996:127166.
248. Nencini P. Sensitization to the ingestive eects of
opioids. In: Cooper SJ, Clifton PG, eds. Drug
Receptor Subtypes and Ingestive Behaviour. San
Diego: Academic Press, 1996:193218.
249. Vaccarino FJ. Dopamine-opioid mechanisms in ingestion. In: Cooper SJ, Clifton PG, eds. Drug
Receptor Subtypes and Ingestive Behaviour. San
Diego: Academic Press, 1996:219232.
250. Carr KD. Opioid receptor subtypes and stimulationinduced feeding. In: Cooper SJ, Clifton PG, eds. Drug
Receptor Subtypes and Ingestive Behavior. San Diego:
Academic Press, 1996:167192.
251. Reid LD. Endogenous opioid peptides and regulation
of drinking and feeding (Review) Am J Clin Nutr
1985; 42:10991132.
252. Morley JE, Levine AS, Gosnell BA, Kneip J, Grace
M. The kappa opioid receptor, ingestive behaviors and
the obese mouse (ob/ob). Physiol Behav 1983; 31:603
606.
253. Cooper SJ. Evidence for opioid involvement in
controls of drinking and water balance. In: Rodgers
RJ, Cooper SJ, eds. Endorphins, Opiates and Behavioural Processes. New York: John Wiley & Sons, 1988:
187216.
254. Bodnar RJ, Beczkowska IW, Koch JE. Opioid
receptor subtypes dierentially alter palatable uid
intake in rats. Appetite 1993; 21:165.
255. Badiani A, Rajabi H, Nencini P, Stewart J. Modulation of food intake by the kappa opioid U-50,488H:
evidence for an eect on satiation. Behav Brain Res
2001; 118:17986.
256. Leibowitz SF, Hor L. Endorphinergic and alphanoradrenergic systems in the paraventricular nucleus:
eects on eating behavior. Peptides 1982; 3:421428.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
353
Poncelet M, Soubrie P, et al. Selective inhibition of
sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology (Berl) 1997; 132:104106.
289. Heshmati HM, Fatourechi V, Dagam SA, Piepgras
DG. Hypopituitarism caused by intrasellar aneurysms.
Mayo Clin Proc 2001; 76:789793.
290. Dieguez C, Carro E, Seoane LM, Garcia M, Camina
JP, Senaris R, et al. Regulation of somatotroph cell
function by the adipose tissue. Int J Obes Relat Metab
Disord 2000; 24(suppl 2):S100S103.
291. Dickson PR, Vaccarino FJ. GRF-induced feeding:
evidence for protein selectivity and opiate involvement. Peptides 1994; 15:13431352.
292. Dickson PR, Feifel D, Vaccarino FJ. Blockade of
endogenous GRF at dark onset selectively suppresses
protein intake. Peptides 1995; 16:79.
293. Vaccarino FJ, Feifel D, Rivier J, Vale W. Antagonism
of central growth hormonereleasing factor activity
selectively attenuates dark-onset feeding in rats.
J Neurosci 1991; 11:39243927.
294. Vaccarino FJ, Hayward M. Microinjections of growth
hormone-releasing factor into the medial preoptic
area/suprachiasmatic nucleus region of the hypothalamus stimulate food intake in rats. Regul Pept 1988;
21:2128.
295. Luckman SM, Rosenzweig I, Dickson SL. Activation
of arcuate nucleus neurons by systemic administration
of leptin and growth hormonereleasing peptide-6 in
normal and fasted rats. Neuroendocrinology 1999;
70:93100.
296. Okada K, Ishii S, Minami S, Sugihara H, Shibasaki T,
Wakabayashi I. Intracerebroventricular administration of the growth hormone-releasing peptides KP-102
increases food intake in free-feeding rats. Endocrinology 1996; 137:51555158.
297. Vaccarino FJ, Taube MR. Intra-arcuate opiate actions
stimulate GRF-dependent and protein-selective feeding. Peptides 1997; 18:197205.
298. Lawrence CB, Snape AC, Baudoin FM, Luckman
SM. Acute central ghrelin and GH secretagogues
induce feeding and activate brain appetite centers.
Endocrinology 2002; 143:155162.
299. Scacchi M, Pincelli AI, Cavagnini F. Growth hormone
in obesity. Int J Obes Relat Metab Disord 1999; 23:
260271.
300. Cai A, Hyde JF. The human growth hormonereleasing hormone transgenic mouse as a model of
modest obesity: dierential changes in leptin receptor
(OBR) gene expression in the anterior pituitary and
hypothalamus after fasting and OBR localization in
somatotrophs. Endocrinology 1999; 140:36093614.
301. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo
H, Kangawa K. Ghrelin is a growth-hormonereleasing acylated peptide from stomach. Nature
1999; 402:656660.
354
302.
330.
331.
332.
333.
334.
335.
336.
337.
338.
339.
340.
341.
342.
343.
355
344.
345.
346.
347.
348.
349.
350.
351.
352.
353.
354.
355.
356.
357.
358.
356
359.
374. Hurd YL, Fagergren P. Human cocaine- and amphetamine-regulated transcript (CART) mRNA is highly
expressed in limbic- and sensory-related brain regions.
J Comp Neurol 2000; 425:583598.
375. Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS,
Couceyro PR, et al. Leptin activates hypothalamic
CART neurons projecting to the spinal cord. Neuron
1998; 21:13751385.
376. Elias CF, Lee CE, Kelly JF, Ahima RS, Kuhar M,
Saper CB, et al. Characterization of CART neurons in
the rat and human hypothalamus. J Comp Neurol
2001; 432:119.
377. Chang GQ, Leibowitz SF. CART and galanin coexist
in hypothalamic neurons: high-fat diet increases the
number of double-labeled neurons exclusively in the
PVN. 31st Annual Meeting of the Society for Neurosciences, San Diego, CA, Nov 1015, 2001.
378. Vrang N, Larsen PJ, Clausen JT, Kristensen P. Neurochemical characterization of hypothalamic cocaineamphetamine-regulated transcript neurons. J Neurosci
1999; 19:RC5.
379. Broberger C. Hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons: histochemical relationship to thyrotropin-releasing hormone,
melanin-concentrating hormone, orexin/hypocretin
and neuropeptide Y. Brain Res 1999; 848:101113.
380. Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wul BS, et al. Hypothalamic CART is a
new anorectic peptide regulated by leptin. Nature
1998; 393: 7276.
381. Lambert PD, Couceyro PR, McGirr KM, Dall Vechia
SE, Smith Y, Kuhar MJ CART peptides in the central
control of feeding and interactions with neuropeptide
Y. Synapse 1998; 29:293298.
382. Pothos EN, Creese I, Hoebel BG. Restricted eating
with weight loss selectively decreases extracellular
dopamine in the nucleus accumbens and alters
dopamine response to amphetamine, morphine and
food intake. J Neurosci 1995; 15:66406650.
383. Wang C, Billington CJ, Levine AS, Kotz CM. Eect
of CART in the hypothalamic paraventricular nucleus
on feeding and uncoupling protein gene expression.
Neuroreport 2000; 11:32513255.
384. Okumura T, Yamada H, Motomura W, Kohgo Y.
Cocaine-amphetamine-regulated transcript (CART)
acts in the central nervous system to inhibit gastric
acid secretion via brain corticotropin-releasing factor
system. Endocrinology 2000; 141:28542860.
385. Larsen PJ, Vrang N, Petersen PC, Kristensen P.
Chronic intracerebroventricular administration of
recombinant CART(42-89) peptide inhibits and causes
weight loss in lean and obese Zucker (fa/fa) rats. Obes
Res 2000; 8:590596.
386. Pothos EN, Hernandez L, Hoebel BG. Chronic food
deprivation decreases extracellular dopamine in the
nucleus accumbens: implications for a possible neuro-
387.
388.
389.
390.
391.
392.
393.
394.
395.
396.
397.
398.
399.
357
Heard AD, Hollis JH, et al. Abnormal adaptations to
stress and impaired cardiovascular function in mice
lacking corticotropin-releasing hormone receptor-2.
Nat Genet 2000; 24:403409.
400. Bradbury MJ, McBurnie MI, Denton DA, Lee KF,
Vale WW. Modulation of urocortin-induced hypophagia and weight loss by corticotropin-releasing
factor receptor 1 deciency in mice. Endocrinology
2000; 141:27152724.
401. Uehara Y, Shimizu H, Ohtani K, Sato N, Mori M.
Hypothalamic corticotropin-releasing hormone is a
mediator of the anorexigenic eect of leptin. Diabetes
1998; 47:890893.
402. Menzaghi F, Heinrichs SC, Pich EM, Tilders FJ,
Koob GF. Functional impairment of hypothalamic
corticotropin-releasing factor neurons with immunotargeted toxins enhances food intake induced by
neuropeptide Y. Brain Res 1993; 618:7682.
403. Bchini-Hooft van Huijsduijnen OB, Rohner-Jeanrenaud F, Jeanrenaud B. Hypothalamic neuropeptide Y
messenger ribonucleic acid levels in pre-obese and genetically obese (fa/fa) rats; potential regulation thereof
by corticotropin-releasing factor. J Neuroendocrinol
1993; 5:381386.
404. Bchini-Hooft van Huijsduijnen OB, Rohner-Jeanrenaud F, Jeanrenaud B. Hypothalamic neuropeptide Y
messenger ribonucleic acid levels in pre-obese and genetically obese (fa/fa) rats; potential regulation thereof
by corticotropin-releasing factor. J Neuroendocrinol
1993; 5:381386.
405. Halford JC, Blundell JE. Separate systems for
serotonin and leptin in appetite control. Ann Med
2000; 32:222232.
406. Cavagnini F, Croci M, Putignano P, Petroni ML,
Invitti C. Glucocorticoids and neuroendocrine function. Int J Obes Relat Metab Disord 2000; 24(suppl
2):S77S79.
407. Krahn DD, Gosnell BA, Grace M, Levine AS. CRF
antagonist partially reverses CRF- and stress-induced
eects on feeding. Brain Res Bull 1986; 17:285289.
408. Uehara A, Habara Y, Kuroshima A, Sekiya C,
Takasugi Y, Namiki M. Increased ACTH response
to corticotropin-releasing factor in cold-adapted rats
in vivo. Am J Physiol 1989; 257:E336-E339.
409. Inui A. Feeding and body-weight regulation by
hypothalamic neuropeptidesmediation of the actions of leptin. Trends Neurosci 1999; 22:6267.
410. Erlanson-Albertsson C, York D. Enterostatina peptide regulating fat intake. Obes Res 1997; 5:360372.
411. Okada S, York DA, Bray GA, Mei J, ErlansonAlbertsson C. Diferential inhibition of fat intake in
two strains of rat by the peptide enterostatin. Am J
Physiol 1992; 262(Pt 2):R1111R1116.
412. Lin L, McClanahan S, York DA, Bray GA. The
peptide enterostatin may produce early satiety. Physiol
Behav l993; 53789794.
358
413.
428. Lee TF, Rezvani AH, Hepler JR, Myers RD. Neurotensin releases norepinephrine dierentially from
perfuse hypothalamus of sated and fasted rat. Am J
Physiol 1987; 252:E102E109.
429. Glimeher PG, Giovino AA, Hoebel BG. Neurotensin
self-injection in the ventral tegmental area. Brain Res
1987; 403:147150.
430. kalivas PW, Taylor S. Behavioral and neurochemical
eect of daily injection with neurotensisn into the
ventral tegmental area. Brain Res 1985; 358:7076.
431. Rompre P-P, Gratton A. Mesencephalic microinjections of neurotensin-(1-13) and its C-terminal fragment neurotensin-(8-13), potentiate brain stimulation
reward. Brain Res 1993; 616:154162.
432. Angulo JA, McEwen BS. Molecular aspects of
neuropeptide regulation and function in the corpus
striatum and nucleus accumbens. Brain Res Rev 1994;
19:128.
433. Hayashi H, Nutting DF, Fujimoto K, Cardelli JA,
Black D, Tso P. Transport of lipid and apolipoproteins A-I and A-IV in intestinal lymph of the rat.
J Lipid Res 1990; 31:16131625.
434. Fujimoto K, Fukagawa K, Sakata T, Tso P. Suppression of food intake by apolipoprotein A-IV is mediated through the central nervous system in rats.
J Clin Invest 1993; 91:18301833.
435. Okumura T, Fukagawa K, Tso P, Taylor IL, Pappas
TN. Mechanism of action of intracisternal apolipoprotein A-IV in inhibiting gastric acid secretion in rats.
Gastroenterology 1995; 109:15831588.
436. Tso P,.Liu M, Kalogeris TJ, Thomson AB. The role of
apolipoprotein. A-IV in the regulation of food intake.
Annu Rev Nutr 2001; 21:231254.
437. Elshourbagy NA, Walker DW, Paik YK, Boguski MS,
Freeman M, Gordon JI, et al. Structure and expression of the human apolipoprotein A-IV gene. J Biol
Chem 1987; 262:79737981.
438. Liu Z, Leibowitz SF. Apolipoprotein D interacts with
the long form leptin receptor: a hypothalamic function
in control of energy homeostasis. FASEB J 2001.
439. Smith GP, Gibbs J. Satiating eect of cholecystokinin.
Ann NY Acad Sci 1994; 713:236241.
440. Lenard L, Jando G, Karadi Z, Hajnal A, Sandor P.
Lateral hypothalamic feeding mechanisms; iontophoretic eects of kainic acid ibolenic acid and 6hydroxydopamine. Brain Res Bull 1988; 20:847856.
441. Rassart E, Bedirian A, Do CS, Guinard O, Sirois J,
Terisse I, et al. Apolipoprotein D [in process citation].
Biochim Biophys Acta 2000; 1482:185198.
442. Bernardis LL, Bellinger LL. The lateral hypothalamic
area revisited: neuroanatomy, body weight regulation,
neuroendocrinology and metabolism. Neurosci Biobehav Rev 1993; 17:141193.
443. Powley TL, Opsahl CA. Autonomic components of
the hypothalamic feeding syndromes. In: Novin D,
Wyrwicka W, Bray GA, eds. Hunger: Basic Mecha-
444.
445.
446.
447.
448.
449.
450.
451.
452.
453.
454.
455.
456.
359
457.
360
lying the satiety actions of cholecystokinin (CCK). In:
Cooper SJ, Clifton PG, eds. Drug Receptor Subtypes
and Ingestive Behaviour. London: Academic Press,
1996:118.
471. Moran TH. Cholecystokinin and satiety: current
perspectives. Nutrition 2000; 16:858865.
472. Crawley JN, Corwin RL. Biological actions of
cholecystokinin. Peptides 1994; 15:731755.
473. Smith GP, Dorre D, Melville L. CCK-33 inhibits food
intake after intraportal and intravenous administration. Soc Neurosci Abstr 1996:22.
474. Verbalis JG, McCann MJ, McHale CM, Stricker EM.
Oxytocin secretion in response to cholecystokinin and
food: dierentiation of nausea from satiety. Science
1986; 232:14171419.
475. Deutsch JA, Hardy WT. Cholecystokinin produces
bait shyness in rats. Nature 1977; 266:196.
476. Mueller K, Hsaie S. Specicity of cholecystokinin
satiety eect: reduction of food but not water intake.
Pharmacol Biochem Behav 1977; 6:643646.
477. Flood JF, Silver AJ, Morley JE. Do peptide-induced
changes in feeding occur because of changes in
motivation to eat? Peptides 1990; 11:265270.
478. Degen L, Matzinger D, Drewe J, Beglinger C. The
eect of cholecystokinin in controlling appetite and
food intake in humans. Peptides 2001; 22:12651269.
479. Melton PM, Kissile HR. Pi-Sunyer FX. Cholecystokinin (CCK-8) aects gastric pressure and ratings of
hunger and fullness in women. Am J Physiol 1992;
263:452456.
480. Dourish CT. Behavioral analysis of the role of CCK-A
and CCK-B receptors in the control of feeding in
rodents. In: Dourish CT, Cooper SJ, Inverson SD,
Iverson LL, eds. Multiple Cholecystokinin Receptors
in the CNS. Oxford: Oxford University Press, 1992:
234253.
481. Zippel U, Heidel E, Davidowa H. Action of cholecystokinin and serotonin on lateral hypothalamic
neurons of rats. Eur J Pharmacol 1999; 379:135140.
482. Burton-Freeman B, Gietzen DW, Schneeman BO.
Cholecystokinin and serotonin receptors in the regulation of fat- induced satiety in rats. Am J Physiol
1999; 276:429434.
483. Geary N, Trace D, McEwen B, Smith GP. Cyclic
estradiol replacement increases the satiety eect of
CCK- 8 in ovariectornized rats. Physiol Behav 1994;
56:281289.
484. Eckel LA, Geary N. Endogenous cholecystokinins
satiating action increases during estrus in female rats.
Peptides 1999; 20:451456.
485. Covasa M. Ritter RC. Rats maintained on high-fat
diets exhibit reduced satiety in response to CCK and
bombesin. Peptides 1998; 19:14071415.
486. Sodersten P, Bednar I, Qureshi GA, Carrer H, Qian
M, Mamoun H, Kaplan JM, Johnson AE. Cholecystokinin-dopamine interactions in satiety. In: Cooper
487.
488.
489.
490.
491.
492.
493.
494.
495.
496.
497.
498.
499.
500.
501.
502.
503.
504.
505.
506.
507.
508.
509.
510.
511.
512.
513.
361
metabolic disease. (Review) Endocr Rev 1994; 15:163
201.
514. Edwards BJ, Morley JE. Amylin. Life Sci 1992;
51:18991912.
515. Lutz TA, Geary N, Szabady MM, Del Prete E,
Scharrer E. Amylin decreases meal size in rats. Physiol
Behav 1995; 58:11971202.
516. Lawrence CB, Celsi F, Brennand J, Luckman SM.
Alternative role for prolactin-releasing peptide in the
regulation of food intake. Nat Neurosci 2000; 3:645
646.
517. Banks WA, Kastin AJ, Maness LM, Huang W, Jaspan
JB. Permeability of the blood-brain barrier to amylin.
Life Sci 1995; 57:19932001.
518. Sexton PM, Paxinos. G, Kenney MA, Wookey PJ,
Beaumont K. In vitro autoradiographic localization of
amylin binding sites in rat brain. Neuroscience 1994;
62:553567.
519. Banks WA, Kastin AJ. Dierential permeability of the
blood-brain barrier to two pancreatic peptides: insulin
and amylin. Peptides 1998; 19:883889.
520. Woods SC, Seeley RJ. Adiposity signals and the control
of energy homeostasis. Nutrition 2000; 16:894902.
521. Chance WT, Balasubramaniam A, Zhang FS, Wimalawansa SJ, Fischer JE. Anorexia following the
intrahypothalamic administration of amylin. Brain
Res 1991; 539:352354.
522. Rushing PA, Hagan MM, Seeley RJ, Lutz TA,
DAlessio DA, Air EL, et al. Inhibition of central
amylin signaling increases food intake and body
adiposity in rats. Endocrinology 2001; 142:5035.
523. Chance WT, Balasubramaniam A, Stallion A, Fischer
JE. Anorexia following the systemic injection of
amylin. Brain Res 1993; 607:185188.
524. Gebre-Medhin S, Mulder H, Pekny M, Westermark
G, Tornell J, Westermark P, et al. Increased insulin
secretion and glucose tolerance in mice lacking islet
amyloid polypeptide (amylin). Biochem Biophys Res
Commun. 1998; 250:271277.
525. Chait A, Suaudeau C, De Beaurepaire R. Extensive
brain mapping of calcitonin-induced anorexia. Brain
Res Bull 1995; 36:467472.
526. Krahn DD, Gosnell BA, Levine AS, Morley JE.
Eects of calcitonin gene-related peptide on food intake. Peptides 1984; 5:861864.
527. Freed WJ, Perlow MJ, Wyatt RJ. Calcitonin: inhibitory eect on eating in rats. Science 1979; 206:850
852.
528. Taylor GM, Meeran K, OShea D, Smith DM, Ghatei
MA, Bloom SR. Adrenomedullin inhibits feeding in
the rat by a mechanism involving calcitonin generelated peptide receptors. Endocrinology 1996; 137:
3260.
529. Zelissen PM, Koppeschaar HP, Lips CJ, Hackeng
WH. Calcitonin gene-related peptide in human obesity. Peptides 1991; 12:861863.
362
530.
531.
532.
533.
534.
535.
536.
537.
538.
539.
540.
541.
542.
543.
544.
545.
546.
547.
548.
549.
550.
551.
552.
553.
554.
555.
556.
557.
558.
559.
560.
561.
562.
563.
564.
565.
566.
567.
568.
569.
570.
571.
572.
363
573.
364
Neural and Metabolic Control of Macronutrient Intake. Boca Raton: CRC Press, 2000:447454.
587. Fetissov SO, Meguid MM, Chen C, Miyata G.
Synchronized release of dopamine and serotonin in
the medial and lateral hypothalamus of rats. Neuroscience 2000; 101:657663.
588. De Fanti BA, Hamilton JS, Horwitz BA. Meal-induced
changes in extracellular 5-HT in medial hypothalamus
of lean (Fa/Fa) and obese (fa/fa) Zucker rats. Brain
Res 2001; 902:164170.
589. Mori RC, Guimaraes RB, Nascimento CM, Ribeiro
EB. Lateral hypothalamic serotonergic responsiveness
to food intake in rat obesity as measured by microdialysis. Can J Physiol Pharmacol 1999; 77:286292.
590. Hernandez L, Parada M, Baptista T, Schwartz D,
West HL, Mark GP, et al. Hypothalamic serotonin in
treatments for feeding disorders and depression as
studied by brain microdialysis. J Clin Psychiatry 1991;
52:3240.
591. Schwartz DH, Hernandez L, Hoebel BG. Tryptophan
increases extracellular serotonin in the lateral hypothalamus of food-deprived rats. Brain Res Bull 1990;
25:803807.
592. Schwartz D, Hernandez L, Hoebel BG. Fenuramine
administered systemically or locally increases extracellular serotonin in the lateral hypothalamus as
measured by microdialysis. Brain Res 1989; 482:261
270.
593. Shimizu H, Uehara Y, Negishi M, Shimomura Y,
Takahashi M, Fukatsu A, et al. Altered monoamine
metabolism in the hypothalamus of the genetically
obese yellow (Ay/a) mouse. Exp Clin Endocrinol 1992;
99:4548.
594. Garthwaite TL, Kalkho RK, Guansing AR, Hagen
TC, Menahan LA. Plasma free tryptophan, brain
serotonin, and an endocrine prole of the genetically
obese hyperglycemic mouse at 45 months of age.
Endocrinology 1979; 105:11781182.
595. Cooper SJ, Dourish CT, Barber DJ. Reversal of the
anorectic eect of (+)-fenuramine in the rat by
selective cholecystokinin receptor antagonist MK-329.
Br J Pharmacol 1990; 99:6570.
596. Stallone D, Nicolaidis S, Gibbs J. Cholecystokinininduced anorexia depends on serotoninergic function.
Am J Physiol 1989; 256:11381141.
597. Campbell DB. Dexfenuramine: an overview of its
mechanisms of action. Rev Contemp Pharmacother
1991; 2:93113.
598. Rowland NE, Carlton J. Tolerance to the eects of Dfenuramine in rats, hamsters and mice. In: Ferrari E,
Brambilla F, eds. Disorders of Eating Behaviour: A
Psychoneuroendocrine Approach. Oxford: Pergamon
Journals, 1986:367374.
599. Samanin R, Garattini S. The Neurophamacology of
obesity: experimental studies. Rev Contemp Pharmacother 1991; 2:5359.
615.
616.
617.
618.
619.
620.
621.
622.
623.
624.
625.
626.
627.
365
Novin D, eds. The Neural Basis of Feeding and Reward. Brunswick, ME: Haer Institute, 1982:445454.
628. Fibiger HC, Phillips AG. Reward, motivation, cognition: psychobiology of mesotelencephalic dopamine
system. In: Bloom FE, ed. Handbook of Physiology.
Vol. IV. Intrinsic Regulatory Systems of the Brain.
Bethesda: American Physiological Society 1986:647
675.
629. Hoebel BG, Hernandez L, Mark GP, Schwartz DH,
Pothos E, Steckel JM, Stone EH. Brain microdialysis
as a molecular approach to obesity: serotonin, dopamine, cyclic-AMP. In: Bray G, Ricquier D, Spiegleman
B, eds. Obesity: Towards a Molecular Approach. New
York: Alan R. Liss, 1990:4561.
630. Kornetsky C, Porrino LJ. Brain mechanisms of druginduced reinforcement. In: OBrien CP, Jaee JH, eds.
Addictive States: Association for Research in Nervous
and Mental Diseases. New York: Raven Press, 1992:
5977.
631. Hernandez L, Hoebel BG. Feeding and hypothalamic
stimulation increase dopamine turnover in the accumbens. Physiol Behav 1988; 44:599606.
632. Wilson C, Nomikos. GG, Collu M, Fibiger HC.
Dopaminergic correlates of motivated behavior: importance of drive. J Neurosci 1995; 15:51695178.
633. Di Chiara G, Tanda. G. Blunting of reactivity of
dopamine transmission to palatable food: a biochemical marker of anhedonia in the CMS model? Psychopharmacology (Berl) 1997; 134:351353.
634. Hoebel BG, Monaco AP, Hernandez L, Aulisi EF,
Stanley BG, Lenard L. Self-injection of amphetamine
directly into the brain. Psychopharmacology 1983;
81:158163.
635. Guerin B, Goeders NE, Dworkin SI, Smith JE.
Intracranial self-administration of dopamine into the
nucleus accumbens. Soc Neurosci Abstr 1984; 10:1072.
636. Wise RA, Newton P, Leeb K, Burnette B, Pocock D,
Justice JB Jr. Fluctuations in nucleus accumbens
dopamine concentration during intravenous cocaine
self-administration in rats. Psychopharmacology 1995;
120:1020.
637. Bozarth MA. The mesolimbic dopamine system as a
model reward system. In: Wellner P, Scheel-Kruger J,
eds. The Mesolimbic Dopamine System: From Motivation to Action. New York: John Wiley and Sons,
1991:301333.
638. Glimcher PW, Giovino AA, Hoebel BG. Neurotensin
selnjection in the ventral tegmental area. Brain Res
1987; 403:147150.
639. Mifsud J-C, Hernandez L, Hoebel BG. Nicotine
infused into the nucleus accumbens increases synaptic
dopamine as measured by in vivo microdialysis. Brain
Res 1989; 478:365367.
640. Schilstrom. B, Svensson HM, Svensson TH, Nomikos
GG. Nicotine and food induced dopamine release in
the nucleus accumbens of the rat: putative role of
366
alpha7 nicotinic receptors in the ventral tegmental
area. Neuroscience 1998; 85:10051009.
641. Kalivas PW, Barnes CD. Limbic Motor Circuits and
Neuropsychiatry. Boca Raton: CRC Press, 1993.
642. Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science 1997; 275:
15931599.
643. Berridge KC. Measuring hedonic impact in animals
and infants: microstructure of aective taste reactivity
patterns. Neurosci Biobehav Rev 2000; 24:173198.
644. Smith GP. Dopamine and food reward. In: Fluharty
S, Morrison AM, eds. Progress in Psychobiology and
Physiological Psychology. New York: Academic Press,
1995:83144.
645. Terry P. Dopamine receptor subtypes and ingestive
behaviour. In: Cooper SJ, Clifton PG, eds. Drug Receptor Subtypes and Ingestive Behaviour. London:
Academic Press, 1996:233266.
646. Schultz W, Apicella P, Ljungberg T. Responses of
monkey dopamine neurons to reward and conditioned
stimuli during successive steps of learning a delayed
response task. J Neurosci 1993; 13:900913.
647. Ahn S, Phillips AG. Dopaminergic correlates of
sensory-specic satiety in the medial prefrontal cortex
and nucleus accumbens of the rat. J Neurosci 1999;
19:RC29.
648. Bassareo V, Di Chiara G. Dierential responsiveness
of dopamine transmission to food-stimuli in nucleus
accumbens shell/core compartments. Neuroscience
1999; 89:637641.
649. Carr KD, Papadouka V. The role of multiple opioid
receptors in the potentiation of reward by food
restriction. Brain Res 1994; 639:253260.
650. Carroll ME, France CP, Meisch RA. Food deprivation increases oral and intravenous drug intake in rats.
Science 1979; 205:319321.
651. Stricker EM, Zigmond MJ. Recovery of function after
damage to central catecholamine-containing neurons:
a neurochemical model for the lateral hypothalamic
syndrome. In: Sprague JM, Epstein AN, eds. Progress
in Psychobiology and Physiological Psychology. New
York: Academic Press, 1978:121188.
652. Cousins MS, Salamone JD. Nucleus accumbens
dopamine depletions in rats aect relative response
allocation in a novel cost/benet procedure. Pharmacol Biochem. Behav 1994; 49:8591.
653. Koob GF, Robledo P, Markou A, Caine SB. The
mesocorticolimbic circuit in drug dependence and
rewarda role for the extended amygdala? In: Kalivas
PW, Barnes CD, eds. Limbic Motor Circuits and
Neuropsychiatry. Boca Raton: CRC Press, 1996: 289
310.
654. Kelley AE, Delfs JM. Dopamine and conditioned
reinforcement. Psychopharmacology 1991; 103:187
196.
655. Weiss FMT, Lorang MT, Bloom FE, Koob GF. Oral
656.
657.
658.
659.
660.
661.
662.
663.
664.
665.
666.
667.
668.
669.
670.
alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and
motivational determinants. J Pharmacol Exp Ther
1993; 267:250258.
Grill HJ, Kaplan JM. Caudal brainstem participates in
the distributed neural control of feeding. In: Stricker
EM, ed. Handbook of Behavioral Neurobiology. New
York: Plenum Press, 1990: 125149.
Sclafani A. Nutritionally based learned avor preferences in rats. In: Capaldi ED, Powley TL, eds. Taste,
Experience and Feeding. Washington: Psychological
Association, 1990: 139156.
Mark GP, Blander DS, Hoebel BG. A conditioned
stimulus decreases extracellular dopamine in the nucleus accumbens after the development of a learned
taste aversion. Brain Res 1991; 551:308310.
Horvitz JC, Richardson WB, Ettenberg A. Dopamine
receptor blockade and reductions in thirst produce
dierential eects on drinking behavior. Pharmacol
Biochem Behav 1993; 45:725728.
Leibman JM, Cooper SJ, eds. The Neuropharmacological Basis of Reward. New York: Clarendon Press,
1989.
McGinty JF, ed. Advancing from the ventral striatum
to the extended amygdala. Annals NY Acd Sci 1999.
Vol. 877. New York: New York Acad of Sci. Vol. 877.
Sakata T, Kurokawa M, Oohara A, Yoshimatsu H. A
physiological role of brain histamine during energy
deciency. Brain Res Bull 1994; 35:135139.
Leibowitz SF. Histamine: modication of behavioral
and physiological components of body uid homeostasis. In: Yellin TO, ed. Histamine Receptors. New
York: SP Medical and Scientic Books, 1977:219253.
Sheiner JB, Morris P, Anderson GH. Food intake
suppression by histidine. Pharmacol Biochem Behav
1985; 23:721726.
Ookuma K, Yoshimatsu H, Sakata T, Fujimoto K.
Hypothalamic sites of neuronal histamine action on
food intake by rats. Brain Res 1989; 490:268275.
Ookuma K, Sakata T, Fukagawa K, Yoshimatsu H,
Kurokawa M, Machidori H, et al. Neuronal histamine
in the hypothalamus suppresses food intake in rats.
Brain Res. 1993; 628:235242.
Morimoto T, Yamamoto Y, Yamatodani A. Brain
histamine and feeding behavior. Behav Brain Res
2001; 124:145150.
Machidori H, Sakata T, Yoshimatsu H, Ookuma K,
Fujimoto K, Kurokawa M. Zucker obese rats: defect
in brain histamine control of feeding. Brain Res 1992;
590:180186.
Sakata T. Histamine receptor and its regulation of
energy metabolism. Obes Res 1995; 3(suppl 4): 541S
548S.
Sakata T. Glucose transport and energy metabolism
regulated by brain histamine. Jpn J Physiol 1997;
47(suppl 1): S32S34.
367
accumbens of the rat dierentially aects accumbal
dopamine release. Pharmacol Toxicol 1994; 75:348
352.
686. Mark G, Rada P, Pothos E, Hoebel BG. Eects of
feeding and drinking on acetylcholine release in the nucleus accumbens striatum and hippocampus of freelybehaving rats. J Neurochem 1992; 58:22692274.
687. Mark GP, Weinberg JB, Rada PV, Hoebel BG.
Extracellular acetylcholine is increased in the nucleus
accumbens following the presentation of an aversively
conditioned taste stimulus. Brain Res 1995; 688:184
188.
688. Shoaib MM, Stolerman II. Conditioned taste aversions in rats after intracerebral administration of
nicotine. Behav Pharmacol 1995; 6:375385.
689. Berger-Sweeney J, Stearns NA, Frick KM, Beard B,
Baxter MG. Cholinergic basal forebrain is critical for
social transmission of food preferences. Hippocampus
2000; 10:729738.
690. Miranda MI, Ramirez-Lugo L, Bermudez-Rattoni F.
Cortical cholinergic activity is related to the novelty of
the stimulus. Brain Res 2000; 882:230235.
691. Coscina DV, Castonguay TW, Stern JS. Eects of
increasing brain GABA on the meal patterns of
genetically obese vs. lean Zucker rats. Int J Obes
Relat Metab Disord 1992; 16:425433.
692. Ma YH, Hu JH, Zhou, XG, Zeng RW, Mei ZT, Fei J,
et al. Transgenic mice overexpressing gamma-aminobutyric acid transporter subtype I develop obesity. Cell
Res 2000; 10:303310.
693. Tsujii S, Bray GA. GABA-related feeding control in
genetically obese rats. Brain Res 1991; 540:4854.
694. Kelly J, Rothstein J, Grossman SP. GABA and
hypothalamic feeding systems. I. Topographic analysis
of the eects of microinjections of muscimol. Physiol
Behav 1979; 23:11231134.
695. Kelly J, Grossman SP. GABA and hypothalamic
feeding systems. II. A comparison of GABA, glycine
and actylcholine agonists and their antagonists.
Pharmacol Biochem Behav 1979; 11:647652.
696. Panksepp J, Meeker RB. The role of GABA in the
ventromedial hypothalamic regulation of food intake.
Brain Res Bull 1980; 5:453460.
697. Beverly JL, De Vries MG, Bouman SD, Arseneau LM.
Noradrenergic; and GABAergic systems in the medial
hypothalamus are activated during hypoglycemia. Am
J Physiol Regul Integr Comp Physiol 2001; 280:563
569.
698. Cattabeni F, Maggi A, Monduzzi M, De Angelis L,
Racagni G. GABA: circadian uctuations in rat
hypothalamus. J Neurochem 1978; 31:565567.
699. Meeker RB, Myers RD. GABA and glutamate:
possible metabolic intermediaries involved in the
hypothalamic regulation of food intake. Brain Res
Bull 1980; 5:253259.
700. Rada P, Mendialdua A, Hernandez L, Hoebel BG.
368
701.
702.
703.
704.
705.
706.
707.
708.
709.
710.
711.
712.
713.
714.
715.
716.
717.
718.
719.
720.
721.
722.
723.
724.
725.
369
of cocaine and the delta1 opioid agonist, DPDPE, but
not the delta2 agonist, deltorphin-II [in process citation]. Psychopharmacology (Berl) 2000; 152:200207.
741. Carroll ME. The role of food deprivation in the
maintenance and reinstatement of cocaine seeking behavior in rats. Drug Alcohol Depend 1985; 16:95109.
742. Kornetsky C, Esposito RU, McLean S, Jacobson JO.
Intracranial self-stimulation thresholds: a model for
the hedonic eects of drugs of abuse. Arch Gen
Psychiatry 1979; 36:289292.
743. Hagan MM, Moss DE. An animal model of bulimia
nervosa: opioid sensitivity to fasting episodes. Pharmacol Biochem Behav 1991; 39:421422.
744. Specker SM, Lac ST, Carroll ME. Food deprivation
history and cocaine self-administration: an animal
model of binge eating. Pharmacol Biochem Behav
1994; 48:10251029.
745. Campbell UC, Carroll ME. Reduction of drug self
administration by an alternative non-drug reinforcer
in rhesus monkeys: magnitude and temporal eects.
Psychopharmacology (Berl) 2000; 147:418425.
746. Carroll ME, Lac ST. Dietary additives and the
acquisition of cocaine self-administration in rats.
Psychopharmacology (Berl) 1998; 137:8189.
747. Wyvell CL, Berridge KC. Incentive sensitization by
previous amphetamine exposure: increased cue-triggered wanting for sucrose reward. J Neurosci 2001;
21:78317840.
748. Dess NK, Badia-Elder NE, Thiele TE, Kiefer SW,
Blizard DA. Ethanol consumption in rats selectively
bred for dierential saccharin intake. Alcohol 1998;
16:275278.
749. Gosnell BA. Sucrose intake predicts rate of acquisition
of cocaine self-administration.Psychopharmacology
(Berl) 2000; 149:286292.
750. Sills TL, Crawley JN. Individual dierences in sugar
consumption predict amphetamine-induced dopamine
overow in nucleus accumbens. Eur J Pharmacol 1996;
303:177181.
751. Blass EM, Homeyer LB. Sucrose as an analgesic for
newborn infants. Pediatrics 1991; 87:215218.
752. Le Magnen J. A role for opiates in food reward and
food addiction. In: Capaldi ED, Powley TL, eds.
Taste, Experience, and Feeding. Washington: American Psychological Association, 1990:241254.
753. Hoebel BG, Hernandez L, Rada PV, Parada M, Mark
GP, Taylor KM, et al. A theory of feeding motivation
and its inhibition based on dopamine and acetylcholine in the nucleus acumbens. Appetite 1996; 27:281.
754. Gendall KA, Joyce PR, Abbott RM. The eects of
meal composition on subsequent craving and binge
eating. Addict Behav 1999; 24:305315.
755. Tuomisto T, Hetherington MM, Morris MF, Tuomisto MT, Turjanmaa V, Lappalainen R. Psychological
and physiological characteristics of sweet food addiction. Int J Eat Disord 1999; 25:169175.
370
756.
371
793.
14
Experimental Studies on the Control of Food Intake
Henry S. Koopmans
University of Calgary, Calgary, Alberta, Canada
organs, in the nutrients present in the blood and transferred to tissue, and in the storage of nutrient in muscle
and fat. When force-feeding or starvation stop, any or
all of these organs could be responsible for generating
an internal signal that brings cumulative food intake
and body weight back to normal levels.
Since food intake is a behavior, it must be mediated
by the brain. Although many regions of the brain are
involved in the control of daily intake, several important
studies have shown that two major regions, the paraventricular or ventromedial hypothalamus and the lateral hypothalamus, are critically involved in the control
of daily food intake and body weight (2). If lesions are
made in the ventromedial hypothalamus or in the paraventricular nucleus, an animal will begin to eat soon
after coming out of the anesthesia, will gorge itself for
several hours, and will continue overeating for weeks or
months until a new level of body weight has been
achieved. Thereafter, food intake is stabilized and the
new level of body weight will be defended (3). As with
normal rats, if these lesioned, obese rats are overfed and
forced to reach a new level of body weight, they will
voluntarily reduce their daily food intake and bring
body weight back to the previous obese levels (see
Fig. 1). If they are starved, they will subsequently
increase their food intake until they again reach their
previous level of obesity. These obese rats are no longer
as accurate in their control of food intake: they become
nicky, that is, they respond to improved food quality
by overeating and to food adulteration by undereating.
374
Koopmans
Figure 1 Body weight and food intake of rats given ventromedical hypothalamic lesions, allowed to reach a new level of body
weight, and then force-fed or starved. After being force-fed or starved, the rats alter their food intake and bring their body weight
back to their new obese level. (From Ref. 3.)
Figure 2 Body weight of rats that were free-fed or starved before being given two dierent sizes of lesions in the lateral
hypothalamus. The rats reach a level of body weight related to the size of the lesion and the starved rats increase their food intake
after lesion. (From Ref. 5.)
375
376
Koopmans
Figure 4 Daily food intake of one-way crossed-intestines rats. The surgery was done on day 9. The rat on the right in Figure 3
that lost food or chyme into the partners crossed intestinal segment showed a large increase in daily food intake while its partner
reduced its daily intake. These large changes in daily food intake are sustained for the rest of the animals lives.
II
377
sition into tissues where they can be used for metabolism or for storage of excess food. Long-term signals
that are involved in controlling food intake over several
days are more likely to arise from shifts in metabolism
and from the storage organs. The relative importance
of all of these types of signals for the control of meal
and daily food intake is still in considerable dispute.
There are a wide range of theories about food intake
regulation with some supporting evidence for each
possibility, but there are few denitive explanations
of the underlying control mechanisms.
III
The nose and mouth are the rst organs to come into
contact with food. The neural messages generated by
the smell and taste of food are sent to the olfactory bulb
or to the brainstem and are relayed up to higher centers
of the brain. Taste and smell are usually thought to
provide chemical messages for the decision about
whether and how much to ingest, but they can become
rewards in themselves and lead to overeating and
obesity. While stimuli from the gut and from other
internal organs are certainly involved in the control of
feeding behavior, there is denitely a cognitive component. Animals need to decide when and where to feed
and to remember their past encounters with food. The
particular avors and textures can then be used to guide
feeding behavior. Collier and his collaborators have
been the major contributors to laboratory studies that
examine the decisions that are made about the cost
requirements of nding food and ingesting it. They
have shown that increasing the cost of obtaining food
by increasing the number of lever presses needed to gain
access to a food source leads to a decision to reduce the
number of meals each day (22) (see Fig. 6). While meal
number goes down, the size of the average meal
increases so that total daily food intake is held fairly
constant (22,23). If the tasks become very complex or
require too much eort, the animal may choose to eat
somewhat less than its normal daily portion and,
thereby, trade o the amount of eort in obtaining
food against its level of body weight. Daily food intake
may decrease to 8090% of its previous level. Collier
has argued that there is too much emphasis upon a
depletion-repletion model of the control of food intake
(24). He notes that changes in external requirements
cause large changes in meal patterns, but not in daily
intake. He questions whether there are xed internal
378
Koopmans
Figure 6 Number of daily meals taken by each of three rats (1, 2, 3) when they are free-feeding (FF) or when they have to press
one (CRF) or more times to gain access to food. As the lever-pressing requirement increases, the rats take fewer but larger meals.
They maintain their normal level of daily food intake until they reach the highest levels of bar pressing, when they reduce daily
intake a little. (From Ref. 22.)
IV
rats and fed them glucose, sucrose, and saline solutions (29). He found that when the nutrients were
prevented from reaching the stomach, intake was
greatly increased in a 1-hr test. In addition, the rats
showed a preference for higher concentrations of the
ingested solution. After doing a gastric stula in rats,
Smith et al. (30) found that the rats continued feeding
for more than 2 hr. A rat with an open gastric stula
will eat at a normal rate for 1520 min and, thereafter,
will continue to feed over the next 100 min at a rate
that is about half its previous rate (see Fig. 7). The fact
that the well-trained rat continues to feed suggests that
distension or chemical cues arising in the stomach, in
the small intestine, or beyond are important for the
inhibition of intake during a single meal. The decrease
in the rate of food intake after 20 min shows that
mucosal stimulation inhibits the rats avid desire for
food or that the animal tires of the motor movements
involved in feeding.
There are advantages and disadvantages to the use of
either esophageal or gastric stuli. With an esophageal
stula, the esophagus is transected, usually in the neck,
and both ends of the esophagus are externalized, or,
alternatively, the end leading to the stomach is closed
and a gastric tube is inserted. Thus, the food eaten by the
animal as well as its salivary secretions pass entirely out
of the animal and do not reach the stomach or intestine.
Sucient food and water can be given to the animal by
379
Figure 7 Food intake of rats that have a gastric stula that is either open or closed. When the stula is closed, a 17-hr-deprived
rat will complete its meal in 15 min and then take a few small meals in the next 2 hr. When the stula is open and the food drains
out of the body, the rat will continue to feed throughout the 2-hr period. (From Ref. 30.)
380
Koopmans
the bulk of the food has been lost through the stula,
and the intensity of downstream signals is greatly
reduced. The use of both the esophageal and the gastric
stula leads to considerable overfeeding, called shamfeeding. The sham-feeding animal receives taste stimuli
but little or no postingestive stimuli. Sham feeding will
continue well beyond the usual time when feeding ceases
in an intact animal.
All of the experiments agree that signals arising from
stimulation of the mucosal lining of the mouth, throat
and esophagus by food are not enough to stop feeding
behavior. Some additional signals must arise at the level
of the stomach or the small intestine to inhibit intake
during a single meal. These results are entirely consistent with the results from the crossed-intestines rats
mentioned above (13). After the intestinal surgery (see
Fig. 3), these rats exhibit a threefold dierence in daily
food intake. Since all of the food necessarily passes
through the mouth, throat, and esophagus, these upper
gut organs are stimulated three times as much in one rat
as in its partner. If stimulation of these organs were the
main signals controlling daily food intake, then the large
dierences in food intake would not have been seen in
these rats. The large, long-term dierences in food
intake of these one-way crossed intestines rats show
that these mucosal signals can play only a minor regulatory role in the control of daily food intake.
would not exceed the normal level after a meal. They fed
12-hr-deprived rats a milk meal while measuring gastric
pressure with a water manometer. The rats drank 13.6
mL with the pyloric cu open and 11.5 mL with the cu
closed. These values were not signicantly dierent and
showed that the rats stopped feeding on the basis of
gastric distension and chemoreception and did not
appear to require stimulation of the duodenum with
food. However, the rats drank to stomach capacity,
which was demonstrated in overow experiments to be
f13.6 mL. Thus, it was not clear whether the intake
was regulatory for calories eaten or was inhibited by the
limits of gastric distension. In a subsequent study,
Deutsch and his associates showed rats could eat
smaller meals of a liquid diet without noticing the
surreptitious delivery of saline into the stomach (40).
This study showed that the calories present in the
stomach were somehow sensed by the animal. Deutsch
(41) claimed that there were nutrient receptors embedded in the wall of the stomach, which would become
exposed to the lumenal contents as the gastric volume
increased. The combination of gastric distension and
the caloric concentration, as determined by exposure to
the nutrient receptors, would provide information to
the brain to inhibit feeding behavior.
One diculty with the Deutsch theory is that it pays
little attention to the anatomy of the stomach when
describing the hypothetical nutrient receptors. Neural
receptors are not likely to be present in the lumen of
the stomach or in the lumen of the gastric glands or
pits. First of all, the gastric contents are highly corrosive and nerve terminals would be readily destroyed.
Moreover, there is a constant turnover of mucosal
cells throughout the digestive tract, and these rapidly
dividing cells migrate continuously along the basement
membrane. They would override nerve terminals that
might be aimed toward the lumen. Furthermore, there
have been no descriptions of nerve terminals beyond
the lamina propria, the support tissue for the gastric
mucosa. Thus, nerves would be able to sense the
presence of food in the gastric lumen only if the food
was absorbed into the wall of the stomach. Relatively
little nutrient is absorbed through the gastric mucosa
(42). It remains possible that the food could release
gastric hormones from cells that have villus tufts
projecting into the gastric lumen and that these hormones would stimulate vagal aerents (see below).
Recently, Kaplan et al. (43,44) have challenged the
interpretation of the pyloric cu experiments. They
conrm that rats eat the same amount of food whether
a pyloric cu is open or closed, which is the fundamental
observation in previous studies (31,39,45). However,
381
they have shown that during the rst meal of a fooddeprived rat there is a rapid emptying of the stomach
that may be as much as 2540% of the meal (46). When
they measure the amount of nutrient in the stomach
after a meal with the cu either open or closed, they nd
that the gastric contents were 30% greater in the rat with
the cu closed. They conclude that although the rats
with a closed cu eat the same amount of food as rats
with an open cu, they require a larger gastric distension
signal to terminate a meal. In short, they believe that the
amount of food in the gastrointestinal tract, not just the
amount of food in the stomach, controls short-term
food intake.
Phillips and Powley (47) looked more closely at
whether gastric volume or nutrient sensing occurred in
rats with pyloric cus. They found that when the cus
were closed, the rats showed an equivalent reduction of
food intake when 5 mL of either saline or 10%, 20%, or
40% glucose was delivered to the stomach before injections. Furthermore, it did not matter whether the
infused substance was 40% glucose, fructose, or sucrose
with dierent chemical structures, metabolic pathways,
and caloric values. However, when the cus were open,
the nutritional content of these sugars as well as of the
more balanced liquid diet, Isocal, did inhibit food
intake. They conclude that gastric distension inhibits
food intake, not gastric nutrient sensing, while ingested
nutrients work at the level of the intestine to inhibit
gastric emptying and to limit food intake.
The role of the stomach in the inhibition of food
intake has to be aected by the rate of stomach emptying. As food empties, there is less food in the stomach
and less gastric distension. McHugh and Moran have
done a series of experiments on gastric emptying in rats
and monkeys (4850). They have found that saline
empties rapidly in an exponential way from the stomach. On the other hand, nutrients empty rapidly from
the stomach for the rst 45 min, but, thereafter, the
presence of nutrient in the small intestine slows down
the emptying rate to a steady state until the meal is gone.
A xed number of calories empty from the stomach per
unit time regardless of the composition of the food
placed in the stomach (34,48). They argue that the
intestine inhibits stomach emptying and that distension
of the stomach inhibits food intake. Both stomach and
intestinal signals are important.
Although there is general agreement that the stomach provides part of the signal that inhibits food
intake during a single meal, we still do not know the
nature of the signal or how it is transmitted to the
brain. Nerves are the most likely route of transmission.
The information about the degree of gastric distension
382
Koopmans
Figure 8 Rate at which single bers isolated from the vagus nerve of a cat re as the amount of air in an intragastric balloon is
increased to the designated volume. (From Ref. 51.)
383
384
Koopmans
VI
385
386
Figure 9 Diagram of two-way crossed-intestines rats. A 30cm segment of lower duodenum and upper jejunum is isolated from the gastrointestinal (GI) tract of each rat and is
connected to the intestine of its partner. The preparation is
symmetrical. Each rat loses food into the upper small
intestine of its partner, and some of that food returns to its
own lower jejunum. The stippled GI tract belongs to the rat
on the right.
the lower jejunum of the rat that fed and travels down
along the rest of the length of that rats small intestine
and lower gut. The surgery is symmetrical, so that each
rat loses some of the food that it eats into the upper
small intestine of its partner.
The short-term experiment testing the role of the
intestine in the termination of a meal, is done by feeding
one rat in the pair 10 or 30 min before the partner and
then measuring the partners intake after the crossed
segment has been stimulated by food. A rat will normally complete its rst meal after a 7-hr fast in 68 min.
The results of several experiments show that the food
intake of both rats is not aected by having a delay of 10
or 30 min (94). The rat allowed to feed rst does not
overeat even through its own lower duodenum and
upper jejunum have not come into contact with ingested
food. The unfed partner does not reduce its food intake
Koopmans
387
VII
EFFECT OF GASTROINTESTINAL
HORMONES ON FOOD INTAKE
388
Koopmans
of duodenal phasic activity (105). A meal usually generates an increase in gastric motility and an inhibition of
duodenal activity. Thus, exogenous CCK could be
causing unusual gut motility patterns that are communicated by nerves to the brain to inhibit food intake. It is
now well established that exogenous CCK requires an
intact vagus nerve to cause an inhibition of food intake
(106108). There is also evidence hat doses of CCK that
inhibit food intake produce plasma levels that are an
order of magnitude higher than normal postprandial
CCK levels (109). Moreover, IV infusion of a monoclonal antibody to CCK blocked CCK-stimulated pancreatic enzyme secretion, but had no stimulatory eect
on food intake (110).
One of the most convincing pieces of evidence that
endogenous CCK acts to reduced food intake is that
specic CCK antagonists cause an increase in food
intake (111113). Since these antagonists cause an
increase in feeding behavior, it is unlikely that the
change can be due to some nonspecic cause. There
are two known types of CCK receptors: (1) CCK-A
receptors that are present in the pancreas, gallbladder,
pyloric sphincter, aerent vagal bers (114,115), and
specic brain regions, including the area postrema, the
nucleus tractus solitarius, and the hypothalmus, and (2)
CCK-B receptors that are distributed widely in the brain
and in the stomach (116). Specic blockade of type A
receptors, but not of type B receptors, attenuates the
inhibition of food intake caused by CCK (117,118).
However, these antagonists cross the blood brain barrier, are distributed throughout the body, and could
have their eects either in the periphery or in the brain.
Since CCK-A receptors are found in both the brain and
the periphery, it is not yet clear where the antagonists act
(119). It is possible that CCK-A antagonists act in the
brain to increase food intake and not in the periphery.
Another indication that the CCK-A receptor is involved
in the inhibition of food intake is the existence of
OLETF rats that have been shown to have a deletion
in the CCK-A receptor that makes it nonfunctional
(120). These rats are hyperphagic, have an overexpression of NPY in the dorsomedial hypothalamus, and
become moderate obese (121). As mentioned above, the
role of the mutant CCK-A receptor could be either
central or peripheral.
The ability of the upper gut peptides gastrin, secretin,
and GIP to reduce food intake has been tested using a
sham-feeding paradigm on rats with open gastric stuli
(119). It was found that even at relatively high doses,
none of these peptides had an inhibitory eect on
feeding behavior. However, CCK and CCK octapeptide
were eective in inhibiting sham feeding.
389
by the intraventricular injection of a bombesin receptor antagonist (128). A bombesin antagonist administered at high doses had no eect on normal food intake
but was able to block bombesin-induced satiety (129).
It appears to act independently of CCK.
Serotonin is present in many endocrine cells in the
gut (ECL cells) and is released by a wide variety of
stimuli (130). Its major eect is local since serotonin is
rapidly inactivated in the bloodstream. It appears to
stimulate aerent vagal neurons that terminate in the
intestinal mucosa and project to the brain (131). Recent work has shown that CCK and serotonin activate
dierent vagal aerents (132) and that glucose stimulates 5HT release while peptides stimulate CCK release from endocrine cells (133). Serotonin has also
been shown to inhibit the intake of all the major macronutrients when injected IP (134). Its precursor,
trytophan, also reduces food intake in humans (135).
Both of these studies delivered serotonin (or its precursor) to the periphery, making it dicult to determine whether the eects were central or peripheral
because brain serotonin also inhibits food intake (7).
Another set of hormones are present in endocrine
cells of the lower gut, and some of these have been
shown to inhibit food intake. The hormones, neurotensin (NT), peptide YY (PYY) and glucagon-like peptide 1 and 2 (GLP-1 and GLP-2), are present in
endocrine cells that have an increased frequency as
Figure 10 Percent suppression of food intake during the rst 15 min of food presentation as increasing amounts of the gut
peptides cholecystokinin octapeptide (CCK8) and bombesin (BBS) are injected into the peritoneal cavity of rats. (From Ref. 122.)
390
Koopmans
VIII
When nutrients stimulate the surface of the small intestine, GI hormones are released. Two hormones, one
from the upper small intestine, gastric inhibitory polypeptide (GIP), and another from the lower small intestine, glucagon-like peptide 1 (GLP-1), have been shown
to be incretins for the release of the pancreatic hormones,
insulin and amylin, and to indirectly inhibit the release
of glucagon (97). Thus, after a meal containing carbohydrate, plasma insulin and amylin levels rise and
glucagon levels fall. Glucagon may continue to be released if there is protein in the diet since it helps to
mediate amino acid disposal (136).
The pancreatic hormone glucagon has long been
known to suppress food intake in man and rodents
(137,138). This suppression can be blocked by vagotomy (139) and, more specically, by hepatic vagotomy
(140). Glucagon is the hormone of starvation and
catabolism, and its plasma levels increase during a
fast. It falls soon after a carbohydrate meal or an oral
glucose tolerance test, but can remain elevated or even
go up slowly after a meal containing protein and fat
(136,141). Sometimes it even goes down after a mixed
meal (142). If it has a role in satiety, it must be rather
specic for the noncarbohydrate macronutrients. The
most convincing piece of evidence that glucagon may
be acting as a satiety agent is that the injection of
glucagon antibodies causes an increase in food intake
(143,144). Glucagon reduces food intake when it is
infused into the portal vein (138) and is less eective
when it is infused into the vena cava (145). All of these
results suggest that the glucagon acts on the liver to
inhibit food intake and that the information about the
presence of glucagon is sent to the brain through the
hepatic vagal nerve. Whether its eect is the result of
normal physiology or malaise is not clear. The major
diculty with the glucagon hypothesis is that glucagon
is the hormone of starvation, provoking both glycogenolysis and gluconeogenesis, and glucagon has its
highest concentration in the blood during a fast when
the animals are usually hungry.
Another pancreatic hormone, insulin, has long been
thought to be involved in the control of food intake.
Insulin rises after a meal and gradually declines as
carbohydrate absorption diminishes (21). The gluco-
391
Figure 11 Daily food intake of rats made diabetic after the baseline infusion of saline and, thereafter, infused intravenously
with increasing daily doses of insulin. The open bars indicate the amount of glucose lost in the urine of these rats. Daily food
intake increases at the lower doses of insulin even though there is an elevated blood glucose and substantial loss of glucose
through the urine.
392
Koopmans
IX
393
XI
394
Figure 12 Diagram of conscious rats with continuous crosscirculation of the blood between the two rats. Grafts from
other inbred rats are used to connect the descending aorta of
one rat to the ascending vena cava of its partner. Thirty
percent of cardiac output crosses in each 15-sec circulation
time, and the blood is completely mixed every minute. The
stippled vessels are those that carry only arterial blood.
Koopmans
395
396
Splanchnectomy combined with vagotomy was no different from vagotomy alone, showing once again that
the sympathetic gut nerves did not alter energy balance,
but section of the vagus nerve was very eective in
lowering food intake and body weight. Our study of
vagotomy produced a larger eect than that found in
most other studies in the literature (222,223). We also
tested the size of the rst meal after a 7-hr fast and found
that 15-min meal size was not dierent across any of the
surgical groups even though vagotomy caused a large
reduction in daily intake. Apparently, the section of
both extrinsic aerent and eerent gut nerves had no
eect on short-term intake. We also measured the rats
response to a 50% dilution of the liquid diet by water.
The rats adjusted both the size of their rst meal and
their daily intake on the rst day so that caloric intake
did not change. This result suggests that vagotomized
rats were somehow regulating ingested calories and not
just responding to food volume.
The dramatic eect of our vagotomies on energy
balance and body weight loss can be interpreted in
one of two ways. Either we were very eective in cutting
all the branches of the vagus nerve and the resulting
complete vagotomy led to a substantial reduction in
food intake and body weight relative to other studies in
the literature, or our cutting of the mesenteric membranes supporting the esophagus, stomach, and liver led
to changes in the rats comfort that exacerbated the
reduction in food intake and body weight after vagotomy. In the later case, the changes would be nonregulatory. We used a histochemical method at the end of the
study for verifying that the nerves had been sectioned:
the calcitonin gene-related peptide (CGRP) bers disappeared from the gastric wall and the duodenal
mucosa after total nerve section, showing that aerent
nerves had been destroyed. The observed large decrease
of food intake and body weight following vagotomy is
complicated from a theoretical perspective. If transection of the nerve simply cut vagal sensory bers that
increase their ring rate to inhibit food intake [as seen in
Paintals gastric distension vagal nerve bers (51)], then
vagotomy would be anticipated to cause an increase in
food intake. If, on the other hand, the transections cut
nerves that stimulate food intake when activated or
reduce their ring rate to signal inhibition [as found in
Niijimas hepatic nerve recordings to portal glucose
infusion (227)], then one would expect that food intake
would decrease as has actually been found after most
studies of vagotomy. These alternate explanations
require further research with more selective aerent or
eerent nerve sections. In fact, both vagotomies and
sympathectomies cause large changes in the sensory
Koopmans
XII
397
tical binding, the weight loss depends on patient compliance in food selection. If the selected foods can pass
easily through the narrowed opening of the stomach
pouch, as can milk shakes or blenderized meals, then the
patients rapidly regain their lost weight. In recent years,
obesity surgeons have returned to the gastric bypass operation (243), which combines the restriction of a stomach pouch with the stimulation of the lower gut. In the
gastric bypass surgery, a small isolated pouch of upper
stomach is connected through a restricted outlet to
the upper jejunum. This procedure bypasses the usual
controls of gastric emptying and spreads the emptied
food more rapidly into the lower gut (244). Indeed, the
plasma levels of lower gut hormones following a meal
in gastric bypass patients (245248) were quite similar
to those found after jejunoileal bypass. The 15-fold
integrated postprandial enteroglucagon response after
gastric bypass was comparable to the 14-fold increase
found after j-i bypass (249). Thus, the current surgery of choice, gastric bypass, has a large lower-gut
component. New experimental surgeries are following
the same strategy of greater stimulation of the lower
gut (243).
Greater stimulation of the lower small intestine could
cause reduced food intake and increased weight loss by
stimulating the nerves in the ileum or by greater release
of lower gut hormones. The role of ileal nerves in longterm weight loss has not yet been investigated. There are
four hormones that are released from the lower small
intestine and might play a role in the inhibition of food
intake. Neurotensin (NT) is a tridecapeptide that was
originally isolated from the hypothalamus and has the
same structure in rat, dog, and human. It is found in the
N-cells of the gut, which are present in increased
frequency as one moves down the small intestine
(250). The N-cells have microvilli that make contact
with the lumen of the small intestine and may thus
directly sense luminal contents. Neurotensin is released
after a normal meal or after the infusion of fat into the
duodenum (251). Gastric secretion and motility are
inhibited by high doses of NT (97). When injected IP,
neurotensin causes a reduction of food intake and
grooming and an increase in drinking (252), but plasma
levels were not measured and an eect on gut motility
cannot be ruled out as an explanation of reduced
feeding. A recent study involving the IP injection of a
novel neurotensin analog also appears to inhibit food
intake (253). When NT is injected into the hypothalamic
paraventricular nucleus, it causes a dose-dependent
reduction of food intake without associated changes in
water intake, grooming, or sleeping behavior (254), but
these investigators found no eect of IV infusion.
398
Koopmans
399
400
Koopmans
XIII
duced a signicant 5- or 10-kcal reduction of food intake but there was no dierence in intake between the
portal or vena cava infusions (291). Plasma levels of
glucose or amino acids passing through the liver would
be very dierent in these rats because only f20% of
cardiac output goes directly to the liver. Thus, the
elevation of infused glucose passing through the liver
would be ve times greater in the portal than in the
vena cavainfused rats. This result suggests that the
liver does not sense the total amount of glucose absorbed from the intestine and use this information to
control daily intake.
One way to assess the role of the liver in the control of
meal intake is to allow a substantial amount of watersoluble nutrient to pass through the hepatic sinusoids
and see whether the nutrient has a direct eect on food
intake during a single meal. This objective can be
achieved by feeding one rat in the two-way crossedintestines rat pairs, a symmetrical preparation in which
401
402
and the loose end is sutured end-to-side to the ascending vena cava. As a result of this surgery, all of the blood
leaving the gut passes directly into the systematic circulation and does not go through the liver on its rst pass
into the body. The liver is supported only by blood
arriving through the hepatic artery, and over the next 10
days it is diminished by 30% in wet weight (292). If the
liver were monitoring the total amount of water-soluble
nutrient that was entering through the gut and using this
information to control food intake, one would predict
that the shunted rat would overeat on its rst meal after
the surgery and would continue to overeat until hepatic
signals to the brain had adjusted for the reduced caloric
load passing through the hepatic artery. In fact, it was
found that the rats ate 3.6 F 0.7 kcal on their rst meal
compared to 6.2 F 1.6 kcal for the controls ( P = .18).
Koopmans
Figure 15 Daily food intake of rats provided with a portacaval shunt or given sham surgery. Measurements of meal patterns
were made on the rst day after surgery and during the last 6 days, when the rats had returned to the baseline intake.
403
Figure 16 Body weight of rats with either portacaval shunt or sham surgery. Rats with the portacaval shunt lose more weight
after surgery, but their subsequent weight gain is comparable to that of controls.
404
Koopmans
inform the brain about peripheral changes in metabolism is by the release of some humoral factor. The type
and quantity of food eaten has an eect on the release of
somatomedins or insulinlike growth factors that alter
metabolism and enhance growth (302). A specic inhibitor of food intake secreted from the liver has not been
identied, but remains a possibility.
XIV
METABOLIC SIGNALS
405
Figure 17 Average daily food and energy intake of rats infused intravenously with saline, glucose, amino acids, lipids, and an IV
diet that had the same composition as the oral diet. Slashed bars are the voluntary daily food intake; open bars are the total
number of calories infused. The total height of the bar is the total amount of calories ingested and infused. Rats show a 50%
compensation for glucose and lipids, nearly complete compensation for amino acids, and 7580% compensation for the IV diet.
(From Ref. 317.)
406
Koopmans
407
Another blocker, 2,5-anhydro-d-mannitol (2,5AM), also interferes with glucose metabolism and
increases food intake in a dose-dependent manner
(334). 2,5-AM inhibits glycogenolysis and gluconeogenesis (335). It also produces a small decrease in plasma glucose and a signicant increase in plasma fatty
acids, glycerol, and ketone bodies (336). It is as eective in increasing food intake in diabetic as in normal
rats, suggesting that elevated blood glucose and low
blood insulin levels are not detrimental to its eect.
Low doses of 2,5-AM probably act in the liver. When
infused intraportally, it has a faster and larger capacity
to increase food intake than when infused intravenously. The eects of small doses of 2,5-AM are eliminated by hepatic vagotomy, although higher doses are
still eective in increasing food intake. 2,5-AM also
aects metabolism: it causes an increase in metabolic
rate during the rst hour after injection but has no
long-lasting eect on whole body energy expenditure.
It does lower RQ with a decrease in carbohydrate
metabolism and an increase in fatty acid oxidation
(337). 2,5-AM lowers hepatic ATP, which may provide
a signal that increases food intake (338). On the other
hand, infusion of 100% TPN reduces food intake by
85%, but there are no associated changes in hepatic
ATP or ATP-to-Pi ratio. Thus, this ratio doesnt seem
to control food intake during intravenous infusions of
nutrients (339). On the 5th day of this study, voluntarily daily food intake increased considerably but
there still no changes in hepatic ATP.
There are also a couple of inhibitions of fatty acid
metabolism that cause an increase in food intake. Mercaptoacetate (MA) causes an increase in food intake
during the day in rats fed a high-fat diet but not a lowfat diet (340). MA impairs mitochondrial beta-oxidation of fatty acids (341) and causes elevation of plasma
free fatty acids, no change in plasma glucose, and a
reduction of the ketone, 3-hydroxybutyrate (340). The
eects of MA can be blocked by subdiaphragmatic
vagotomy and by capsaicin destruction of vagal aerents (331), suggesting that the eects of MA are transmitted through the vagus nerve. MA activates the sympathetic nervous system and increases plasma levels of
norepinephrine, fatty acids, and glucose (327).
Another fatty acid oxidation inhibitor, methyl palmoxirate (MP), also causes an increase in food intake
(342). MP lowers fatty acid oxidation by inhibiting carnitine palmitoyltransferase I, which transports longchain fatty acids into mitochondria (343). It elevates
plasma free fatty acids and glycerol while lowering
ketone bodies (344). MP also interacts with 2-DG which
blocks glucose utilization to cause an increase in food
408
Koopmans
XV
STORAGE SIGNALS
409
months later there was no dierence in body composition and no signicant change in cumulative food intake
in the lipectomized squirrels relative to sham controls.
Indeed, the lipectomized ground squirrels ate slightly
less food and gained slightly more weight than their
sham controls, but neither result was signicant. Again,
this study shows some regulation of body fat, but no
necessary connection between changes in body fat and
changes in food intake.
Many studies have shown that the energy balance
regulating mechanism has the most diculty recognizing the caloric content of fat: people eating high-fat
diets tend to gain weight, and low-fat diets help them
to diet and lose weight (356). These well-established
phenomena are probably due to their bodys inability
to recognize fully the fat calories in their diets. The
lipid infusion studies (cited above under Metabolic
Signals) have shown that the adjustment to intravenous body fat is slow and incomplete with rats reducing their daily food intake by only 42% of the calories
infused after 4 days of slow adjustment (317). A more
recent study has shown that both intragastric and
intravenous infusion of glucose was more eective in
reducing food intake than the same caloric amount of
fat (70% compared to 40% of calories infused, respectively) (357). Intragastric infusion caused a greater
reduction of intake than intravenous infusion for both
macronutrients. Control rats overate on a high-fat
diet by 25 kcal/day (compared to a baseline intake
of f77 kcal). These studies suggest that there is not as
good a satiety mechanism for the fat component of the
diet as for the water-soluble macronutrients regardless
of route of delivery.
Another possible way in which food intake could be
disconnected from the amount of body fat is through the
deposition of ingested fat into adipose tissue before it is
noticed by the food intake regulating system. The
ingested or infused fat could be transferred into fat or
muscle by an enzyme, lipoprotein lipase (LPL), present
on the capillary linings of these (358,359) and other
tissues, such as mammary glands (360), before the foods
caloric value has been recognized. This theory actually
assumes that once circulating metabolites are moved
into storage tissues, they are no longer recognized as
having been ingested. It also postulates that activation
of LPL should lead to overeating and obesity (358,359).
The expression of LPL in adipose tissue is controlled
and elevated by increased plasma insulin levels
(361,362), which, in the context of this theory, suggests
that insulin should increase rather than decrease food
intake (see discussion in Pancreatic Hormones above).
Greenwood (363) has argued that lipoprotein lipase acts
410
Koopmans
411
Figure 19 Food intake and body weight of ob/ob mice given a daily IP injection of ob protein for 34 days. n, rats receiving 5 lg/
g/day of ob protein; o and E, rats receiving vehicle or no treatment. Similar treatment of db/db mice produced no eect. (From
Ref. 66.)
obese (374,375). More recently, measurements of immunoreactive leptin have been made in the blood of normal
and obese humans (376). These investigators found a
signicant fourfold increase in the serum levels of leptinlike molecules in obese individuals compared to normal
weight subjects, and there was a strong positive correlation between serum concentrations of a leptinlike
molecule and the percentage of body fat (r = .85). It
is not clear whether these leptinlike molecules are
restraining food intake in these obese patients or are
altered and ineective. When seven these patients were
given a low-calorie diet (800 kcal/d), there was a drop in
both serum leptinlike material and in the expression of
ob mRNA in their adipose tissue. Both of these changes
rebounded, in part, when the patients were put on a
weight maintenance diet and ate more food.
The physiological triggers of leptin release have been
explored by changes in the expression of the ob gene in
the adipose tissues of mice and rats. Fasting led to a
substantial fall in the ob mRNA in the epididymal fat
pad of ob/ob mice, and refeeding brought it back
toward normal levels (377). This reults was conrmed
in Sprague-Dawley rats and was shown to have a
circadian rhythm with the ob gene expression doubling
during the 12 hr of dark when the rats were fed (378).
Fasting prevented this cyclic uctuation. A single large
injection of insulin (1 IU) into fasted rats led to an
increase in ob mRNA expression to the levels of fed
controls. Thus, insulin may play some role in ob gene
expression and leptin release. Injection of hydrocortisone also led to an increase in ob mRNA and a corresponding decrease in food intake and body weight
(379). Although these studies are based only on gene
expression and not on blood leptin levels, they suggest
412
Koopmans
XVII
Obesity occurs when food intake exceeds energy expenditure for an extended period of time (386). One cause of
obesity is the ready availability of a large variety of
food. The alluring tastes of attractive foods seem to
override the internal signals that normally inhibit food
intake. Rats are known to become obese when given an
attractive supermarket diet (387,388). Diets that are
high in both fat and carbohydrate have been shown to
cause overfeeding and weight gain (389,390). This result
is also true of modern man.
Mixed meals that have a high fat content tend to
cause overeating (390). Meals of high caloric value and
high fat content also prevent the oxidation of the fat
component of the diet. Fat oxidation is inhibited by
carbohydrate-containing meals because the absorbed
glucose releases insulin which, at low levels, inhibits
fatty acid release (391). Insulin also activates lipoprotein
lipase which moves some of the fat into adipose tissue
for storage rather than allowing the fat to be transferred
to tissues for oxidation (392). In addition, ingested fat is
stored at a lower energy cost than is fat synthesized from
carbohydrate and protein. The cost of storing fat in
adipose tissue is only 3% of the ingested calories while
the cost of converting carbohydrate into fat requires
23% of the calories consumed (393). When mice are
given an increased percentage of their diet as fat, their
body fat content increases and a larger percent of the
mice have >30% of their body composition as fat
(394). When human subjects have fat removed from
their diet, they lose weight (395). These studies suggest
that fat calories are less eective in inhibiting food
intake than are carbohydrate or protein calories. This
is conrmed in studies in which glucose and lipids
were infused intragastrically or intravenously in rats
(317,357). The lipid infusion by either route was less
eective in the inhibition of daily food intake. One
way to counteract a high fat content of the diet is to
burn fat calories by exercising (396).
The large increase in the proportion of people in
North America who have been identied as obese in the
past decade (397) shows that the recent increases in the
ACKNOWLEDGMENTS
This chapter was supported by grants from NIH and
NSERC.
REFERENCES
1.
413
11.
Brobeck, JR. Food intake as a mechanism of temperature regulation. Yale J Biol Med 1947; 20:545552.
12. Cottle GN, Carlson LD. Adaptive changes in rats
exposed to cold. Am J Physiol 1954; 178:305308.
13. Koopmans HS. Internal signals cause large changes in
food intake in crossed-intestines rats. Brain Res Bull
1985; 14:595603.
14. Koopmans HS, Sclafani A, Fichtner C, Aravich P.
The eects of ileal transposition on food intake and
body weight loss in VMH obese rats. Am J Clin Nutr
1982; 35:284293.
15. Collier GH. Satiety: an ecological perspective. Brain
Res Bull 1985; 14:693700.
16. Johnson DF, Ackro K, Peters J, Collier GH. Changes
in the rats meal patterns as a function of the caloric
density of the diet. Physiol Behav 1986; 36:929936.
17. Booth DA. Conditioned satiety in the rat. J Comp
Physiol Psych 1972; 81:457471.
18. McHugh PR. The control of gastric emptying.
J Auton Nerv Syst 1983; 9:221231.
19. Lin HC, Doty JE, Reedy TJ, Meyer TH. Inhibition of
gastric emptying by sodium oleate depends on the
length of the intestine exposed to acid. Am J Physiol
1990; 259:G1025G1030.
20. Steens AB. Blood glucose and FFA levels in relation
to the meal pattern in the normal and the ventromedial
hypothalamic lesioned rat. Physiol Behav 1969; 4:215
225.
21. Steens AB. Plasma insulin content in relation to
blood glucose level and meal pattern in the normal and
hypothalamic hyperphagic rat. Physiol Behav 1970;
5:147151.
22. Collier G. Hirsch E, Hamlin PH. The ecological
determinants of reinforcement in the rat. Physiol
Behav 1972; 9:705716.
23. Kanarek RB. Availability and caloric density of the
diet as determinants of meal patterns in cats. Physiol
Behav 1975; 15:611618.
24. Collier G. The dialogue between the house economist
and the resident physiologist. Nutr Behav 1986; 3:9
26.
25. Davis JD, Campbell CS. Peripheral control of meal
size in the rat: eect of sham feeding on meal size and
drinking rate. J Comp Physiol Psych 1973; 83:379387.
26. Rosenzweig MR. The mechanisms of hunger and
thrist. In: Postman L, ed. Psychology in the Making.
New York: Knopf, 1962; 73143.
27. Hull CL, Livingston JR, Rouse RO, Barker AN.
Time, sham, and esophageal feeding as reinforcements. J Comp Physiol Psych 1951; 44:236245.
28. Janowitz HD, Grossman MI. Some factors aecting
the food intake of normal dogs and dogs with esophageostomy and gastric stulae. Amer J Physiol 1949;
159:143148.
29. Mook DG. Oral factors in appetite and satiety. Ann
NY Acad Sci 1989; 575:265278.
414
30. Smith GP, Gibbs J, Young RC. Cholecystokinin and
intestinal satiety in the rat. Fed Proc 1974; 33:1146
1149.
31. Scalfani A, Nissenbaum JW. Is gastric sham feeding
really sham feeding? Am J Physiol 1985; 248:R387
R390.
32. Grill HJ, Berridge KC, Ganster DJ. Oral glucose is the
prime elicitor of preabsorptive insulin secretion. Am J
Physiol 1984; 246:R8895.
33. Plato. The Timeaus of Plato. New York:Arno Press
1973:271.
34. Hunt JN, Stubbs DF. The volume and energy content
of meals as determinants of gastric emptying.
J. Physiol (Lond) 1975; 245:209255.
35. Hunt JN. A possible relation between the regulation of
gastric emptying and food intake. Am J Physiol 1980;
239:G1G4.
36. Adolph BK. Urges to eat and drink in rats. Am J
Physiol 1947; 151:11025.
37. Janowitz HD, Grossman MI. Eects of variations in
the nutritive density on intake of food in dogs and
cats. Am J Physiol 1949; 258:184193.
38. Tomlin J. The eect of the gel forming liquid bre on
feeding behavior in man. Br J Nutr 1995; 74:427436.
39. Deutsch JA, Young WG, Kalogeris TJ. The stomach
signals satiety. Science 1978; 201:165167.
40. Deutsch JA, Gonzales MF. Gastric nutrient content
signals satiety. Behav Neural Biol 1980; 30:113116.
41. Deutsch JA. Dietary control and the stomach. Prog
Neurobiol 1983; 20: 313332.
42. Karel L. Gastric absorption. Physiol Rev 1948;
28:433450.
43. Kaplan JM, Siemers W, Grill HJ. Ingestion, gastric ll
and gastric emptying before and after withdrawal of
gastric contents. Am J Physiol 1994; 267:R1257
R1265.
44. Seeley RJ, Kaplan JM, Grill HJ. Eect of occluding
the pylorus on intraoral intake: a test of the gastric
hypothesis of meal termination. Physiol Behav 1995;
58:245249.
45. Kraly FS, Smith GP. Combined pregastric and gastric
stimulation by food is sucient for normal meal size.
Physiol Behav 1978; 21:405408.
46. Kaplan JM, Spector AC, Grill HJ. Dynamics of
gastric emptying during and after stomach ll in the
rat. Am J Physiol 1992; 263:R813R820.
47. Phillips RJ, Powley TL. Gastric volume rather than
nutrient content inhibits food intake. Am J Physiol
1996; 271:R766R796.
48. McHugh PR, Moran TH. Calories and gastric
emptying: a regulatory capacity with implications for
feeding. Am J Physiol 1979; 236:R254R260.
49. McHugh PR, Moran TH. Accuracy of the regulation
of caloric ingestion in the rhesus monkey. Am J
Physiol 1978; 235:R29R34.
50. McHugh PR, Moran TH, Wirth JB. Postpyloric
Koopmans
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
415
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
416
99. Go VLW, Michner S, Roddy D, Koch M. Clinical
relevance of regulatory gastrointestinal peptides, Clin
Biochem 1984; 17:8288.
100. Glick Z, Thomas DW, Mayer J. Absence of eect of
injections of the intestinal hormones secretin and
cholecystokinin-pancreozymin upon feeding behavior.
Physiol Behav 1971; 6:58.
101. Koopsman HS, Deutsch JA, Branson PJ. The eect of
cholecystokinin pancreozymin on hunger and thirst in
mice. Behav Biol 1972; 7:441444.
102. Gibbs J, Young RC, Smith GP. Cholecystokinin
decreases food intake in rats. J Comp Physiol Psych
1973; 84:488495.
103. Smith GP, Gibbs J, Young RC. Cholecystokinin and
intestinal satiety in the rat. Fed Proc 1974; 33:1146
1149.
104. Deutsch JA, Hardy WT. Cholecystokinin produces
bait shyness in rats. Nature 1977; 266:196.
105. Shillabeer G, Davison JS. Endogenous and exogenous
cholecystokinin may reduce food intake by dierent
mechanism. Am J Physiol 1987; 253:R379R382.
106. Smith GP, Jerome C, Cushin BJ, Eterno R, Simansky
KJ. Abdominal vagotomy blocks the satiety eect of
cholecystokinin in the rat. Science 1981; 213:1036
1037.
107. Lorenz DN, Goldman SA. Vagal mediation of the
cholecystokinin satiety eect in rats. Physiol Behav
1982; 29:599604.
108. Reidelberger RD. Abdominal vagal mediation of the
satiety eects of exogenous and endogenous cholecystokinin in rats. Am J Physiol 1992; 263:R1354R1358.
109. Reidelberger RD, Kalogeris TJ, Soloman TE. Plasma
CCK levels after food intake and infusion of CCK
analogs that inhibit feeding in dogs. Am J Physiol
1989; 256:R1148R1154.
110. Reidelberger RD, Varga G, Rosenquiest GL, Liehr
RM, Wong H, Walsch JH. Comparative eects of CCK
monoclonal antiboby on food intake and pancreatic
exocrine secretion in rats. Int J Obes 1991; 15:12.
111. Hewson G, Leighton RG, Hughes J. The cholecystokinin receptor antagonist L364,718 increases food
intake in the rat by attenuation of the action of
endogenous cholecystokinin. Br J Pharm 1988; 93:79
84.
112. Dourish CT, Rycroft W, Iverson SD. Postponement of
satiety by blockade of brain cholecystokinin (CCK-B)
receptors. Science 1989; 245:15091511.
113. Reidelberger RD, ORourke MF. Potent cholecystokinin antagonist L364,718 stimulates food intake in
rats. Am J Physiol 1989; 257:R1512R1518.
114. Davison JS, Clarke GD. Mechanical properties and
sensitivity to CCK of vagal gastric slowly adapting
mechanoreceptors. Am J Physiol 1988; 255:G55G60.
115. Schwartz GJ, Mchugh PR, Moran TH. Integration of
vagal aerent responses to gastric loads and cholecystokinin in rats. Am J Physiol 1991; 261:R64R69.
Koopmans
116. Reidelberger RD. Cholecystokinin and control of food
intake. J Nutr 1994; 124:1327S1333S.
117. Corwin RL, Gibbs J, Smith GP. Increased food intake
after type A but not type B cholecystokinin receptor
blockade. Physiol Behav 1991; 50:255258.
118. Moran TH, Ameglio PJ, Schwartz GJ, McHugh PR.
Blockade of type A, not type B, CCK receptors attenuates satiety actions of exogenous and endogenous
CCK. Am J Physiol 1992; 262:R46R50.
119. Lorenz DN, Kreielsheimer G, Smith GP. Eect of
cholecystokinin, gastrin, secretin and GIP on sham
feeding in the rat. Physiol Behav 1979, 23:10651072.
120. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi
M, Natori T. Spontaneous long-term hyperglycemic
rat with diabetic complications: Otsuka Long-Evans
Tokushima Fatty (OLETF) strain. Diabetes 1992;
41:14221428.
121. Bi S, Ladenheim EE, Schwartz GJ, Moran TH. A role
for NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats. Am
J Physiol 2001; 281:R254R260.
122. Gibbs J, Fauser DJ, Rowe EA, Rolls BJ, Rolls ET,
Maddison SP. Bombesin suppresses feeding in rats.
Nature 1979; 282:208210.
123. Gibbs J, Kulkosky PJ, Smith GP. Eects of peripheral
and central bombesin on feeding behavior in rats.
Peptides 1981; 2(S2):179183.
124. Ghatei MA, Jung RT, Stevenson JC, Hilllyard CJ,
Adrian TE, Lee YC, Christodes ND, Sarson DL,
Mashiter K, MacIntyre I, Bloom SR. Bombesin:
action on gut hormones and calcium in man. J Clin
Endocrinol Metab 1982; 54:980985.
125. Gibbs J, Kulkosky J, Smith GP. Eects of peripheral
and central bombesin on feeding behavior of rats.
Peptides 1981; 2(S2):179183.
126. Stuckey JA, Gibbs J, Smith GP. Neural disconnection
of gut from brain blocks bombesin-induced satiety.
Peptides 1985; 6:12491252.
127. Plamondon H, Merali Z. Push-pull perfusion reveals
meal-dependent changes in the release of bombesinlike peptides in the rat paraventricular nucleus. Brain
Res 1994; 668:54-61.
128. Motamedi F, Rashidy-Pour A, Zarrindast MR,
Bavadi M. Bombesin-induced anorexia requires central bombesin receptor activation: independence from
interaction with central catecholinergic systems. Psychopharmacology 1993; 110:193197.
129. Laferrere B, Leroy F, Bonhomme G, Le Gall A,
Basdevat A, Guy-Grand B. Eects of bombesin, of a
new bombesin agonist (B1M187) and a new antagonist
(B1M189) on food intake in rats, in relation to
cholecystokinin. Eur J Pharm 1992; 215:2328.
130. Racke K, Schworer H. Regulation of serotonin release from the intestinal mucosa. Pharm Res 1991; 23:
1325.
131. Blackshaw LA, Grundy D. Eects of 5-hydroxytrypt-
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
417
W, Bray GA, eds. Hunger: Basic Mechanisms and
Clinical Implications. New York: Raven Press,
1976:273280.
148. Bagdade JD, Bierman EL, Porte DJ. The signicance
of basal insulin levels in the evaluation of the insulin
response to glucose in diabetic and nondiabetic
subjects. J Clin Invest 1967: 46:1549-1557.
149. Polonsky KS, Given BD, Van Cauter E. Twenty-four
hour proles and pulsatile patterns of insulin secretion
in normal and obese subjects. J Clin Invest 1988;
81:442448.
150. Porikos KP, Pi-Sunyer FX. Regulation of food intake
in human obesity: studies with caloric dilution and
exercise. Clin Endocrinol Metab 1984; 13:547561.
151. Woods SC, Lotter EC, McKay LD, Porte D. Chronic
intracerebroventricular infusion of insulin reduces
food intake and body weight in baboons. Nature
1979; 282:503505.
152. Brief DJ, Davis JD. Reduction of food intake and
body weight by chronic intraventricular insulin infusion. Brain Res Bull 1984; 12:571575.
153. Schwartz MW, Bergman RN, Kahn SE, Taborsky J,
Fisher LD, Sipols AJ, Woods SC, Steil GM, Porte D.
Evidence for entry of plasma insulin into cerebrospinal
uid through an intermediate compartment in dogs. J
Clin Invest 1991; 88:12721281.
154. Vanderweele DA, Pi-Sunyer FX, Novin D, Bush MJ.
Chronic insulin infusion suppresses food ingestion
and body weight gain in rats. Brain Res Bull 1980;
5(S4):711.
155. Vanderweele DA. Insulin and satiety from feeding in
pancreatic normal and diabetic rats. Physiol Behav
1993; 54:477485.
156. Vanderweele DA. Insulin is a prandial satiety hormone. Physiol Behav 1994; 56:619622.
157. Willing AE, Walls EK, Koopmans HS. Insulin
administration leads to increased food intake in
diabetic rats eating high and low fat diets. Physiol
Behav 1994; 56:983991.
158. Willing AE, Koopmans HS, Walls EK. Hepatic portal
and vena cava insulin infusions lead to increased food
intake in diabetic rats. Physiol Behav 1994; 56:9931001.
159. Walls EK, Koopmans, HS. Increased food intake
following carotid and systemic insulin infusions. Int J
Obes 1992; 16:153160.
160. Woo R, Kissile HR, Pi-Sunyer FX. Elevated postprandial insulin levels do not induce satiety in normalweight humans. Amer J Pysiol 1984; 247:R745R749.
161. Rodin J, Wack J, Ferrannini E, DeFronzo RA. Eect
of insulin and glucose on feeding behavior. Metabolism 1985; 34:826831.
162. Holt SH, Miller JB. Increased insulin responses to
ingested foods are associated with lessened satiety.
Appetite 1995; 24:4354.
163. DCCT Research Group. The eect of intensive treat-
418
ment of diabetes on the development and progression
of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977986.
164. Morley JE, Flood JF. Amylin decreases food intake in
mice. Peptides 1991; 12:865869.
165. Chance WT, Balasubramaniam S, Stallion A, Fischer
JE. Anorexia following the systemic injection of amylin. Brain Res 1993; 607:185188.
166. Ohsawa H, Kanatsuka A, Yamaguchi T, Makino H,
Yoshida S. Islet amylin polypeptide inhibits glucosestimulated insulin secretion from isolated rat pancreatic islets. Biochem Biophys Res Commun 1989;
160:961967.
167. Chance WT, Balasubramaniam S, Zhang FS, Wimalawamsa SJ, Fischer JE. Anorexia following intrahypothalmic administration of amylin. Brain Res
1991; 352354.
168. Rushing PA, Hagan MM, Seeley RJ, Lutz TA, Woods
SC. Amylin: a novel action in the brain to reduce body
weight. Endocrine 2000; 141:850853.
169. Sexton PM, Paxinos G, Kenney MA, Wookey PJ,
Beaumont K. In vitro autoradiographic localization of
amylin binding sites in rat brain. Neuroscience 1994;
62:553567.
170. Reidelberger RD, Arnelo U, Granqvist L, Permert J.
Comparative eects of amylin and cholecystokinin on
food intake and gastric emptying in rats. Am J Physiol
2001; 280:R605R611.
171. Lutz TA, Del Prete E, Scharrer E. Subdiaphragmatic
vagotomy does not inuence the anorexic eect of
amylin. Peptides 1995; 16:457462.
172. Brazeau P, Vale W, Burgus R, Ling N, Butcher M,
Rivier J, Guillemin R. Hypothalamic polypeptide that
inhibits the section of immunoreactive pituitary
growth hormone. Science 1973; 179:7779.
173. Polak JM, Pearse AGE, Grimelius L, Bloom SR,
Arimura A. Growth-hormone release-inhibiting hormone in gastrointestinal and pancreatic D cells. Lancet
1975; 1:12201224.
174. Larsson LI, Gottermann N, De Magistris L, Reheld
J, Schwartz TW. Somatostatin cell processes as pathways for paracrine secretion. Science 1979; 205:1393
1395.
175. Konturek SJ, Kwiecien N, Obtulowicz W, Bielinski
W, Olesky J, Schally AV. Eects of somatostatin-14
and somatostatin-28 on plasma hormonal and gastric
sensory responses to cephalic and gastrointestinal
stimulation in man. Scand J Gastroenterol 1985; 20:
3138.
176. Park J, Chiba T, Yamada T. Mechanisms for the
direct inhibition of canine gastric parietal cells by
somatostatin. J Biol Chem 1987; 262:1419014196.
177. Dollinger HC, Raptis S, Pfeier EF. Eects of
somatostatin on exocrine and endocrine pancreatic
function stimulated by intestinal hormones in man.
Horm Metab Res 1976; 8:7478.
Koopmans
178. Koerker DJ, Reul W, Chideckel E, Palmer J, Geodner
CJ, Ensich J, Gule CC. Somatostatin: hypothalamic
inhibitor of the endocrine pancreas. Science 1974;
184:482484.
179. Schusdiarra V, Rouiller D, Harris V, Unger RH.
Splanchnic somatostatin: a hormonal regulator of
nutrient homeostasis. Science 1980; 207:530532.
180. Lotter EC, Krinsky R, McKay JM, Treneer CM,
Porte D, Woods SC. Somatostatin decreases food intake of rats and baboons, J Comp Physiol Psych 1981;
5:278287.
181. Smedh U, Kaplan JM, Bjorkstrand E, Uvnas-Moberg
K. Dual eects of somatostatin analog octreotide on
gastric emptying during and after intragastric ll. Am
J Physiol 1999; 277:R1291R1296.
182. Erlanson-Albertsson C, Larson A. A possible physiological function of pancreatic procolipase activation
peptide in appetite regulation. Biochemistry 1988;
70:12451250.
183. Erlanson-Albertsson C. Pancreatic colipase. Structure
and physiological aspects. Biochim Biophys Acta
1992; 1125:17.
184. Erlanson-Albertsson C, Mei J, Okada S, York D, Bray
GA. Pancreatic procolipase propeptide, enterostatin,
specically inhibits fat intake. Physiol Behav 1991;
49:11911194.
185. Bouras M, Huneau JF, Luengo C, Erlanson-Albertsson C, Tome D. Metabolism of enterostatin in rat
intestine, brain membranes, and serum: dierential
involvement of proline-specic peptidases. Peptides
1995; 16:399405.
186. Mei J, Erlanson-Albertsson C. Role of intraduodenally administered enterostatin in rats: inhibition of
food intake. Obesity Res 1995; 4:161165.
187. Sorhede M, Erlanson-Albertsson C, Mei J, Nevalainen
T, Aho A, Sundler F. Enterostatin in gut endocrine
cellsimmunocytochemical evidence. Peptides 1996;
17:609614.
188. Winsell MS, Lowe ME, Erlanson-Albertsson C. Rat
gastric procolipase: sequence, expression and secretion
during high-fat feeding. Gastroenterology 1998;
115:11791185.
189. Sorhede M, Mulder H, Mei J, Sundler F, ErlansonAlbertsson C. Procolipase is produced in rat stomach
a novel source of enterostatin. Biochim Biophys Acta
1996; 1301:207212.
190. Rice HB, Corwin RL. Eects of enterostatin on the
consumption of optional food in non-food-deprived
rats. Obes Res 1998; 6:5461.
191. Brantl V, Teschemacher H, Blasig J, Hneschen A,
Lottspeich F. Opioid activities of b-casomorphins.
Life Sci 1981; 28:19031909.
192. Daniel H, Vohwinkel M, Rehner G. Eect of casein
and b-casomorphins on gastrointestinal motility in
rats. J Nutr 1990; 120:252257.
193. Allesher HD, Storr M, Piller C, Brantl V, Schudsd-
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
419
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
420
Koopmans
222.
239. Bray GA, Greenway FL, Barry RE. Surgical treatment of obesity: a review of our experience and an
analysis of published results. Int J Obes 1977; 1:331
367.
240. Sclafani A, Koopmans HS, Vasselli JR, Reichmann
M. Eects of intestinal bypass surgery on appetite,
food intake and body weight in obese and lean rats.
Am J Physiol 1978; 234:E389E398.
241. Nightengale ML, Sarr MG, Kelly KA, Jensen MD,
Zinsmeister AR, Palumbo PJ. Prospective evaluation
of vertical banded gastroplasty as the primary operation for morbid obesity. Mayo Clin Proc 1991; 66:
773782.
242. Mason EE, Ito C. Gastric bypass in obesity. Surg Clin
North Am 1967; 47:13451351.
243. Balsinger BM, Murr MM, Poggio JL, Sarr MG.
Bariatric surgery: surgery for weight control in
patients with morbid obesity. Med Clin North Am
2000; 84:477489.
244. Sugerman HJ, Kellum JM, Engle KM, Wolfe L,
Starkey JV, Birkenhauer R, Fletcher P, Sawyer MJ.
Gastric bypass for treating severe obesity. Am J Clin
Nutr 1992; 55:560S566S.
245. Lawaetz O, Blackburn AM, Bloom SR, Aritas Y,
Ralphs DNL. Gut hormone prole and gastric
emptying in the dumping syndrome: a hypothesis
concerning the pathogenesis. Scand J Gastroenterol
1983; 18:7380.
246. Sirinek KR, ODorisio TM, Howe B, McFee AS.
Neurotensin, vasoactive intestinal peptide and Rouxen-Y gastrojejunostomy. Arch Surg 1985; 120:605609.
247. Meryn S, Stein D, Strauss EW. Pancreatic polypeptide, pancreatic glucagon and enteroglucagon in
morbid obesity and following gastric bypass operation. Int J Obes 1986; 10:3752.
248. Kellum JM, Kuemmerle JF, ODorosio TM, Rayford
P, Martin D, Engle K, Wolf L, Sugerman H. Gastrointestinal hormone responses to meals before and after
gastric bypass and vertical banded gastroplasty. Ann
Surg 1990; 211:763770.
249. Sarson DL, Scopinaro N, Bloom SR. Gut hormone
change after jejunoileal (JIB) or biliopancreatic bypass
(BPB) for morbid obesity. Int J Obesity 1981; 5:471
480.
250. Wang XM, Thomas RP, Evers BM. Eect of gut
transposition on the expression of the endocrine gene
neurotensin. J Gastroenterol Surg 1998; 2:230237.
251. Ferris CF, George JK, Eastwood G, Potegal M,
Carraway RE. Plasma levels of neurotensin: methodological and physiological considerations. Peptides
1991; 12:215220.
252. Sandoval SL, Kulkosky PJ. Eects of peripheral
neurotensin on behavior of the rat. Pharm Biochem
Behav 1992; 41:385390.
253. Boules M, Cusack B, Zhao L, Fauq A, McCormick
DJ, Richelson E. A novel neurotensin analog given
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
421
267.
268.
269.
270.
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
422
Koopmans
281.
liver enzymes and metabolites after total liver denervations. Physiol Behav 1995; 58:625628.
Louis-Sylvestre J, Servant JM, Molimard R, Le
Magnen J. Eect of liver denervation on feeding
pattern of rats. Am J Physiol 1980; 239:R66R70.
Louis-Sylvestre J, Larue-Achagiotis C, Michel A,
Houssin D. Feeding pattern in liver transplanted rats.
Physiol Behav 1990; 48:321326.
Beverly JL, Yang ZJ, Meguid MM. Hepatic vagotomy
eects on metabolic challenges during parenteral
nutrition in rats. Am J Physiol 1994; 266:R646R649.
Phillips LS Nutritional regulation of somatomedin
activity and growth. In: Giordano G, Van Wyk JJ,
Minuto F, eds. Somatomedins and Growth. London:
Academic Press, 1979; 311323.
Signal RJ, Purdon C, Bilinski D, Vranik M, Marliss E.
Glucoregulation during and after intense exercise:
eects of beta-blockade. J Clin Endocrinol Metab
1994; 78:359366.
Mayer J, Bates MW. Blood glucose and food intake in
normal and hypophysectomized, alloxan-treated rats.
Am J Physiol 1952; 168:812819.
Mayer J. Regulation of energy intake and body
weight: the glucostatic theory and the lipostatic hypothesis. Ann NY Acad Sci 1955; 63:1542.
Van Itallie TB. The glucostatic theory 1953-1988:
roots and branches. Int J Obes 1990; 14(S3):110.
Hanson ME, Grossman MI. The failure of intravenous glucose to inhibit food intake in dogs. Fed
Proc 1948; 7:50.
Janowitz HD, Hanson ME, Grossman MI. Eect of
intravenously administered glucose on food intake in
the dog. Am J Physiol 1949; 156:8791.
Mellinko SM, Frankland M, Boyle M, Griepel M.
Relation between serum amino acid concentration and
uctuations in appetite. J Appl Psychol 1956; 8:535
538.
Peters JC, Harper AE. Adaptation of rats to diets
containing dierent levels of protein: eects on food
intake, plasma and brain amino acid concentrations
and brain neurotransmitter metabolism. J Nutr 1985;
115:382398.
Moundras C, Remesy C, Demigne C. Dietary protein
paradox: decrease of amino acid availability induced
by high-protein diets. Am J Physiol 1993; 264:G1057
G1065.
Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc
B 1952; 140:578592.
Nicolaidis S, Rowland N. Metering of intravenous
versus oral nutrients and the regulation of energy
balance. Am J Physiol 1976; 231:661668.
Woods SC, Stein LJ, McKay LD, Porte D. Suppression of food intake by intravenous nutrients and insulin
in the baboon. Am J Physiol 1984; 247:R393R401.
Walls EK, Koopmans HS. Eect of intravenous
299.
300.
301.
302.
303.
304.
305.
306.
307.
308.
309.
310.
311.
312.
313.
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
331.
423
quired for lipoprivic but not glucoprivic feeding in
rats. Am J Physiol 1990; 258:R1395R1401.
332. Tordo MG, Hopfenbeck, Novin D. Hepatic vagotomy (partial hepatic denervation) does not alter
ingestive responses to metabolic challenges. Physiol
Behav 1982; 28:417424.
333. Bellinger CL, Williams FE. Liver denervation does not
modify feeding responses to metabolic challenges or
hypertonic NaCl induced water consumption. Physiol
Behav 1983; 30:463470.
334. Tordo MG, Rafka R, DiNovi MJ, Friedman MI.
2,5-Anhydro-D-mannitol: a fructose analogue that
increases food intake in rats. Am J Physiol 1988;
254:R150R153.
335. Hanson RL, Ho RS, Wisenberg JJ, Simpson R,
Younathan ES, Blair JB. Inhibition of gluconeogenesis and glycogenolysis by 2,5-anhydro-d-mannitol.
J Biochem 1984; 259:218233.
336. Tordo MG, Rawson N, Friedman MI. 2,5-AnhydroD-mannitol acts in liver to initiate feeding. Am J
Physiol 1991; 261:R283R288.
337. Park CR, Seeley RJ, Bentham L, Friedman MI,
Woods SC. Whole body energy expenditure and fuel
oxidation after 2,5-anhydro-D-mannitol administration. Am J Physiol 1995; 268:R299R302.
338. Rawson NE, Blum H, Osbakken MD, Friedman MI.
Hepatic phosphate trapping decrease ATP and increase feeding after 2,5-anhydro-D-mannitol. Am J
Physiol 1994; 266:R112R117.
339. Bodoky G, Yang ZJ, Mequid MM, Laviano A,
Szeverenyi N. Eects of fasting, intermittent feeding
or continuous parenteral nutrition of fat liver and
brain energy metabolism as assessed by 31P-NMR.
Physiol Behav 1995; 58:521527.
340. Scharrer E, Langhans W. Control of food intake by
fatty acid oxidation. Am J Physiol 1986; 250:R1003
R1006.
341. Bauche F, Sabourault D, Giudicelli Y, Nordmann J,
Nordmann R. Inhibition in vitro of acyl-CoAdehydrogenases by 2-mercaptoacetate in rat liver
mitochondria. Biochem J 1983; 215:457464.
342. Friedman MI, Tordo MG, Ramirez I. Integrated
metabolic control of food intake. Brain Res Bull 1986;
17:855859.
343. Tutwiler GF, Ho W, Mohrbacher RJ. 2-Tetradeclycidic acid. Methods Enzymol 1981; 2:533551.
344. Friedman MI, Tordo MG. Fatty acid oxidation and
glucose utilization interact to control food intake in
rats. Am J Physiol 1986; 251:R840R845.
345. Friedman MI, Ramirez I, Bowden CR, Tordo MG.
Fuel partitioning and food intake: role of mitochondrial
fatty acidtransport. Am J Physiol1990; 258:R216R221.
346. Lazzarini SJ, Schneider JF, Wade GN. Inhibition of
fatty acid oxidation and glucose metabolism does not
alter food intake or hunger motivation in Syrian
hamsters. Physiol Behav 1988; 44:209213.
424
Koopmans
347.
425
388.
15
Diet Composition and the Control of Food Intake in Humans
John E. Blundell
University of Leeds, Leeds, England
James Stubbs
Rowett Research Institute, Aberdeen, Scotland
428
Diet Composition
dierent groups of subjects and in dierent environments. If this factor is thought to be fundamental to
biological regulation, it should be shown to operate in a
number of dierent species.
II
METHODOLOGICAL APPROACHES
TO STUDIES OF HUMAN
FOOD INTAKE
429
Figure 1 Constraints and limitations that the experimental environment places on studies of human feeding. In general, the
environment ranges from totally free-living, which is realistic but very dicult to make measurements in, to the laboratory, where
measurement are easy but may be contaminated by artifacts due to the articiality of the laboratory surroundings.
430
Studies are therefore measuring not how the biobehavioral system functions, but how it functions
under dierent circumstances. Is any of this relevant
to how the system functions when it is not in an experiment and not being measured? Currently we favor
(where possible) a methodological approach which
attempts to bridge the gap between the laboratory and
the real world by overlapping protocols that explore the
same issue in dierent environmental contexts. Few
individual studies are likely to unequivocally resolve
major issues in appetite research.
B
Demand Characteristics
Diet Composition
methodologies employed. The literature on the inuence of sweetness on appetite, and publications on the
inuence of dietary fat on PI satiety and the role of
CCK as a PI satiety hormone are three clear examples
where a number of conicting results can be obtained
from various studies in the literature. At the present
time there is a considerable degree of selective presentation of research results by interested parties who
aim to use the scientic literature to market products
which may or may not inuence human feeding
behavior or energy balance. The appetite literature
is a spin doctors paradise. It is therefore important to
consider all of the literature on a given area.
Researchers have a responsibility to acknowledge
the limitations of their own experimental designs
and to avoid overgeneralizing results or drawing
premature conclusions from individual studies conducted in specic experimental environments, on
small numbers of subjects. Since the majority of
positive results usually provide indirect support for
a hypothesis, the limitations of that support should be
acknowledged. The perfect experimental protocol to
study human feeding behavior does not exist.
431
III
A
432
Figure 2 Anatomy of the human appetite system is represented by the relationship between peripheral physiology and the
central nervous system. Only the main sites of physiological signals thought to be important in producing feedback signals that
aect feeding are outlined. It is of note that all putative signals identied operate along the sequence of ingestion, absorption,
metabolism, and storage. All such putative satiety signals have other primary functions.
Diet Composition
expenditure? Why is it that a decrease in energy expenditure does not exert a restraining eect over food
intake? (Are these the same questions?) Why does a
positive energy balance fail to generate a negative signal
to suppress food intake? Does the body contain a
mechanism(s) capable of detecting a positive energy
balance (or positive nutrient balances)?
Can we attribute current secular trends in body
weight to a greater per capita drive to consume more
food and energy, or could it be that the mechanisms
concerned with resisting overconsumption are simply
too weak?
B
Satiety Signals
Some physiological responses which follow food consumption are believed to terminate eating and/or maintain inhibition over further intake. These responses are
usually referred to as satiety signals (17). What are the
features of foods that are believed to be monitored and
which give rise to satiety signals? What is the status of
the putative satiety signals?
It has been assumed or claimed that volume, weight,
energy content, macronutrient proportion, and energy
density may all be monitored and constitute the source
of specic satiation or postingestive (PI) satiety signals.
These may be divided into general factors (e.g., weight,
volume) which apply to all foods, and specic factors
(nutrient content, taste, and smell) which depend on the
particular food consumed. Why should weight and
volume appear as important features that aect food
intake in some studies? (A liter of water would have
weight and volume but would provide no energy or
nutrients.) The ultimate function of satiation and PI
satiety signals is to monitor the biological value of
foods and to play a role in the processing of ingested
nutrients (all physiological signals involved in satiation,
e.g., rate of gastric stretch, release of CCK, gastric
emptying, nutrient oxidation, etc., have functions in
addition to their role in a negative feedback system). A
satiety signal is a function assumed by some underlying
physiological property. Given a history of food seeking
and consumption, it is inevitable that weight and
volume of food will have become associated with (conditioned to) the important biological components of
food, namely, energy value and nutrient composition.
The system has learned how to operate in a real environment, and the objective of the system is to produce a
veridical response.
Brunswiks theory of perception provides a model
for understanding this (18). Weight and volume are
learned cues with high functional validity (proximal
433
434
Figure 3 Schematic representation (not to scale) of the relationship between the subjectively expressed constructs of motivation
in relation to feeding, and their relationship to quantitative and qualitative feeding behavior.
satiety. Evidence suggests that this is so (14). Additionally, the palatability (and variety) of food would
exert a major inuence during consumption but less
inuence afterward. It may be inferred that cognitions
would be markedly dierent during and after ingestion. Consequently, biological, environmental, and
cognitive inuences dier during the operation of
satiation (intrameal satiety) and (intermeal) satiety.
As regards overconsumption, there is little if any direct
evidence that satiety signals function in a manner
consistent with mechanisms geared to the tight regulation of body weight. It follows that speaking about
satiety in general can be quite confusing. Conceptual understanding would be improved by an increase
in semantic precision. A scheme illustrating the relationship among hunger, appetite, satiation, and PI
satiety and their purported inuence on feeding behavior is illustrated in Figure 3.
D
should enhance compliance on weight-reducing programs. Being able to increase the drive to eat may
increase longevity and quality of life in patients experiencing cachexia. Understanding how to manage hunger
and satiety also has important implications for the
nutritional support of a number of clinical conditions.
One of the great benets of using human subjects is that
they can be asked about their sensations and motivations. Understanding the prole of physiological
changes that attend and underlie changes in the hunger
state oers key sites for intervention and manipulation
of the hunger state. Both indices of carbohydrate
oxidation (24) and a preprandial drop in plasma glucose have been shown to predict the onset of feeding in
rats (25) and humans (26). Furthermore, in animals,
abolition of the small but reproducible preprandial
drop in blood glucose, by a small intravenous infusion,
has been shown to inhibit eating for several hours (27).
Under these conditions satiety is maintained and hunger is inhibited.
While there is little evidence that satiety signals
strongly defend against overconsumption, there is
ample evidence that acute (28,29) or prolonged negative energy balance (30) leads to an elevation of
hunger. In extremis, signicant loss of body tissue
leads to an obsessive and unabating drive to eat.
Understanding how the intact system operates and
which physiological events underlie changes in motivation to eat and feeding behavior can help unravel
and manipulate the mechanisms that inuence meal
Diet Composition
435
IV
Figure 4 Interaction between physiology and behavior in their response to food and food-related environmental stimuli. It is
notable that food illicits potent cognitive, learned behavioral and physiological responses which together determine the feeding
strategies of an individual.
436
Orosensory Components
Gastrointestinal Components
Diet Composition
action potentials along gastrointestinal nerves) including the nutrients themselves to the postabsorptive
circulation (44). It is interesting that patients with
short intestines (and few secondary complications)
attempt to eat to energy requirements. This means
they are hyperphagic, presumably to compensate for
the decreased absorptive capacity of the shortened
small intestine (M. Elia, personal communication). In
addition, stretch, CCK receptors and osmoreceptors,
and a variety of gastrointestinal peptides all appear to
play some role in aecting short-term feeding.
C
The Liver
The liver is the main organ that receives and deals with
the digestion products of a meal, except for chylomicrons, which initially bypass the liver, since they are
absorped through the lymphatic system. It has been
suggested that this eect contributes to the delayed
eects of fat in suppressing appetite (32). It has been
suggested from preference-conditioning experiments
using portal infusions of fructose (45) that the liver
also functions as a sensory organ. This is because rats
learn to prefer avors that are paired with a glucose
infusion into the hepatic portal vein. The liver possesses extensive neural connections to the brain which
appear to be involved in glucoprivic and lipoprivic
feeding, at least in rodents (46). Pharmacological
impairment of nutrient oxidation in the liver stimulates intake (47). A detailed discussion of these links
between nutrient metabolism and the CNS is given
below. The liver is the main site of assimilation,
metabolism, and distribution of nutrients subsequent
to ingestion. The liver is most likely the central organ
that communicates information about peripheral fuel
status to the brain (48).
D Circulating Factors
The circulation and the peripheral nervous system
together inform the brain of the overall status of
energy and nutrients that are 1) in the circulation, 2)
moving into the circulation from the gut (and hence
indirectly of their concentration in the gut), and 3)
available in nutrient stores. While the gut provides
important cues which probably alert the brain to the
likely inux of energy and nutrients, failure to reinforce this message by actual delivery of energy and
nutrients will lead to diminished sensations of satiation
and PI satiety. Thus, sham-feeding dogs (49) and rats
are hyperphagic (50,51). On the other hand, nutrient
infusions as lipid or glucose fail to elicit the same
437
438
the oxidation of one nutrient is blocked, other energyproviding nutrients can to some extent be used.
However, inhibition of the oxidation of both major
energy-providing macronutrients leads the rat to seek
metabolic fuels from the environment (60). This in turn
suggests that the CNS is responsive to the combined
eects of macronutrient metabolism rather than being
driven by negative feedback from a single nutrient.
What, then, are the combined eects of nutrient
oxidation on appetite and subsequent feeding likely to
be? As regards diet composition, nutrient processing,
and peripheral signals related to feeding, there is now
sucient evidence to provisionally link changes in diet
composition to changes in the signaling systems concerned with the control of macronutrient balance. This
notion is schematically illustrated in Figure 5 and
summarized as follows:
1. Changes in energy and nutrient intake can inuence peripheral fuel selection (6269).
2. Peripheral changes in fuel selection are determined by physiological and thermodynamic constraints
which dene a hierarchy in the immediacy with which
the balance of recently ingested macronutrients are
autoregulated by increases in their own oxidative disposal (protein>carbohydrate>fat) (3,11,58,59).
3. This hierarchy appears to parallel a hierarchy
in the satiating eciency of the macronutrients (3,58).
Thus while protein, carbohydrate, and fat each contribute to satiety, they do so to diering degrees.
4. These two hierarchies may be causatively related
since a growing body of literature suggests that nutrient
oxidation in the periphery is monitored by the CNS as a
component of satiety (46,60). In particular, Ritter and
Calingasan have provided important evidence which
suggests that neural pathways monitor fat oxidation
in the periphery and CHO oxidation (perhaps more
precisely) in both the periphery and the CNS (46).
Currently less is known about protein oxidation, except
that at the level of nutrient metabolism, protein is the
most satiating macronutrient (58).
5. Langhans notes that the midbrain centers, concerned with monitoring peripheral fuel utilization, are
connected via extensive neural relays to the areas of the
forebrain (especially the hypothalamus and the paraventricular nucleus) that are the sites of action of
peptide systems concerned with the control of protein,
CHO, and fat balance (70).
Thus, an integrative model is beginning to emerge
which may account for the manner in which the CNS is
capable of monitoring physiological signals concerned
with overall macronutrient intake and fuel ux (5860).
This model accounts for the manner in which feeding
There has long been a belief that changes in macronutrient stores exert negative feedback on energy
intake. It is interesting in this context that, despite the
critical role of protein-energy relationships for survival
time during under nutrition (30,68,69,71), few models
have considered lean tissue changes as a major source
of feedback signals that inuence appetite control
(see below).
Mayer proposed that peripheral CHO utilization
exerts negative feedback on EI through the actions of
hypothalamic glucosensors (22), which could be corrected by longer-term lipostatic regulation. In 1963,
Russek postulated the presence of glucose receptors in
the liver and formulated the hepatostatic theory of EB
regulation (72). These receptors have never been localized, although it has recently been suggested that sensory vagal aerents function as hepatic glucosensors
(48,70). Flatt proposed that CHO stores exert negative
feedback on EI in 1987 (65). The robustness of these
models has been reviewed elsewhere (58,59).
Kennedy in 1953 argued for feedback information
reaching the hypothalamus from adipose tissue, which
he presumed to be closely monitored in normal rats (57).
The simplest way that such lipostasis could operate
would be through the sensitivity of the hypothalamus
to the concentration of circulating metabolites. Hervey
in 1969 (73) proposed a mechanism for lipostatic regulation, based on endogenous measurement of the fat
mass by means of a fat-soluble hormone. It was proposed that such a hormone would act as a physiological
tracer that monitors adipose tissue mass by the dilution
principle. Experiments in parabiotic rats (74,75) suggest
Diet Composition
439
Figure 5 Schematic diagram illustrating putative connections between diet composition, fuel metabolism, peripheral satiety
signals, and central control of feeding. Diet composition aects satiety. Protein is more satiating than carbohydrate, which is
more satiating than fat. Diet composition also aects postingestive fuel metabolism, since increases in protein and carbohydrate,
but not fat balance, are tightly modulated by autoregulatory increases in their oxidative disposal. It is known that nutrient
oxidation in peripheral tissues appears to be associated with satiety. The hierarchical regulation of macronutrient balance by
oxidative disposal may partially underlie the hierarchy in the satiating eciency of the macronutrients. Indeed, high levels of
protein and carbohydrate (but not fat) oxidation are indicative of the fed state. High rates of fat oxidation are usually
synonymous with energy decits. It has also been suggested that changes in peripheral fuel metabolism may act as and trigger
additional peripheral satiety signals that are relayed to feeding centers of the brain believed to be concerned with the control of
macronutrient balance.
440
there is an exchange of some bloodborne factors between lean and obese animals that aects the food
intake of the lean rat.
Similar experiments in the late 1970s using genetically obese rodents (76) created the conceptual context
for the studies that have led to the identication of the
protein leptin (77). Since the discovery of leptin in 1994,
there has been an intense focus on signals from adipose
tissue as key controllers of longer-term energy balance.
The importance of leptin should not be underplayed.
However, the strength of negative feedback arising
from adipose tissue in humans should not be overestimated. It is abundantly clear from the current prevalence of overweight and obesity (15) that adipose
tissue accumulation does not exert strong negative
feedback which restores energy balance, at least from
the point of excess EI. There is far more evidence that
loss of adipose tissue leads to its regain. For instance,
the majority of people who lose weight eventually
regain it (78). There is now an extensive literature on
leptin and other putative feedback signals arising from
adipose tissue (see 79 for a recent review). There is a
minuscule literature on the extent to which changes in
adipose tissue exert feedback on appetite and energy
intake at the whole body level. Neither the metabolism
nor size of storage of any single nutrient per se exerts a
powerful unconditioned negative feedback on quantitative feeding behavior (3,4,11,14). It is therefore
important to examine how changes in nutrient stores
and metabolism collectively inuence appetite and
energy balance, longitudinally under conditions where
specic components of energy balance have been perturbed. It is critical that putative physiological and
molecular mechanisms of appetite control should be
related where possible to the actual feeding behavior
they are supposed to inuence. In this context it is
useful to consider the value of underfeeding studies as a
means of assessing the relationship between tissue loss
and subsequent feeding behavior.
As regards disturbances of this system in the development of obesity, the evidence from the human literature suggests the following.
1. In the short term, it is remarkably easy to perturb
energy balance in either a positive or a negative direction. Modications of the composition or energy density of the diet can be used to generate considerable
energy imbalances (3,4,14).
2. In the medium to longer term, the evidence
suggests that humans defend against induced energy
decits, regardless of body weight at the outset of the
induced decit (15,78). Over the same time window,
humans are remarkably tolerant of moderate increases
Diet Composition
441
Figure 6 Primary ways in which food and nutrient ingestion inuences the main compartments of the human appetite system.
Food inuences this system through multiple feedbacks at multiple levels which can be traced through the processes of food
location, ingestion, digestion, absorption, and metabolism. Satiety is therefore maintained by a functional sequence or cascade of
sequential physiological events which reinforce each other. Removing parts of a food or nutrients eects on this sequence will
therefore diminish its impact on satiety.
Protein
Protein appears to be the macronutrient which suppresses energy intake to a greater extent than any of the
other macronutrients. Careful retrospective analysis of
food records (14,84) indicate that protein exerts postingestive action over and above the contribution from
energy per se. In studies where subjects record their food
intake, the percentage energy intake from protein has
been found to predict decreases in intake. Percent
energy intake from fat is a signicant predictor of increase in energy intake and carbohydrate is very weakly
related to energy intake. (14,84,85).
Protein also exerts a large inuence on satiety in
the laboratory. Some studies using pure macronutrient loads delivered to the stomach or solutions
quickly swallowed by subjects wearing noseclips
(86,87) have found that all macronutrients have equal
satiating power. It is intriguing in this regard that
sensory cues (especially taste) may be important in
clearly identifying the eects of nutrient ingestion.
Miller and Teates (88) found that male Sprague
Dawley rats were able to select from nutritionally
dierent diets in a way that stabilized the protein
442
energy ratio at 0.14. However, when rats were subjected to impairment of oral somatosensory input,
they were unable to maintain a stable selection pattern. The authors hypothesized that selection between
protein and carbohydrate (or energy) at least
involves an associative learning process in which
somatosensory inputs eect feeding activity and/or
the properties of the food link dietary choice behaviour to later metabolic consequences.
It also appears that there may be a critical threshold
in the amount of protein required to suppress subsequent energy intake since studies that have found little
eect of protein relative to other macronutrient preloads have only used small amounts of energy as protein
in the preload (86,89). Hill and Blundell (90) found that
a high-protein (HP) meal (31% of 2.1 MJ) produced a
greater sensation of fullness and a decreased desire to
eat, relative to a high-carbohydrate (HC) meal (52%) of
the same energy content. Hill and Blundell (91) also
found that both obese and normal-weight subjects
reduced their subsequent meal intakes by 19% and
22% respectively after a HP (54% of 2 MJ) meal
compared to a HC meal (63% of 2 MJ) with weight of
food held constant. Barkeling et al. (92) gave 20 normalweight women a high-protein (43% of 2.6 MJ) or a highcarbohydrate (69% of 2.6 MJ) lunch and measured the
energy intake at a subsequent evening meal. They found
that energy intake was depressed by 12% after consumption of the HP meal. Booth et al. (93) also found
that an HP meal reduced the intake of a subsequent test
meal by 26% relative to a virtually protein-free meal in
normal-weight individuals. Thus, protein appears to be
particularly satiating when given at moderate and
large amounts.
This apparent appetite-restraining eect of protein
has not yet been given a strong theoretical basis, and
there has been little recent investigation of the proteinstat. It is perhaps pertinent to note that essential amino
acids when ingested in excess of requirements form a
physiological stress that must be disposed of by oxidation. It is known than animals will alter feeding behavior
in order to alleviate a physiological stress (94). Pigs, in
particular, appear capable of learning to select a protein:energy ratio in the diet that is optimal for growth
(95,96), as can rats (88). There is also evidence that the
kind of animo acids ingested may inuence satiety.
Imbalances in single essential amino acids can greatly
aect the feeding behavior of rats (97). The protein:
energy ratio of foods may be important in inuencing
feeding. Malnourished children nd it dicult to tolerate nutritional supplements whose protein:energy ratio
is too high. Millward has hypothesized that lean tissue
Diet Composition
443
Figure 7 (A) Relationship between energy intake and tissue change during 6 months severe undernutrition, 3 months
rehabilitation, and 2 months ad libitum feeding in 12 of the subjects who took part in the Minnesota study. Of particular note is
the fact that ad libitum energy intake returned to preunderfeeding levels at approximately the time lean tissue returned to baseline
values. By this time fat mass had overshot baseline and reached f170% of original levels. (B) predicted eects of protein
supplementation on the relationship between tissue deposition and postweight loss hyperphagia. Depletion of lean tissue may
act as a signal for hyperphagia once original fat mass has been repleted. Dietary protein supplements, after weight loss, may help
replete lean tissue more rapidly, diminish postweight loss hyperphagia, and promote weight stability below preweight
loss levels.
Carbohydrates
444
Diet Composition
445
Fat
446
The apparently ambivalent eects of fat have generated a phenomenon referred to as the fat paradox. On
the one hand, a fat such as corn oil infused into the
jejunum has been shown to slow gastric emptying,
increase feelings of fullness, and reduce food intake in
a test meal. Infusions into the ileum bring about
similar eects and also reduce feelings of hunger
(125). On the other hand, similar infusions made
intravenously exerted no eect on gastric emptying
or measures of appetite. Lipid infusions at f80% of
resting energy requirements, over 3 days, produce
only partial compensation (43%) of energy intake
(126). Similar experiments have been carried out in
rats where intraduodenal infusions inhibited food
intake whilst intravenous infusions did not (127).
These ndings imply that, after the ingestion of fat,
Diet Composition
447
Micronutrients
There are very few data on the eect of micronutrients on feeding behavior and body weight under
normal feeding conditions. There is evidence that
rodents will learn to select a diet whose ingestion
will alleviate a micronutrient deciency (38,94). It
may also be supposed that the administration of a
micronutrient that will, for instance, improve a deciency-related defect in nutrient metabolism, will
improve appetite for that nutrient, and perhaps
appetite in general.
Figure 8 Pie charts illustrating the percentage of the variability in energy intake ascribable to dierent sources in 102 subjects
recording their food intake for 7 consecutive days. Approximately 39% of the variability was due to diet and f40% was due to
intersubject variability. These two major sources of variation are subdivided further. These charts clearly illustrate that the
determinants of energy intake in human adults are multifactorial.
448
Two further issues can be envisaged which are important and still to be resolved.
1
Postabsorptive Satiety
Diet Composition
449
450
Figure 9 Scheme illustrating the selection and study of phenotypes believed to be resistant and susceptible to diet-induced
obesity. At the present time it is important to characterize the dierences between these phenotypes at the psychometric,
behavioral, physiological, and even genetic levels.
Diet Composition
451
452
Diet Composition
453
Meal Patterns
454
VII
CONCLUSION
signalling systems, and (iv) how macronutrient mimetics may inuence feeding responses. While a number
of issues are becoming resolved (e.g., the role of dietary
fat vs. energy density in producing hyperphagia), other
important issues emergefor instance, the role of lean
tissue depletion as a signal for postweight loss hyperphagia and the characterization of phenotypes susceptible and resistant to diet-induced obesity. Greater
progress has been made in understanding specic
aspects of the appetite system and in identifying its
components (through molecular and biochemical studies, often in animal models) than in understanding how
these components operate and interact to inuence
patterns of feeding behavior linked to weight control
and weight gain in humans.
The eld of appetite and energy balance is becoming
increasingly specialized and fragmented. Many researchers concerned with elucidating molecular and
genetic mechanism of appetite control have become
somewhat divorced from whole body studies of feeding
behavior. In some cases, there is less evidence at the
whole-body level of the phenomenon being regulated
than there is for the mechanisms supposed to regulate it!
Thus, the unravelling of the leptin system, believed
important in regulating fat mass, proceeds apace. However, clear, direct, empirical evidence that fat mass is
actually regulated in humans is embarrassingly scant. It
is of critical importance that putative mechanisms of
appetite and energy balance control be related to the
behavior of the intact organism. Human studies of diet
composition and food intake control need to be related
to mechanistic work in other species, in order to assess
the relevance of these mechanisms to our own species.
Feeding studies of our own species in the laboratory
need to be related to the general population going about
their everyday lives in their natural setting. Given the
current emphasis on directing research toward promoting greater human health and well-being, animal and
molecular models of compartments of the appetite
system provide invaluable information if related to
parallel (but less invasive) protocols in human. However, these models need to be made more relevant to
appetite and energy balance control in humans.
It is now more important than ever to attempt to
integrate the increasingly disparate areas of research
specializing in aspects of appetite and energy balance
control. We still do not have a synthetic theory of
feeding behavior as exists, for example, for biological
evolution or quantum physics. A multidisciplinary
approach to the construction of integrated models
that provide a satisfactory theoretical basis for understanding mechanisms of feeding behavior and inter-
Diet Composition
455
11.
12.
13.
14.
15.
16.
REFERENCES
1.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
456
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
Diet Composition
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
457
74.
458
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
Diet Composition
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
459
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
460
nutrition labels on fat and energy intakes. Am J Clin
Nutr 1998; 68:282290.
154. Rolls B, Rowe E, Rolls E. Appetite and obesity:
inuences of sensory stimuli and external cues. In:
Turner M, ed. Nutrition and Lifestyles. London: Applied Science Publishers, 1979.
155. Rolls BJ, Rolls E, Rowe EA, Kingston B, Megson A,
Gunary R. Variety in a meal enhances food intake in
man. Physiol Behav 1981; 26:215221.
156. Rolls BJ, Rolls ET, Rowe EA. The inuence of variety
on human food selection and intake. In: Eliot Stellar
AVI, ed. The Psychobiology of Human Food Selection. 1982.
157. Rodin J. Current status of the internal-external
hypothesis for obesity: what went wrong. Am Psychol
1981; 36:361372.
158. Drummond S, Crombie N, Kirk T. A critique of the
eects of snacking on body weight status. Eur J Clin
Nutr 1996; 50:779783.
159. Gatenby SJ. Eating frequency: methodological and
dietary aspects. Br J Nutr 1997; 77(suppl 1):S7S20.
Review.
160. Grogan SC, Bell R, Conner M. Eating sweet snacks:
gender dierences in attitude and behaviour. Appetite
1997; 28:1931.
161. Nunez C, Carbajal A, Moreiras O. Body mass index
162.
163.
164.
165.
166.
167.
168.
16
Central Integration of Peripheral Signals in the Regulation of Food
Intake and Energy Balance: Role of Leptin and Insulin
L. Arthur Campfield and Francoise J. Smith
Colorado State University, Fort Collins, Colorado, U.S.A.
Bernard Jeanrenaud
University of Geneva, Geneva, Switzerland
INTRODUCTION
461
462
Campeld et al.
Figure 1 Schematic model of some of the important elements of the leptin signaling pathway that regulates body energy
balance. See text for additional details. (From Ref. 8.)
insulin system is the other peripheral hormonal pathway from adipose tissue to the brain that is critical in
the regulation of energy balance (9,10).
Leptin is a polypeptide hormone that is secreted
primarily from adipose tissue, circulates in the blood,
is bound to a family of binding proteins, enters the
brain, binds to its receptors in hypothalamic nuclei and
other brain areas, and acts on central neural networks.
The ob gene is expressed in adipose tissue, bone marrow,
and placenta, and leptin is synthesized and secreted
Figure 2 Schematic representation of the brain insulin hypothesis. (From Ref. 9.)
464
Campeld et al.
III
of signals: (1) hypothalamic neuropeptides and neurotransmitters; (2) brain insulin; (3) leptin; (4) metabolic
signals including transient declines in blood glucose
concentrations; and (5) ascending and descending
neural inputs (1,17,18,21). These signals interact and
provide the central and peripheral integration necessary
to regulate food intake and match energy intake to
energy expenditure to maintain body energy balance
and composition.
Many experimental studies in mice, rats, and many
other species demonstrate that several neuropeptides
modulate food intake when injected centrally and, in
some cases, peripherally (see Chaps. 13 and 14).
Among the neuropeptides that have been extensively
studied and have major eects on food intake are
neuropeptide Y (NPY), cholecystokinin (CCK), corticotropin-releasing hormone (CRH), and enterostatin
(9,10). Synaptic concentrations of central neuropeptides and classical monoamine neurotransmitters are
thought to be modulated by the central representations
of peripheral metabolic state and act on postsynaptic
receptors to control energy intake (1,3,9,14,17). Although some investigators still seek the identity of the
one major neuropeptide controlling human feeding
behavior, most of the eld has adopted a parallel
model in which multiple neuropeptides and hormones
involved each play a role in determining human feeding
behavior (1,3,8,18).
B
465
IV
EXPERIMENTAL MODELS OF
OBESITY DUE TO ALTERED
LEPTIN PATHWAY
470
Campeld et al.
IX
and the descending sympathetic nervous system following peripheral and central administration of leptin is
beginning to emerge (81).
Studies of neuronal activity indicate that multiple
brain regions contain neurons that are responsive to
leptin and are involved in detection of its presence and
in generation of its eects. Hyperpolarization of glucose-receptive ATP-sensitive potassium channels and
stimulation and inhibition of ring rates have been
reported in ventromedial and lateral neurons (83).
Direct application of leptin to VMH and LH neurones
resulting in both stimulation and inhibition of ring
rates have been reported (84). Patterns of activation of
brain areas in response to central or peripheral administration of leptin have been measured using c-fos
immunoreactivity. Numerous studies have implicated
hypothalamic nuclei (arcuate, VMH, DMH, PVN) and
other brain areas thought to be involved in the control
of energy balance (52,84,85). Brain administration of
leptin leads to neuronal activation in many brain areas
known to be involved in regulation of food intake and
body energy balance including the hypothalamus, periform, and cortex. In addition, brown fat was clearly
activated in the periphery. This demonstration of leptin
activation of the sympathetic nervous system was consistent with norepinephrine turnover studies in brown
fat (86) and c-fos studies (63,87,88). In addition, direct
recording of eerent sympathetic bers innervating
multiple organs in anesthetized rats demonstrated that
intravenous administration of leptin increased sympathetic nerve activity to multiple target organs (89).
Colocalization studies using selective antibodies have
demonstrated that leptin acts through its receptor on
neurons that contain NPY, ACTH, POMC, and melanin-concentrating hormone (MCH) (87). These converging lines of evidence strongly suggest that in
addition to several nuclei of the hypothalamus (ventromedial, dorsomedial, paraventricular, and arcuate),
other brain areas are involved including periform cortex, brainstem, cerebellum, basal ganglia, and cortex
(3,14) Thus, the biological actions of leptin to regulate
energy balance are the result of a distributed leptinresponsive neural network within the brain.
Recent studies focusing on the arcuate nucleus has
provided important insights into the integration of
peripheral signals within the brain. Leptin and insulin
have been shown to interact on specic receptors on
neurons in the arcuate nucleus of the hypothalamus,
and the local application of each peripheral signal
within the vicinity of the arcuate has profound and
predictable eects on food intake and body weight
(10,74,77,78,80). Specically, elevations of either hor-
471
472
Campeld et al.
Recent genetic and pharmaceutical research has provided strong evidence that the melanocortins and their
receptors, particularly MC4-R and MC3-R, play an
important role in the regulation of energy balance. In
mice lacking MC4-R, late-onset obesity and altered
peripheral metabolism have been observed (109). This
result, combined with experiments with MC3,4-R agonists (decreased food intake) and antagonists (increased
food intake) that are based on alpha-MSH, indicates
that the MC4-R participates in a physiological pathway
that normally inhibits food intake and fat storage, and
may play an important role in late-onset obesity (91).
The naturally occurring ligand for MC4-R is unknown,
but is widely believed to be alpha-MSH. However, an as
yet unidentied protein product of pro-opiomelanocortin (POMC) processing could also be natural ligand.
Two other peptides, melanin-concentrating hormone
(MCH) (110112) and agouti-related peptide (AgRP)
(92), also act to stimulate feeding.
The evidence for the interaction between leptin and
the melanocortin system includes (1) central administration of leptin increases the expression of the POMC
gene in the arcuate nucleus (113); (2) a nonselective
peptide MC3,4-R antagonist blocked inhibition of food
intake by leptin (however, the same antagonist also
blocks NPY induced feeding); (3) mice lacking MC4-R
responded to ICV leptin by decreasing food intake; (4)
when agouti (Ay/a) mice and ob/ob mice were crossed,
the combined phenotype appeared to be independent
and additive (114); (5) mice lacking MC3 receptor
(MC3-R) were also obese (115,116); and (6) when mice
lacking MC4-R and MC3-R were crossed, mice with
even greater obesity resulted (115), strongly suggesting
that the MC4-R and MC3-R are involved in the regulation of energy balance (117). These studies suggest
that the melanocortin signaling pathway appears to be
downstream of the leptin pathway and that the
two pathways converge and may interact at one or
more points.
The mouse mutations mahogany (mg) and mahoganoid (md) are negative modiers of the Agouti
coat color gene, which encodes a paracrine signaling
molecule that induces a switch in melanin synthesis.
Both md and mg suppressed the eects of mutation Ay
on both coat color and obesity. These results suggest
that md and mg interfere directly with Agouti signaling,
473
XI
474
Campeld et al.
and/or states of one or more presynaptic and/or postsynaptic ion channels can be considered responsible for
the short-term, acute, or immediate behavioral
(suppression of food intake) and metabolic eects
(decreased serum concentrations of insulin and glucose). This dual-function mechanism of action, regulation of gene expression and modulation of ongoing
cellular function such as neurosecretion, is a common
and classical property of hormones. If additional experiments support this dual-function mechanism of action
for leptin, it would provide additional evidence for the
concept that leptin is a hormone that plays a critical role
in the regulation of brain mechanisms involved in the
regulation of energy balance.
One representation of this hypothesis at the molecular levels in the hypothalamus is shown in Figure 5.
Several classes of parallel neural pathways are represented by the ve model neurons depicted. Each neuron
Figure 5 Schematic diagram of hypothetical neural networks controlling energy balance. Several classes of parallel neural
pathways are represented by the four model neurons depicted. Each neuron is assumed to express the gene, synthesize and release
one dominant type of neuropeptideNPY, CRH, POMC, AgRP (ARP)? Each neuron has the long form of the OB-R receptor
(ellipses) and the nal common pathway, the neuronal network controlling ingestive behavior, metabolism, and energy
balance, and has distinct receptors for OB, NPY, CRH, POMC, AgRP and ? Leptin is shown as circles containing OB. Note that
leptin can express its biological action through ve parallel paths, each mediated by a dierent neuropeptideNPY, CRH,
POMC, AgRP or ? The ability of leptin to inhibit the actions of released NPY is also shown. (From Ref. 8.)
475
5.
6.
7.
8.
9.
10.
ACKNOWLEDGMENTS
We thank Jack F.R. Curtis for assistance with the
conceptualization and execution of some of the artwork. We also thank our many colleagues and collaborators in many laboratories throughout the world for
important experiments and stimulating discussions and
suggestions. Special thanks to Professor S.C. Woods for
pioneering the pathway from the periphery to the brain
and back again and sharing his insights.
11.
12.
13.
14.
REFERENCES
1.
2.
3.
4.
15.
16.
17.
18.
19.
20.
CC, McKee LJ, Baur TL, Caro JF. Serum immunoreactive-leptin concentrations in normal-weight and
obese humans. N Engl J Med 1996; 334:192295.
Maei M, Halaas J, Ravussin E, Pratley RE, Lee GH,
Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S,
Kern PA, and Friedman JM. Leptin levels in human
and rodent: measurement of plasma leptin and ob
mRNA in obese and weight-reduced subjects. Nat
Med 1995; 1:11551161.
Kennedy GC. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond
Ser B 1953; 140:578592.
Campeld LA, Smith FJ, Burn P. The OB protein
(leptin) pathwaya link between adipose tissue mass
and central neural networks. Horm Metab Res 1996;
28:619632.
Campeld LA, Smith FJ, Burn P. OB protein: a
hormonal controller of central neural networks
mediating behavioral, metabolic and neuroendocrine
responses. Endocrinol Metab 1997; 4:81102.
Kaiyala KJ, Woods SC, Schwartz MW. New model
for the regulation of energy balance and adiposity by
the central nervous system. Am J Clin Nutr 1995;
62:1123s1134s.
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ,
Baskin DG. Central nervous system control of food
intake. Nature 2000; 404:661671.
De Matteis R, Dashtipour K, Ognibene A, Cinti S.
Localization of leptin receptor splice variants in mouse
peripheral tissues by immunohistochemistry. Proc
Nutr Soc 1998; 57:441448.
Zhang Y, Proenca R, Maei M, Barone M, Leopold
L, Friedman JM. Positional cloning of the mouse
obese gene and its human homologue. Nature 1994;
372:425431.
Leibel RL, Rosenbaum M, Hirsch J. Changes in
energy expenditure resulting from altered body weight.
N Engl J Med 1995; 232:621628.
Campeld LA, Smith FJ. Overview: neurobiology
of OB protein (leptin). Proc Nutr Soc 1998; 57:429440.
Le Magnen J. The metabolic basis of the dual
periodicity of feeding in rats. Behav Brain Sci 1980;
4:561607.
Le Magnen J. Hunger. London: Cambridge University
Press, 1985.
Le Magnen J. Neurobiology of Feeding and Nutrition.
San Diego: Academic Press, 1992.
Campeld LA, Smith FJ. Systemic factors in the
control of food intake: evidence for patterns as signals.
In: Stricker EM, ed. Handbook of Behavioral Neurobiology, Vol 10. Neurobiology of Food and Fluid Intake.
New York: Plenum Press, 1990:183206.
Campeld LA. Metabolic and hormonal controls of
food-intake: highlights of the last 25 year19721997.
Appetite 1997; 29:135152.
Woods SC, Seeley RJ, Porte D Jr, Schwartz MW.
476
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
Campeld et al.
Signals that regulate food intake and energy homeostasis. Science 1998; 280:13781383.
Bray GA, Campfeld LA. Metabolic factors in the
control of energy stores. Metabolism 1975; 24:99117.
Bogardus C, Lillioja S, Ravussin E, Abbott W,
Zawadzki JK, Young A. Familial dependence of the
resting metabolic rate. N Engl J Med 1986; 315:96
100.
Keesey RE. Physiological regulation of body weight
and the issue of obesity. Med Clin North Am 1989;
73:1527.
Hill JO, Douglas HJ, Peters JC. Physical activity, tness,
and moderate obesity. In: Bouchard C, Shepard RJ,
Stephens T, eds. Physical Activity Fitness, and Health:
International Proceedings and Consensus Statement.
Champaign (Illinois): Human Kinetics Publisher Inc.,
1994.
World Health Organization. Obesity: Preventing and
Managing the Global Epidemic. Geneva: World Health
Organization, 1998.
Astrup A. Obesity as an adaptation to a high-fat diet:
evidence from a cross-sectional study. Am J Clin Nutr
1994; 59:350355.
Ingalls AM, Dickie MM, Snell GD. Obese, a new mutaion in the house mouse. J Hered 1950; 41:317325.
Coleman DI. Obese and diabetes: two mutant genes
causing diabetes-obesity syndromes in mice. Diabetologia 1978; 14:1411148.
Coleman DL. Eects of parabiosis of obese with
diabetes and normal mice. Diabetologia 1973; 9:294
298.
Coleman DL. Inherited obesity-diabetes syndromes in
the mouse. Prog Clin Biol Res, 1981; 45:145158.
Coleman DL, Hummel KP. The inuence of genetic
background on the expression of the obese (ob) gene in
the mouse. Diabetologia 1973; 9:287293.
Herberg L, Coleman DL. Laboratory animals exhibiting obesity and diabetes syndromes. Metabolism 1977;
26:5999.
Sinha MK, Ohannesian JP, Heiman ML, Kriaucinunas A. Nocturnal rise in leptin in lean, obese, and noninsulin-dependent diabetes mellitus subjects. J Clin
Invest 1996; 97:13441347.
Van Aggel-Leijssen DP, Van Baak MA, Tenenbaum
R, Campeld LA, Saris WHM. Regulation of average
4h human plasma leptin level; the inuence of exercise
and physiological changes in energy balance. Int J
Obes Relat Metab Disord 1999; 23:151158.
Porte D Jr. Banting Lecture 1990. Beta-cells in type II
diabetes mellitus. Diabetes 1991; 40:16680.
Woods SC, Nolan LJ. The insulin story: a 25-year
perspective. Appetite 1997; 28:281282.
Schwartz MW, Figlewicz DP, Baskin DG, Woods SC,
Porte D Jr. Insulin and the central regulation of energy
balance: Update 1994. Endocr Rev 1994; 2:109113.
Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
477
63. Schwartz MW, Seeley RJ, Campeld LA, Burn P,
Baskin DG. Identication of targets of leptin action in
rat hypothalamus. J Clin Invest 1996; 98:11011106.
64. Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper
CB. Distributions of leptin receptor mRNA isoforms
in the rat brain. J Comp Neurol 1998; 395:535547.
65. Lee G, Proenca R, Montez JM, Carrol KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of
the leptin receptor in diabetic mice. Nature 1996;
379:632635.
66. Chua SC, Chung WK, Wu-Peng XS, Zhang Y, Liu
S-M, Tartaglia L, Leibel RL. Phenotypes of mouse
diabetes and rat fatty due to mutations in the OB
(leptin) receptor. Science 1996; 271:994996.
67. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng
X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ,
Breitbart RF, Duyk GM, Tepper RI, Morgenstern JP.
Evidence that the diabetes gene encodes the leptin
receptor: identication of a mutation in the leptin
receptor gene in db/db mice. Cell 1996; 84:491495.
68. Takaya K, Ogawa Y, Hiroaka J, Hosoda K, Yamori
Y, Nakao K, Koletsky RJ. Nonsense mutation of
leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat Gene 1996; 14:130131.
69. Wu-Peng XS, Chau SCJ, Okada N, Liu SM, Nicolson
M, Leibel RL. Phenotype of the obese Koletsky (f) rat
due to tyr763stop mutation in the extracellular
domain of the leptin receptor (LEPR): evidence for
decient plasma -to-csf transport of leptin in both the
Zucker and Koletsky obese rat. Diabetes 1997; 46:
513518.
70. Tartaglia LA. The leptin receptor. J Biol Chem 1997;
272:60936096.
71. White DW, Tartaglia LA. Leptin and OB-R: body
weight regulation by a cytokine receptor. Cytokine
Growth Factor Rev 1996; 7:303309.
72. Campeld LA, Smith FJ, Yu J, Renzetti M, Simko B,
Baralt M, Mackie G, Tenenbaum R, Smith W. Dietary
obesity induces decreased central sensitivity to exogenous OB protein (leptin) which is reversed by weight
loss. Soc Neurosci Abstr 1997; 23:815.
73. Schwartz MW, Marks J, Sipols AJ, Baskin DB,
Woods SC, Kahn SE, Prote JD. Central insulin
administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean
( fa/fa) but not obese ( fa/fa) Zucker rats. Endocrinology 1991; 128:26452647.
74. Elmquist JK. Hypothalamic pathways underlying
the endocrine, autonomic, and behavioral eects of
leptin. Int J Obes Relat Metab Disord 2001; 25:S78
S82.
75. Elias CF, Lee CE, Kelly JF, Ahima RS, Kuhar M,
Saper CB, Elmquist JK. Characterization of CART
neurons in the rat and human hypothalamus. J Comp
Neurol 2001; 432:119.
76. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin
478
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
Campeld et al.
regulation of neuroendocrine systems. Front Neuroendocrinol 2000; 21:263307.
Elias CF, Kelly JF, Lee CE, Ahima RS, Drucker DJ,
Saper CB, Elmquist JK. Chemical characterization of
leptin-activated neurons in the rat brain. J Comp
Neurol 2000; 423:261281.
Elmquist JK. Anatomic basis of leptin action in the
hypothalamus. Front Horm Res 2000; 26:2141.
Ahima RS, Kelly J, Elmquist JK, Flier JS. Distinct
physiologic and neuronal responses to decreased leptin
and mild hyperleptinemia. Endocrinology 1999;
140:49234931.
Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS,
Bjorbaek C, Flier JS, Saper CB, Elmquist JK. Leptin
dierentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 1999;
23:775786.
Elmquist JK, Maratos-Flier E, Saper CB, Flier JS.
Unraveling the central nervous system pathways
underlying responses to leptin. Nat Neurosci 1998;
1:445450.
Huang Q, Rivest R, Richard D. Eects of leptin on
corticotropin-releasing factor (CRF) synthesis and
CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ob) mice. Endocrinology
1998; 139:15241532.
Spanswick D, Smith MA, Groppi VE, Logan SD,
Ashford MLJ. Leptin inhibits hypothalamic neurons
by activation of ATP-senstive potassium channels.
Nature 1997; 390:521525.
Yokosuka M, Xu B, Pu S, Karla SP. The magnocellular part of the paraventricular hypothalamic nucleus
(PVN): a selective site for inhibition of NPY-induced
food intake by leptin. Soc Neurosci Abstr 1997; 23:
852.
Van Dijk G, Theile TE, Donahey JCK, Campeld LA,
Smith FJ, Burn P, Bernstein IL, Woods SC, Selley RJ.
Central infusion of leptin and GLP-1(736) amide
deerentially stimulate c-FLI in the rat brain. Am J
Physiol 1996; 271:R1096Rl100.
Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk
BA, Surwit RS. Role of leptin in fat regulation. Nature
1996; 380:677.
Hakansson M-L, Brown H, Ghilardi N, Skoda RC,
Meister B. Leptin receptor immunoreactivity in chemically dened target neurons of the hypothalamus.
J Nueorosci 1998; 18:559572.
Chen SC, Kochan JP, Campeld LA, Burn P, Smeyne
RJ. Splice variants of the OB receptor gene are differentially expressed in brain and peripheral tissues of
mice. J Recept Signal Transduct Res 1999; 19:245266.
Haynes WG, Morgan DA, Walsh SA, Marks AL,
Sivitz WI. Receptor-mediated regional sympathetic
nerve by leptin. J Clin Invest 1997; 100:270278.
Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS,
Couceyro PR, Kuhar MJ, Saper CB, Elmquist JK.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 1998; 21:13751385.
Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone
RD. Melanocortinergic inhibition of feeding behavior
and disruption with an agouti-mimetic. Nature 1997;
385:165168.
Arvaniti K, Huang Q, Richard D. Eects of leptin and
corticosterone on the expression of corticotropinreleasing hormone, agouti-related protein, and proopiomelanocortin in the brain of ob/ob mouse. Neuroendocrinology 2001; 73:227236.
Rohner-Jeanrenaud F, Jeanrenaud B. Obesity, leptin,
and the brain. N Engl J Med 1996; 334:324325.
Ezzell C. Fat times for obesity research: Tons of new
information, but how does it all t together. J NIH
Res 1995; 7:3945.
Stanley BG, Kyrkouli SE, Lampert S, Leibowitz SF.
Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 1986; 7:189192.
Stricker-Krongrad A, Chiesi M, Cumin F, Spanka C,
Whitesbread S, Rentsch J, Lollman B, Hofbauer KG,
Levens N. Interactions between leptin and neuropeptide Y in the control of food intake in the rat. Obes
Res 1996; 4(1):37s.
Smith FJ, Campeld LA, Moschera JA, Bailon P,
Burn P. Feeding inhibition by neuropeptide Y. Nature
1996; 382:307.
Erickson JC, Clegg KE, Palmiter RD. Sensitivity to
leptin and susceptibility to seizures of mice lacking
neuropeptide Y. Nature 1996; 381:415418.
Erickson JC, Hollopetter G, Palmiter RD. Attenuation of the obesity syndrome of ob/ob mice by the loss
of neuropeptide Y. Science 1996; 274:17041707.
Jeanrenaud B, Rohner-Jeanrenaud F. Eects of
neuropeptides and leptin on nutrient partitioning:
dysregulations in obesity. Annu Rev Med 2001;
52:339351.
Jeanrenaud B, Rohner-Jeanrenaud F. CNS-periphery
relationships and body weight homeostasis: inuence
of the glucocorticoid status. Int J Obes Relat Metab
Disord 2000; 24:S74S76.
Zakrzewska KE, Cusin I, Sainsbury A, RohnerJeanrenaud F, Jeanrenaud B. Glucocorticoids as
counterregulatory hormones of leptin: toward an
understanding of leptin resistance. Diabetes 1997;
46:717719.
Zakrzewska KE, Sainsbury A, Cusin I, Rouru J,
Jeanrenaud B, Rohner-Jeanrenaud F. Selective dependence of intracerebroventricular neuropeptide Y
elicited eects on central glucocorticoids. Endocrinology 1999; 140:31833187.
Sainsbury A, Cusin I, Rohner-Jeanrenaud F, Jeanrenaud B. Adrenalectomy prevents the obesity syndrome
produced by chronic central neuropeptide Y infusion
innormal rats. Diabetes 1997; 46:209214.
479
105.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
17
Development of White Adipose Tissue
Gerard Ailhaud
Centre National de la Recherche Scientifique, Nice, France
Hans Hauner
German Diabetes Research Institute, Dusseldorf, Germany
INTRODUCTION
The development of white adipose tissue (WAT) represents a dynamic process throughout life. It was long
assumed that the acquisition of fat cells was irreversible,
but recent observations suggest that apoptosis may also
occur in WAT, although to a much smaller extent than
in brown adipose tissue (BAT). At the cellular level,
there is still limited and partially contradictory information about the characteristics of the cells constituting
the adipose tissue organ. This leads in turn to the
question of the nature of the factors that regulate the
formation of new fat cells from dormant adipose precursor cells or even multipotent mesenchymal stem cells.
Once adipose tissue is formed, adipocytes represent
between one-third and two-thirds of the total number
of cells. The remaining cells are blood cells, endothelial
cells, pericytes, adipose precursor cells of varying degree
of dierentiation, and, most likely, other cell types (1).
The existence of very small fat cells in addition to
mature adipocytes has also been documented (2). Figure
1 summarizes the various cell types present in this tissue,
based on ultrastructural studies in vivo and biological
studies in vitro (3).
At present, it cannot be assessed to which extent
various morphological descriptions represent only
dierent stages of the cell lineage leading to the
characteristic adipocyte phenotype. From a biological
481
482
Figure 1 Relationships between morphological types in vivo and stages of cell dierentiation in vitro. The adipocyte fraction
corresponds to adipocytes and very small fat cells. The stromal cell fraction corresponds to a mixture of the other cell types.
483
(7). This is interesting, since the morphological development in vitro resembles the developmental steps in vivo.
Preadipose cells either from clonal cell lines or from
primary cultures usually exhibit a multilocular morphology, not only during early, but also during late
stages of in vitro dierentiation when the characteristic
markers of mature fat cells are fully expressed. The
available data do not provide any evidence of signicant
site- and sex-related dierences in early development,
supporting the concept that the marked regional dierences in adipose tissue distribution in males and females
develop later in life, presumably under the control of sex
steroids and other hormones. Although some microscopic studies postulate that the second trimester may
be a critical period for the development of obesity in
later life, the descriptive nature of these data does not
allow any rm conclusion in this respect.
At the beginning of the third trimester, adipocytes
are found in the principal fat depot areas but are still
rather small (7). At birth, body fat accounts for 16% of
body weight as assessed by whole-body counting of
40
K. Analysis of biopsy samples of adipose tissue
revealed that the increase in body fat during the rst
year of life from about 0.7 to 2.8 kg is entirely due to an
increase in fat cell size, while fat cell number remains
unchanged (15). Other studies on this issue gave controversial results, particularly with regard to the development of fat cell number during the rst year of life.
Such dierences may be largely explained by variations
in methodology and the general diculties in assessing
total-body fat cell number. In addition, most studies
were cross-sectional, which makes interpretation of
results more dicult. Longitudinal studies showed a
continuous increase in fat cell weight between 1 and
12 months of age (16). It has also been pointed out that
in fetal life and early infancy adipose tissue is composed
of dierent cell populations: lipid-containing cells but
also many cells that are essentially lipid-free and not
readily recognized as adipocytes. Small fat cells in the
early stages of fat accumulation may make an important contribution to the adipose cell mass at this age.
Therefore, it is tempting to conclude that a gradual
accumulation of body fat after birth is mainly reected
by increasing fat cell size (17).
C
484
Figure 2 Human adipose precursor cells before and after terminal dierentiation. Human adipose precursor cells were
maintained in dierentiation medium (23) for 12 hr (a), 4 days (b), and 15 days (c). Micrographs were taken with interference
contrast. Magnication 250.
485
Thyroid Hormones
Not determined.
Fat cell
size
Fat cell
number
Fat
mass
(z)
(z)
#
z
z
#
#
z
n.d.a
#
Normal
#
#
Normal
z
#
n.d.
#
z
Normal
#
#
#
z
486
Insulin
Growth Hormone
Glucocorticoids
487
adipose tissue. However, visceral, head, and neck adipose tissue depots were more markedly reduced than
other depots (42). Studies of adipose tissue cellularity in
Cushings syndrome have shown that this expansion is
primarily due to enlarged abdominal fat cells (43). This
eect can be at least partly explained by the nding that
fat cells from the abdominal depot exhibit more cytoplasmatic glucocorticoid receptors and higher receptor
mRNA compared with adipocytes from other regions
(44). In Cushings syndrome, fat cell hypertrophy in the
abdomen appears to be due to elevated adipocyte LPL
activity and also to low lipolytic activity (43). Moreover,
glucocorticoids are known to be potent promoters of the
adipose dierentiation process, a mechanism that may
also contribute to adipose tissue expansion during
glucocorticoid excess (23).
The role of glucocorticoids and the importance of
the hypothalamic-pituitary-adrenal axis in the excessive development of adipose tissue have been documented in two models of transgenic mice. In one
model (45), a reduction of the glucocorticoid receptor
in the brain and also in liver and kidneys was
obtained with an antisense mRNA, whereas in a
second model (46) overexpression of corticotropinreleasing factor (CRF) was achieved. In both cases,
the observed increase in corticotropin and corticosterone levels was accompanied by an increase in
adipose tissue mass, with the development of Cushings syndrome in CRF-overexpressing mice.
Studies by magnetic resonance imaging (MRI) indicate that puberty in girls is associated with the preferential accumulation of adipose tissue in the gluteal and
femoral region (51), suggesting that the divergence of
sex steroid metabolism and serum levels among boys
and girls may be responsible for the development of sexspecic fat distribution patterns at this age (52). In
women, decreased ovarian estrogen production during
menopause and the subsequent change in the balance
between estrogens and androgens may cause a shift in
fat distribution toward more abdominal pattern. Estrogen replacement therapy appears to result in a reduced
amount of trunk adipose tissue as determined by dualenergy x-ray absorptiometry (53).
In men, low testosterone levels are associated with
enlarged visceral adipose tissue depots (54). When middle-aged, abdominally obese men are treated with testosterone, a small decrease in visceral fat mass in
conjunction with an improvement of insulin resistance
and associated metabolic disturbances is observed (55).
A possible explanation for this observation is that
androgens are positive eectors of lipolysis in concert
with GH, thereby decreasing the size of the abdominal
fat cells, but may not be directly involved in the regulation of fat cell formation (54). Another interesting
nding is that alcoholic men have more adipose tissue
localized in the intra- and retroperitoneal depots than
abstinent men, also possibly due to a lower androgen
activity (56).
Sex Steroids
Nutrients
488
Lipectomy
Surgical removal of adipose tissue and careful observation of its regeneration is another appropriate approach
to study the regulation of adipose tissue growth and
body weight in vivo. To date, many studies have been
performed to investigate the eect of lipectomy on
adipose tissue regeneration in a variety of species and
depots and under various conditions. However, the
results of these studies were inconclusive, since the
response to lipectomy was found to depend on various
factors such as species, region of excision, time after
operation, extent of removal, and type of diet. Nevertheless, in most animal studies a clear tendency for
regeneration of the lost tissue was apparent at least in
the perirenal and subcutaneous fat depots, but restoration at the site of excision was not always complete. In
both rat and rabbit, the regenerative response was
highest in the perirenal fat depot (63,64). In contrast,
surgical removal of the epididymal fat pads did not lead
to regeneration. These data are to some extent compatible with in vitro ndings indicating that adipocyte
precursor cells from the perirenal region have a higher
capacity for proliferation and dierentiation than stromal cells from other depots (33,65). Morphological
studies in rats showed that adipose tissue regeneration
at the inguinal site occurred in close association with
revascularization and blood supply. Immediately after
lipectomy, thymidine kinase activities are elevated at the
sites of removal, but subsequently slowly drop to a level
that is still above normal. Both total fat cell number and
average fat cell size continuously increase during this
process. Thus, the regeneration of adipose tissue resem-
489
490
III
A
491
492
jugated linoleic acid (CLA) to mice resulted in a reduction of body fat due to apoptosis. Under these conditions, TNFa and UCP-2 expression were 12- and sixfold
upregulated in adipocytes from CLA-fed mice compared to fat cells from control mice. With decreasing
body fat the mice developed lipodystrophy associated
with hepatomegaly and insulin resistance (96).
In humans, it has been demonstrated that patients
with some malignancies exhibit signs of adipocyte
apoptosis in vivo (97). This and another report (98)
showed that apoptosis is higher in omental than in
subcutaneous adipose cells indicating that regional fat
distribution may be partly regulated by dierences in
apoptosis. The in vitro data currently available suggest
that apoptosis is mainly found in human preadipocytes.
During in vitro dierentiation, preadipocytes appear to
acquire a relative resistance to apoptosis due to an
increasing synthesis of the cell survival proteins Bcl-2
and neuronal apoptosis inhibitory protein (99).
Other studies suggest that mature fat cells can be
induced to reverse the adipocyte phenotype under certain circumstances. TNFa was found to cause a dedifferentiation of cultured human fat cells after long-term
exposure leading to a complete loss of stored lipids
without a change in total cell number (100). It was
recently reported that adenovirus-induced hyperleptinemia in normal rats results in rapid body fat loss. The
elevated leptin concentrations not only depleted adipocyte lipids but transformed the adipocytes into cells that
oxidize lipids, lose characteristic adipocyte markers,
and express preadipocyte markers (101).
Although the existence of apoptosis and dedierentiation in white adipose tissue is now established the
physiological importance of these phenomena is still
unknown. It is also unclear whether apoptosis is
involved in the pathophysiology of obesity and, if so,
to what extent and by what mechanisms. The question
may also arise whether this new insight can be used to
develop new therapeutic strategies.
IV
A
493
Origin
Phenotypes
Ref.
Mouse blastocysts
All
Mouse embryo
3,103
White
White
White
White
adipocytes
adipocytes
adipocytes
adipocytes
3,103
3,103
3,103
3,103
White adipocytes
White adipocytes
105
106
Rat
White adipocytes
3,103
Rat
Mouse
Mouse
Rabbit
Pig
White
White
White
White
White
adipocytes
adipocytes
adipocytes
adipocytes
adipocytes
3,103
3,103
3,103
5,103
3,103
Bovine
Ovine
Human
White adipocytes
White adipocytes
White adipocytes
108
108
3,103
Human
Human
White adipocytes
White adipocytes
107
109
102
104
not to that of multiple lineage-committed cells present in the cell population. Transdierentiation appears also possible as both myoblasts of C2C12 clonal
line and muscle satellite cells are able to convert signicantly to adipose cells upon exposure of the cells
to long-chain fatty acids or BRL49653, a ligand agonist of PPARg (113).
Wnts, which are secreted signaling proteins regulating developmental processes, behave as molecular
switch, likely through Wnt 10-b, which governs adipogenesis. Active Wnt signaling is required for commitment to the myocyte lineage, whereas prevention of
active Wnts signaling pathway triggers adipogenesis
(114). Collectively, these observations emphasize that
cell plasticity is more important than anticipated and
that unipotentiality should be better and more cautiously dened in vitro as the only pathway that
494
General Considerations
Table 3 summarizes the receptor composition of adipoblasts, preadipocytes, and adipocytes. Not unexpectedly, preadipocytes express the cognate receptors of
adipogenic hormones required for subsequent events
to occur. The alterations in hormone responsiveness as a
function of dierentiation correspond to a critical time
window of action in preadipocytes during which adipogenic hormones induce the terminal dierentiation
process.
Growing adipoblasts express cell surface receptors
of the major prostaglandins which are produced
by these cells [prostacyclin (PG12), prostaglandin
F2a (PGF2a), and prostaglandin E2 (PGE2)] as well
as nuclear receptors recognizing glucocorticoids, T3,
and retinoic acid (RA). The adenosine receptor A2
subtype, the prostacyclin IP receptor, and the PGE2
receptor (EP4 subtype), all positively coupled to
adenylate cyclase, are present in preadipocytes and
then become expressed at low levels, if any, in
adipocytes, consistent with the importance of the
protein kinase A (PKA) pathway to trigger terminal
dierentiation of preadipocytes (see Sec. IV. C. 1).
These observations are also consistent with those
made in the comparative study of prostaglandin
sensitivity of adenylate cyclase of rat primary preadipocytes and isolated adipocytes which show that
Gi activity is reduced or absent in preadipocytes
(116). The EP3 subtype (a, h, and g isoforms) of
the PGE2 receptor and the adenosine receptor A1
subtype (118121), all coupled negatively to adenylate cyclase, then become detectable in adipocytes,
consistent with the well-known antilipolytic eects of
PGE2 and adenosine observed in mature fat cells.
Commitment to preadipocytes is characterized by the
emergence of the cell surface receptor of leukemia
inhibitory factor (LIF) as well as that of nuclear
receptor PPARy and transcription factors C/EBPh
and y (117).
Of growing interest are cell surface proteins
which are membrane associated or potentially
secreted (122,123). Pref-1 and dlk proteins are members of the EGF-like homeotic family of proteins
and are polymorphic variants of the same dlk
Figure 3 Multiple stages of adipose cell dierentiation. The scheme is based on data obtained with 3T3-L1, 3T3-F442A, and
Ob17 cells as well as with rodent adipose precursor cells. Abbreviations: Pref-1, preadipocyte factor-1; LPL, lipoprotein lipase;
A2COL6/pOb24, a2-chain of collagen VI; LIF-R, leukemia inhibitory factor-receptor; ADRP, adipocyte-dierentiation related
protein; PGAR/FIAF, PPARg-angiopoietin related/fasting-induced factor; C/EBP, CCAAT/enhancer-binding protein;
PPAR, peroxisome proliferatoractivated receptor; IGF-1, insulinlike growth factor-1; ADD-1, adipocyte determination and
dierentiation factor-1; FAT/CD36, fatty acid translocase; ALBP, adipocyte lipid-binding protein (aP2); ACBP, acyl CoA
binding protein; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; GLUT4, insulin-sensitive glucose transporter-4;
GPDH, glycerol-3-phosphate dehydrogenase; GPAT, glycerophosphate acyltransferase; LPAT, lysophosphatidate acyltransferase; DGAT, diglyceride acyltransferase; PEPCK, phosphoenolpyruvate carboxykinase; h2-AR, h2-adrenoreceptor; h3-AR, h3adrenoreceptor; low Km PDE, low Km phosphodiesterase; HSL, hormone-sensitive lipase; PAI-1 plasminogen activator
inhibitor-1.
496
Table 3 Cell Surface Receptors, Nuclear Receptors, and Transcription Factors of Adipose Precursor Cells and Adipocytes
Markersa
Cell surface receptors
LIF-R
IP-R
FP-R
EP1-R
EP4-R
EP3-R (a, h, g isoform)
A1-R
A2-R
GH-R
IR
Pref-1/dlk
Nuclear receptors
GR
AR
ER
PR
RARa and RARg
RARa and RARh
TR
PPARy (NR1C2)
PPARg (NR1C3)
AhR
Arnt
Transcription factors
CREB
C/EBPh and C/EBPy
ADD1/SRBP-1c
C/EBPa
AP-2a
Id2
Id3
GATA-2&3
Adipoblastsb
Preadipocytesb
Adipocytesb
++
++
++
++
n.d.c
n.d.
n.d.
+
+
+
+
+
+
+
+
+
++
+
+
(+)
(+)
(+)
+
+
(+)
+
++
+
n.d.
n.d.
n.d.
+
+
+
+
+
+
(+)
(+)
+
++
++
+
+
(+)
(+)
(+)
+
+
+
(+)
+++
+++
++
++
++
+
(+)
+
+
+
+
+
+
+
(+)
(+)
(+)
(+)
(+)
+
(+)
+
++
Ref.
117
118,119
120
119
119
119
121
121
103
103
122,123
3,103
47,124
48,49,124,125
50,124
126
126
127,128
129
130
131134
131,132
135
117,136
137
138,139
140
141,142
141,142
143
Based upon data obtained in cells of clonal lines and primary cultures.
a
Abbreviations: LIF-R, leukemia inhibitory factor receptor; IP-R, prostacyclin receptor; FP-R, PGF2a receptor; EP-R, PGE2 receptor; Al-R
and A2-R, adenosine (subtypes 1 and 2) receptor; GH-R, growth hormone receptor; IR, insulin receptor; pref-1/dlk, preadipocyte factor-1/delta
like factor; GR, glucocorticoid receptor; AR, androgen receptor; ER estrogen receptor; PR, progesterone receptor; RAR, retinoic acid receptor;
RXR, retinoic X receptor; TR, triiodothyronine receptor; PPAR, peroxisome proliferatoractivated receptor; AhR, arylhydrocarbon receptor;
Arnt, Ahr nuclear translocator; CREB, cAMP response elementbinding protein; C/EBP, CCAAT/enhancer binding protein; ADD1/SREBP-1c,
adipocyte determination and dierentiation factor-1/sterol regulatory element binding protein-1c; Id, inhibitory protein of DNA binding.
b
The signs refer to comparative levels of each mRNA or protein between adipoblasts, preadipocytes, and adipocytes, i.e., the absence () or the
presence at very low levels (+), low levels +, or higher levels ++ and +++.
c
Not determined.
The responsiveness of preadipose cells to external signals may vary according to dierences in the stage of
adipose lineage at which clonal lines have been established and that at which cells of a given line are exposed
to various agents. Moreover, the requirement for adipogenic hormones shows dierences between clonal and
primary preadipocytes. Last but not least, serum-supplemented media are (too) often used, as many serum
components are uncharacterized and thus not controllable, this renders comparisons between various studies
rather dicult. The use of serum-free, chemically
dened media appears more appropriate. In serum-free
conditions, the most common requirements of primary
preadipocytes appear to be glucocorticoids, IGF-1, and
insulin. Clonal preadipocytes also require GH and T3
and/or retinoids. A salient feature is that the required
hormones have to be present simultaneously within a
physiological range above threshold concentrations to
trigger terminal dierentiation.
1
Glucocorticoids, cAMP-Elevating
Agents, and Leukemia Inhibitory Factor
497
498
EBPh, PPARg, and adipogenesis (174), but its adipogenic activity on authentic target cells, i.e., preadipocytes, remains to be shown.
4
Tri-iodothyronine appears to be required for the dierentiation of clonal preadipocytes (127,175). This
requirement remains questionable, as no obvious
requirement for T3 is observed in primary preadipocytes
isolated from pig, rat, rabbit, and human, suggesting as
for GH that prior exposure to T3 in vivo has primed
the cells (3,176).
The ability of retinoic acid (RA) and synthetic retinoids to promote or inhibit dierentiation processes has
been recognized for several years. At supraphysiological
concentrations, RA inhibits adipogenesis of clonal and
primary preadipocytes via RA receptors (RARs). Inhibition appears to take place at an early stage, i.e.,
through C/EBPh repression (177). In contrast, at concentrations close to the Kd values of RARs, RA and
retinoids behave like potent adipogenic hormones in
triggering the dierentiation of Ob1771 preadipocytes
and primary rat preadipocytes (126).
5
Both long-chain FA (saturated, unsaturated, nonmetabolizable) and peroxisome proliferators, which are
like FA amphipatic carboxylate molecules, are able in
clonal preadipocytes to act like hormones, by activating
the transcription of several lipid-related genes and
promoting adipogenesis in synergy with other adipogenic factors (57,178). Similar observations have been
made in rat and human preadipocytes. Moreover, the
main adipogenic component of serum is arachidonic
acid (ARA) (179). Its adipogenic eect is blocked by
cyclo-oxygenase inhibitors, suggesting that prostanoid(s) are involved. Prostacyclin (used in the form of
stable carbacyclin) is the only active prostanoid in
promoting adipogenesis (180), and this stimulatory
eect can be extended to rat and human primary
preadipocytes (149). In addition to binding to the cell
surface prostacyclin receptor (IP-R), carbacyclin binds
to the nuclear receptor PPARy (181). This suggests a
dual role of ARAdirectly, as agonist of PPARs, and
indirectly, as a precursor of prostacyclin then active via
IP-R at the cell surface and via PPARy within the
nucleus. The natural ligand(s) of PPARy may dier
from prostacyclin, but this prostanoid along with PGE2
and trace levels of PGF2a is the only metabolite of ARA
so far characterized in preadipocytes (182).
Angiotensin II
499
MOLECULAR MECHANISMS
OF ADIPOGENESIS
D Antiadipogenic Factors
Postmitotic growth arrest is followed by terminal dierentiation of preadipocytes to adipocytes (stages 4 and 5)
(Fig. 3), which are states of irreversible growth arrest as
mature fat cells do not divide. Upon activation by FA or
specic agonists, PPARy mediates postconuent mitoses in a cAMP-dependent manner (195,196). As PPARy
is implicated in the activation of a limited set of genes
including PPARg (196198) and as PPARg induces cell
cycle withdrawal and irreversible growth arrest, it
would appear that PPARy and PPARg are playing
both opposite and complementary roles (199). Recent
evidence indicates that PPARg is essential for cardiac
and adipose tissue development during mouse embryogenesis (200,201). Various redundant signaling pathways as well as several transcription factors are
converging to upregulate PPARg, which acts as com-
500
mon and essential regulator of terminal events of adipogenesis and also as a regulator of adipocyte hypertrophy
(Fig. 4), emphasizing the importance of adipose tissue
development to ensure physiological functions.
Forced ectopic expression of C/EBPh in cells of
various clonal lines of broblastic origin, which normally express very low levels of C/EBPh, C/EBPa,
and PPARg, induces adipogenesis, with C/EBPy acting in synergy with C/EBPh (136). In most studies,
signicant adipogenesis of stable broblast transfectants requires the simultaneous presence of PPARg
ligands, in contrast to authentic preadipocyte target
cells (3T3-L1,3T3-F442A, Ob1771 cells), suggesting
that authentic dierentiating cells are able to express
PPARg and simultaneously to synthesize uncharacterized PPARg ligand(s).
Intracellular pathways that upregulate in clonal preadipocytes the expression of C/EBPh and C/EBPy are
also able to trigger adipogenesis. It has been shown that
preadipocytes have the unique capacity both (1) to synthesize and secrete LIF and prostacyclin, and (2) to
express at the same time their cognate cell surface receptors LIF-R and IP-R. Binding to L1F-R and IP-R
triggers the ERK and PKA pathways, respectively,
which in turn activate the critical expression of C/EBPh
and C/EBPy and promote adipogenesis (117,152). Signal transduction proteins involved in the upregulation
of transcriptional activators may also regulate adipogenesis as reported for ectopic expression of the dierentiation-enhancing factor-1 (DEF-1) in NIH-3T3 and
Figure 4 Transcriptional activators (bold face) and transcriptional repressors (italics) of adipogenesis. (See text for
comments and abbreviations.)
501
Table 4 Overexpression/Reexpression of Lipid-Related Genes in Adipose Tissue: Relationships with WAT Development
Gene
Angiotensinogen
Transcription factors
A-ZIP/F
insulin injections
Z WAT
WAT absent
(lipoatrophy)
WAT
WAT)
(intra-abdominal
depot
Z
Adipose
tissue
Adipose
tissue
WAT
Z
FOXC2
Adipose
tissue
ZWAT
ADD1/SREBP-1c
Adipose
tissue
Adipose
tissue
Z WAT
Z
Secreted proteins
Agouti
Adipose
tissue
WAT
Mitochondrial proteins
UCP-1
Remarks
Z
Adipose
tissue
Adipose
tissue
Adipose
tissue
Tissue
specicity
Refs.
Resistance to HFD
Adipocyte hypotrophy
HFD-induced obesity
Adipocyte hyperplasia
Low glucose levels and enhanced
glucose disposal
Adipocyte hyperplasia
210
212
213
Insulin resistance
Dyslipemia
Increased metabolic rate
Immature fat depots
Enlargement of liver, spleen and pancreas
Resistance to HFD
UCP-1 induction in WAT
BAT hypertrophy
Increased sensitivity of h-adrenergic/
cAMP/PKA pathway
Increased insulin sensitivity
211
61
188
214
215
216
UCP-1, uncoupling protein-1; a2-AR, a2-adrenoreceptor; h1-AR, h1-adrenoreceptor; GLUT-4, glucose transporter-4; ADD-1/SREB-1c, adipocyte
determination and dierentiation factor-1/sterol regulatory element binding protein-1c; HFD, high-fat diet.
502
Tissue
specicity
WAT
Z
PTP-1B
WAT
Z
DGAT
WAT
Z
Perilipin
ZWAT at age 5-6 weeks
ZWAT at age 7-8 weeks
n
n
WAT
Z
WAT
Z
ACC-2
Z
Secreted proteins
Angiotensinogen
WAT at weaning
and onwards
ZWAT
Remarks
Male sterility
Adipocyte hypertrophy
Dispensable for
lipolysis
Hyperphagy
Resistance to HFD
Resistance to h-AR
agonist stimulation
with increased basal
lipolysis
Adipocyte hypertrophy
Resistance to HFD
Increased energy
expenditure
Lean and resistance
to HFD
Increased energy
expenditure
Increased insulin
sensitivity
Hyperphagy
Increased h-oxidation
in muscles
Decreased hepatic fat
Adipocyte hypotrophy
Hyperphagy
Retinal degeneration
Heterozygous +/tub
indistinguishable
from wild-type
Resistance to HFD
Smaller length than
wild-type
Adipocyte hypotrophy
Ref.
217
218
219
220,221
222
223
224
225
Decreased lipogenesis
in WAT
Increased locomotor
activity
Adipocyte hypotrophy
226
No change in food
intake
227
Growth-retarded
Postprandial
hyperinsulinemia
Abdominal fat more
aected than other
depots
62
ZWAT
Mac-1
GLUT-4
PRL-R
Z
WAT
Z
WAT
(female>male)
228
503
Table 5 Continued
Genes
WAT
Z
VLDL-R
Tissue
specicity
(female>male)
RXRa
WAT on standard
Z
diet
WAT
Z
Hmgic (architectural
transcription factor)
Z
C/EBPa
WAT absent
Z
PPARg (NR1C3)
WAT
Z
PPARy (NR1C2)
Remarks
Ref.
Resistance to HFD
Increased plasma
triglycerides
after high-fat
feeding
Adipocyte
hypotrophy
229
Dyslipemia
Steatosis
230
231
200,201,206
232
233
234
235
HSL, hormone-sensitive lipase; DGAT, diacylglycerol acyltransferase; ACC-2, acetyl-CoA carboxylase-2; MT, metallothioenia; PKA, protein
kinase A; PTP-1B, protein tyrosine phosphatase-1B; ICAM-1, intercellular adhesion molecule-1; PRL-R, prolactin receptor; VLDL-R, receptor
of very low density lipoproteins; PPAR, peroxisome proliferatoractivated receptor; C/EBP, CCAAT/enhancer B, protein tyrosine phosphatase1B; BP, binding protein; RXR, retinoic X receptor; HFD, high-fat diet.
504
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
505
16.
506
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
507
precursors in primary culture. Biol Cell 1990; 69:215
222.
71. Wang H, Kirkland JL, Hollenberg CH. Varying
capacities for replication of rat adipocyte precursor
clones and adipose tissue growth. J Clin Invest 1989;
83:17411746.
72. Crandall DL, Goldstein BM, Huggins F, Cervoni P.
Adipocyte blood ow: inuence of age, anatomic
location, and dietary manipulation. Am J Physiol
1984; 247:R46R51.
73. Cousin B, Casteilla L, Lafontan M, Ambid L, Langin
D, Berthault M-F, Penicaud L. Local sympathetic
denervation of white adipose tissue in rats induces
preadipocyte proliferation without noticeable changes
in metabolism. Endocrinology 1993; 133:22552262.
74. Krotkiewski M, Sjostrom L, Bjorntorp P, Smith U.
Regional adipose tissue cellularity in relation to
metabolism in young and middle-aged women. Metabolism 1975; 24:703710.
75. Pettersson P, Van RLR, Karlsson M, Bjorntorp P.
Adipocyte precursor cells in obese and nonobese
humans. Metabolism 1985; 34:808812.
76. Adams M, Montague CT, Prins JB, Holder JC, Smith
SA, Sanders L, Digby JE, Sewter CP, Lazar MA,
Chatterjee VK, ORahilly S. Activators of peroxisome
prolifetoractivated receptor g have depot-specic
eects on human preadipocyte dierentiation. J Clin
Invest 1997; 100:31493153.
77. van Harmelen V, Dicker A, Rydem M, Hauner H,
Lonnqvist F, Naslund E, Arner P. Increased lipolysis
and decreased leptin production by human omental as
compared with subcutaneous preadipocytes. Diabetes
2002; 51:20292036.
78. Hauner H, Entenmann G. Regional variation of
adipose dierentiation in cultured stromal-vascular
cells from the abdominal and femoral adipose tissue of
obese women. Int J Obes 1991; 15:121126.
79. Faust IM, Johnson PR, Stern JS, Hirsch J. Dietinduced adipocyte number increase in adult rats: a new
model of obesity. Am J Physiol 1978; 235: E279E286.
80. Roncari DAK, Lau DCW, Kindler S. Exaggerated
replication in culture of adipocyte precursors
from massively obese persons. Metabolism 1981; 30:
425427.
81. Gregoire FM, Johnson PR, Greenwood MRC. Comparison of the adipoconversion of preadipocytes
derived from lean and obese Zucker rats in serumfree cultures. Int J Obes 1995; 19:664670.
82. Martorell R, Stein AD, Schroeder DG. Early nutrition
and later adiposity. J Nutr 2001; 131:874S880S.
83. Miller WH, Faust IM, Goldberger AC, Hirsch J.
Eects of severe long-term food deprivation and
refeeding on adipose tissue cells in the rat. Am J
Physiol 1983; 245:E74E80.
84. Hausberger FX. Eect of dietary and endocrine
factors on adipose tissue growth. In: Renold AE,
508
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
509
adipocyte dierentiation. Mol Cel Biol 1997; 17:
977988.
123. Garces C, Ruiz-Hidalgo MJ, Bonvini E, Goldstein J,
Laborda J. Adipocyte dierentiation is modulated by
secreted delta-like (dlk) variants and requires the
expression of membrane associated dlk. Dierentiation 1999; 64:103114.
124. Pedersen SB, Fuglsig S, Sjogren P, Richelsen B.
Identication of steroid receptors in human adipose
tissue. Eur J Clin Invest 1996; 26:10511056.
125. Mizutani I, Nishikawa Y, Adachi H, Enomoto T,
Ikegami H, Kurachi H, Nomura T, Miyake A.
Identication of estrogen receptor in human adipose
tissue and adipocytes. J Clin Endocrinol Metab 1994;
78:950954.
126. Safonova I, Darimont C, Amri E, Grimaldi P, Ailhaud
G, Reichert U, Shroot B. Retinoids are positive
eectors of adipose cell dierentiation. Mol Cell
Endocrinol 1994; 104:201211.
127. Flores-Delgado G, Marsh-Moreno M, Kuri-Harcuch
W. Thyroid hormone stimulates adipocyte dierentiation of 3T3 cells. Mol Cell Biochem 1987; 76:3543.
128. Darimont C, Gaillard D, Ailhaud G, Negrel. Terminal
dierentiation of mouse preadipocyte cells: adipogenic
and antimitogenic role of triiodothyronine. Mol Cell
Endocrinol 1993; 98:6773.
129. Amri EZ, Bonino F, Ailhaud G, Abumrad NA,
Grimaldi PA. Cloning of a protein that mediates
transcriptional eects of fatty acids in preadipocytes.
Homology to peroxisome proliferatoractivated receptors J Biol Chem 1995; 270:23672371.
130. Lemberger T, Desvergne B, Wahli W. Peroxisome
proliferator-activated receptors: A nuclear receptor
signaling pathway in lipid physiology. Annu Rev Dev
Biol 1996; 12:335363.
131. Liu PCC, Phillips MA, Matsumura F. Alteration by
2,3,7,8-tetrachlorodibenzo-p-dioxin of CCAAT/enhancer binding protein correlates with suppression of
adipocyte dierentiation in 3T3-L1 cells. Mol Pharmacol 1996; 49:989997.
132. Alexander DL, Ganem LG, Fernandez-Salguero P,
Gonzalez F, Jefcoate CR. Arylhydorcarbon receptors
is an inhibitory regulator of lipid synthesis and of
commiment to adipogenesis. J Cell Sci 1998; 111:3311
3322.
133. Brodie AE, Manning VA, Hu Cy. Inhibitors of
preadipocyte dierentiation induce COUP-TF binding
to a PPAR/RXR binding sequence. Biochem Biophys
Res Commun 1996; 228:655661.
134. Shimba S, Todoroki K, Aoyagi T, Tezuka M.
Depletion of arylhydrocarbon receptor during adipose
dierentiation in 3T3-L1 cells. Biochem Biophys Res
Commun 1998; 249:131137.
135. Reusch JEB, Colton LA, Klemm DJ. CREB activation induces adipogenesis in 3T3-L1 cells. Mol Cell
Biol 2000; 20:10081020.
510
136.
dierentiation: its dual role as a cAMP- and Ca2+elevating agent. J Biol Chem 1992; 267:1109211097.
Yarwood SJ, Kilgour E, Anderson NG. Cyclic AMP
potentiates growth hormonedependent dierentiation of 3T3-F442A preadipocytes: possible involvement of the transcription factor CREB. Mol Cell
Endocrinol 1998; 138:4150.
Shi H, Halvorsen YD, Ellis PN, Wilkison WO, Zemel
MB. Role of intracellular calcium in human adipocyte
dierentiation. Physiol Genomics 2000; 3:7582.
Aubert J, Saint-Marc P, Belmonte N, Dani C, Negrel
R, Ailhaud G. Prostacyclin IP receptor up-regulates
the early expression of C/EBPh and C/EBPy in
preadipose cells. Mol Cell Endocrinol 2000; 160:149
156.
Belmonte N, Phillips B, Massiera F, Villageois P,
Nichols J, Aubert J, Saeki K, Yuo A, Narumiya S,
Ailhaud G, Dani C. Activation of extracellular signalregulated kinases and CREB/ATF-1 mediate the
expression of C/EBPh and C/EBPy in preadipocytes.
Mol Endocrinol 2001; 15:20372049.
Accili D, Taylor SI. Targeted inactivation of the
insulin receptor gene in mouse 3T3-L1 broblasts via
homologous recombination. Proc Natl Acad Sci USA
1991; 88:47084712
Benito M, Potras A, Nebreda AR, Santos E. Dierentiation of 3T3-L1 broblasts to adipocytes induced
by transfection of ras oncogenes. Science 1991;
253:565568.
Klemm DJ, Leitner JW, Watson P, Nesterova A,
Reusch JEB, Goalstone ML, Draznin B. Insulininduced adipocyte dierentiation: activation of CREB
rescues adipogenesis from the arrest caused by
inhibition of prenylation. J Biol Chem 2001; 276:
2843028435.
Magun R, Burgering BMT, Coer P, Pardasani D,
Lin Y, Chabot J, Sorisky A. Expression of a
constitutively activated form of protein kinase B (cAkt) in 3T3-L1 preadipose cells causes spontaneous
dierentiation. Endocrinology 1996; 137:35903593.
Gagnon AM, Chen CS, Sorisky A. Activation of
protein kinase B and induction of adipogenesis by
insulin in 3T3-L1 preadipocytes. Contribution of
phosphoinositide-3,4,5-triphosphate versus phosphoinositide-3,4-biphosphate. Diabetes 1999; 48:691698.
Xia X, Serrero G. Inhibition of adipose dierentiation
by phosphatidylinositol 3-kinase inhibitors. J Cell
Physiol 1999; 178:916.
Boney CM, Smith R, Gruppuso P. Modulation of
insulin-like growth factor-1 mitogenic signaling in
3T3-L1 preadipocyte dierentiation. Endocrinology
1998; 139:16381644.
Boney CM, Gruppuso P, Faris RA, Frackelton AR Jr.
The critical role of Shc in insulinlike growth factorImediated mitogenesis and dierentiation in 3T3-L1
preadipocytes. Mol Endocrinol 2000; 14:805813.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
511
of growth hormone on primary preadipocyte dierentiation. Mol Endocrinol 1998; 12:11401149.
174. Nanbu-Wakao R, Fujitani Y, Masuho Y, Muramatu
M, Wakao H. Prolactin enhances CCAAT enhancerbinding protein-h (C/EBPh) and peroxisome proliferatoractivated receptor g (PPARg) messenger RNA
expression and stimulates adipogenic conversion of
NIH-3T3 cells. Mol Endocrinol 2000; 14:307316.
175. Grimaldi P, Djian P, Negrel R, Ailhaud G. Dierentiation of Ob17 preadipocytes to adipocytes: requirement of adipose conversion factor(s) for fat cell
cluster formation. EMBO J 1982; 1:687692.
176. Darimont C, Gaillard D, Ailhaud G, Negrel R.
Terminal dierentiation of mouse preadipocyte cells:
adipogenic and antimitogenic role of triiodothyronine.
Mol Cell Endocrinol 1993; 98:6773.
177. Xue JC, Schwartz EJ, Chawla A, Lazar MA. Distinct
stages in adipogenesis revealed by retinoid inhibition
of dierentiation after induction of PPARg. Mol Cell
Biol 1996; 16:15671575.
178. Amri E, Bertrand B, Ailhaud G, Grimaldi P.
Regulation of adipose cell dierentiation I. Fatty
acids are inducers of the aP2 gene expression. J Lipid
Res 1991; 32:14491456.
179. Gaillard D, Negrel R, Lagarde M, Ailhaud G. Requirement and role of arachidonic acid in the dierentiation
of preadipose cells. Biochem J 1989; 257:389397.
180. Negrel R, Gaillard D, Ailhaud G. Prostacyclin as a
potent eector of adipose cell dierentiation. Biochem
J 1989; 257:399405.
181. Forman BM, Vhen J, Evans RM. Hypolipidemic
drugs, polyunsaturated fatty acids, and eicosanoids
are ligands for peroxisome proliferator-activated
receptors a and y. Proc Natl Acad Sci USA 1997;
94:43124317.
182. Negrel R, Ailhaud G. Metabolism of arachidonic
acid and prostaglandin synthesis in Ob17 preadipocyte
cell line. Biochem Biophys Res Commun 1981; 98:
768777.
183. Cassis LA, Saye J, Peach M. Location and regulation
of rat angiotensinogen messenger RNA. Hypertension
1988; 11:591596.
184. Aubert J, Darimont C, Safonova I, Ailhaud G, Negre1
R. Regulation by glucocorticoids of angiotensinogen
gene expression and secretion in adipose cells.
Biochem J 1997; 328:701706.
185. Jones B, Standbridge MK, Moustaid N. Angiotensin
II increases lipogenesis in 3T3-L1 and human adipose
cells. Endocrinology 1997; 138:15121519.
186. Darimont C, Vassaux G, Ailhaud G, Negrel R.
Dierentiation of preadipose cells: paracrine role
of prostacyclin upon stimulation of adipose cells by
angiotensin II. Endocrinology 1994; 135:20302036.
187. Engeli S, Negrel R, Sharma AM. Physiology and
pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 2000; 35:12701277.
512
Massiera F, Block-Faure M, Ceiler D, Murakami K,
Fukamizu A, Gasc JM, Quignard-Boulange A, Negrel
R, Ailhaud G, Seydoux J, Meneton P, Teboul M.
Adipose angiotensinogen is involved in adipose tissue
growth and blood pressure regulation. FASEB J 2001.
In press.
189. Selvarajan S, Lund LR, Takeuchi T, Craik CS, Werb
Z. A plasma kallikreindependent plasminogen cascade required for adipocyte dierentiation. Nat Cell
Biol 2001; 3:267275.
190. Vassaux G, Negrel R, Ailhaud G, Gaillard D.
Proliferation and dierentiation of rat adipose precursor cells in chemically dened medium: dierential
action of anti-adipogenic agents. J Cell Physiol 1994;
161:249256.
191. Zhang B, Berger J, Hu E, Szalkowski D, WhiteCarrington S, Spiegelman BM, Moller DE. Negative
regulation of peroxisome proliferatoractivated receptor-g gene expression contributes to the antiadipogenic
eects of tumor necrosis factor-a. Mol Endocrinol
1996; 10:14571466.
192. Lyle RE, Richon VM, McGehee Jr RE. TNFa
disrupts mitotic clonal expansion and regulation of
retinoblastoma proteins p130 and p107 during 3T3-L1
adipocyte dierentiation. Biochem Biophys Res Commun 1998; 274:373378.
193. Harmon AW, Harp JB. Dierential eects of avonoids on 3T3-L1 adipogenesis and lipolysis. Am J
Physiol 2001; 280:C807C813.
194. Kawada T, Aoki N, Kamei Y, Maeshige K, Nishiu S,
Sugimoto E. Comparative investigation of vitamins
and their analogs on terminal dierentiation, from
preadipocytes to adipocytes, of 3T3-L1 cells. Comp
Biochem Physiol 1990; 96:323326.
195. Jehl-Pietri C, Bastie C, Gillot I, Luquet S, Grimaldi
PA. Peroxisome proliferatoractivated receptor delta
mediates the eects of long-chain fatty acids on
post-conuent cell proliferation. Biochem J 2000; 350:
9398.
196. Hansen JB, Zhang H, Rasmussen TH, Petersen RK,
Flindt EN, Kristiansen K. Peroxisome proliferatoractivated receptor y (PPARy)-mediated regulation of
preadipocyte proliferation and gene expression is
dependent on cAMP signaling. J Biol Chem 2001;
276:31753182.
197. Bastie C, Holst D, Gaillard D, Jehl-Pietri C, Grimaldi
P. Expression of peroxisome proliferator-activated
receptor PPARs promotes induction of PPARg and
adipocyte dierentiation in 3T3C2 broblasts. J Biol
Chem 1999 274:2192021925.
198. Bastie C, Luquet S, Holst D, Jehl-Pietri C, Grimaldi P.
Alterations of peroxisome proliferatoractivated receptor delta activity aect fatty acidcontrolled
adipose dierentiation. J Biol Chem 2000; 275:
3876838773.
199. Morrisson RF, Farmer SR. Role of PPARg in
188.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
513
221.
222.
223.
224.
225.
226.
227.
228.
229.
230.
231.
514
from targeted disruption of the mouse peroxisome
proliferatoractivated receptor h(y). Mol Cell Biol
2000; 20:51195128.
232. Wang N, Finegold MJ, Bradley A, Ou CN,
Abdelsayed SV, Wilde MD, Taylor LR, Wilson
DR, Darlington GJ. Impaired energy homeostasis in
C/EBPa knockout mice. Science 1995; 269:1108
1112.
233. Tanaka T, Yoshida N, Kishimoto T, Akira S.
Defective adipocyte dierentiation in mice lacking
18
Lipolysis and Lipid Mobilization in Human Adipose Tissue
Dominique Langin and Max Lafontan
Obesity Research Unit, INSERM U586, Louis Bugnard Institute, Universite Paul Sabatier-Centre Hosp`tal`er
Universitaire de Rangueil, Toulouse, France
INTRODUCTION
516
Figure 1 Control of human adipocyte lipolysis. Diagram of signal transduction pathways for catecholamines via adrenergic
receptors (AR), atrial natriuretic peptide via type A receptor and insulin. Protein kinases (PKA, PKG, and PKB) are involved in
target proteins phosphorylations. HSL phosphorylation promote its translocation from the cytosol to the surface of the lipid
droplet. Perilipin phosphorylation induces an important physical alteration of the droplet surface that facilitates the action of
HSL and lipolysis. Docking of ALBP to HSL favors the evacuation of NEFA released by the hydrolysis of triglycerides.
Question marks show pathways which are still hypothetical or the relevance of which has not been fully demonstrated in human
fat cells. Abbreviations: AC, adenylyl cyclase; ALBP, adipocyte lipid-binding protein; AR, adrenergic receptor; FA, fatty acid;
GC, guanylyl cyclase; Gi, inhibitory GTP-binding protein; Gs, stimulatory GTP-binding protein; HSL, hormone-sensitive lipase;
IRS, insulin receptor substrate; NEFA, nonesteried fatty acid; PDE-3B, phosphodiesterase 3B; P13-K, phosphatidylinositol-3phosphale kinase; PKA, protein kinase A; PKB, protein kinase B; PKG, protein kinase G.
TRIGLYCERIDE HYDROLYSIS
Protein-Lipid Interactions
triglyceride is broken in a stepwise fashion via diglyceride and monoglyceride intermediates into 3 moles
of free fatty acid and 1 mole of glycerol. In vitro, HSL
catalyzes the hydrolysis of triglycerides into diglycerides, and diglycerides into monoglycerides. The rst
step occurs at a 10-fold lower rate than the second
step. The enzyme is also responsible for the hydrolysis
of cholesterol and retinyl esters. Although HSL has
the capacity to hydrolyze monoglycerides in vitro,
monoglyceride lipase (MGL) is required to obtain
complete hydrolysis of monoglycerides in vivo. It is
important to note that MGL also hydrolyzes 2-monoglycerides resulting from the action of lipoprotein
lipase. Unlike other known mammalian triglyceride
lipases, HSL phosphorylation by protein kinase A
517
518
Activators and inhibitors of the adenylyl cyclase system and hormones and enzymes controlling intracellular cyclic AMP levels are direct regulators of
lipolysis. Intracellular cyclic AMP (cAMP) increases
lipolysis while antilipolysis is associated with the lowering of cAMP levels. In vitro studies on human fat
cells have established that the tuning of cAMP levels
and lipolysis by hormones and paracrine agents is
dependent on the balanced cross-talk between stimu-
Gs-protein-Coupled Receptors
Gi-protein-Coupled Receptors
In addition to lipolysis-promoting agents neuropeptides, paracrine factors, and autacoid agents (adenosine,
prostaglandins and their metabolites) originating from
the adipocytes themselves, preadipocytes, endothelial
cells, macrophages, and sympathetic nerve terminals are
known to negatively control adenylyl cyclase activity
and inhibit lipolysis by their interaction with plasma
membrane receptors belonging to the seven-transmembrane domain receptor family. The major antilipolytic
Tyrosine-Kinase Receptors
and Signaling Pathways
519
Natriuretic Peptides
520
Growth Hormone
Miscellaneous Agents
521
Aging
Aging is associated with a diminished ability to mobilize fatty acids and to use fat as a fuel (increase skeletal
muscle fatty acid uptake and oxidation) during betaadrenergic receptor stimulation (83). There is a selective
decrease in the beta-adrenergic lipolytic capacity with
aging, which may be caused by disturbances at the adrenergic receptor level or at the postadrenergic receptor
level. These alterations are independent from the ageexpected increase in total adiposity (84). The impairment in sympathetic nervous system (SNS)-mediated
lipolysis and fat oxidation may be of importance in the
age-related increase in adiposity and obesity.
C
Stress
Exercise
522
DYSREGULATION OF LIPOLYSIS
IN OBESITY
523
Catecholamine Action
It is commonly accepted that the action of catecholamines is impaired in obesity. This defect might be an
early event since it has been observed in obese adolescents (104,105). A summary of the modications of the
Table 1 Physiological and Pathological Modications of the Human Lipolytic Responses to Catecholamines In Vitro in
Isolated Fat Cells and In Situ Using Adipose Tissue Microdialysis
Physiological and pathological situations
Neonatal period
Aging
Sex-related dierences
Lipolytic responsea
1
Decreased
Decreased1
Variable1
Anatomical dierences
Very low calorie diet
Endurance training
Obesity
Variable1
Increased1
Increased1,2
Decreased1
Insulin resistance
syndrome
Catecholamine resistance
in normal population
Combined familial
hyperlipidemia
Polycystic ovary
syndrome
Hypothyroidism
Hyperthyroidism
Cushing syndrome
Phaeochromocytoma
Type I diabetes
Microgravity
Adrenaline infusion
Decreased1
Decreased1
Decreased1
Decreased1
Decreased1
Increased1
Decreased1
Decreased1
Increased2
Increased2
Decreased2
Modulatory eects
a2-adrenergic responsiveness z
Activation of HSL #
Changes in the balance between
a2- and h-adrenergic eects
HSL expression correlated
positively with fat cell size
idem
HSL expression z
h-adrenergic response z
HSL expression #
h2-adrenergic receptor expression #
a2-adrenergic receptor response z
HSL activation #
h2-adrenergic receptor number #
h2-adrenergic response #
h2-adrenergic receptor number #
HSL expression #
HSL activation #
h2-adrenergic receptor number #
HSL activation
h-adrenergic receptor number z
Unknown
Unknown
h-adrenergic response z
h-adrenergic response z
h-adrenergic response #
Ref.
142
143
78
144
107,108
101
91
100
145
107
117
80
146
147
148
148
79
149
150
151
87
524
marked increase in portal NEFA in relation to peripheral venous NEFA. Excess in portal NEFA could be a
mechanism responsible for the hepatic insulin resistance
usually observed in abdominal obesity. Unfortunately,
a number of these speculations are based on in vitro
studies and in vivo measurements of subcutaneous
adipose tissue responses. For practical and ethical reasons, it is dicult to perform a direct study of portal
NEFA ux in vivo in humans; it is the major limitation
of such studies.
Moreover, in addition to catecholamines, and owing
to technical limitations, the contribution of other hormones and paracrine agents exerting antilipolytic
actions has not been investigated so deeply in visceral
obesity. It is not clear to what extent insulin action is
altered in obesity. Controversial results have been published. Insulin resistance has been demonstrated in
obese subjects when insulin action is studied on glucose
transport and glucose uptake by adipose tissue. Data on
insulin-induced antilipolysis have shown that insulin
exerts a stronger antilipolytic action in subcutaneous
than in visceral fat deposits; controversies persist probably owing to the diculties existing for the investigation of the antilipolytic actions of insulin in obese
subjects. Increased, decreased or normal antilipolytic
actions of insulin have been described in fat cells
obtained from obese subjects (79,117). Preservation or
partial or tissue-dependent reduction of antilipolytic
actions of insulin could be important for the maintenance or acceleration of obesity in overweight subjects.
There is a generalized resistance to insulin suppression
of lipolysis in type 2 diabetes compared with equally
obese nondiabetic individuals (118). Modications of
other antilipolytic mechanisms may also be involved in
the adipocyte of obese subjects. Decreased antilipolytic
actions of prostaglandins and adenosine have been
reported in subcutaneous fat cells of obese subjects in
vitro. These results must be interpreted cautiously since
the design of in vitro assays for in vivo demonstrations
do not exist for the moment. Whatever the number of in
vitro studies on isolated adipocytes and small tissue
samples, it is still dicult to extrapolate a number of in
vitro ndings to the in vivo situation.
VI
525
526
VII
REFERENCES
Bouchard C, Despres J-P, Maurie`ge P. Genetic and
nongenetic determinants of regional fat distribution.
Endocr Rev 1993; 14:7293.
2. Abumrad N, Harmon C, Ibrahimi A. Membrane
transport of long-chain fatty acids: evidence for a
facilitated process. J Lipid Res 1998; 39:23092318.
3. Hamilton JA, Kamp F. How are free fatty acids
transported in membranes? Is it by proteins or by free
diusion through the lipids? Diabetes 1999; 48:2255
2269.
4. Frohnert BI, Bernlohr DA. Regulation of fatty acid
transporters in mammalian cells. Prog Lipid Res 2000;
39:83107.
5. Anthonsen MW, Ronnstrand L, Wernstedt C, Degerman E, Holm C. Identication of novel phosphorylation sites in hormone-sensitive lipase that are
phosphorylated in response to isoproterenol and
govern activation properties in vitro. J Biol Chem
1998; 273:215221.
6. Greenberg AS, Shen WJ, Muliro K, Patel S, Souza SC,
Roth RA, Kraemer FB. Stimulation of lipolysis and
hormone-sensitive lipase via the extracellular signalregulated kinase pathway. J Biol Chem 2001; 276:
4545645461.
7. Holm C, Osterlund T, Laurell H, Contreras JA.
Molecular mechanisms regulating hormone-sensitive
lipase and lipolysis. Annu Rev Nutr 2000; 20:365393.
8. Hirsch AH, Rosen OM. Lipolytic stimulation modulates the subcellular distribution of hormone-sensitive lipase in 3T3-L1 cells. J Lipid Res 1984; 25:665
677.
9. Egan JJ, Greenberg AS, Chang M-K, Wek SA, Moos
J, Londos C. Mechanism of hormone-stimulated lipolysis in adipocytes: translocation of hormonesensitive lipase to the lipid storage droplet. Proc Natl
Acad Sci USA 1992; 89:85378541.
10. Brasaemle DL, Levin DM, Adler-Wailes DC, Londos
C. The lipolytic stimulation of 3T3-L1 adipocytes
1.
527
promotes the translocation of hormone-sensitive lipase
to the surfaces of lipid storage droplets. Biochim
Biophys Acta 2000; 1483:251262.
11. Osuga J, Ishibashi S, Oka T, Yagyu H, Tozawa R,
Fujimoto A, Shionoiri F, Yahagi N, Kraemer FB,
Tsutsumi O, Yamada N. Targeted disruption of
hormone-sensitive lipase results in male sterility and
adipocyte hypertrophy, but not in obesity. Proc Natl
Acad Sci USA 2000; 97:787792.
12. Wang SP, Laurin N, Himms-Hagen J, Rudnicki MA,
Levy E, Robert M-F, Pan L, Oligny L, Mitchell GA.
The adipose tissue phenotype of hormone-sensitive
lipase deciency in mice. Obesity Res 2001; 9:119
128.
13. Haemmerle G, Zimmermann R, Hayn M, Theussl C,
Waeg G, Wagner E, Sattler W, Magin TM, Wagner E,
Zechner R. Hormone-sensitive lipase deciency in
mice causes diglyceride accumulation in adipose tissue, muscle and testis. J Biol Chem 2002; 277:4806
4815.
14. Shen WJ, Sridhar K, Bernlohr DA, Kraemer FB.
Interaction of rat hormone-sensitive lipase with
adipocyte lipid-binding protein. Proc Natl Acad Sci
USA 1999; 96:55285532.
15. Syu LJ, Saltiel AR. Lipotransin: a novel docking
protein for hormone-sensitive lipase. Mol Cell 1999;
4:109115.
16. Scheja L, Makowski L, Uysal KT, Wiesbrock SM,
Shimshek DR, Meyers DS, Morgan M, Parker RA,
Hotamisligil GS. Altered insulin secretion associated
with reduced lipolytic eciency in aP2-/- mice.
Diabetes 1999; 48:19871994.
17. Coe NR, Simpson MA, Bernlohr DA. Targeted
disruption of the adipocyte lipid-binding protein
(aP2 protein) gene impairs fat cell lipolysis and
increases cellular fatty acid levels. J Lipid Res 1999;
40:967972.
18. Londos C, Brasaemle DL, Schultz CJ, Adler-Wailes
DC, Levin DM, Kinimel AR, Rondinone CM. On the
control of lipolysis in adipocytes. Ann NY Acad Sci
1999; 892:155168.
19. Martinez-Botas J, Anderson JB, Tessier D, Lapillonne
A, Chang BH, Quast MJ, Gorenstein D, Chen KH,
Chan L. Absence of perilipin results in leanness and
reverses obesity in Leprdb/db mice. Nat Genet 2000;
26:474479.
20. Tansey JT, Sztalryd C, Gruia-Gray J, Roush DL, Zee
JV, Gavrilova O, Reitman ML, Deng C-X, Li C,
Kimmel AR, Londos C. Perilipin ablation results in a
lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to dietinduced obesity. Proc Natl Acad Sci USA 2001;
98:64946499.
21. Raclot T, Groscolas R. Selective mobilization of
adipose tissue fatty acids during energy depletion in
the rat. J Lipid Res 1995; 36:21642173.
22. Halliwell KJ, Fielding BA, Samra JS, Humphreys SM,
528
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
529
alpha stimulates lipolysis in adipocytes by decreasing
Gi protein concentrations. J Biol Chem 1999; 274:
67706775.
63. Ryden M, Dicker A, Harmelen VV, Hauner H,
Brunnberg M, Perbeck L, Lonnqvist F, Amer P.
Mapping of early signalling events in TNF-a-mediated
lipolysis in human fat cells. J Biol Chem 2002;
277:10851091.
64. Gaudiot N, Jaubert A-M, Charbonnier E, Sabourault
D, Lacasa D, Giudicelli Y, Ribie`re C. Modulation of
white adipose tissue lipolysis by nitric oxide. J Biol
Chem 1998; 273:1347513481.
65. Andersson K, Gaudiot N, Ribie`re C, Elizalde M,
Giudicelli Y, Arner P. A nitric oxidemediated
mechanism regulates lipolysis in human adipose tissue
in vivo. Br J Pharmacol 1999; 126:16391645.
66. Tisdale M. Wasting in cancer. J Nutr 1999; 129
(1suppl):243S246S.
67. Groundwater M, Bulcavage L, Barton C, Adamson C,
Ferrier I, Tisdale M. Alteration of serum and urinary
lipolytic activity with weight loss in cachectic cancer
patients. Br J Cancer 1990; 62:816821.
68. Coppack SW, Jensen MD, Miles JM. In vivo regulation of lipolysis in humans. J Lipid Res 1994; 35:
177193.
69. Large V, Arner P, Reynisdottir S, Grober J, Harmelen
VV, Holm C, Langin D. Hormone-sensitive lipase
expression and activity in relation to lipolysis in human fat cells. J Lipid Res 1998; 39:16881695.
70. Lafontan M, Berlan M. Fat cell adrenergic receptors
and the control of white and brown fat cell function.
J Lipid Res 1993; 34:10571091.
71. Arner P. Catecholamine-induced lipolysis in obesity.
Int J Obes 1999; 23(suppl 1):1013.
72. Langin D, Lucas S, Lafontan M. Millenium fat-cell
lipolysis reveals unsuspected novel tracks. Horm
Metab Res 2000; 32:443452.
73. Kissebah A, Krakower GR. Regional adiposity and
morbidity. Physiol Rev 1994; 74:761811.
74. Leibel R, Edens NK, Fried SK. Physiologic basis for
the control of body fat distribution in humans. Annu
Rev Nutr 1989; 9:417443.
75. Abate N, Garg A. Heterogeneity in adipose tissue
metabolism: causes, implications and management of
regional adiposity. Prog Lipid Res 1995; 34:5370.
76. Jensen MD. Lipolysis: contribution from regional fat.
Annu Rev Nutr 1997; 17:127139.
77. Hellstrom L, Rossner S, Hagstrom-Toft E, Reynisdottir S. Lipolytic catecholamine resistance linked to
h2-adrenoceptor sensitivitya metabolic predictor of
weight loss in obese subjects. Int J Obes 1997; 21:314
320.
78. Maurie`ge P, Imbeault P, Langin D, Lacaille M,
Almeras N, Tremblay A, Despres JP. Regional and
gender variations in adipose tissue lipolysis in response
to weight loss. J Lipid Res 1999; 40:15591571.
530
79. Arner P. Control of lipolysis and its relevance to
development of obesity in man. Diabetes Metab Rev
1988; 4:507515.
80. Lonnqvist F, Wahrenberg H, Hellstrom L, Reynisdottir
S, Arner P. Lipolytic catecholamine resistance due
to decreased h2-adrenoceptor expression in fat cells.
J Clin Invest 1992; 90:21752186.
81. Zierath J, Livingston J, Thorne A, Bolinder J, Reynisdottir S, Lonnqvist F, Arner P. Regional dierence
in insulin inhibition of non-esteried fatty acid release
from human obese adipocytes: relation to insulin
receptor phosphorylation and intracellular signalling
through the insulin receptor substrate-1 pathway.
Diabetologia 1998; 41:13431354.
82. Meek SE, Nair KS, Jensen MD. Insulin regulation of
regional free fatty acid metabolism. Diabetes 1999;48:
1014.
83. Blaak EE. Adrenergically stimulated fat utilization
and ageing. Ann Med 2000; 32:380382.
84. Imbeault P, PrudHomme D, Tremblay A, Despres J,
Maurie`ge P. Adipose tissue metabolism in young and
middle-aged men after control for total body fatness.
J Clin Endocrinol Metab 2000; 85:24552462.
85. Wolfe R. Substrate utilization/insulin resistance in
sepsis/trauma. Bailleres Clin Endocrinol Metab 1997;
11:645657.
86. Townsend R, Klein S, Wolfe R. Changes in lipolytic
sensitivity following repeated epinephrine infusion in
humans. Am J Physiol 1994; 266:E155E160.
87. Stallnecht B, Bulow J, Frandsen E, Galbo H.
Desensitization of human adipose tissue to adrenaline stimulation studied by microdialysis. J Physiol
1997;500:271282.
88. Horowitz J, Klein S. Lipid metabolism during endurance exercise. Am J Clin Nutr 2000; 72(suppl):558S
563S.
89. Head A. Exercise metabolism and h-blocker therapy.
An update. Sports Med 1999; 27:8196.
90. Stallknecht B, Simonsen L, Bulow J, Vinten J, Galbo
H. Eect of training on epinephrine-stimulated lipolysis determined by microdialysis in human adipose
tissue. Am J Physiol 1995; 269:E1059E1066.
91. De Glisezinski I, Crampes F, Harant I, Berlan M,
Hejnova J, Langin D, Rivie`re D, Stich V. Endurance
training changes in lipolytic responsiveness of obese
adipose tissue. Am J Physiol 1998; 275:E951E956.
92. Stich V, De Glisezinski I, Galitzky J, Hejnova J,
Crampes F, Rivie`re D, Berlan M. Endurance training
increases the h-adrenergic lipolytic response in subcutaneous adipose tissue in obese subjects. Int J Obes
1999; 23:374381.
93. Maurie`ge P, PrudHomme D, Marcotte M, Yoshioka
M, Tremblay A, Despres JP. Regional dierences in
adipose tissue metabolism between sedentary and
endurance-trained women. Am J Physiol 1997;
273:E497E506.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
531
120.
532
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
19
Lipodystrophy and Lipoatrophy
Steven R. Smith
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
I INTRODUCTION
Excess adipose tissue is associated with metabolic disturbances and disease, i.e., the metabolic syndrome
(1,2). Somewhat paradoxically, inadequate adipose tissue manifests itself in a similar fashion (3,4). This
observation demonstrates that adipose tissue is required
for normal metabolic function. The inherited and
acquired lipodystrophies constitute a heterogeneous
group of disorders that share the common feature of
inadequate adipose tissue stores.
Although the lipodystrophic disorders represent a
variety of underlying pathophysiological states, their
common sequelae are instructive, as they are likely to be
similar to the metabolic complications associated with
garden-variety obesity/metabolic syndrome X. Our
understanding of the pathophysiology of these patients
and parallel models of lipodystrophy in animals point
toward the concept of an optimal adipose tissue mass
that matches the energy requirements of the organism.
In addition, these disorders illustrate the central role of
adipose tissue to (1) sequester lipid, and (2) adipose
tissue as an endocrine organ.
This chapter is divided into three main sections.
First, the characterized lipodystrophies and their salient features will be briey reviewed. Second, the
common pathophysiological mechanisms will be discussed in light of the available animal models. Last,
based on the mechanisms by which inadequate adipose
II LIPODYSTROPHIES
A Congenital Generalized Lipodystrophy (CGL)
CGL, OMIM 269700, i.e., Berardinelli-Seip syndrome,
is an autosomal-recessive disorder that manifests at
birth as a complete absence of adipose tissue, hepatomegaly, and severe nonketotic insulin resistant diabetes.
Additional features include acanthosis nigricans and an
elevated basal metabolic rate. Mechanical fat in the
hands, feet, orbit, scalp, and periarticular fat are usually
preserved (3).
B Familial Partial Lipodystrophy (FPL)
FPL, OMIM 151660, familial partial lipodystrophy, an
autosomal-dominant disorder, is dierentiated from
congenital generalized lipodystrophy, an autosomalrecessive disorder, by the timing of the onset (4). FPL
533
534
Smith
known to include elevated triglycerides, insulin resistance, a decrease in facial fat, particularly in the cheeks
and temporal area, and loss of subcutaneous fat in the
buttocks, arms, and legs. These latter changes have been
described as roping of the supercial veins in the arms
and a muscular appearance to the lower extremities.
535
Recent progress in our understanding of the transcriptional cascade involved in the dierentiation of adipocyte precursors into mature adipocytes led to the
development of transgenic models of lipodystrophy.
These models came from the laboratories of Shimomura
(24) and Reitman (25). The models are instructive
regarding the pathophysiology of the adipose tissue
deciency and are useful in testing pharmacological
interventions. A spontaneous mutation in the lipin gene
is responsible for the d lipodystrophic mouse, a novel
model of the complete lipodystrophy syndrome (26,27).
Detailed studies of these animal models may reveal
unexpected mechanisms by which a failure to develop
adipose tissue results in diabetes and metabolic derangements (2831).
IV THERAPY
Because of the rarity of these syndromes, little is known
regarding specic therapies for lipodystrophy. There are
three basic approaches based on the pathophysiology of
the syndromes.
First, given that an inability to sequester lipid in
adipose tissue is likely to lead to the accumulation of
lipid in abnormal locations such as the liver and skeletal
muscle, creating a negative fat and calorie balance is
recommended. This is dicult in practice, however, and
may be due to anecdotal reports of increased appetite,
especially in the setting of uncontrolled diabetes. Along
these same lines, the standard medical therapies for
dyslipidemia are indicated, but for patients with hypertriglyceridemia in the face of maximal lipid and diabetes
medications, plasmapheresis may be necessary. Newer
therapies that target specic metabolic defects are likely
to supplant this therapy.
A second approach is based on the known pathways
aecting insulin sensitivity. For example, the thiazolidinediones have been used with success in the treatment of these patients (32). As a cautionary note, one
of these patients developed liver complications during
therapy with troglitazone, and liver enzyme testing at
regular intervals may be more important than in the
routine diabetic patient. Given this caveat, the newer
TZDs, which are less likely to cause liver toxicity, are
likely to become a rst-line therapy for lipodystrophic
metabolic syndromes.
536
Smith
4.
5.
6.
7.
8.
V THE FUTURE
Understanding the underlying genetic causes of the
CGL syndrome is an important short-term milestone.
As we understand the common mechanism by which
inadequate adipose tissue stores contribute to disease,
we will develop specic therapies. These therapies will
consist of treatment not only for the metabolic sequelae
but also for the defects in adipocyte proliferation and/or
dierentiation that cause these diverse syndromes. Several of these can be anticipated; i.e., drugs that increase
fat oxidation, improve insulin resistance, or replace
decreased hormones (e.g., leptin) are likely to occur in
a shorter time span. Other therapies will not be obvious
until we understand the complex mechanisms of genes
such as laminin A/C or lipin and the pathophysiology of
CGL.
9.
10.
11.
3.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
21a.
21b.
22.
23.
24.
25.
26.
27.
537
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
20
Uncoupling Proteins
Daniel Ricquier
UPR 9078, Centre National de la Recherche Scientifique, Faculty of Medicine, Necker-Sick Children,
Paris, France
Leslie P. Kozak
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
INTRODUCTION
II
UCP1
Pharmacological and genetic manipulations of experimental rodents suggest that nonshivering thermogenesis is one of the most eective strategies for reducing
adiposity in obese individuals. While there are many
systems of thermogenesis that are theoretically capable
of increasing energy expenditure, in fact, a body of
evidence conrming that a specic mechanism for
increasing thermogenesis is eective in reducing
adiposity is available only for mitochondrial uncoupling protein (UCPI)-dependent thermogenesis of
brown adipose tissue. The previous edition of the
Handbook of Obesity described the biology of brown
adipose tissue, the biochemistry of UCP1, and the
adrenergic signaling mechanisms that controlled the
activation of nonshivering thermogenesis. Although
the eectiveness of UCP1 in reducing adiposity in
obese rodents is clear its relevance to obesity in
humans has remained questionable because of the
paucity of brown adipocytes in adult humans. Since
the previous edition of the handbook was issued,
important developments in mitochondrial uncoupling
proteins and the regulation of brown adipocyte dier539
540
Uncoupling Proteins
541
An alternative approach to increasing Ucpl gene expression is based on increasing the number of brown adipocytes in an individual. This approach directly addresses
the problem of limiting numbers of brown adipocytes in
adult humans that preclude a robust response to an
adrenergic agonist. It has been observed among several
mammalian species that chronic sympathetic stimulation by either cold exposure or adrenergic agonists leads
to an increase in brown adipocytes in traditional white
fat depots as evidenced by increases in the Ucpl expression or by the histological appearance of adipocytes
with a multilocular morphology (10,11,19,20). This
inductive response may also occur in humans. For
example, Finnish laborers working outdoors in the
winter months are reported to have larger deposits of
brown adipocytes (21), and patients carrying catecholamine-secreting pheochromocytoma develop large
depots of brown fat (22). The former report suggests
that the increase in brown adipocytes enhances the
thermogenic capacity of the laborers; the latter report
underscores the possibility that humans have the
capacity to increase the number of brown adipocytes.
There is evidence that increased numbers of brown
adipocytes in rats treated with h3-adrenergic agonists
reduce obesity caused by either a mutation to the leptin
receptor or a high-fat diet (11,13). Rats treated with the
drugs lost weight and also had elevated numbers of
brown adipocytes. However, it is not clear whether rats
with induced levels of brown adipocytes lost weight
because of increased energy expenditure derived from
increased numbers of brown adipocytes or weight was
lost by some other mechanism. Similarly, when inbred
strains of mice that varied in the numbers of brown
adipocytes were treated with a h3-agonist, those strains
with more brown adipocytes lost more adipose tissue
(23). The same caveat holds for this experiment, since it
is possible that other biochemical dierences, rather
than brown adipocyte number among the strains,
aected adiposity.
There has been a careful quantication of UCP1
expression in human adipose tissue from lean and obese
individuals by quantitative RTPCR (24). In this study,
542
Uncoupling Proteins
subunit binds cAMP with higher avidity than in wildtype mice, thereby lowering its threshold for activation
and subsequent stimulation of CREB-mediated transcription. In a second study, a winged helix/forkhead
transcription factor FOXC2 was overexpressed in adipose tissue of transgenic mice with the aP2 promoter
(31). Similar to the RIIh regulatory subunit targeted
mice, the FOXC2 transgenic mice had increased expression of Ucp1 in brown adipose tissue and, in addition,
had an increase in the expression of the brown adipocytes in white fat depots. The increase in PGC1,
PPARg, and ADD1/SREBP in the white fat depots of
transgenic mice suggests that the overexpression of
FOXC2 stimulates the brown adipocyte dierentiation
program in the white fat depots. The mechanism by
which FOXC2 induces these changes appears to be
mediated by changes in the expression of the regulatory
subunits of protein kinase A. FOXC2 preferentially
stimulates the expression of the RIa regulatory subunit,
thereby establishing a cAMP system with heightened
activity. The results with FOXC2 show how the induction of both Ucp1 expression and the brown adipocyte
dierentiation are exquisitely sensitive to cAMP signaling. Consistent with these models is an earlier transgenic
model in which the h1-adrenergic receptor was overexpressed from the aP2 promoter and resulted in an
increase in brown adipocyte expression (32). However,
in a follow-up analysis of the eects of the RIIh subunit
gene inactivation on gene expression associated with
lipolysis and gene expression in white fat depots, those
eects that would indicate a striking increase in brown
adipocyte expression in the white fat of the knockout
mice were much more modest (33). Whether the dierences between the RIIh knockout and FOXC2 overexpression systems are due to background strain eects,
sex, or type of fat pads analyzed need to be resolved.
In summary, alternative strategies are being discovered by which an enhancement of cAMP signalling can
activate the brown adipocyte dierentiation program in
white fat as follows: 1.) The FOXC2 transgenic model
has revealed a novel mechanism by which sensitivity of
PKA signalling can be modulated by regulating expression of the PKA regulatory subunits; 2.) the genetic
analysis of brown fat induction in mice has identied at
least four more chromosomal regions in which reside
novel genes that can also stimulate Ucp1 expression.
Accordingly, it is possible that additional strategies for
upregulating brown adipocyte dierentiation will be
discovered. The fact that FOXC2 is abundantly
expressed in human adipose tissue suggests that the
machinery for inducing brown fat expression also exists
in the human (31).
543
544
role in determining changes in peripheral energy expenditure initiated by the action of leptin. Given that even
UCP1-decient mice are not obese (48), the relative
contributions that changes in Ucp1 expression may have
in modulating energy expenditure and adiposity by
anorexic and orexigenic peptides remains uncertain.
Even more uncertain is the contribution that this mechanism has in modulating energy expenditure in humans.
F
Ucp1 is activated in response to growth and development, environmental temperature, and nutrition status.
Much of this regulation is coordinated centrally from
the hypothalamus via the sympathetic nervous system;
however, other aspects of regulation appear to proceed
independent of the sympathetic nervous system, and
some regulation may require both the SNS and mechanisms independent of the SNS. In parallel with these
expression studies, several research groups have been
characterizing the regulatory motifs, located in the 5V
anking region of the gene, and identifying the transcription factors that interact with these motifs. The
picture emerging from these studies is that a number of
motifs and factors have been identied that may interact in various combinations to regulate Ucp1 transcription under a specic set of conditions. What these
combinations may be for a given function remains to
be determined.
The general structure of the 5V regulatory region
of Ucp1, depicted in Figure 1, highlights two major
domainsthe proximal promoter, and a distal enhancer region. These regions are highlighted because
expression studies based on transgenic mice and transient expression assays in cultured cells of the regulatory
motifs from the mouse and rat genes have shown
consistent results. Other motifs, principally those
located between the proximal promoter and the distal
enhancer, have been identied by comparative sequence
analysis, but have not been clearly veried by expression
studies. In addition, there is evidence for a silencer
located f1 kb from the transcription start site, but the
identity of the sequences specifying this function has not
been determined. Finally, strong DNase hypersensitive
regions 16 kb upstream of the transcription start site of
Ucp1 have been mapped. Whether these sites are the
location of Ucp1 regulatory motifs, such as a distal
locus-controlling element, is not known.
An absolute requirement for a CRE in the proximal
promoter has been shown by site-direct mutagenesis of
the CRE in both the mouse and the rat gene (49,50). It is
probable that cJun is involved in regulation from this
Figure 1 Schematic representation of the 5V anking regulatory region of the Ucp1 gene. Known transcription factors
and eectors are listed. The nucleotide positions of the
enhancers and proximal promoter regions are those that have
been determined for the mouse gene, but the mouse and
human genes have comparable locations for these regulatory
elements. The overall size and relationship of transmembrane
domains to exon/intron structure is also similar among the rat,
mouse, and human (173175). Additional elements are likely
to reside between the proximal promoter and distal enhancer,
but these have not been well characterized at this time.
site, but it is not determining the dierentiation-dependent expression of Ucp1 (50). Whether the proxima
CRE is required for retinoic aciddependent induction
of gene expression is not known. Sp1 and NF1 motifs
have been identied by sequence analysis; however,
there is no other evidence that these motifs have a
function in the promoter (51).
The distal enhancer region is extremely complex
with evidence for the involvement of 10 or more
transcription factors (Fig. 1). The importance of this
region was rst identied in transgenic mice (52) and
subsequently by deletion and mutation analysis in
transient expression assays in brown adipocyte cultures (49,53). PPRE region in the distal enhancer was
rigorously characterized as the PPARg-binding site by
Sears et al. (54), thereby providing the groundwork
that led to the discovery of PGC1 as a coactivator of
PPARg together with RXRa (55). Corroboration of
Uncoupling Proteins
545
Perspectives on UCP1
III
546
Biochemical Studies
Uncoupling Proteins
translocation to the cell surface by activating a PI3Kdependent pathway (106). Such an eect could be
related to uncoupling activity of UCP3 and a subsequent requirement for substrate utilization. Another
study of overexpression of human UCP3 in cultured
human muscle was shown to favor fatty acid over
glucose oxidation (107).
In summary, it is obvious that unphysiological levels
of UCP2 or UCP3 can uncouple respiration in yeast or
mammalian cell and translocate protons through a
membrane, but it is not certain whether the low physiological levels of these proteins may be sucient to
induce a net uncoupling of respiration in vivo. The
divergent observations of the regulation of the activities
of UCP2 or UCP3 by fatty acids or nucleotides will
require further studies. Interestingly, Moore et al.
recently proposed that UCP2 and UCP3 could export
fatty acid anion under conditions of elevated fatty acid
oxidation (108). Expression studies of UCP2 in pancreatic cells agree with an uncoupling activity, but the
demonstration that a concomitant decrease of ATP
content directly results from respiration uncoupling
should be further conrmed. Another important role
for UCP2 and UCP3 may be related to the control of
reactive oxygen species (this point is discussed in the
section on transgenic mice).
B
Genetic Studies
547
548
Several studies have aimed at understanding the physiological signicance and regulation of UCP2 and
UCP3. These studies were related to (1) eects of hormones, substrates or drugs on UCP expression, (2)
status of UCPs in obese or diabetic patients, and (3)
the relationship between UCP2 and UCP3 and physical exercise.
The identication of UCP homologs able to uncouple respiration in recombinant systems prompted the
authors to propose that such proteins were involved in
basal or regulatory thermogenesis. In agreement with
this hypothesis, Barbe et al. reported that the level of
UCP2 mRNA in adipose tissue of obese humans after
25 days of hypocaloric diet correlated with resting
metabolic rate adjusted for lean body mass (144). The
hypothesis that the UCP homologs could stimulate
thermogenesis is supported by several studies showing
that they were upregulated by thyroid hormones in
rodents (76,145,146). The eect of thyroid hormones
was tested in humans receiving an amount of T3 causing
a 1.7-fold increase in plasma-free T3 level, a 14%
increase in resting metabolic rate, a small decrease in
respiratory quotient, and no change in plasma level of
nonesteried fatty acids (147). In this study, T3
increased UCP2 mRNA levels in adipose tissue as well
as UCP2 and UCP3 mRNA levels in skeletal muscle. In
addition, the direct eect of T3 on skeletal muscle and
adipose tissue UCP2 and UCP3 mRNA was demonstrated in vitro with human primary cultures. A marked
upregulation of UCP2 mRNA was also described in
adipose tissue of hyperthyroid patients (148).
Soon after the discovery of UCP2 and UCP3, an
upregulation of UCP2 and UCP3 mRNAs upon starvation was described both in humans (78) and rodents
(79,149). Such data questioned the hypothetical role
for the novel UCPs in energy expenditure in the face of
depleted energy reserves; however, it was suggested
that the UCPs could provide for the important function of maintaining body temperature that could occur
during starvation. Dulloo and Samec have proposed
that the function of UCP2 and UCP3 was rather to
adapt cell metabolism to lipid utilization rather than
thermogenesis (149). In agreement with this proposal,
the upregulation of UCP2 and UCP3 mRNAs by a
high-fat diet in humans is more pronounced in humans
with high proportions of type IIA bers, which are
known to have a high capacity to shift from carbohydrate to fat oxidation (150).
To explain Ucp3 induction in skeletal muscle during
food restriction of rats, Weigle et al. proposed that the
free fatty acids are the mediators of such a change (151).
In agreement with this work, infusion of lipids for 5 hr in
human volunteers induces a rise in nonesteried fatty
acids and a doubling of UCP3 mRNA level in skeletal
Uncoupling Proteins
muscles (152). Thiazolidinediones stimulate UCP2 expression in rat or human skeletal muscle cells in culture
(153,154). A positive eect of a PPARh agonist on
UCP3 mRNA levels in rat L6 myotubes was obtained
(155). Chevillotte et al. demonstrated that omega-6
polyunsaturated fatty acids, acting through PPARh,
can stimulate UCP2 expression in primary culture of
human skeletal muscle cells (154). Fatty acids have been
shown to induce UCP2 expression in adipocyte cultures
of both rodents (153,156) and humans (157).
A survey of articles reporting on UCP2 or UCP3
mRNA levels in humans does not give a clear picture.
Identical (78,158) or reduced UCP2 gene expression was
measured in skeletal muscle (159) and intraperitoneal
adipose tissue (160) of human obese subjects compared
to lean individuals. Although body mass index was
negatively correlated with UCP2 expression in skeletal
muscle of Pima Indians (161), in two other studies it was
found that UCP3 mRNA levels in skeletal muscle did
not dier between obese and lean subjects (78,162).
However, a prolonged hypocaloric diet downregulated
UCP3 mRNA expression in muscle of obese patients
(162). No dierence in the mRNA level of UCP2 in
skeletal muscle was measured between NIDDM and
control subjects; in contrast, mRNA levels of UCP3 is
signicantly reduced in skeletal muscle of NIDDM
patients (163).
In comparison with untrained subjects, exercisetrained subjects exhibit lower levels of UCP3 mRNA
in their skeletal muscle (141). These data led the authors
to hypothesize that endurance training makes athletes
more energy ecient. The status of UCP2 and UCP3
was also investigated in skeletal muscle of tetraplegic
subjects before and after an 8-week exercise program
consisting of electrically stimulated leg cycling (164). In
agreement with data of able-bodied people trained to
physical exercise (141), tetraplegia was shown to be
associated with increased expression of UCP2 and
UCP3 in skeletal muscle, and exercise training of tetraplegic patients normalized UCP2 mRNA levels.
Although it is dicult to understand the signicance
of decreased UCP expression during exercise and
increased UCP expression in absence of exercise, it
appears that physical activity regulates UCP expression
in skeletal muscle. Whether expression of UCP2 and
UCP3 in skeletal muscle is related to oxygen utilization
remains to be investigated.
In conclusion, an unclear picture emerges from analysis of UCP2 and UCP3 expression in physiological or
pathophysiological situations. On the one hand, the
upregulation of the UCPs in skeletal muscle during
starvation, as well as the level of mRNAs in obese
549
individuals compared to lean individuals do not illustrate an obvious role for UCP2 or UCP3 in substrate
utilization and energy partitioning. On the other hand,
the positive eect of T3, a hormone known to induce
mitochondrial proton leak and substrate oxidation, on
expression of UCP2 and UCP3 in tissues, supports their
possible role in energy dissipation. Analysis of UCP2
and UCP3 function in nonactive or activated skeletal
muscle of tetraplegic patients indicates that a role for the
UCPs in thermogenesis and maintenance of body temperature cannot be ruled out.
D
550
Besides UCP1, which has a well-demonstrated uncoupling activity and an essential role in maintenance of
body temperature in small rodents exposed to the cold,
the exact biochemical and physiological roles of UCP2
and UCP3 remain to be further identied. Certain data
support a true activity of these UCPs in respiration
uncoupling; other data do not agree with a role for these
UCPs in controlling body weight or adiposity. Whereas
the physiological role of UCP3 remains rather
unknown, UCP2 and UCP3 appear to be genes limiting
ROS level in cells and UCP2 as a gene controlling
insulin secretion.
Uncoupling Proteins
Since UCP2 and UCP3 homologues exist in ectothermic animals, it may be hypothesized that UCP2
and UCP3 are closer to a UCP ancestor than is UCP1,
which only exists in mammals. The UCPs belong to the
family of the mitochondrial anion carriers. UCP1 translocates protons, whereas UCP2 and UCP3 can also
transport protons. The ability of UCP2 and UCP3 to
transport ions other than protons should be investigated. A depiction of the putative functions for the
UCPs is provided in Figure 2.
Undoubtedly, a central question is that of the
amount of UCP2 and UCP3 in tissues. Experiments of
overexpression of the novel UCPS in transgenic mice or
mammalian cells have shown that these proteins can
uncouple respiration from ATP synthesis and therefore
represent putative targets for antiobesity compounds.
However, the amount of UCP2 or UCP3 normally
present in vivo seems to be very low and insucient to
provoke a discernible uncoupling of respiration. It
remains to be determined whether the amount (or
activity?) of UCP2 or UCP3 in cells can be suciently
elevated to uncouple respiration under selective natural
or pharmacological conditions. The observation that
the level of UCP2 protein can be rapidly and strongly
increased in tissues in absence of variation in the
amount of UCP2 mRNA indicates that a rather high
level of UCP2 can be obtained, at least in certain cells. It
should not be forgotten that a very small, but prolonged, change in level of coupling of mitochondrial
respiration, i.e., change in eciency of substrate oxidation, can signicantly aect body adiposity.
REFERENCES
1.
2.
3.
4.
5.
6.
Neel JV. Diabetes mellitus: A thrifty genotype rendered detrimental by progress. Am J Hum Genet
1962; 14:353362.
Coleman DL. Obesity genes: benecial eects in
heterozygous mice. Science 1979; 203:663665.
Rothwell NJ, Stock MJ. A role for brown adipose
tissue in diet-induced thermogenesis. Nature 1979;
281: 3135.
Himms-Hagen J. Brown adipose tissue thermogenesis
and obesity. Prog Lipid Res 1989; 28:67115.
Arch JRS, Ainsworth AT, Cawthorne MA, Piercy V,
Senitt MV, Thody VE, Wilson C, Wilson S. Atypical
h-adrenoreceptor on brown adipocytes as targets for
antiobesity drugs. Nature 1984; 309:163165.
Holloway BR, Howe R, Rao BS, Stribling D, Mayers
RM, Briscoe MG, Jackson JM. ICI D7114 a novel
selective beta-adrenocoptor agonist selectively stimu-
551
lates brown fat and increases whole body oxygen
consumption. Br J Pharmacol 1991; 104:97104.
7. Bloom JD, Dutia MD, Johnson BD, Wissner A, Burns
MG, Largis EE, Dolan JA, Claus TH. Disodium (R,R)5-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-l,3-benzodioxole-2,2-dicarboxylate (CL 316,243). A
potent beta-adrenergic agonist virtually specic for
beta 3 receptors. A promising antidiabetic and antiobesity agent. J Med Chem 1992; 35:30813084.
8. Arch JRS. The brown adipocyte h-adrenoceptor. Proc
Nutr Soc 1989; 48:215223.
9. Emorine LJ, Marullo S, Briend-Sutren M-M, Patey G,
Tate K, Delavier-Klutchko C, Strosberg AD. Molecular characterization of the human h3-adrenergic
receptor. Science 1989; 245:11181121.
10. Champigny O, Ricquier D, Blondel O, Mayers RM,
Briscoe MG, Holloway BR. Beta 3-adrenergic receptor stimulation restores message and expression of
brown-fat mitochondrial uncoupling protein in adult
dogs. Proc Natl Acad Sci USA 1991; 88:1077410777.
11. Himms-Hagen J, Cui J, Danforth E Jr, Taatjes DJ,
Lang SS, Waters BL, Claus TH. Eect of CL-316,243,
a thermogenic beta 3-agonist, on energy balance and
brown and white adipose tissues in rats. Am J Physiol
1994; 266:R1371R1382.
12. Ghorbani M, Claus TH, Himms-Hagen J. Hypertrophy of brown adipocytes in brown and white
adipose tissues and reversal of diet-induced obesity
in rats treated with a h3-adrenoreceptor agonist.
Biochem Pharmacol 1997; 54:121131.
13. Ghorbani M, Himms-Hagen J. Appearance of brown
adipocytes in white adipose tissue during CL 316,243induced reversal of obesity and diabetes in Zucker fa/
fa rats. Int J Obes 1997; 21:465475.
14. Kopecky J, Clarke G, Enerback S, Spiegelman B,
Kozak LP. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter
prevents genetic obesity. J Clin Invest 1995; 96:2914
2923.
15. Li B, Nolte LA, Ju JS, Han DH, Coleman T, Holloszy
JO, Semenkovich CF. Skeletal muscle respiratory
uncoupling prevents diet-induced obesity and insulin
resistance in mice. Nat Med 2000; 6:11151120.
16. Kopecky J, Hodny Z, Rossmeisl M, Syrovy I, Kozak
LP. Reduction of dietary obesity in aP2-Ucp transgenic mice: physiology and adipose tissue distribution.
Am J Physiol 1996; 270:E768E775.
17. Ste B, Janovska A, Hodny Z, Rossmeisl M,
Horakova M, Syrovy I, Bemova J, Bendlova B,
Kopecky J. Brown fat is essential for cold-induced
thermogenesis but not for obesity resistance in aP2Ucp mice. Am J Physiol 1998; 274:E527E533.
18. Matthias A, Ohlson KB, Fredriksson JM, Jacobsson
A, Nedergaard J, Cannon B. Thermogenic responses
in brown fat cells are fully UCP1-dependent. UCP2 or
UCP3 do not substitute for UCP1 in adrenergically or
552
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Uncoupling Proteins
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
553
nuclear receptors linked to adaptive thermogenesis.
Cell 1998; 92:829839.
56. Barbera MJ, Schluter A, Pedraza N, Iglesias R,
Villarroya F, Giralt M. Peroxisome proliferator
activated receptor alpha activates transcription of the
brown fat uncoupling protein-1 gene. A link between
regulation of the thermogenic and lipid oxidation
pathways in the brown fat cell. J Biol Chem 2001;
276:14861493.
57. Alvarez R, De Andres J, Yubero P, Vinas O, Mampel
T, Iglesias R, Giralt M, Villarroya F. A novel
regulatory pathway of brown fat thermogenesis.
Retinoic acid is a transcriptional activator of the
mitochondrial uncoupling protein gene. J Biol Chem
1995; 270:56665673.
58. Rabelo R, Schifman A, Rubio A, Sheng X, Silva JE.
Delineation of thyroid hormone-responsive sequences
within a critical enhancer in the rat uncoupling protein
gene. Endocrinology 1995; 136:10031013.
59. Larose M, Cassard-Doulcier AM, Fleury C, Serra F,
Champigny O, Bouillaud F, Ricquier D. Essential
cis-acting elements in rat uncoupling protein gene are
in an enhancer containing a complex retinoic acid
response domain. J Biol Chem 1996; 271:31533
31542.
60. Del Mar Gonzalez-Barroso M, Pecqueur C, Gelly C,
Sanchis D, Alves-Guerra MC, Bouillaud F, Ricquier
D, Cassard-Doulcier AM. Transcriptional activation
of the human ucpl gene in a rodent cell line. Synergism
of retinoids, isoprotererenol, and thiazolidinedione is
mediated by a multipartite response element. J Biol
Chem 2000; 275:3172231732.
61. Giralt M, Martin I, Iglesias R, Vinas O, Villarroya F,
Mampel T. Ontogeny and perinatal modulation of
gene expression in rat brown adipose tissue. Unaltered
iodothyronine 5V-deiodinase activity is necessary for
the response to environmental temperature at birth.
Eur J Biochem 1990; 193:297302.
62. Bronnikov G, Houstek J, Nedergaard J. h-Adrenergic,
cAMP-mediated stimulation of proliferation of brown
fat cells in primary culture. J Biol Chem 1992;
267:20062013.
63. Kozak UC, Kozak LP. Norepinephrine-dependent
selection of brown adipocyte cell lines. Endocrinology
1994; 134:906913.
64. Kogure A, Yoshida T, Sakane N, Umekawa T, Takakura Y, Kondo M. Synergic eect of polymorphisms in
uncoupling protein 1 and beta3-adrenergic receptor
genes on weight loss in obese Japanese. Diabetologia
1998; 41:1399.
65. Oppert J, Vohl M, Chagnon M, Dionne FT, CassardDoulcier A-M, Ricquier D, Perusse L, Bouchard C.
DNA polymorphism in the uncoupling protein (UCP)
gene and human body fat. Int J Obes 1994; 18:526
531.
66. Fumeron F, Durack-Bown I, Betoulle D, CassardDoulcier AM, Tuzet S, Bouillaud F, Melchior JC,
554
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
of the uncoupling protein 2 gene and resting metabolic rate in humans. Hum Mol Genet 1997; 6:1887
1889.
Millet L, Vidal H, Andreelli F, Larrouy D, Riou JP,
Ricquier D, Laville M, Langin D. Increased uncoupling protein-2 and -3 mRNA expression during
fasting in obese and lean humans. J Clin Invest 1997;
100:26652670.
Boss O, Samec S, Kuhne F, Bijlenga P, Assimacopoulos-Jeannet F, Seydoux J, Giacobino JP, Muzzin
P. Uncoupling protein-3 expression in rodent skeletal
muscle is modulated by food intake but not by changes
in environmental temperature. J Biol Chem 1998;
273:58.
Stuart JA, Harper JA, Brindle KM, Brand MD.
Uncoupling protein 2 from carp and zebrash,
ectothermic vertebrates. Biochim Biophys Acta 1999;
1413:5054.
Sanchis D, Fleury C, Chomiki N, Goubern M, Huang
Q, Neverova M, Gregoire F, Easlick J, Raimbault S,
Levi-Meyrueis C, Miroux B, Collins S, Seldin M,
Richard D, Warden C, Bouillaud F, Ricquier D.
BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and
rodents, and respiration uncoupling activity in recombinant yeast. J Biol Chem 1998; 273:3461134615.
Mao W, Yu XX, Zhong A, Li W, Brush J, Sherwood
SW, Adams SH, Pan G. UCP4, a novel brain-specic
mitochondrial protein that reduces membrane potential in mammalian cells [published erratum appears in
FEBS Lett 1999; 449(23):293]. FEBS Lett 1999;
443:326330.
Laloi M, Klein M, Riesmeier JW, Muller-Rober B,
Fleury C, Bouillaud F, Ricquier D. A plant coldinduced uncoupling protein. Nature 1997; 389:135136.
Raimbault S, Dridi S, Denjean F, Lachuer J, Couplan
E, Bouillaud F, Bordas A, Duchamp C, Taouis M,
Ricquier D. An uncoupling protein homologue
putatively involved in facultative muscle thermogenesis in birds. Biochem J 2001; 353: 441444.
Vianna CR, Hagen T, Zhang CY, Bachman E, Boss
O, Gereben B, Moriscot AS, Lowell BB, Bicudo JE,
Bianco AC. Cloning and functional characterization
of an uncoupling protein homolog in hummingbirds.
Physiol Genomics 2001; 5:137145.
Rial E, Gonzalez-Barroso MM. Physiological regulation of the transport activity in the uncoupling
proteins UCP1 and UCP2. Biochim Biophys Acta
2001; 1504:7081.
Bouillaud F, Couplan E, Pecqueur C, Ricquier D.
Homologues of the uncoupling protein from brown
adipose tissue (UCP1): UCP2, UCP3, BMCP1 and
UCP4. Biochim Biophys Acta 2001; 1504:107119.
Klingenberg M, Echtay KS. Uncoupling proteins: the
issues from a biochemist point of view. Biochim
Biophys Acta 2001; 1504:128143.
Uncoupling Proteins
89. Paulik MA, Buckholz RG, Lancaster ME, Dallas WS,
Hull-Ryde EA, Weiel JE, Lenhard JM. Development
of infrared imaging to measure thermogenesis in cell
culture: thermogenic eects of uncoupling protein-2,
troglitazone, and beta-adrenoceptor agonists. Pharm
Res 1998; 15:944949.
90. Hinz B, Schroder H. Vitamin C attenuates nitrate
tolerance independently of its antioxidant eect. FEBS
Lett 1998; 428:9799.
91. Zhang CY, Hagen T, Mootha VK, Slieker LJ, Lowell
BB. Assessment of uncoupling activity of uncoupling
protein 3 using a yeast heterologous expression
system. FEBS Lett 1999; 449:129134.
92. Rial E, Gonzalez-Barroso M, Fleury C, Iturrizaga S,
Sanchis D, Jimenez-Jimenez J, Ricquier D, Goubern
M, Bouillaud F. Retinoids activate proton transport
by the uncoupling proteins UCP1 and UCP2. EMBO J
1999; 18:58275833.
93. Jaburek M, Yarov-Yarovoy V, Paucek P, Garlid KD.
State-dependent inhibition of the mitochondrial
KATP channel by glyburide and 5-hydroxydecanoate.
J Biol Chem 1998; 273:1357813582.
94. Echtay KS, Winkler E, Frischmuth K, Klingenberg
M. Uncoupling proteins 2 and 3 are highly active
H(+) transporters and highly nucleotide sensitive
when activated by coenzyme Q (ubiquinone). Proc
Natl Acad Sci USA 2001; 98:14161421.
95. Stuart JA, Harper JA, Brindle KM, Jekabsons MB,
Brand MD. Physiological levels of mammalian uncoupling protein 2 do not uncouple yeast mitochondria. J Biol Chem 2001; 276:1863318639.
96. Cadenas S, Buckingham JA, Samec S, Seydoux J, Din
N, Dulloo AG, Brand MD. UCP2 and UCP3 rise in
starved rat skeletal muscle but mitochondrial proton
conductance is unchanged. FEBS Lett 1999; 462:257
260.
97. Chomiki N, Voss JC, Warden CH. Structure-function
relationships in UCP1, UCP2 and chimeras: EPR
analysis and retinoic acid activation of UCP2. Eur J
Biochem 2001; 268:903913.
98. Jaburek M, Vaecha M, Gimeno RE, Dembski M,
Jezek P, Zhang M, Burn P, Tartaglia LA, Garlid KD.
Transport function and regulation of mitochondrial
uncoupling proteins 2 and 3. J Biol Chem 1999;
274:2600326007.
99. Echtay KS, Winkler E, Klingenberg M. Coenzyme Q
is an obligatory cofactor for uncoupling protein
function. Nature 2000; 408:609613.
100. Chan CB, MacDonald PE, Saleh MC, Johns DC,
Marban E, Wheeler MB. Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin
secretion from rat islets. Diabetes 1999; 48:14821486.
101. Chan CB, De Leo D, Joseph JW, McQuaid TS, Ha
XF, Xu F, Tsushima RG, Pennefather PS, Salapatek
AM, Wheeler MB. Increased uncoupling protein-2
levels in beta-cells are associated with impaired
555
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
556
protein-2 gene, and juxtaposition to the uncoupling
protein-3 gene. Biochem Biophys Res Commun 1999;
255:4046.
113. Urhammer SA, Dalgaard LT, Sorensen TI, TybjaergHansen A, Echwald SM, Clausen JO, Pedersen O.
Organisation of the coding exons and mutational
screening of the uncoupling protein 3 gene in subjects
with juvenile-onset obesity. Diabetologia 1998; 41:
241244.
114. Yamada M, Hashida T, Shibusawa N, Iwasaki T,
Murakami M, Monden T, Satoh T, Mori M. Genomic
organization and promoter function of the mouse
uncoupling protein 2 (UCP2) gene. FEBS Lett 1998;
432:6569.
115. Tu N, Chen H, Winnikes U, Reinert I, Marmann G,
Pirke KM, Lentes KU. Molecular cloning and functional characterization of the promoter region of the
human uncoupling protein-2 gene. Biochem Biophys
Res Commun 1999; 265:326334.
116. Tu N, Chen H, Winnikes U, Reinert I, Pirke KM,
Lentes KU. Functional characterization of the 5Vanking and the promoter region of the human UCP3
(hUCP3) gene. Life Sci 2000; 67:22672279.
117. Pecqueur C, Alves-Guerra MC, Gelly C, Levi-Meyrueis C, Couplan E, Collins S, Ricquier D, Bouillaud F,
Miroux B. Uncoupling protein 2, in vivo distribution,
induction upon oxidative stress, and evidence for
translational regulation. J Biol Chem 2001; 276:8705
8712.
118. Medvedev AV, Snedden SK, Raimbault S, Ricquier
D, Collins S. Transcriptional regulation of the mouse
uncoupling protein-2 gene. Double E-box motif is
required for peroxisome proliferator-activated receptor-gamma-dependent activation. J Biol Chem 2001;
276:1081710823.
119. Acin A, Rodriguez M, Rique H, Canet E, Boutin JA,
Galizzi JP. Cloning and characterization of the 5V
anking region of the human uncoupling protein 3
(UCP3) gene. Biochem Biophys Res Commun 1999;
258:278283.
120. Solanes G, Pedraza N, Iglesias R, Giralt M, Villarroya
F. The human uncoupling protein-3 gene promoter
requires MyoD and is induced by retinoic acid in
muscle cells. FASEB J 2000; 14:21412143.
121. Chagnon YC, Rice T, Perusse L, Borecki IB, Ho-Kim
MA, Lacaille M, Pare C, Bouchard L, Gagnon J, Leon
AS, Skinner JS, Wilmore JH, Rao DC, Bouchard C.
Genomic scan for genes aecting body composition
before and after training in Caucasians from HERITAGE. J Appl Physiol 2001; 90:17771787.
122. Elbein SC, Leppert M, Hasstedt S. Uncoupling
protein 2 region on chromosome 11q13 is not linked
to markers of obesity in familial type 2 diabetes.
Diabetes 1997; 46:21052107.
123. Campbell DA, Sundaramurthy D, Gordon D, Markham AF, Pieri LF. Association between a marker in the
124.
125.
126.
127.
128.
129.
130.
131.
132.
Uncoupling Proteins
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
557
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
558
in cell lines representing white and brown adipose
tissues and skeletal muscle. Endocrinology 1998;
139:428431.
154. Chevillotte E, Rieusset J, Roques M, Desage M, Vidal
H. The regulation of uncoupling protein-2 gene
expression by omega-6 polyunsaturated fatty acids in
human skeletal muscle cells involves multiple pathways, including the nuclear receptor peroxisome
proliferator-activated receptor beta. J Biol Chem
2001; 276:1085310860.
155. Nagase I, Yoshida S, Canas X, Irie Y, Kimura K,
Yoshida T, Saito M. Up-regulation of uncoupling
protein 3 by thyroid hormone, peroxisome proliferatoractivated receptor ligands and 9-cis retinoic acid
in L6 myotubes. FEBS Lett 1999; 461:319322.
156. Aubert J, Champigny O, Saint-Marc P, Negrel R,
Collins S, Ricquier D, Ailhaud G. Up-regulation of
UCP-2 gene expression by PPAR agonists in preadipose and adipose cells. Biochem Biophys Res Commun 1997; 238:606611.
157. Viguerie-Bascands N, Saulnier-Blache JS, Dandine M,
Dauzats M, Daviaud D, Langin D. Increase in
uncoupling protein-2 mRNA expression by BRL49653
and bromopalmitate in human adipocytes. Biochem
Biophys Res Commun 1999; 256:138141.
158. Millet L, Vidal H, Larrouy D, Andreelli F, Laville M,
Langin D. mRNA expression of the long and short
forms of uncoupling protein-3 in obese and lean
humans. Diabetologia 1998; 41:829832.
159. Nordfors L, Hostedt J, Nyberg B, Thorne A, Arner
P, Schalling M, Lonnqvist F. Reduced gene expression
of UCP2 but not UCP3 in skeletal muscle of human
obese subjects. Diabetologia 1998; 41:935939.
160. Oberkoer H, Liu YM, Esterbauer H, Hell E, Krempler
F, Patsch W. Uncoupling protein-2 gene: reduced
mRNA expression in intraperitoneal adipose tissue of
obese humans. Diabetologia 1998; 41:940946.
161. Schrauwen P, Xia J, Bogardus C, Pratley RE,
Ravussin E. Skeletal muscle uncoupling protein 3
expression is a determinant of energy expenditure in
Pima Indians. Diabetes 1999; 48:146149.
162. Esterbauer H, Oberkoer H, Liu YM, Breban D, Hell
E, Krempler F, Patsch W. Uncoupling protein-1
mRNA expression in obese human subjects: the role
of sequence variations at the uncoupling protein-1
gene locus. J Lipid Res 1998; 39:834844.
163. Krook A, Digby J, ORahilly S, Zierath JR, WallbergHenriksson H. Uncoupling protein 3 is reduced in
skeletal muscle of NIDDM patients. Diabetes 1998;
47:15281531.
164. Hjeltnes N, Fernstrom M, Zierath JR, Krook A.
Regulation of UCP2 and UCP3 by muscle disuse and
physical activity in tetraplegic subjects. Diabetologia
1999; 42:826830.
165. Clapham JC, Arch JR, Chapman H, Haynes A, Lister
C, Moore GB, Piercy V, Carter SA, Lehner I, Smith SA,
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
21
Peroxisome ProliferatorActivated Receptor g and the
Transcriptional Control of Adipogenesis and Metabolism
Lluis Fajas and Johan Auwerx
Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch, and Universite Louis Pasteur,
Strasbourg, France
INTRODUCTION
560
hypocaloric diets for a longer period result in a downregulation of PPARg expression (7). In rodents, PPARg
was downregulated by fasting and insulin-dependent
diabetes mellitus (8), whereas its expression was induced
by a high-fat diet. Most interesting, however, was the
observation that in normal-weight subjects PPARg
expression is highly enriched in subcutaneous fat,
whereas its expression in visceral adipose tissue is signicantly higher in obese subjects (9). Insulin and
glucocorticoids induce PPARg expression in cultured
human adipocytes (7,10), whereas TNFa was reported
to decrease PPARg expression (11,12).
III
PPARg
g and Adipogenesis and Metabolism
a precise anchoring surface for the coactivator together with H3-H4. Interestingly, in the structure with
the partial agonist GW0072, H12 does not seem to
interact directly with the ligand and hence is found in a
position more similar to the unliganded (apo) than to
the liganded (holo) structure (24). Unlike full agonists,
partial agonists would therefore not be able to stabilize the activation helix in the proper position, owing
to the lack of a few key interactions, and such a slight
malpositioning of H12 may result in an attenuated
transcriptional response.
Recently, the structure of a PPARg-RXRa LBD
heterodimer was reported (25). The heterodimerization
interface is topologically the same as the homodimerization interface in RXR (19), ER (26), and PPAR (15),
and as the heterodimerization interface in the RARaRXRa heterodimer (27). An interesting feature is the
salt bridge between the C-terminal carboxylate of
PPARg (Tyr477, 4 residues downstream of H12) and
Lys431 in H10 of RXRa. In the case of heterodimers,
transcription may be regulated by the respective ligands
for both receptors, such as is the case in the permissive
PPAR-RXR heterodimer, whereas this is not the case
for the nonpermissive RAR-RXR and TR-RXR heterodimers (28). The interaction between the C-terminus of
the PPARg LBD and H10 of RXR suggests a structural
basis for such permissiveness, as it may stabilize H12 of
PPARg in the holo conformation allowing the recruitment of coactivators, even in the absence of a bound
agonist (25).
IV
561
Whereas the terminal stages of adipocyte dierentiation are well understood, the molecular mechanisms
underlying the transition between cell proliferation
and dierentiation of preadipocytes remain elusive.
Since these early phases of adipogenesis involve clonal
expansion of the precursor cells, it was logical to start
looking for factors that are involved in the control of
the cell cycle as potential triggers for these early
phases. The E2F family of transcription factors, which
are major regulators of the cell cycle and which have
been shown to have an important role in the regulation of other dierentiation systems, were hence
good candidates (3133). E2Fs trigger the expression
of PPARg directly by binding to and transactivating
the PPARgl promoter during the clonal expansion of
the adipocyte dierentiation process. In contrast to
E2Fs, the role of the retinoblastoma (RB) protein
family members, or the pocket proteins RB, p130,
and p107, in adipocyte dierentiation seems more
complex. The negative role of pocket proteins in cell
cycle progression, repressing the expression of the E2F
target genes, has been demonstrated in several settings
(for review see 34,35). Pocket proteins are inactivated
by phosphorylation by the cyclin-dependent kinases,
resulting in the activation of the E2F target genes.
Consistent with an active cell cycle in the early stages
of adipogenesis, pocket proteins have been found to
be hyperphosphorylated following hormonal induction of preadipocytes (36). However, an apparent
paradox arises from the nding that pRB inactivation
by SV40 large T-antigen inhibits adipogenesis (37).
Moreover, pRB-decient broblasts fail to dierentiate into adipocytes when properly stimulated (38,39).
This apparent paradox was explained by the participation of RB in the growth arrest following clonal
expansion (39a). This suggests that RB is involved in
two phases of adipocyte dierentiation. First, inactivation of RB enables clonal expansion, whereas
growth arrest after this expansion phase requires
active RB, which positively inuences adipocyte dierentiation. A dierent role, independent of the control
of cell cycle, has also been attributed to RB in another
aspect of the regulation of adipogenesis, i.e., the
enhancement of the transactivation capability of C/
EBPa and h, via direct protein-protein interaction
(39). In contrast to RB, the other members of the
retinoblastoma family, p130 and p107, have been
562
Figure 2 Coordinate regulation of adipogenesis by E2Fs, PPARg, C/EBPs, and ADD-1/SREBP-1. Interactions among these
dierent transcription factors determine the cascade of events during adipocyte dierentiation. The right part of the gure depicts
the three dierent cellular stagesadipocyte precursors, adipoblasts, and adipocytes. The quiescent adipocyte precursor cells
undergo an obligatory phase of clonal expansion which requires reentry into the cell cycle. This phase generates adipoblasts,
which upon further lipid accumulation become mature adipocytes.
PPARg
g and Adipogenesis and Metabolism
563
564
considerably during the induction of adipocyte dierentiation, with RAR expression being strongly reduced
and PPARg levels being induced (43). A change in the
relative levels of RAR and PPARg in the dierentiating
adipocytes will hence induce a switch for RXR from one
partner to another one (43,45). This will change RXR
activity from the nonpermissive state when bound to
RAR to the permissive state when complexed to
PPARg. This switch in partners induces the recruitment
of a distinct set of cofactors, ultimately translating in an
alteration of the transcriptional activity of the downstream target genes (Fig. 3) (45). Such a switch in
partners might underlie not only how PPARg agonists
but also how RXR agonists exert their eects on adipogenesis and glucose homeostasis. Proof that RXR is
involved in adipose tissue homeostasis in vivo was
recently provided by the spatiotemporally controlled
mutagenesis of the RXRa gene in adipose tissue (66).
Mice lacking RXRa in fat tissue have signicantly
reduced fat mass and are resistant against the induction
of obesity (66). This model further points out that most
likely both partners of the RXR/PPARg heterodimer
are important in inducing and maintaining adipose
tissue homeostasis.
The basic helix-loop-helix (bHLH) protein ADD-1/
SREBP-1c is also induced during terminal adipocyte
dierentiation (67,68). ADD-1/SREBP-1c accelerates
PPARg
g and Adipogenesis and Metabolism
adipocyte dierentiation when coexpressed in broblasts, which also contain PPARg. ADD-1/SREBP-1
belongs to a family of transcription factors that are
synthesized as membrane-bound precursors that are
released by proteolysis (69). Whereas the proteolytic
cleavage of SREBP-2 is regulated by cellular cholesterol
levels, it is at present unknown what controls the
cleavage of ADD-1/SREBP-1 (69). ADD-1/SREBP-1c
induces the expression of several genes involved in
lipogenesis in both adipocytes and liver. These genes
include the genes encoding for fatty acid synthase
(68,70,71), acetyl coenzyme A carboxylase (71,72), glycerol-3-phosphate acyltransferase (73), and the lipoprotein lipase (LPL) gene (68,71) (74). Stimulation of
lipogenesis contributes to the massive cholesterol and
fatty acid accumulation seen in the livers of transgenic
animals expressing the mature form of SREBP-1a (71),
and to the more moderate fatty acid accumulation
observed upon overexpression of the weaker transactivator SREBP-1c (75). The observation that transgenic
mice overexpressing SREBP-1c under the control of the
adipose tissue-specic aP2 promoter are lipodystrophic
(76) appears inconsistent with these adipo- and lipogenic eects (68,71,75) and suggests that SREBP-1c,
under certain conditions, could also negatively inuence
adipogenesis. The dierences between this last study
(76) and previous work (68,71,75) are unclear and will
require further investigation.
Finally, terminal adipocyte dierentiation requires
the concerted action of PPARg and C/EBPa (58,59,
77), another C/EBP family member which appears only
relatively late in the dierentiation process. In contrast
to the relatively early eects of C/EBPh and y, C/EBPa
seems to play an important role in the later stages of
dierentiation by sustaining high levels of PPARg
expression and by maintaining the dierentiated adipocyte phenotype. Several lines of evidence support an
important role of C/EBPa in adipocyte dierentiation.
First, temporal activation of C/EBPa expression occurs
immediately before the coordinate expression of a
group of adipocyte-specic genes, suggesting its
involvement in their regulation. Second, antisense C/
EBPa RNA can inhibit adipocyte dierentiation.
Third, premature induction or overexpression of C/
EBPa triggers adipocyte dierentiation. And nally,
adipocytes from C/EBPa -/- mice failed to accumulate
lipids in adipose tissue (78,79). PPARg controls not
only the expression of C/EBPa, but this last factor in its
turn also induces PPARg gene expression, via interaction with C/EBP response elements present in the
human (63) and mouse (2,77) PPARg promoter. Interestingly, introduction of PPARg in cells decient for
565
Glucocorticoid Receptor
566
Adipocyte Apoptosis
coupled with its capacity to enhance de novo dierentiation of adipocytes, favors the formation of small
adipocytes which tend to replace the large adipocytes
normally constituting white adipose tissue (93,94). It is
therefore tempting to speculate that PPARg activation
results in a continuous remodeling of adipose tissue
(Fig. 4). The ultimate fate of these small freshly dierentiated adipocytes remains unclear. It will therefore be
important to determine whether over time they will store
more and more energy and nally become hypertrophic
leading to a state of resistance to PPARg activation.
PPARg
g and Adipogenesis and Metabolism
567
VI
568
Figure 5 Natural and synthetic PPARg ligands. Rosiglitazone, troglitazone, pioglitazone, and MCC-555 are members of the
thiazolidinedione family of PPARg ligands, whereas L-tyrosine-based ligands and JTT-501 are not. Rosiglitazone, troglitazone,
and pioglitazone have all received market approval, but only rosiglitazone and pioglitazone are actually on the market.
PPARg
g and Adipogenesis and Metabolism
VII
569
570
PPARg
g and Adipogenesis and Metabolism
VIII
571
572
IX
PPARg
g AND THE CONTROL
OF LIPID METABOLISM
AND ATHEROSCLEROSIS
REGULATING PPARg
g ACTIVITY
THROUGH PROTEIN-PROTEIN
INTERACTIONS
PPARg
g and Adipogenesis and Metabolism
573
574
PPARg
g and Adipogenesis and Metabolism
575
576
REFERENCES
1.
2.
3.
4.
5.
6.
7.
ACKNOWLEDGMENTS
We thank Laurent Gelman and Jean-Paul Renaud for
help with the cofactor and structural sections, respectively. The members of the Auwerx lab are acknowledged for support and discussions. Actual work in the
laboratory of the authors is supported by grants of
8.
9.
PPARg
g and Adipogenesis and Metabolism
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
577
Glass CK, Rosenfeld MG. The transcriptional coactivator p/CIP binds CBP and mediates nuclearreceptor function [see comments]. Nature 1997;
387(6634):677684.
23. Heery DM, Kalkhoven E, Hoare S, Parker MG. A
signature motif in transcriptional coactivators mediates binding to nuclear receptors. Nature 1997;
387:733736.
24. Obereld JL, Collins JL, Holmes CP, Goreham DM,
Cooper JP, Cobb JE, Lenhard JM, Hull-Ryde EA,
Mohr CP, Blanchard SG, Parks DJ, Moore LB,
Lehmann JM, Plunket K, Miller AB. A peroxisome
proliferator-activated receptor gamma ligand inhibits
adipocyte dierentiation. Proc Natl Acad Sci USA
1999; 96(11):61026106.
25. Gampe RTJ, Montana VG, Lambert MH, Miller AB,
Bledsoe RK, Milburn MV, Kliewer SA, Willson TM,
Xu HE. Asymmetry in the PPAR gamma-RXR alpha
crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell 2000;
5:545555.
26. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE,
Bonn T, Engstrom O, Ohman L, Greene GL,
Gustafsson JA, Carlquist M. Molecular basis of
agonism and antagonism in the oestrogen receptor.
Nature 1997; 389(6652):753758.
27. Bourguet W, Vivat V, Wurtz JM, Chambon P,
Gronemeyer H, Moras D. Crystal structure of a
heterodimeric complex of RAR and RXR ligandbinding domains. Mol Cell 2000; 5:289298.
28. Mangelsdorf DJ, Evans RM. The RXR heterodimers
and orphan receptors. Cell 1995; 83:841850.
29. Spiegelman BM, Flier JS. Adipogenesis and obesity:
rounding out the big picture. Cell 1996; 87:377389.
30. Fajas L, Fruchart JC, Auwerx J. Transcriptional
control of adipogenesis. Curr Opin Cell Biol 1998;
10:165173.
31. Ding Q, Wang Q, Dong Z, Evers BM. Characterization and regulation of E2F activity during Caco-2
cell dierentiation. Am J Physiol Cell Physiol 2000;
278(1):C110C117.
32. Rempel RE, Saenz-Robles MT, Storms R, Morham S,
Ishida S, Engel A, Jakoi L, Melhem MF, Pipas JM,
Smith C, Nevins JR. Loss of E2F4 activity leads to
abnormal development of multiple cellular lineages.
Mol Cell 2000; 6(2):293306.
33. Persengiev SP, Kondova, II, Kilpatrick DL. E2F4
actively promotes the initiation and maintenance of
nerve growth factor-induced cell dierentiation. Mol
Cell Biol 1999; 19(9):60486056.
34. Harbour JW, Dean DC. The Rb/E2F pathway:
expanding roles and emerging paradigms. Genes Dev
2000; 14(19):23932409.
35. Helin K. Regulation of cell proliferation by the E2F
transcription factors. Curr Opin Genet Dev 1998;
8(1):2835.
578
36. Richon V, Lyle RE, McGehee REJ. Regulation and
expression of retinoblastoma proteins p107 and p130
during 3T3-L1 adipocyte dierentiation. J Biol Chem
1997; 272:1011710124.
37. Higgins C, Chatterjee S, Cherington V. The block of
adipocyte dierentiation by a C-terminally truncated,
but not by full-length, simian virus 40 large tumor
antigen is dependent on an intact retinoblastoma
susceptibility protein family binding domain. J Virol
1996; 70(2):745752.
38. Classon M, Kennedy BK, Mulloy R, Harlow E.
Opposing roles of pRB and p107 in adipocyte dierentiation [in process citation]. Proc Natl Acad Sci
USA 2000; 97(20):1082610831.
39. Chen PL, Riley DJ, Chen Y, Lee WH. Retinoblastoma
protein positively regulates terminal adipocyte dierentiation through direct interaction with C/EBPs.
Genes Dev 1996; 10(21):27942804.
39a. Fajas L, Egler V, Reiter R, Hausen J, Kristiansen K,
Debril M-B, Miarol S, Auwerx J. The retinoblastomahistone deacetylase 3 complex inhibits PPARJ and adipocyte dierentiation. Developmental Cell 2002; 3:903
910.
40. He GP, Muise A, Li AW, Ro HS. A eucaryotic
transcriptional repressor with carboxypeptidase activity. Nature 1995; 378:9296.
41. Park J-G, Muise A, He G-P, Kim S-W, Ro H-S.
Transcriptional regulation by the g5 subunit of a
heterotrimeric G protein during adipogenesis/. EMBO
J 1999; 18:40044012.
42. Tong Q, Dalgin G, Xu H, Ting CN, Leiden JM,
Hotamisligil GS. Function of GATA transcription
factors in preadipocyte-adipocyte transition [in process citation]. Science 2000; 290(5489):134138.
43. Xue JC, Schwarz EJ, Chawla A, Lazar MA. Distinct
stages in adipogenesis revealed by retinoid inhibition
of dierentiation after induction of PPARg. Mol Cell
Biol 1996; 16:15671575.
44. Schwarz EJ, Reginato MJ, Shao D, Krakow SL, Lazar
MA. Retinoic acid blocks adipogenesis by inhibiting
C/EBPh-mediated transcription. Mol Cell Biol 1997;
17(3):15521561.
45. DiRenzo J, Soderstrom M, Kurokawa R, Ogliastro
MH, Ricote M, Ingrey S, Horlein A, Rosenfeld MG,
Glass CK. Peroxisome proliferator-activated receptors
and retinoic acid receptors dierentially control the
interactions of retinoid X receptor heterodimers with
ligands, coactivators and corepressors. Mol Cell Biol
1997; 17:21662176.
46. Brodie AE, Manning VA, Hu CY. Inhibitors of
preadipocyte dierentiation induce COUP-TF binding
to PPAR/RXR binding sequences. Biochem Biophys
Res Commun 1996; 228:655661.
47. Zhang B, Berger J, Hu E, Szalkowski D, WhiteCarrington S, Spiegelman BM, Moller DE. Negative
regulation of peroxisome proliferator-activated recep-
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
PPARg
g and Adipogenesis and Metabolism
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
579
74.
580
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
PPARg
g and Adipogenesis and Metabolism
111. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose tissue expression of tumor necrosis factor-a:
direct role in obesity-linked insulin resistance. Science
1993; 259:8791.
112. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White
MF, Spiegelman BM. IRS-1-mediated inhibition of
insulin receptor tyrosine kinase activity in TNF-a- and
obesity-induced insulin resistance. Science 1996;
271:665668.
113. Hotamisligil GS, Murray DL, Choy LN, Spiegelman
BM. Tumor necrosis factor a inhibits signaling from
the insulin receptor. Proc Natl Acad Sci USA 1994;
91:48544858.
114. Hofmann C, Lorenz K, Braithwaite SS, Colca JR,
Palazuk BJ, Hotamisligil GS, Spiegelman BM. Altered
gene expression for tumor necrosis factor-a and its
receptor during drug and dietary modulation of
insulin resistance. Endocrinology 1994; 134:264270.
115. Souza SC, Yamamoto MT, Franciosa MD, Lien P,
Greenberg AS. BRL 49653 blocks lipolytic actions of
tumor necrosis factor-alpha: a potential new insulinsensitizing mechanism for thiazolidinediones. Diabetes
1998; 47:691695.
116. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee
RR, Wright CM, Patel HR, Ahima RS, Lazar MA.
The hormone resistin links obesity to diabetes. Nature
2001; 409(6818):307312.
117. Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee
RR, Dai CY, Enders GH, Silberg DG, Wen X, Wu
GD, Lazar MA. A family of tissue-specic resistin-like
molecules. Proc Natl Acad Sci USA 2001; 98(2):502
506.
118. Schoonjans K, Auwerx J. Thiazolidinediones: an
update [In Process Citation]. Lancet 2000; 355(9208):
10081010.
119. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-D12,14 prostaglandin
J2 is a ligand for the adipocyte determination factor
PPARg. Cell 1995; 83:803812.
120. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris
DC, Lehman JM. A prostaglandin J2 metabolite binds
peroxisome proliferator-activated receptor g and
promotes adipocyte dierentiation. Cell 1995;
83:813819.
121. Krey G, Braissant O, LHorset F, Kalkhoven E,
Peroud M, Parker MG, Wahli W. Fatty acids,
eicosanoids, and hypolipidemic agents identied as
ligands of peroxisome proliferator-activated receptors
by co-activator-dependent receptor ligand assay. Mol
Endocrinol 1997; 11:779791.
122. Ma H, Sprecher HW, Kolattukudy PE. Estrogeninduced production of a peroxisome proliferatoractivated receptor (PPAR) ligand in PPARg-expressing tissue. J Biol Chem 1998; 273:3013130138.
123. Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely
GB, Koble CS, Devchand P, Wahli W, Willson TM,
581
Lenhard JM, Lehmann JM. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated
receptors a and g. Proc Natl Acad Sci USA 1997;
94:43184323.
124. Forman BM, Chen J, Evans RM. Hypolipidemic
drugs, polyunsaturated fatty acids, and eicosanoids
are ligands for peroxisome proliferator-activated
receptors a and y. Proc Natl Acad Sci USA 1997;
94:43124317.
125. Nagy L, Tontonez P, Alvarez JG, Chen H, Evans RM.
Oxidized LDL regulates macrophage gene expression
through ligand activation of PPARg. Cell 1998; 93:
229240.
126. Willson TM, Cobb JE, Cowan DJ, Wiethe RW,
Correa ID, Prakash SR, Beck KD, Moore LB,
Kliewer SA, Lehmann JM. The structure activity
relationship between peroxisome proliferator activated
receptor g agonism and the antihyperglycemic activity
of thiazolidinediones. J Med Chem 1996; 39:665668.
127. Henke BR, Blanchard SG, Brackeen MF, Brown KK,
Cobb JE, Collins JL, Harrington WW, Jr., Hashim
MA, Hull-Ryde EA, Kaldor I, Kliewer SA, Lake DH,
Leesnitzer LM, Lehmann JM, Lenhard JM. N-(2benzoylphenyl)-L-tyrosine PPARgamma agonists. 1.
Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 1998;
41(25):50205036.
128. Lehmann JM, Lenhard JM, Oliver BB, Ringold GM,
Kliewer SA. Peroxisome proliferatoractivated receptors a and g are activated by indomethacin and other
non-steroidal anti-inammatory drugs. J Biol Chem
1997; 272:34063410.
129. Berger J, Bailey P, Biswas C, Cullinan CA, Doebber
TW, Hayes NS, Saperstein R, Smith RG, Leibowitz
MD. Thiazolidinediones produce a conformational
change in peroxisomal proliferator-activated receptorg: binding and activation correlate with antidiabetic
actions in db/db mice. Endocrinology 1996; 137:4189
4195.
130. Mukherjee R, Davies PAJ, Crombie DL, Bischo ED,
Cesario RM, Jow L, Hamann LG, Boehm MF,
Mondon CE, Nadzan AM, Paterniti JR, Heyman
RA. Sensitization of diabetic and obese mice to insulin
by retinoid X receptor agonists. Nature 1997; 386:407
410.
131. Davies PJ, Berry SA, Shipley GL, Eckel RH,
Hennuyer N, Crombie DL, Ogilvie KM, PeinadoOnsurbe J, Fievet C, Leibowitz MD, Heyman RA,
Auwerx J. Metabolic eects of rexinoids: tissuespecic regulation of lipoprotein lipase activity. Mol
Pharmacol 2001; 59(2):170176.
132. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P,
Evans RM. PPAR-gamma dependent and independent
eects on macrophage-gene expression in lipid metabolism and inammation. Nat Med 2001; 7(l):4852.
582
133.
PPARg
g and Adipogenesis and Metabolism
156. Wu Z, Xie Y, Morrison RF, Bucher NLR, Farmer
SR. PPARg induces the insulin-dependent glucose
transporter GLUT4 in absence of C/EBPa during the
conversion of 3T3 broblast into adipocytes. J Clin
Invest 1998; 101:2232.
157. Smith U, Gogg S, Johansson A, Olausson T, Rotter V,
Svalstedt B. Thiazolidinediones (PPARgamma agonists) but not PPAR alpha agonists increase IRS-2
gene expression in 3T3-L1 and human adipocytes.
FASEB J 2001; 15(1):215220.
158. Ribon V, Johnson JH, Camp HS, Saltiel AR.
Thiazolidinediones and insulin resistance: peroxisome
proliferatoractivated receptor g activation stimulates
expression of the CAP gene. Proc Natl Acad Sci USA
1998; 95:1475114756.
159. Baumann CA, Ribon V, Kanzaki M, Thurmond DC,
Mora S, Shigematsu S, Bickel PE, Pessin JE, Saltiel
AR. CAP denes a second signalling pathway required
for insulin-stimulated glucose transport. Nature 2000;
407(6801):202207.
160. Rieusset J, Auwerx J, Vidal H. Regulation of gene
expression by activation of the peroxisome proliferatoractivated receptor gamma with rosiglitazone
(BRL 49653) in human adipocytes. Biochem Biophys
Res Commun 1999; 265(1):265271.
161. Burant CF, Sreenan S, Hirano K-I, Tai T-AC,
Lohmiller J, Lukens J, Davidson NO, Ross S, Graves
RA. Troglitazone action is independent of adipose
tissue. J Clin Invest 1997; 100:29002908.
162. Kim JB, Sarraf P, Wright M, Yao KM, Mueller E,
Solanes G, Lowell BB, Spiegelman BM. Nutritional
and insulin regulation of fatty acid synthetase and
leptin gene expression through ADD1/SREBP1. J Clin
Invest 1998; 101:19.
163. Shimomura I, Bashmakov Y, Ikemoto S, Horton JD,
Brown MS, Goldstein J. Insulin selectively increases
SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA
1999; 96:1365613661.
164. Foretz M, Guichard C, Ferre P, Foufelle F. Sterol
regulatory element binding protein 1c is a major
mediator of insulin action on the hepatic expression of
glucokinase and lipogenesis-related genes. Proc Natl
Acad Sci USA 1999; 96:1273712742.
165. Shimomura I, Matsuda M, Hammer RE, Bashmakov
Y, Brown MS, Goldstein JL. Decreased IRS-2 and
increased SREBP-1c lead to mixed insulin resistance
and sensitivity in livers of lipodystrophic and ob/ob
mice [In Process Citation]. Mol Cell 2000; 6(1):77
86.
166. Fajas L, Schoonjans K, Gelman L, Kim JB, Najib J,
Martin G, Fruchart JC, Briggs M, Spiegelman BM,
Auwerx J. Regulation of PPARg expression by ADD1/SREBP-1: implications for adipocyte dierentiation
and metabolism. Mol Cell Biol 1999; 19:54955503.
167. Kim JB, Wright HM, Wright M, Spiegelman BM.
583
ADD1/SREBP1 activates PPARg through the production of endogeneous ligand. Proc Natl Acad Sci
USA 1998; 95:43334337.
168. Croniger C, Trus M, Lysek-Stupp K, Cohen H, Liu Y,
Darlington GJ, Poli V, Hanson RW, Reshef L. Role of
the isoforms of CCAAT/enhancer-binding protein in
the initiation of phosphoenolpyruvate carboxykinase
(GTP) gene transcription at birth. J Biol Chem 1997;
272(42):2630626312.
169. Lee YH, Sauer B, Johnson PF, Gonzalez FJ.
Disruption of the c/ebp alpha gene in adult mouse
liver. Mol Cell Biol 1997; 17(10):60146022.
170. Liu S, Croniger C, Arizmendi C, Harada-Shiba M,
Ren J, Poli V, Hanson RW, Friedman JE. Hypoglycemia and impaired hepatic glucose production in
mice with a deletion of the C/EBPbeta gene. J Clin
Invest 1999; 103(2):207213.
171. Bouchard C, Perusse L. Genetics of obesity. Annu Rev
Nutrition 1993; 13:337354.
172. Ristow M, Muller-Wieland D, Pfeier A, Krone W,
Kahn CR. Obesity associated with a mutation in a
genetic regulator of adipocyte dierentiation. N Engl J
Med 1998; 339:953959.
173. Hu E, Kim JB, Sarraf P, Spiegelman BM. Inhibition
of adipogenesis through MAP-kinase mediated phosphorylation of PPARg. Science 1996; 274: 21002103.
174. Adams M, Reginato MJ, Shao D, Lazar MA,
Chatterjee VK. Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogenactivated protein kinase site. J Biol Chem 1997;
272:51285132.
175. Camp HS, Tafuri SR. Regulation of peroxisome
proliferator-activated receptor gamma activity by
mitogen-activated protein kinase. J Biol Chem 1997;
272:1081110816.
176. Zhang B, Berger J, Zhou G, Elbrecht A, Biswas S,
White-Carrington S, Szalkowski D, Moller DE.
Insulin and mitogen-activated protein kinase-mediated
phosphorylation and activation of peroxisome proliferator-activated receptor gamma. J Biol Chem 1996;
271:3177131774.
177. Yen CJ, Beamer BA, Negri C, Silver K, Brown KA,
Yarnall DP, Burns DK, Roth J, Shuldiner AR.
Molecular scanning of the human peroxisome proliferator activated receptor gamma gene in diabetic
Caucasians: identication of a Pro12Ala PPARgamma
2 missense mutation. Biochem Biophys Res Commun
1997; 241:270274.
178. Deeb S, Fajas L, Nemoto M, Laakso M, Fujimoto W,
Auwerx J. A Pro12Ala substitution in the human
peroxisome proliferator-activated receptor gamma2 is
associated with decreased receptor activity, improved
insulin sensitivity, and lowered body mass index. Nat
Genet 1998; 20:284287.
179. Vigouroux C, Fajas L, Khallouf E, Meier M, Gyapay
584
G, Auwerx J, Weissenbach J, Capeau J, Magre J.
Human peroxisome proliferator-activated receptor
gamma 2: genetic mapping, identication of a variant
in the coding sequence, and exclusion as the gene
responsible for lipoatrophic diabetes. Diabetes 1998;
47:490492.
180. Beamer BA, Yen CJ, Andersen RE, Muller D, Elahi
D, Cheskin LJ, Andres R, Roth J, Shuldiner AR.
Association of the Pro12Ala variant in peroxisome
proliferatoractivated receptor gamma2 gene with
obesity in two Caucasian populations. Diabetes 1998;
47:18061808.
181. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaner SF,
Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ,
Daly M, Groop L. The common PPARgamma
Pro12Ala polymorphism is associated with decreased
risk of type 2 diabetes [In Process Citation]. Nat Genet
2000; 26(1):7680.
182. Mori Y, Kim-Motoyama H, Katakura T, Yasuda K,
Kadowaki H, Beamer BB, Shuldiner AR, Akanuma
Y, Yazaki Y, Kadowaki T. Eect of the Pro12Ala
variant of the human peroxisome proliferator activated receptor g2 gene on adiposity, fat distribution,
and insulin sensitivity in Japanese men. Biochem
Biophys Res Commun 1998; 251:195198.
183. Werman A, Hollenberg A, Solanes G, Bjorbaek C,
Vidal-Puig A, Flier JS. Ligand-independent activation
domain in the N terminus of peroxisome proliferator
activated receptor g (PPARg). J Biol Chem 1997;
272:2023020235.
184. Shao D, Rangwala SM, Bailey ST, Krakow SL,
Reginato MJ, Lazar MA. Interdomain communication regulating ligand binding by PPAR gamma.
Nature 1998; 396(6505):377380.
185. Norman RA, Thompson DB, Foroud T, Garvey WT,
Bennett PH, Bogardus C, Ravussin E. Genomewide
search for genes inuencing percent body fat in Pima
Indians: suggestive linkage at chromosome 11Q21
Q22. Am J Hum Genet 1997; 60:166173.
186. Barak Y, Nelson MC, Ong ES, Jones YZ, RuizLozano P, Chien KR, Koder A, Evans RM. PPARgamma is required for placental, cardiac, and adipose
tissue development. Mol Cell 1999; 4:585595.
187. Kubota N, Terauchi Y, Miki H, Tamemoto H,
Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii
C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A,
Murakami K, Sekihara H. PPARg mediates high-fat
dietinduced adipocyte hypertrophy and insulin resistance. Mol Cell 1999; 4:597609.
188. Miles PD, Barak Y, He W, Evans RM, Olefsky JM.
Improved insulin-sensitivity in mice heterozygous for
PPAR-gamma deciency. J Clin Invest 2000; 105(3):
287292.
189. Schoonjans K, Staels B, Auwerx J. The peroxisome
proliferatoractivated receptors (PPARs) and their
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
eects on lipid metabolism and adipocyte dierentiation. Biochim Biophys Acta 1996; 1302: 93109.
Staels B, Vu-Dac N, Kosykh V, Saladin R, Fruchart
JC, Dallongeville J, Auwerx J. Fibrates down-regulate
apolipoprotein C-III expression independent of induction of peroxisomal Acyl Co-enzyme A Oxidase.
J Clin Invest 1995; 95:705712.
Hertz R, Bishara-Shieban J, Bar-Tana J. Mode of
action of peroxisome proliferators as hypolipidemic
drugs, suppression of apolipoprotein C-III. J Biol
Chem 1995; 270:1347013475.
Castle CK, Colca JR, Melchior GW. Lipoprotein
prole characterization of the KKAy mouse, a rodent
model of type II diabetes, before and after treatment
with the insulin-sensitizing agent pioglitazone. Arterioscler Thromb 1993; 13:302309.
Schwartz S, Raskin P, Fonseca V, Graveline JF. Eect
of troglitazone in insulin-treated patients with type II
diabetes. N Engl J Med 1998; 338:861866.
Kumar S, Boulton AJM, Beck-Nielsen H, Berthezene
F, Muggeo M, Persson B, Spinas GA, Donoghue S,
Lettis S, Stewart-Long P. Troglitazone, an insulin
action enhancer, improves metabolic control in
NIDDM patients. Diabetologia 1996; 39:701709.
Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH,
Huang SM, Faja BW, Whitcomb RW. Cardiac and
glycemic benets of troglitazone treatment in
NIDDM. Diabetes 1997; 46:433439.
Berthezene F. Non-insulin dependent diabetes and
reverse cholesterol transport. Atherosclerosis 1996;
124:S39S42.
Sasahara T, Yamashita T, Sviridov D, Fidge N, Nestel
P. Altered properties of high density lipoprotein
subfractions in obese subjects. J Lipid Res 1997;
38:600611.
Vague J. The degree of masculine dierentiation of
obesities: a factor determining predisposition to
diabetes, atherosclerosis, gout and uric calculous
disease. Am J Clin Nutr 1956; 34:416422.
Wajchenberg BL. Subcutaneous and visceral adipose
tissue: their relation to the metabolic syndrome.
Endocr Rev 2000; 21:697738.
Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski
W, Glass CK. Peroxisome proliferatoractivated receptor gamma ligands inhibit development of atherosclerosis in LDL receptodecient mice. J Clin Invest
2000; 106(4):523531.
Claudel T, Leibowitz MD, Fievet C, Tailleux A,
Wagner B, Repa JJ, Torpier G, Lobaccaro JM,
Paterniti JR, Mangelsdorf DJ, Heyman RA, Auwerx
J. Reduction of atherosclerosis in apolipoprotein E
knockout mice by activation of the retinoid X receptor.
Proc Natl Acad Sci USA 2001; 98(5):26102615.
Glass CK, Rose DW, Rosenfeld MG. Nuclear
receptor coactivators. Curr Opin Cell Biol 1997;
9:222232.
PPARg
g and Adipogenesis and Metabolism
203. Abraham SE, Lobo S, Yaciuk P, Heidi HG, Moran E.
p300 and p300-associated proteins, are components of
the TATA-binding protein (TBP) complexes. Oncogene 1993; 8:16391647.
204. Nakajima T, Uchida C, Anderson S, Lee CG, Hurwitz
J, Parvin JD, Montmimy M. RNA helicase A mediates
association of CBP with RNA polymerase II. Cell
1997; 90:11071112.
205. Kingston RE, Narlikar GJ. ATP-dependent remodeling and acetylation as regulators of chromatin uidity.
Genes Dev 1999; 13(18):23392352.
206. Vignali M, Hassan AH, Neely KE, Workman JL.
ATP-dependent chromatin-remodeling complexes.
Mol Cell Biol 2000; 20(6):18991910.
207. Sudarsanam P, Winston F. The Swi/Snf family
nucleosome-remodeling complexes and transcriptional
control [In Process Citation]. Trends Genet 2000;
16(8):345351.
208. Muchardt C, Yaniv M. A human homologue of
Saccharomyces cerevisiae SNF2/SW12 and Drosophila
brm genes potentiates transcriptional activation by the
glucocorticoid receptor. EMBO J 1993; 12(11):4279
4290.
209. Fryer CJ, Archer TK. Chromatin remodelling by the
glucocorticoid receptor requires the BRGI complex.
Nature 1998; 393(6680):8891.
210. Wallberg AE, Neely KE, Hassan AH, Gustafsson JA,
Workman JL, Wright AP. Recruitment of the SWISNF chromatin remodeling complex as a mechanism
of gene activation by the glucocorticoid receptor taul
activation domain. Mol Cell Biol 2000; 20(6):2004
2013.
211. Di Lorenzo D, Williams P, Ringold G. Identication
of two distinct nuclear factors with DNA binding
activity within the glucocorticoid regulatory region of
the rat alpha-1-acid glycoprotein promoter. Biochem
Biophys Res Commun 1991; 176:13261332.
212. Chiba H, Muramatsu M, Nomoto A, Kato H. Two
human homologues of Saccharomyces cerevisiae
SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the oestrogen
receptor and the retinoic acid receptor. Nucl Acids Res
1994; 22(10):18151820.
213. Dilworth FJ, Fromental-Ramain C, Yamamoto K,
Chambon P. ATP-Driven chromatin remodeling
activity and histone acetyltransferases act sequentially
during transactivation by RAR/RXR In vitro. Mol
Cell 2000; 6(5):10491058.
214. Lovell-Badge R. Living with bad architecture. Nature
1995; 376:725726.
215. Zhou X, Benson KF, Ashar HR, Chada K. Mutation
responsible for the mouse pygmy phenotype in the
developmentally regulated factor HMGI-C. Nature
1995; 376(6543):771774.
216. Schoenmakers EFPM, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJW.
585
Recurrent rearrangements in the high mobility group
protein gene, HMGI-C, in benign mesenchymal
tumours. Nat Genet 1995; 10:436443.
217. Ashar HR, Schoenberg Fejzo M, Tkachenko A, Zhou
X, Fletcher JA, Weremowicz S, Morton CC, Chada K.
Disruption of the architectural factor HMGI-C: DNA
binding AT hook motifs fused in lipomas to distinct
transcriptional regulatory domains. Cell 1995;
82(1):5765.
218. Battista S, Fidanza V, Fedele M, Klein-Szanto AJ,
Outwater E, Brunner H, Santoro M, Croce CM,
Fusco A. The expression of a truncated HMGI-C gene
induces gigantism associated with lipomatosis. Cancer
Res 1999; 59(19):47934797.
219. Melillo RM, Pierantoni GM, Scala S, Battista S,
Fedele M, Stella A, De Biasio MC, Chiappetta G,
Fidanza V, Condorelli G, Santoro M, Croce CM,
Viglietto G, Fusco A. Critical role of the hmgi(y)
proteins in adipocytic cell growth and dierentiation.
Mol Cell Biol 2001; 21(7):24852495.
220. Bannister AJ, Kouzarides T. The CBP co-activator is a
histone acyltransferase. Nature 1996; 384:641643.
221. Chen H, Lin RJ, Louis Schiltz L, Chakravarti D, Nash
A, Nagy L, Privalsky ML, Nakatani Y, Evans RM.
Nuclear receptor coactivator ACTR is a novel histone
acetyltransferase and forms multimeric activation
complexes with P/CAF and CBP/p300. Cell 1997;
90:569580.
222. Korzus E, Torchia J, Rose DW, Xu L, Kurokawa R,
McInerney EM, Mullen TM, Glass CK, Rosenfeld
MG. Transcription factorspecic requirements for
coactivators and their acetyltransferase functions.
Science 1998; 279:703707.
223. Ogryzko VV, Schiltz RL, Russanova V, Howard BH,
Nakatani Y. The transcriptional coactivators p300
and CBP are histone acetyltransferases. Cell 1996;
87:953959.
224. Spencer TEJ, G., Burcin MM, Allis CD, Zhou J,
Mizzen CA, McKenna NJ, Onate SA, Tsai SY,
OMalley BW. Steroid receptor coactivator-1 is a
histone acetyltransferase. Nature 1997; 389:194198.
225. Martinez-Balbas MA, Bannister AJ, Martin K, HausSeuert P, Meisterernst M, Kouzarides T. The acetyltransferase activity of CBP stimulates transcription.
EMBO J 1998; 17:28862893.
226. Imhof A, Yang XJ, Ogryzko VV, Nakatani Y, Wole
AP, Ge H. Acetylation of general transcription factors
by histone acetyltransferases. Curr Biol 1997; 7:689
692.
227. Nagy L, Kao HK, Chakravarti D, Lin RJ, Hassig CA,
Ayer DE, Schreiber SL, Evans RM. Nuclear receptor
repression mediated by a complex containing SMRT,
mSin3A, and histone deacetylase. Cell 1997; 89:373
380.
228. Alland L, Muhle R, Hou H, Potes J, Chin L,
Schreiber-Agus N, DePinho RA. Role for N-CoR
586
and histone deacetylase in Sin3-mediated transcriptional repression. Nature 1997; 387:4955.
229. Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M,
Laherty CD, Torchia J, Yang W-M, Brard G, Davie
JR, Seto E, Eisenman RN, Rose DW, Glass CK,
Rosenfeld MG. A complex containing N-CoR, mSin3
and histone deacetylase mediates transcriptional repression. Nature 1997; 387:4348.
230. Glass CK, Rosenfeld MG. The coregulator exchange
in transcriptional functions of nuclear receptors.
Genes Dev 2000; 14(2):121141.
231. Chen JD, Evans RM. A transcriptional co-repressor
that interacts with nuclear hormone receptors. Nature
1995; 377:454457.
232. Chen DJ, Umesono K, Evans RM. SMRT isoforms
mediate repression and anti-repression of nuclear
receptor heterodimers. Proc Natl Acad Sci USA
1996; 93:75677571.
233. Lavinsky RM, Jepsen K, Heinzel T, Torchia J, Mullen
TM, Schi R, Del-Rio AL, Ricote M, Gemsch J,
Hilsenbeck SG, Osborne CK, Glass CK, Rosenfeld M,
Rose DW. Diverse signalling pathways modulate
nuclear receptor recruitment of N-CoR and SMRT
complexes. Proc Natl Acad Sci USA 1998; 95:2920
2925.
234. Zamir I, Zhang J, Lazar M. Stochiometric and steric
principles governing repression by nuclear hormone
receptors. Genes Dev 1997; 11:835846.
235. Misiti S, Schomburg L, Yen PM, Chin WW. Expression
and hormonal regulation of co-activator and corepressor genes. Endocrinology 1998; 139:24932500.
236. Chrivia JC, Kwok RP, Lamb N, Hagiwara M,
Montminy MR, Goodman RH. Phosphorylated
CREB binds specically to the nuclear protein CBP.
Nature 1993; 365:855859.
237. Eckner R, Ewen ME, Newsome D, Gerdes M,
DeCaprio JA, Bentley Lawrence J, Livingston DM.
Molecular cloning and functional analysis of the
adenovirus E1A-associated 300 kD protein (p300)
reveals a protein with properties of a transcriptional
adaptator. Genes Dev 1994; 8:869884.
238. Janknecht R, Hunter T. Transcriptional control:
versatile molecular glue. Curr Biol 1996; 6:951954.
239. Chakravarti D, LaMorte VJ, Nelson MC, Nakajima
T, Schulman IG, Juguilon H, Montminy M, Evans
RM. Role of CBP/p300 in nuclear receptor signalling.
Nature 1996; 383:99103.
240. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R,
Gloss B, Lin S-C, Heyman RA, Rose DW, Glass CK,
Rosenfeld MG. A CBP integrator complex mediates
transcriptional activation and AP-1 inhibition by
nuclear receptors. Cell 1996; 85:403414.
241. Hanstein B, Eckner R, DiRenzo J, Halachmi S, Liu H,
Searcy B, Kurokawa R, Brown M. p300 is a
component of an estrogen receptor coactivator complex. Proc Natl Acad Sci USA 1996; 93:1154011545.
PPARg
g and Adipogenesis and Metabolism
254. Jain S, Pulikuri S, Zhu Y, Qi C, Kanwar YS, Yeldandi
AV, Rao MS, Reddy JK. Dierential expression of the
peroxisome proliferator-activated receptor g (PPARg)
and its coactivators steroid receptor coactivator-1 and
PPAR-binding protein PBP in the brown fat, urinary
bladder, colon, and breast of the mouse. Am J Pathol
1998; 153:349354.
255. Fondell JD, Ge H, Roeder RG. Ligand induction of a
transcriptionally active thyroid hormone receptor
coactivator complex. Proc Natl Acad Sci USA 1996;
93(16):83298333.
256. Rachez C, Suldan Z, Ward J, Chang CP, Burakov D,
Erdjument-Bromage H, Tempst P, Freedman LP. A
novel protein complex that interacts with the vitamin
D3 receptor in a ligand-dependent manner and
enhances VDR transactivation in a cell-free system.
Genes Dev 1998; 12(12):17871800.
257. Naar AM, Beaurang PA, Zhou S, Abraham S,
Solomon W, Tjian R Composite co-activator ARC
mediates chromatin-directed transcriptional activation. Nature 1999; 398(6730):828832.
258. Gu W, Malik S, Ito M, Yuan CX, Fondell JD, Zhang
X, Martinez E, Qin J, Roeder RG. A novel human
SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol Cell 1999;
3(1):97108.
259. Rachez C, Lemon BD, Suldan Z, Bromleigh V,
Gamble M, Naar AM, Erdjument-Bromage H,
Tempst P, Freedman LP. Ligand-dependent transcription activation by nuclear receptors requires the
DRIP complex. Nature 1999; 398(6730):824828.
260. Yuan CX, Ito M, Fondell JD, Fu ZY, Roeder RG.
The TRAP220 component of a thyroid hormone
receptorassociated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a
ligand-dependent fashion [published erratum appears
in Proc Natl Acad Sci USA 1998; 95(24):14584]. Proc
Natl Acad Sci USA 1998; 95(14):79397944.
261. Zhu Y, Qi C, Jia Y, Nye JS, Rao MS, Reddy JK.
Deletion of PBP/PPARBP, the gene for nuclear
receptor coactivator peroxisome proliferatoractivated receptor-binding protein, results in embryonic
lethality. J Biol Chem 2000; 275(20):1477914782.
262. Ito M, Yuan CX, Okano HJ, Darnell RB, Roeder RG.
Involvement of the TRAP220 component of the
TRAP/SMCC coactivator complex in embryonic
development and thyroid hormone action. Mol Cell
2000; 5(4):683693.
263. Wu Z, Puigserver P, Andersson U, Zhang C,
Adelmant G, Mootha V, Troy A, Cinti S, Lowell B,
Scarpulla RC, Spiegelman BM. Mechanisms control-
587
ling mitochondrial biogenesis and respiration through
the thermogenic coactivator PGC-1. Cell 1999; 98(1):
115124.
264. Vega RB, Huss JM, Kelly DP. The coactivator
PGC-1 cooperates with peroxisome proliferator
activated receptor alpha in transcriptional control
of nuclear genes encoding mitochondrial fatty acid
oxidation enzymes. Mol Cell Biol 2000; 20(5):1868
1876.
265. Tcherepanova I, Puigserver P, Norris JD, Spiegelman
BM, McDonnell DP. Modulation of estrogen receptor-alpha transcriptional activity by the coactivator
PGC-1. J Biol Chem 2000; 275(21):1630216308.
266. Knutti D, Kaul A, Kralli A. A tissue-specic coactivator of steroid receptors, identied in a functional
genetic screen. Mol Cell Biol 2000; 20(7):24112422.
267. Puigserver P, Adelmant G, Wu Z, Fan M, Xu J,
OMalley B, Spiegelman BM. Activation of PPARgamma coactivator-1 through transcription factor
docking. Science 1999; 286(5443):13681371.
268. Michael LF, Wu Z, Cheatham RB, Puigserver P,
Adelmant G, Lehman JJ, Kelly DP, Spiegelman BM.
Restoration of insulin-sensitive glucose transporter
(GLUT4) gene expression in muscle cells by the
transcriptional coactivator PGC-1. Proc Natl Acad
Sci USA 2001; 98(7):38203825.
269. Monsalve M, Wu Z, Adelmant G, Puigserver P, Fan
M, Spiegelman BM. Direct coupling of transcription
and mRNA processing through the thermogenic
coactivator PGC-1. Mol Cell 2000; 6(2):307316.
270. Treuter E, Albrektsen T, Johansson L, Leers J,
Gustafsson JA. A regulatory role for RIP140 in
nuclear receptor activation. Mol Endocrinol 1998;
12(6):864881.
271. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA,
Evans RM. PPARg promotes monocyte/macrophage
dierentiation and uptake of oxidized LDL. Cell 1998;
93:241252.
272. Lefebvre A, Chen I, Desreumaux P, Najib J, Fruchart
J, Geboes K, Briggs M, Heyman R, Auwerx J. Activation of the peroxisome proliferator-activated receptor g promotes the development of colon tumors in
C57BL/6J-APCMin /+ mice. Nat Med 1998; 4:1053
1057.
273. Saez E, Tontonoz P, Nelson MC, Alvarez JGA, Ming
UT, Baird SM, Thomazy VA, Evans RM. Activators
of the nuclear receptor PPARg enhance colon polyp
formation. Nat Med 1998; 4:10581061.
274. Watkins PB, Whitcomb RW. Hepatic dysfunction
associated with troglitazone. N Engl J Med 1998;
338:916917.
22
Biology of Visceral Adipose Tissue
Susan K. Fried
University of Maryland and Baltimore Veterans Administration Medical Center, Baltimore, Maryland, U.S.A.
Robert R. Ross
Queens University, Kingston, Ontario, Canada
INTRODUCTION
589
590
Table 1 Major Fat Depots in Humans and Rodents
Humans
I. Intra-abdominal or viscerala adipose tissue depots
A. Intraperitoneal
1. omentalgreater and lesser
2. mesentericsmall intestine, colon-rectum, epiploic
3. umbilical/round/falciform ligament
B. Extraperitoneal (including pre- or properitoneal)
1. perirenalb
2. peripancreaticb
3. urogenital (bladder, uterus, prostate)
II. Subcutaneous fat depots (deep and supercial
compartments)
A. Truncal (anterior or posterior chest)
B. Mammary (only one compartment)
C. Abdominal
D. Lumbar
E. Gluteal
F. Femoral
Rodents
I. Intra-abdominal
A. Mesenteric
B. Omental
C. Gonadal (parametrial or epididymal)
D. Perirenal (retroperitoneal)
II. Subcutaneous
A. Truncal
1. cervicalb
2. axillaryb
3. interscapularc
4. dorsal
B. Inguinal
a
vivo activity and therefore high portal fatty acid delivery in humans (16,17). Some animal data do support the
possibility that an increased mass of visceral adipose
tissues lead to increased portal fatty acids levels in vivo
(1820).
C
Recent evidence that adipose tissues are also heterogeneous in their endocrine functions raises the possibility
for additional mechanistic links between visceral
adiposity and metabolic derangements (18,21). A growing body of literature indicates that there are marked
dierences in the secretory products of visceral and
subcutaneous adipose tissues, including leptin, interleukin-6, plasminogen activator inhibitor-1, and adiponectin, that may contribute to the development of the
metabolic syndrome (21,22).
D
II
DEFINITION, ANATOMICAL
DESCRIPTION, AND MEASUREMENT
OF VISCERAL ADIPOSE TISSUE
591
Figure 1 Axial computerized tomography (CT) and magnetic resonance imaging (MRI) images obtained in the midabdomen.
Adipose tissue appears black on the CT image and white on the MRI image. VAT, visceral adipose tissue; ASAT, abdominal
subcutaneous adipose tissue.
592
Intra-abdominal fat depots of rats include the perirenal, retroperitoneal, gonadal, and mesenteric and
omental (40) (note that in rodents, the so-called retroperitoneal fat depot is not outside the peritoneal cavity). Of these, only the mesenteric depot is associated
with the digestive tract, is substantial in size, and drains
portally. The omental fat depot in rodents, in contrast
to that in humans, is much smaller than mesenteric and
not usually dissected or studied. Thus, the mesenteric
depot of rodents would probably be the best model
of a human (visceral)portal depot. Data from Warden
(41) indicate that genes that determine the size of
mesenteric depot are distinct from those regulating
the size of other depots, supporting the contention that
this visceral fat depot is anatomically and probably
metabolically distinct.
The relative distribution of fat appears to dier in
humans and rats because the latter deposits relatively
more total fat within intra-abdominal depots. Over
50% of the total fat mass of rats is accounted for by
intraabdominal fat (42). In contrast, in humans the total intra-abdominal (including omental and mesenteric)
fat mass is only f20% of the total (most is subcutaneous). Furthermore, whereas in humans the size of
subcutaneous fat cells are as large as or larger than
intra-abdominal ones, in rats subcutaneous fat cells
tend to be smaller than those from intra-abdominal depots such as epididymal or retroperitoneal (40,42,43).
Thus, the metabolic eects of removal of intra-abdominal fat depots should not be assumed to be comparable
to the removal of the portal adipose tissues. Caution
should be used in extrapolating data about the metabolic eects of altered fat distribution in rodent models
to the human (e.g., 44).
III
A
DESCRIPTIVE CHARACTERISTICS
EFFECTS OF GENDER, RACE
Gender
593
Race
All fat depots contain adipocytes, preadipocytes, endothelial cells, mast cells, and broblasts. There are no
systematic studies that characterize and quantify the
dierent cell types present in visceral compared to
subcutaneous fat. The omental fat depot is also rich in
mesothelial cells, apparently derived from the peritoneum (5456).
There appear to be more macrophages present in
omental than subcutaneous adipose tissue (57). The
abundance of lymph nodes in visceral depots may also
be of importance in determining the metabolic activity
of surrounding adipocytes (58).
The number of preadipocytes in omental fat may be
lower than in subcutaneous (59). Because nonadipose
cells including preadipocytes produce many cytokines
including tumor necrosis factor-a (60) and interleukin-6
(61,62) and other proteins that may inuence adipocyte
metabolism, it seems likely that the paracrine environment of dierent depots diers between visceral and
subcutaneous fat, at least in part, by virtue of the different cell types present. These dierences in cellular
composition may underlie regional dierences in adipocyte metabolism, and hence variations in the regional
deposition of fat or its function.
594
METABOLIC CHARACTERISTICS
OF VISCERAL ADIPOSE TISSUE
Maximally beta-adrenergic-stimulated rates of lipolysis by a nonspecic agonist are similar in omental and
subcutaneous adipose tissues (72,73). Because of the
lower basal, the increment (delta) over basal is higher
in omental than in subcutaneous. Mesenteric fat cells
appear to also exhibit increased responsiveness to isoproterenol, particularly in men (73). Omental fat cells
exhibit about twofold higher responses to physiologic
catecholamines that activate both beta (stimulatory)
and alpha2- (inhibitory) adrenergic receptors (66). Only
minor but statistically higher responses to beta1-adrenergic receptors occur in omental than in subcutaneous fat cells of lean men (66). However, there are
impressive dierences in the sensitivity of omental fat
cells to adrenergic receptor subtypes. Omental fat
cells of obese men exhibit markedly increased sensitivity (ED50) as well as increased responsiveness to
beta-adrenergic agonists, particularly to the beta3 agonist CGP 12177 and decreased responsiveness to the
antilipolytic eects of alpha 2-adrenergic receptors
(66,72,79,80). Omental fat cells of men as compared to
women are markedly more sensitive to the lipolytic effects of beta-adrenergic agonist, particularly the beta3
component (79).
The dierences in beta-adrenergic responsiveness
between omental and subcutaneous fat cells appear
to derive from alterations in receptor expression rather
than postreceptor events (74). No dierences in Gi or Gs
subtypes (76) are reported. Levels of HSL expression
(protein and mRNA) are reported to be lower in omental than in subcutaneous (SC), predicting the lower
maximal rates of lipolysis in omental that were in fact
observed is some studies (64).
C
Studies are consistent in reporting a decreased sensitivity and responsiveness to the antilipolytic eect of
insulin in omental compared to fat cells. The ED50 for
595
Acylation-Stimulating Protein
596
Lipoprotein Lipase
VI
PHYSIOLOGICAL DETERMINANTS OF
VISCERAL ADIPOSE TISSUE FUNCTION
Blood Flow
Blood ow to the rat mesenteric fat pad is about vefold higher than other intra-abdominal depots (102,103).
Other than casual observations that visceral adipose
tissues are highly enriched in endothelial cells, suggesting high vascularization, no published information is
available comparing the rate of blood ow or its regulation in these depots in humans.
B
Innervation
Hormonal Determinants
Sex Steroids
597
Growth Hormone
Cortisol
598
The antidiabetic TDZs are ligands of peroxisome proliferatingactivating receptor-g (PPARg) and thus
increase adipogenesis as well as improving insulin sensitivity. TDZs appear to be less potent in stimulating
preadipocyte dierentiation in cultures derived from human omental versus subcutaneous fat depots despite
similar levels of PPARg. Clinical studies show that
treatment of type 2 diabetics with troglitazone leads to
a selective decrease in visceral adiposity and may also
increase the mass of subcutaneous fat stores (135,136).
VII
The adipocyte hormone leptin has been studied extensively with regard to depot dierences. Omental
adipose tissue expressed lower levels of leptin mRNA,
and produces less leptin (per cell or per gram) independent of fat cell size in lean and obese men and women
(63,89,128,140,141). Thus, omental adipose tissue production of leptin is a minor determinant of systemic
levels, but may be of importance via its impact on
hepatic metabolism via the portal circulation.
IL-6 is considered an adipose hormone because arteriovenous studies show a net release of IL-6 across the abdominal subcutaneous fat in vivo (16,142,143). Of note,
in vivo and in vitro production of IL-6 in subcutaneous
fat and serum IL-6 levels are increased in proportion to
BMI (144,145). One study indicates that omental produces more IL-6 in severely obese subjects (men and
women) (62). Further studies of omental IL-6 production in lean and moderately obese subjects are needed,
because it could be playing an important paracrine as
well as endocrine role. It has been suggest that IL-6
overproduction by visceral fat delivered directly to the
liver via the portal vein may contribute to the development of the metabolic syndrome (62). Animal studies
show that IL-6 increases VLDL production and increasing the synthesis of acute phase proteins, both features
of visceral obesity. Most of the IL-6 produced derives
from stromal elements, but adipocytes also appear to
produce it (62). More needs to be known about cellspecic and depot-specic regulation of IL-6 synthesis
and secretion. Interestingly, isoproternol administration in vivo appears to increase serum and adipose tissue
IL-6 (145147). As the omental depot is more responsive
to h-adrenergic eects, this may be one factor in the
increased omental production of this cytokine.
High levels of omental IL-6 and perhaps other
cytokines (if they are secreted from the omentum) may
also greatly impact hepatic metabolism. Both these
hormones may contribute to hepatic insulin resistance,
and IL-6 is a potent stimulator of hepatic VLDL production and the acute phase protein synthesis that
appears to be a feature of visceral obesity (148150).
1
599
Adiponectin
Estrogen is produced via P450 aromatase that is expressed in the stromal compartment of adipose tissue,
particularly in postmenopausal women (162). Adipose
tissue also possesses enzymes involved in androgen
metabolism (109). Possible depot dierences in sex steroid metabolism have not yet been extensively studied.
However, there appears to be evidence to depot-specic
estrogen action. The estrogen receptor-a limits fat deposition (163,164). The expression of the estrogen receptor-a is poorly feedback-regulated in human omental as
compared to subcutaneous fat, suggesting a mechanism
for depot-specic eects of estrogen on fat distribution
(165). Additionally, estrogen receptor-h is expressed in
lower relative abundance in omental than subcutaneous
adipose tissue of women and men (116), but the physiological implications of this observation are unclear.
4
600
Renin-Angiotensin System
Lipodystrophies
Methodological Considerations
601
in total and subcutaneous adipose tissue, a 25% reduction in VAT was observed. Together these results
suggest that regularly performed aerobic exercise without weight loss results in marked reductions in VAT,
which are in general greater than the change in total
or abdominal subcutaneous adipose tissue.
In contrast to these observations, Poehlman et al.
(197) report that 6 months of either endurance or
resistance exercise training did not reduce VAT or abdominal subcutaneous adipose tissue in young, premenopausal women, a nding consistent with that of
DiPietro et al. (198), who report that in older men and
women, 4 months of supervised aerobic exercise had no
eect on abdominal subcutaneous or visceral adipose
tissue. A rationale to explain the equivocal ndings is
unknown. However, it is noted that in the Poehlman
et al. (197) study, the average VAT values pretreatment
for the exercise groups approximated 40 cm2, a value
substantially below the values thought to be associated
with metabolic risk (199,200). Taken together, available
evidence does not permit rm conclusions regarding the
eects of exercise training in the absence of weight loss
on VAT distribution.
3
Lifestyle-Based Strategies
Exercise
602
Table 3
Reference
Subjects
Study
duration
(months)
Reduction Reduction
in weight in body fat
(kg)
(kg)
Reduction
in VAT
(cm2) [%]
Reduction
in ASAT
(cm2) [%]
0 [0]
52 [28]a
32 [16]a
+4 [11]
0 [0]
+1 [2]
18 [13]
10 [9]
5 [3]
76 [48]a
[3]
[18]a
[6]
NR
0[
1[
+20 [8]
+11 [6]
9 [3]
41 [18]a
BMI
(kg/m2)
Treatment
31
33
32
22
22
22
27
27
30
30
Control group
Exercise (WL)
Exercise (WWL)
Control group
Aerobic exercise
Resistance exercise
Control group
Aerobic exercise
Control group
Aerobic exercise
25
Aerobic exercise
0.6
1.9 L
26
25
25
Aerobic exercise
Aerobic exercise
Resistance exercise
5
4
0.4b
0.1
0.1
0.9b
0.5b
0.4
6 [7]b
3 [5]b
14 [10]b
10 [5]b
8 [3]b
17 [6]
[82]
Aerobic exercise
5.0b
5.0b
29 [36]b
67 [27]b
26
26
34
Aerobic exercise
Aerobic exercise
Aerobic exercise
0.5
2.5b
3.7b
1.6
2.4b
4.6b
11 [17]b
35 [25]b
3 [3]
21 [10]b
35 [20]b
60 [11]b
4
2
14
0.8
7.6a
0.5
+1.0
+2.0
0.0
0.0
1.0
0.2
1.5
0.6
6.1a
0.8
0.0
+1.0
1.0
NR
0.8
0.8
0.4 L [25]
NR
WL, weight loss; WWL, without weight loss; BMI, body mass index: VAT, visceral adipose tissue; ASAT, abdominal subcutaneous adipose tissue;
NR, not reported; L, liters.
a
Signicantly dierent from change in control group (P<.05).
b
Signicant within group change (P<.05).
Caloric restriction has been the principal means of assessing the inuence of weight loss on VAT (Table 4).
From the studies reviewed it is noted that the magnitude of the diet-induced weight loss ranges from 4.4 to
18.8 kg (Table 4). The corresponding reductions in VAT
vary according to the weight loss; the greater the weight
loss, the greater the reduction in VAT. When expressed
per kilogram of body weight lost [mean absolute VAT
loss (cm2) H mean weight loss (kg)], the corresponding
reduction in VAT varied from 2.5 to 13.8 cm2/kg. In
relative terms (i.e., controlling for initial dierences in
VAT accumulation), the relative loss per kg is f3% (4).
Thus, for a 10-kg weight loss, the relative reduction in
VAT is f30%. It is important to note the large
interindividual variations observed in VAT reduction
Pharmacotherapy
603
Table 4 Inuence of Diet-Induced Weight Loss on Visceral and Abdominal Subcutaneous Adipose Tissue
Subjects
Study
Sex
Bosello et al.,
1990 (219)
Fujioka et al.,
1991 (220)
19
Young
women
Young
women
VO
SO
Young
women
Older
women
Women
14
26
Gray et al.,
1991 (221)
Stallone et al.,
1991 (222)
Armellini et al.,
1991 (223)
Leenen et al.,
1992 (224)
10
11
26
40
38
Chowdhury et al.,
1993 (225)
Zamboni et al.,
1993 (226)
Nicklas et al.,
1997 (227)
Zamboni et al.,
1997 (228)
Janand-Delenne et al.,
1998 (229)
Goodpaster et al.,
1999 (230)
17
15
10
10
Kockx et al.,
1999 (232)
25
25
Riches et al.,
1999 (233)
Ross et al.,
1994 (38)
Doucet et al.,
2000 (234)
12
16
9
34
13
38
45
Kamel et al.,
2000 (235)
19
17
Ross et al.,
2000 (194)
14
BMI
(kg/m2)
40
34
Duration
(weeks)
Weight loss
Abs [kg] (%)
VAT lossa
Abs [cm2] (%)
23
6.7 (6)
29.1 (20)
810
36
VAT loss/kg
weight loss
Abs [cm2] (%)
4.3 (3.0)
ASAT lossa
Abs [cm2] (%)
34.4 (6)
12.0 (14)
2.6 (38)
(3.2)
3.1 (25)b
12.3 (14)
1.3 (33)b
(2.7)
4.0 (23)b
35
10
10.5 (12)
26 (27)
2.5 (2.6)
62 (13)
37
26
18.8 (20)
52.9 (36)
2.8 (1.9)
152.8 (33)
39
24 (15)
4.0 (2.5)
Young
women,
men
Men
31
30
13
11.7 (14)
12.6 (13)
35 (30)
61 (39)
3.0 (2.6)
4.8 (3.1)
35
4.4 (4)
0.9 (10)b
Young
women
Older
women
Men and
women
Young
women
Young
women,
men
Young
women,
men
Young
women,
men
Men
38
16
16.2 (16)
73.7 (44)
4.5 (2.7)
145.3 (24)
74
26
9.8 (12)
26 (17)
2.7 (1.7)
65 (15)
f36
7.0 (7)
27.3 (16)
3.9 (2.3)
35.9 (10)
34
6.6 (7)
29 (22)
4.4 (3.3)
55 (15)
34
34
16
12.2 (13)
17.6 (16)
44 (30)
78 (47)
3.6 (2.5)
4.4 (2.7)
118 (23)
159 (34)
34
32
16
10.7 (11)
11.7 (12)
51 (37)
58 (30)
4.8 (3.5)
4.9 (2.6)
7 (18)
6 (23)
31
30
13
11.4 (13)
12.1 (12)
32 (33)
61 (39)
2.8 (2.9)
5.0 (3.2)
122 (30)
109 (35)
34
16
10.2 (9)
100 (31)c
9.8 (3.0)
NR
34
26
8.2 (9)
15 (19)
1.8 (2.3)
6 (21)
93
103
7.9 (9)
10.7 (11)
27 (18)
79 (38)
3.4 (2.3)
7.4 (3.6)
56 (10)
84 (21)
33
33
26
10.6 (12)
9.5 (9)
106 (44)
132 (37)
10.0 (4.2)
13.8 (3.9)
204 (21)
177 (24)
31
12
7.4 (8)
44 (26)
5.9 (3.5)
NR
Young
women
Young
women,
men
Young
women,
men
Men
6 (6)
2.3
6 (1)
117 (30)
113 (36)
1.0 (6)b
Abs = absolute reduction; % = percentage (relative) reduction; VAT = visceral adipose tissue; ASAT = abdominal subcutaneous adipose
tissue; NR = not reported; VO = visceral obesity; SO = subcutaneous obesity.
a
Image obtained at L4-L5 unless otherwise indicated.
b
Volume (liters).
c
L3 level.
604
present there is limited evidence regarding the independent inuence of the two drugs currently approved for
obesity treatment in North America. We are unaware of
trials wherein the eects of orlistat, a pancreatic lipase
inhibitor, on VAT are considered. Preliminary evidence
suggests that the serotonin reuptake inhibitor sibutramine is associated with marked reduction of VAT
(f22%) in response to a 6-month trial (205). However,
in that trial the subjects received sibutramine in conjunction with a hypocaloric diet and were encouraged
to exercise. Given the demonstrated importance of
visceral obesity in the development of metabolic risk,
further study to consider the independent eects of
pharmacotherapy on VAT is warranted.
IX
605
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
ACKNOWLEDGMENTS
14.
15.
16.
REFERENCES
1.
2.
17.
18.
606
19. Getty L, Panteleon AE, Mittelman SD, Dea MK,
Bergman RN. Rapid oscillations in omental lipolysis
are independent of changing insulin levels in vivo. J
Clin Invest 2000; 106(3):421430.
20. Masuzaki H, Paterson J, Shinyama H, Morton NM,
Mullins JJ, Seckl JR, Flier JS. A transgenic model of
viseral obesity and the metabolic syndrome. Science
2001; 294:21662170.
21. Montague CT, ORahilly S. The perils of portliness:
causes and consequences of visceral adiposity. Diabetes 2000; 49(6):883888.
22. Arner P. Regional dierences in protein production by
human adipose tissue. Biochem Soc Trans 2001; 29(Pt
2):7275.
23. Perusse L, Rice T, Chagnon YC, Despres JP, Lemieux
S, Roy S, Lacaille M, Ho- Kim MA, Chagnon M,
Province MA, Rao DC, Bouchard C. A genome-wide
scan for abdominal fat assessed by computed tomography in the Quebec Family Study. Diabetes 2001;
50(3):614621.
24. Rossner S, Bo WJ, Hiltbrandt E, Hinson W, Karstaedt
N, Santago P, Sobol WT, Crouse JR. Adipose tissue
determinations in cadaversa comparison between
cross-sectional planimetry and computed tomography.
Int J Obes 1990; 14(10):893902.
25. Abate N, Burns D, Peshock RM, Garg A, Grundy
SM. Estimation of adipose tissue mass by magnetic
resonance imaging: validation against dissection in
human cadavers. J Lipid Res 1994; 35(8):14901496.
26. Matsuzawa Y, Shimomura I, Nakamura T, Keno Y,
Kotani K, Tokunaga K. Pathophysiology and pathogenesis of visceral fat obesity. Obes Res 1995; 3(suppl
2):187S194S.
27. Baumgartner RN, Heymseld SB, Roche AF,
Bernardino M. Abdominal composition quantied by
computed tomography. Am J Clin Nutr 1988; 48(4):
936945.
28. Kvist H, Sjostrom L, Tylen U. Adipose tissue volume
determinations in women by computed tomography:
technical considerations. Int J Obes 1986; 10(1):5367.
29. Rissanen J, Hudson R, Ross R. Visceral adiposity,
androgens, and plasma lipids in obese men. Metabolism 1994; 43(10):13181323.
30. Ross R, Rissanen J, Pedwell H, Cliord J, Shragge P.
Inuence of diet and exercise on skeletal muscle and
visceral adipose tissue in men. J Appl Physiol 1996;
81(6):24452455.
31. Ross R, Aru J, Freeman J, Hudson R, Janssen I.
Abdominal adiposity and insulin resistance in obese
men. Am J Physiol Endocrinol Metab 282:E657663.
32. Abate N, Garg A, Peshock RM, Stray-Gundersen J,
Grundy SM. Relationships of generalized and regional
adiposity to insulin sensitivity in men. J Clin Invest
1995; 96(1):8898.
33. Abate N, Garg A, Peshock RM, Stray-Gundersen J,
Adams-Huet B, Grundy SM. Relationship of general-
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
607
59.
608
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
609
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
610
sistance by reducing visceral fat and increasing muscle
mass in obese type 2 diabetic patients. Int J Obes Relat
Metab Disord 2001; 25(8):11011107.
121. Johannsson G, Marin P, Lonn L, Ottosson M, Stenlof
K, Bjorntorp P, Sjostrom L, Bengtsson BA. Growth
hormone treatment of abdominally obese men reduces
abdominal fat mass, improves glucose and lipoprotein
metabolism, and reduces diastolic blood pressure. J
Clin Endocrinol Metab 1997; 82(3):727734.
122. Ottosson M, Vikman-Adolfsson K, Enerback S,
Olivecrona G, Bjorntorp P. The eects of cortisol on
the regulation of lipoprotein lipase activity in human
adipose tissue. J Clin Endocrinol Metab 1994; 79(3):
820825.
123. Lonn L, Kvist H, Ernest I, Sjostrom L. Changes in
body composition and adipose tissue distribution after
treatment of women with Cushings syndrome. Metabolism 1994; 43(12):15171522.
124. Joyner JM, Hutley LJ, Cameron DP. Glucocorticoid
receptors in human preadipocytes: regional and gender
dierences. J Endocrinol 2000; 166(1):145152.
125. Miller LK, Kral JG, Strain GW, Zumo B. Dierential binding of dexamethasone to ammonium sulfate
precipitates of human adipose tissue cytosols. Steroids
1987; 49(6):507522.
126. Rebue-Scrive M, Lundholm K, Bjorntorp P. Glucocorticoid hormone binding to human adipose tissue.
Eur J Clin Invest 1985; 15(5):267271.
127. Sjogren J, Weck M, Nilsson A, Ottosson M, Bjorntorp
P. Glucocorticoid hormone binding to rat adipocytes.
Biochim Biophys Acta 1994; 1224(1):1721.
128. Russell CD, Petersen RN, Rao SP, Ricci MR, Prasad
A, Zhang Y, Brolin RE, Fried SK. Leptin expression
in adipose tissue from obese humans: depot-specic
regulation by insulin and dexamethasone. Am J Physiol 1998; 275(3 Pt 1):E507E515.
129. Bujalska IJ, Kumar S, Stewart PM. Does central
obesity reect Cushings disease of the omentum?
Lancet 1997; 349(9060):12101213.
130. Bujalska IJ, Kumar S, Hewison M, Stewart PM.
Dierentiation of adipose stromal cells: the roles of
glucocorticoids and 11beta-hydroxysteroid dehydrogenase. Endocrinology 1999; 140(7):31883196.
131. Katzmarzyk PT, Malina RM, Perusse L, Rice T,
Province MA, Rao DC, Bouchard C. Familial resemblance in fatness and fat distribution. Am J Human Biol 2000; 12(3):395404.
132. Rosmond R, Chagnon M, Bouchard C, Bjorntorp P.
A missense mutation in the human melanocortin-4
receptor gene in relation to abdominal obesity and
salivary cortisol. Diabetologia 2001; 44(10):13351338.
133. Rosmond R, Chagnon YC, Chagnon M, Perusse L,
Bouchard C, Bjorntorp P. A polymorphism of the 5Vanking region of the glucocorticoid receptor gene
locus is associated with basal cortisol secretion in men.
Metabolism 2000; 49(9):11971199.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
611
160.
612
172.
183. Crandall DL, Busler DE, McHendry-Rinde B, Groeling TM, Kral JG. Autocrine regulation of human
preadipocyte migration by plasminogen activator inhibitor-1. J Clin Endocrinol Metab 2000; 85(7):2609
2614.
184. Schafer K, Fujisawa K, Konstantinides S, Loskuto
DJ. Disruption of the plasminogen activator inhibitor
1 gene reduces the adiposity and improves the metabolic prole of genetically obese and diabetic ob/ob
mice. FASEB J 2001; 15(10):18401842.
185. Garg A. Lipodystrophies. Am J Med 2000; 108(2):
143152.
186. Engelson ES, Kotler DP, Tan Y, Agin D, Wang J,
Pierson RN Jr, Heymseld SB. Fat distribution in
HIV-infected patients reporting truncal enlargement
quantied by whole-body magnetic resonance imaging. Am J Clin Nutr 1999; 69(6):11621169.
187. Esterbauer H, Krempler F, Oberkoer H, Patsch W.
The complement system: a pathway linking host defence and adipocyte biology. Eur J Clin Invest 1999;
29(8):653656.
188. Choy LN, Rosen BS, Spiegelman BM. Adipsin and
an endogenous pathway of complement from adipose
cells. J Biol Chem 1992; 267(18):1273612741.
189. Ross R, Fortier L, Hudson R. Separate associations
between visceral and subcutaneous adipose tissue distribution, insulin and glucose levels in obese women.
Diabetes Care 1996; 19(12):14041411.
190. Pare A, Dumont M, Lemieux I, Brochu M, Almeras
N, Lemieux S, Prudhomme D, Despres JP. Is the
relationship between adipose tissue and waist girth
altered by weight loss in obese men? Obes Res 2001;
9(9):526534.
191. Ross R, Janssen I. Is abdominal fat preferentially reduced in response to exercise-induced weight loss?
Med Sci Sports Exerc 1999; 31(11 suppl):S568S572.
192. Ross R, Janssen I, Stallknecht B. Inuence of endurance exercise on adipose tissue distribution. In:
Nicklas B,. Endurance Exercise and Adipose Tissue
Boca Raton, FL: CRC Press, 2001:122152.
193. Ross R, Janssen I. Physical activity, total and regional
obesity: dose-response considerations. Med Sci Sports
Exerc 2001; 33(6 suppl):S521S527.
194. Ross R, Dagnone D, Jones PJ, Smith H, Paddags
A, Hudson R, Janssen I. Reduction in obesity and
related comorbid conditions after diet-induced weight
loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann Intern Med 2000; 133(2):
92103.
195. Mourier A, Gautier JF, De Kerviler E, Bigard AX,
Villette JM, Garnier JP, Duvallet A, Guezennec CY,
Cathelineau G. Mobilization of visceral adipose tissue
related to the improvement in insulin sensitivity in response to physical training in NIDDM, Eects of
branched-chain amino acid supplements. Diabetes Care
1997; 20(3):385391.
613
208.
614
221.
23
Resting Energy Expenditure, Thermic Effect of Food, and Total
Energy Expenditure
Yves Schutz and Eric Jequier
University of Lausanne, Lausanne, Switzerland
Three main methods are used to measure energy expenditure in man: indirect calorimetry, direct calorimetry,
and the doubly labeled water technique. These methods
are based on dierent principles and do not measure the
same type of energy.
Indirect calorimetry is the best method to measure
resting energy expenditure, the thermic eect of food
and the energy expended for physical activity. It has the
great advantage of being relatively simple; it can be used
either with a ventilated hood system (for a resting
subject), or with a respiration chamber, when a 24-hr
measurement is needed. A rst advantage of indirect
calorimetry is the immediate response of oxygen consumption (measured by the method of respiratory gas
exchange) in relation with the real oxygen consumption
in the tissues and organs within the body. There is no
delay in measuring oxygen consumption because the
body has negligible O2 stores. A second advantage of
indirect calorimetry in comparison with other methods
is the possibility to assess nutrient oxidation rates, when
oxygen consumption, CO2 production, and urinary
nitrogen excretion are measured.
Direct calorimetry is the method of choice for studies
aiming at assessing thermoregulatory responses. The
615
616
.
.
Figure 1 Metabolic rate ( M),. total .heat losses ( H), radiative
and convective
heat losses ( R + C), and evaporative heat
.
losses ( E) in a male subject aged 25 years, exposed at 28jC in
a direct calorimeter. Note that after 30 min of temperature
.
.
equilibration within the calorimeter, the values of M and H
are similar, indicating that heat production is identical to
heat losses.
equilibrium of 2H2 18O in the water pool and equilibrium of 18O with carbon dioxide, 18O is lost both as
H218O and CO18O, whereas 2H is lost only as 2H2 O.
The dierence in the rate of turnover of H218O and
2
H2O is an estimate of CO2 production rate. In order
to calculate the subjects energy expenditure, the mean
respiratory quotient (RQ) must be known.
Energy
.
expenditure is obtained by multiplying VCO2 by the
energy equivalent of CO2 production. The latter varies
from 21.0 to 27.7 kJ/L CO2 at respiratory quotients of
1.00.7, respectively. The disappearance rates of the
isotopes can be measured in urine, blood or saliva, for
a period equivalent to two to three biologic half-lives.
This corresponds to f14 days in adult subjects. Thus,
the method provides a mean value of energy expenditure for a 2-week period. It is not possible to calculate
the day-to-day variation in energy expenditure with
the doubly labeled water technique.
Several validation studies in both infants and adults
have. consistently shown a good agreement between
the VCO2 determined by the doubly labeled water and
that assessed by indirect calorimetry. Issues have been
raised in regard to the question of two-point versus
multiple points isotopic sampling, the extent of the
fractionation of the isotopes, the dierence between
the oxygen and hydrogen dilution space, as well as the
inherent precision of the analysis by mass spectrome-
Energy Expenditure
617
.
oxygen consumption ( VO2). The main reason for
. the
close relation between energy metabolism and VO2 is
that the oxidative phosphorylation in the respiratory
chain is coupled with a continuous synthesis of adenosine triphosphate (ATP). The energy expended within
the body to maintain electrochemical gradients, to
support biosynthetic processes, and to generate muscular contractions cannot be directly provided by
nutrient oxidation. Almost all chemical processes
requiring energy depend on ATP hydrolysis. It is the
rate of ATP utilization that determines the
. overall rate
of substrate oxidation and therefore VO2. With the
exception of anaerobic glycolysis, ATP synthesis is
coupled with substrate oxidation.
Because there is a
.
proportionality between VO2 and ATP synthesis, and
because each mole of ATP synthesized is accompanied
by the production of a given amount
of heat, one
.
understands the rationale of using VO2 measurement
to calculate heat production within the body (7).
The study of the regulation of energy metabolism
and nutrient utilization in humans has recently raised
a great interest thanks to advances in the construction
of open-circuit ventilated hood indirect calorimeters
and comfortable respiration chambers.
.
With the measurement of VO2 (in liters of O2/min) at
STPD conditions [standard temperature (OjC), pressure (760 mmHg), and gas dry], metabolic rate (M),
which corresponds to heat production, can be calculated (in kJ/min) as follows:
:
M 20:3 VO2
1
The number 20.3 is a mean value (in kJ/L) of the
energy equivalent for the consumption of 1 L (STPD)
Table 1 Oxygen Consumed, CO2 Produced, and Heat Released from Oxidation of Nutrients
Nutrients
Starch
Saccharose
Glucose
Lipid
Protein
Lactic acid
a
Heat released
(per gram)
O2
consumeda
CO2
produceda
RQ
kJ/g
kcal/g
kJ/L
kcal/L
kJ/L
kcal/L
0.829
0.786
0.746
2.019
1.010
0.746
0.829
0.786
0.746
1.427
0.844
0.746
1.00
1.00
1.00
0.71
0.83
1.00
17.6
16.6
15.6
39.6
19.7
15.1
4.20
3.96
3.74
9.46
4.70
3.62
21.2
21.1
21.0
19.6
19.5
20.3
5.06
5.04
5.01
4.69
4.66
4.85
21.2
21.1
21.0
27.7
23.3
20.3
5.06
5.04
5.01
6.63
5.58
4.85
618
Other metabolic processes (such as lipogenesis, gluconeogenesis, and ketogenesis) may inuence the
calculated oxidation rates of nutrients. However,
intermediate metabolic processes do not inuence
the results of Eqs. (6) and (7), provided intermediate
substrates do not accumulate within the body or are
not excreted from the body. When there is accumulation or excretion of an intermediate or end product
other than CO2 and H2O, this approach to compute
the oxidation rates of nutrients is no longer valid, and
correction factors must be applied to take into
account the changes in the pool size of the intermediates or end products.
II
Table 2 Contribution of Dierent Organs and Tissues to Total Body Weight and Basal Metabolic Rate (BMR) in an
Average Man of 70 kg with a BMR of 1680 kcal/day (7.03 MJ/day)
Tissue or organ Contribution of tissue or organ Organ metabolic rate per unit Contribution to BMR
weight (kg)
weight to body weight (%)
weight (kcal/kg/day)
(% total)
Liver
Brain
Heart
Kidneys
Muscle
Adipose tissue
D = miscellaneous
tissues (bones,
skin, intestines,
lungs, etc.)
1.8
1.4
0.33
0.31
28.0
15.0
23.2
Total
70.00
2.6
2.0
0.5
0.4
40.0
21.4
33.1
100
200
240
440
440
13
4.5
12
21
20
9
8
22
4
16
24
100
Energy Expenditure
The excess body weight of the obese is primarily constituted by fat tissue, but also a small component of
associated lean tissue. Although the exact nature of
extra lean tissue in obesity is largely unknown, it seems
logical to expect a greater absolute RMR in obese adults
(13) and children (14) characterized by an excess fat
mass and a slight increase in fat-free mass (FFM).
Numerous studies have demonstrated that the major
factor explaining the variation in RMR between individuals is FFM (15). FFM is a heterogeneous component that can be partitioned into muscle mass and
nonmuscle mass. Unfortunately, there is no simple
and accurate way to assess these two subcomponents.
Owing to the larger variation, between individuals, in
fat mass, as compared to FFM, and because, in grossly
obese women, fat mass can represent a nonnegligible
component of total RMR, the prediction models for
RMR that include both FFM and fat mass explain
signicantly more variance in RMR than FFM alone
(15). In addition, age, sex, and family membership are
additional factors which should be taken into account.
The eects of gender on resting metabolic rate are
explained by dierences in body composition. Caution
should be used when comparing resting metabolic rate
expressed per kilogram FFM in men and women,
because the composition of FFM is inuenced by
gender. The muscle mass of men being larger than that
of women, this fact tends to lower the value of RMR per
kilogram FFM in men when compared to that of
women. This is explained by a greater component of a
tissue with a low metabolic rate (resting muscle) in men
than in women (Table 2). According to recent data
(16,17), women have a lower RMR than men (310%)
even after adjustment for FFM, fat mass, age, and
VO2max. Various mechanisms could explain this obser-
619
620
Hormonal Factors
Energy Expenditure
621
III
622
Energy Expenditure
623
624
physical activity and the degree of obesity would indicate that the greater absolute cost of physical activity
among obese subjects is largely oset by the depressed
activity level. A study by Rising et al. (103) has shown
that obesity was associated with lower levels of physical
activity. The key question is to know whether a low level
of physical activity is the consequence or the cause of
obesity, or both.
Normalization of total energy expenditure in the
obese appears to be dicult since the RMR is proportional to FFM (and fat mass) whereas the energy
expenditure related physical activity is proportional
to body weight. Although there is a statistical bias in
normalizing the TEE by RMR (104), it seems to be a
reasonable way (as compared to other alternatives) to
express as such the free-living energy expenditure. The
fact that both the absolute RMR and the energy cost
for a given activity are greater in the obese explain why
the TEE expressed in relative value (TEE/RMR) is not
expected to be dramatically dierent from that
observed in a nonobese subject. In this context, it
seems of interest to review the magnitude of the ratio
TEE/RMR in nonobese and obese adult subjects.
Table 3 shows an overview of dierent experimental
studies recently published in the literature (105112).
Globally considered, there is no strong evidence that
the ratio TEE/RMR is systematically lower in obese
individuals than in lean subjects, although the variations among and within studies was substantial (Table
3). This conrms our previous results in the respiration
chamber (13).
Compilations of total daily energy expenditure
results (using a meta-analysis approach) in individuals
of various body weight and gender have been made by
Schulz and Schoeller (113) and Carpenter et al. (104). In
all these studies, energy expenditure was assessed by the
doubly labeled water technique. In the former study
(113), it was found that the increased weight of men (but
not of women) was associated with a tendency for the
TEE/RMR ratio to be lower, corroborating the notion
that obesity tends to depress physical activity in obese
men. This tendency was conrmed in a subsequent
meta-analysis by Prentice et al. (109).
Because of the increase in prevalence and incidence
of childhood obesity, it seems also important to study
the energy metabolism in children as they grow
through puberty in order to initiate early therapeutic
intervention and prevent subsequent obesity in adults.
Blunted physical activity due to a greater placidity and
sedentary life-style are associated with low TEE (114
116). A classic study by Dietz et al. (117) has shown
that the amount of time dedicated to watch television
Energy Expenditure
625
Table 3 Total Energy Expenditure (TEE) Expressed as a Multiple of Resting Metabolic Rate (RMR) in Obese and
Nonobese Subjects (Physical Activity Level; PAL)
Obese individuals
American women
American women
British women
Pima Indian
Average overweight men (BMI 2530)
Average overweight women (BMI 2530)
Average moderately obese men (BMI 3035)
Average moderately obese women (BMI 3035)
Average obese men (BMI z 35)
Average obese women (BMI z 35)
Nonobese individuals
American men
American men
British men
Dutch men
Average men (auent society)
Average women (auent society)
Authors
Ref.
TEE/RMR
105
106
107
108
109
109
109
109
109
109
1.68
1.73
1.39
1.56
1.86
1.73
1.82
1.73
1.52
1.65
110
111
107
112
109
109
1.70
1.98
1.88
1.64
1.80
1.67
When signicant weight loss occurs, energy expenditure decreases, whereas weight gain leads to a rise in
energy expenditure. This will depend on the respective
eect of the individual factors inuencing the three
components of TEE: resting energy expenditure will
decrease as a function of the loss of FFM; the absolute thermic eect of food will be lower as a result
of the restricted dietary intake; and, for a given rate
of physical activity, the absolute energy expenditure
due to physical activity will drop because of the lower
body size. In a prospective study of weight loss and
relapse in body weight gain, we found that the rate
of TEE and RMR essentially followed the change in
body weight and body composition. The progressively
reduced (or increased) energy expenditure accompanying weight loss (or weight gain) constitutes one of the
major factors that explain the decrease in the rate of
weight loss (or weight gain) with time. Another factor is
the change in dietary compliance during dieting, which
seems to be an individual characteristic.
Finally, it should be recalled that the compensatory
energetic processes mentioned above tend to jeopardize
the persistence of the altered body weight in obese
626
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Energy Expenditure
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
627
ship between circulating leptin and energy expenditure
in adult men and women aged 18 years to 81 years.
Obes Res 1997; 5:459463.
49. Kennedy A, Gettys TW, Watson P, et al. The
metabolic signicance of leptin in humans: genderbased dierences in relationship to adiposity, insulin
sensitivity, and energy expenditure. J Clin Endocrinol
Metab 1997; 82:12931300.
50. Campostano A, Grillo G, Bessarione D, De Grandi R,
Adami GF. Relationships of serum leptin to body
composition and resting energy expenditure. Horm
Metab Res 1998; 30:646647.
51. Jorgensen JO, Vahl N, Dall R, Christiansen JS.
Resting metabolic rate in healthy adults: relation to
growth hormone status and leptin levels. Metabolism
1998; 47:11341139.
52. Neuhauser-Berthold M, Herbert BM, Luhrmann PM,
et al. Resting metabolic rate, body composition, and
serum leptin concentrations in a free-living elderly
population. Eur J Endocrinol 2000; 142:486492.
53. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz
WI. Receptor-mediated regional sympathetic nerve
activation by leptin. J Clin Invest 1997; 100:270278.
54. Reed GW, Hill JO. Measuring the thermic eect of
food. Am J Clin Nutr 1996; 63:164169.
55. Tappy L, Jequier E. Fructose and dietary thermogenesis. Am J Clin Nutr 1993; 58(suppl):766S770S.
56. Suter PM, Jequier E, Schutz Y. Eect of ethanol on
energy expenditure. Am J Physiol 1994; 266:R1204
R1212.
57. Thiebaud D, Acheson K, Schutz Y, et al. Stimulation
of thermogenesis in men after combined glucose longchain triglyceride infusion. Am J Clin Nutr 1983; 37:
603611.
58. Golay A, Schutz Y, Broquet C, Moeri R, Felber JP,
Jequier E. Decreased thermogenic response to an oral
glucose load in older subjects. J Am Geriatr Soc 1983;
31:144148.
59. Bloesch D, Schutz Y, Breitenstein E, Jequier E, Felber
JP. Thermogenic response to an oral glucose load in
man: comparison between young and elderly subjects.
J Am Coll Nutr 1988; 7:471483.
60. Tai MM, Castillo TP, Pi-Sunyer FX. Thermic eect of
food during each phase of the menstrual cycle. Am J
Clin Nutr 1997; 66:11101115.
61. Melanson KJ, Saltzman E, Russell R, Roberts SB.
Postabsorptive and postprandial energy expenditure
and substrate oxidation do not change during the
menstrual cycle in young women. J Nutr 1996; 126:
25312538.
62. Jequier E, Schutz Y. Energy expenditure in obesity
and diabetes. Diabetes Metab Rev 1988; 4:583593.
63. De Jonge L, Bray GA. The thermic eect of food and
obesity: a critical review. Obes Res 1997; 5:622631.
64. Bracco D, Ferrarra JM, Arnaud MJ, Jequier E, Schutz
Y. Eects of caeine on energy metabolism, heart rate,
628
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
Energy Expenditure
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
eects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood
ow in humans. J Clin Invest 1993; 92:147154.
Acheson KJ, Jequier E, Wahren J. Inuence of hadrenergic blockade on glucose-induced thermogenesis
in man. J Clin Invest 1983; 72:981986.
Tappy L, Girardet K, Schwaller N, et al. Metabolic
eects of an increase of sympathetic activity in healthy
humans. Int J Obes 1995; 19:419422.
Berthoud HR, Bereiter DA, Trimble ER, Siegel EG,
Jeanrenaud B. Cephalic phase, reex insulin secretion.
Neuroanatomical and physiological characterization.
Diabetologia 1981; 20:393401.
Nacht C, Christin L, Temler E, Chiolero R, Jequier E,
Acheson K. Thermic eect of food: possible implication of parasympathetic nervous system. Am J Physiol
1987; 253:E481E488.
Prentice AM, Black AE, Coward WA, et al. High
levels of energy expenditure in obese women. BMJ
1986; 292:983987.
Schutz Y, Jequier E. Energy needs: assessment and
requirements. In: Shils ME, Olson JA, Shike M, eds.
Modern Nutrition in Health and Disease. Philadelphia: Lea & Febiger, 1994:101111.
Schutz Y. Role de lactivite physique dans letiologie
de lobesite. Rev Ther 1989; 5:281290.
Rising R, Harper IT, Fontvielle AM, Ferraro RT,
Spraul M, Ravussin E. Determinants of total daily
energy expenditure: variability in physical activity. Am
J Clin Nutr 1994; 59:800804.
Carpenter WH, Poehlman ET, OConnell M, Goran
MI. Inuence of body composition and resting
metabolic rate on variation in total energy expenditure: a meta-analysis. Am J Clin Nutr 1995; 61:410.
Lichtman SW, Pisarska K, Raynes Berman E, et al.
Discrepancy between self-reported and actual caloric
intake and exercise in obese subjects. N Engl J Med
1992; 327:18931898.
Welle S, Forbes GB, Statt M, Barnard RR, Amatruda
JM. Energy expenditure under free-living conditions in
normal weight and overweight women. Am J Clin
Nutr 1992; 55:1421.
Livingstone MBE, Prentice AM, Strain JJ, et al.
Accuracy of weighted dietary records in studies of diet
and health. BMJ 1990; 300:708712.
Ravussin E, Harper IT, Rising R, Bogardus C. Energy
expenditure by doubly labeled water: validation in lean
and obese subjects. Am J Physiol 1991; 261:E402E409.
Prentice AM, Black AE, Coward WA, Cole TJ. Energy
expenditure in overweight and obese adults in auent
societies: an analysis of 319 doubly-labelled water
measurements. Eur J Clin Nutr 1996; 50:9397.
629
110.
24
Energy Expenditure in Physical Activity
James O. Hill
University of Colorado Health Sciences Center, Denver, Colorado, U.S.A.
W. H. M. Saris
University of Maastricht, Maastricht, The Netherlands
James A. Levine
Mayo Clinic, Rochester, Minnesota, U.S.A.
I
A
There are three principal components to energy expenditure in humans: basal metabolic rate, thermic eect of
food, and the energy expenditure of physical activity
(activity thermogenesis). Basal metabolic rate is the
energy expended when an individual is lying at complete
rest, in the morning, after sleep, in the postabsorptive
state. In individuals with sedentary occupations basal
metabolic rate accounts for f60% of total daily energy
expenditure. About 75% of the variability in basal
metabolic rate is predicted by lean body mass within
and across species (1,2). Resting energy expenditure, in
general, is within 10% of basal metabolic rate and is
measured in subjects at complete rest in the postabsorptive state. The second component of energy expenditure
is the thermic eect of food (36). This is the increase in
energy expenditure associated with the digestion,
absorption, and storage of food and accounts for
f10% of total daily energy expenditure; many believe
there to be facultative (adaptive) as well as xed components. The third component of energy expenditure is
632
Hill et al.
II
METHODOLOGY
Nonspecic information about habitual and occupational activity can be obtained using questionnaires,
interviews, or time-and-motion studies. Predictably,
substantial errors are introduced through inaccurate
recall and inadequate data recording. These approaches
can be used, however, for following trends in certain
activities, particularly with relation to occupational
practices (18).
2
Kinematic Measurements
633
634
Hill et al.
This is a frequently used approach for estimating activity thermogenesis in free-living individuals. First, a
subjects physical activities are logged over the time
period of interest (e.g., 1 week). The energy equivalent
of each of these activities is measured or estimated using
a calorimeter or tables, respectively (39,43,44). The time
spent in each activity is then multiplied by the energy
equivalent for that activity. These values are then
summed to derive an estimate of activity thermogenesis.
Errors for the factoral method may rst result from
inaccurate recording of activities and, secondly, from
inaccurate determinations of the energy costs of the
activities. To log activity, subjects are often asked to
record in a diary the nature and amount of time spent
performing each of their activities throughout the day
(47). This has several limitations: subjects may be
illiterate or anumerate, may report their activities inaccurately or incompletely, and/or may alter their normal
activity patterns during periods of assessment. To limit
these sources of error, one approach is to have trained
enumerators follow subjects and objectively record the
subjects activities (18). This is time-consuming and
expensive but potentially a valuable source of accurate
and objective data.
Newer image gathering technologies may be useful in
the future for this purpose. To determine the energy
costs of physical activities, standard tables are often
used. However, these may introduce substantial (albeit
systematic) errors. First, the tables may not include the
precise activity the subject performed. Second, the
energy cost for a given activity is highly variable between subjects even independent of gender. Third, calorimeter methods for measuring the energy costs of
activities have not been standardized between investigators so that precision and accuracy of data in the
activity tables cannot always be assured.
To limit these errors, the energy costs of each or most
of the activities that the subjects of interest perform can
be measured using calorimeters, as described above. At
best, the energy costs for each subjects activities would
be measured but clearly this is rarely practical except for
small studies. In general, population-, gender-, agespecic group means for the majority of the studied
subjects activities represents a standard that is worth
achieving where optimum precision is warranted.
2
635
It is thereby possible to measure activity thermogenesis. No approach is ideal, but these available technologies readily enable hypotheses to be addressed
regarding activity thermogenesis and its role in energy
balance in free-living individuals.
CO2 H2 O X H2 CO3
Thus, if the O2 in body water is tagged with the
tracer O18, the label will distribute not only in body
water but also in circulating H2CO3 and in expired
CO2. Over time the concentration of the O2 label in
body water will decrease as CO2 is expired and body
water is lost in urine, perspiration, and respiration. If
the H2 in body water is tagged with the tracer D2, the
label will distribute solely in the circulating H2O and
H2CO3. Over time, the concentration of the H2 label
will decrease, as body water is lost (some of the
hydrogen can become partitioned into body protein
or fat, however). Thus, if both the O2 and H2 in body
water are tagged, with known amounts of tracers at
the same time, the dierences in the elimination rates
of the O2 and H2 tracers will represent the elimination rate of CO2.
Subjects are usually given DLW orally after baseline samples of urine, saliva, or blood have been
collected. Time is allowed for complete mixing of
isotopes to occur within the body water space and
then samples of urine, saliva, or blood are collected
over 721 days. These samples are used for measurements of D2 and O18 enrichments using mass spectroscopy. Changes in D2 and O18 concentrations in body
water are then calculated over time, and CO2 production and energy expenditure are calculated. Energy
expenditure can be measured over 721 days using this
technique with an error of f68% (52). This error can
be decreased to a small degree, by collecting samples
repeatedly over the measurement period rather than by
collecting samples only before and after the measurement period.
Doubly labeled water allows total energy expenditure to be measured to within f68% of actual. Basal
metabolic rate can be measured to within 1% of actual,
so the cumulative error for measurements of PAL is
f7%. This is impressive considering the measurements
are performed in completely free-living individuals. A
major limitation of this approach is, however, that no
information is gleaned regarding the components of
physical activity and how these contribute relative to
others. It can thus be dicult to discriminate the
impact of exercise from nonexercise or to ascertain the
importance of the dierent components of nonexercise
activity thermogenesis (NEAT).
III
636
Hill et al.
637
IV
638
Hill et al.
639
Work eciency may vary with age. For example, Villagra et al. (108) demonstrated that children are f10%
more energy ecient during squatting exercises than
adults. There is little information available to evaluate
the eects of aging in adults on work eciency. Skeletal
muscle mass is often lost as a subject ages, and if the loss
involves a greater proportion of type I than type II
bers, work eciency could increase with age.
6
If work eciency varies as a function of exercise training, training induced eects in skeletal muscle could be
important. Alterations in physical activity can alter the
640
Hill et al.
Substrate utilized
Endogenous glycogen (anaerobic)
Endogenous glycogen (aerobic)
Bloodborne glucose (aerobic)
Bloodborne fatty acids (aerobic)
Max. rate of
formation HEP
Mol HEP.min-1
2.4
1.0
0.37
0.40
Rate of utilization
0.07
0.3
2.6
2.0
1.7
1.0
Exercise Intensity
641
Exercise Duration
642
Hill et al.
Training Status
Gender
643
Age
Body Composition
VII
644
Hill et al.
contributing to weight gain. Unfortunately, populationbased records of food intake are not very accurate, and
physical-activity data (especially lifestyle or nonleisure
physical activity) have not been systematically recorded.
It is interesting to note that national household surveys
of several dierent countries show a decrease in energy
intake over time. For example, in Great Britain, energy
intake decreased by more than 500 kcal from 1970 to
1990 (177). During the same time, however, body mass
index and average body weight increased by 1.0 BMI
unit and 2.5 kg, respectively. These gures would imply that energy expenditure must have declined by
even >500 kcal. The problem is, we do not have any
data to show whether this might be the case other than
anecdotal information on the number of automobiles
and occupational mechanization. While denitive data
may be lacking, in this section we will examine the
available data suggesting a causal link between physical
activity and obesity.
A
Epidemiological studies have consistently shown a negative relationship between measures of physical activity
(usually self-reports) and indices of obesity (usually
body mass index) (178). This relationship is present in
most datasets obtained from the general U.S. population (179,180). The relationship appears to be similar in
men and women, and across all ages (181184). Further,
there is evidence for a similar relationship in AfricanAmericans (185), Hispanics (186), and Native Americans (187). This inverse relationship between BMI and
physical activity has been seen using both self-reports of
amount of physical activity (180) and actual energy
expended in physical activity assessed from doubly
labeled water measures (188,189).
Given that there is a negative relationship between
obesity and physical activity and given that obesity is
increasing dramatically in the population, can we attribute some of this weight gain to reduced energy expenditure due to declines in energy expended in physical
activity, and can we reduce this weight gain with eorts
to promote physical activity?
B
645
646
Hill et al.
While denitive randomized controlled studies showing that increasing physical activity can prevent weight
gain are lacking, substantial indirect evidence suggests
that increasing physical activity is likely to be one of
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
647
26.
Westerterp KR, Bouten CV. Physical activity assessment: comparison between movement registration and
doubly labeled water method. Ernahrungswiss Z 1997;
36:263267.
27. Levine JA, Baukol PA, Westerterp KR. Validation of
the Tracmor triaxial accelerometer system for walking.
Med Sci Sports Exerc 2001; 33:15931597.
28. Bouten CV, VerboeketVan de Venne WP, Westerterp
KR, Verduin M, Janssen JD. Daily physical activity
assessment: comparison between movement registration and doubly labeled water. J Appl Physiol 1996;
81:10191026.
29. Cunningham JJ. Calculation of energy expenditure
from indirect calorimetry: assessment of the Weir
equation. Nutrition 1990; 6:222223.
30. Weir JB. New methods for calculating metabolic rate
with special reference to protein metabolism. Nutrition
1949; 6:213221.
31. Jequier E, Felber JP. Indirect calorimetry. Baillieres
Clin Endocrinol Metab 1987; 1:911935.
32. Sun M, Reed GW, Hill JO. Modication of a whole
room indirect calorimeter for measurement of rapid
changes in energy expenditure. J Appl Physiol 1994;
76:26862691.
33. Levine JA, Schleusner SJ, Jensen MD. Energy
expenditure of nonexercise activity. Am J Clin Nutr
2000; 72:14511454.
34. Lum L, Saville A, Venkataraman ST. Accuracy of
physiologic deadspace measurement in intubated pediatric patients using a metabolic monitor: comparison
with the Douglas bag method. Crit Care Med 1998;
26:760764.
35. De Groot G, Schreurs AW, Van Ingen Schenau GJ. A
portable lightweight Douglas bag instrument for use
during various types of exercise. Int J Sports Med
1983; 4:132134.
36. Yoshida T, Nagata A, Muro M, Takevchi N, Suda Y.
The validity of anaerobic threshold determination by a
Douglas bag method compared with arterial blood
lactate concentration. Eur J Appl Physiol Occup Physiol
1981; 46:423430.
37. Douglas CG. A method for determining the total
respiratory exchange in man. J Physiol 1911; 42:1718.
38. Daniels J. Portable respiratory gas collection equipment. J Appl Physiol 1971; 31:164167.
39. Sujatha T, Shatrugna V, Venkataramana Y, Begom N.
Energy expenditure on household, childcare and
occupational activities of women from urban poor
households. Br J Nutr 2000; 83:497503.
40. Consolazio CF. Energy expenditure studies in military
populations using Kofranyi-Michaelis respirometers.
Am J Clin Nutr 1971; 24:14311437.
41. Rietjens GJ, Kuipers H, Kester AD, Keizer HA.
Validation of a computerized metabolic measurement
system (Oxycon-Pro) during low and high intensity
exercise. Int J Sports Med 2001; 22:291294.
648
42. McLaughlin JE, King GE, Howley ET, Bassett DR,
Ainsworth BE. Validation of the COSMED K4 b2
portable metabolic system. Int J Sports Med 2001;
22:8084.
43. Morio B, Beaufrere B, Montaurier C, Ritz P, Fellmann N, Boirie Y, Vermorel M. Gender dierences in
energy expended during activities and in daily energy
expenditure of elderly people. Am J Physiol 1997;
273:E321E327.
44. Banerjee B, Khew KS, Saha N. A comparative study
of energy expenditure in some common daily activities
of non-pregnant and pregnant Chinese, Malay and
Indian women. J Obstet Gynaecol Br Commonw 1971;
78:113116.
45. Black AE, Coward WA, Cole TJ, Prentice AM.
Human energy expenditure in auent societies: an
analysis of 574 doubly-labelled water measurements.
Eur J Clin Nutr 1996; 50:7292.
46. Prentice AM, Goldberg GR, Murgatroyd PR, Cole
TJ. Physical activity and obesity: problems in correcting expenditure for body size. Int J Obes 1996; 20:688
691.
47. Ferro-Luzzi A, Scaccini C, Taese S, Aberra B,
Demeke T. Seasonal energy deciency in Ethiopian
rural women. Eur J Clin Nutr 1990; 44(suppl 1):718.
48. Coward WA, Roberts SB, Cole TJ. Theoretical and
practical considerations in the doubly-labelled water
(2H2O18) method for the measurement of carbon
dioxide production rate in man. Eur J Clin Nutr 1988;
42:207212.
49. Coward WA. Contributions of the doubly labeled
water method to studies of energy balance in the third
world. Am J Clin Nutr 1998; 68:962S969S.
50. Goran MI, Poehlman ET, Nair KS, Danforth E.
Deuterium exchange in humans: eect of gender,
body composition and age. Basic Life Sci 1993; 60:
7981.
51. Kurpad AV, Borgonha S, Shetty PS. Measurement of
total energy expenditure by the doubly labelled water
technique in free living Indians in Bangalore city.
Indian J Med Res 1997; 105:212219.
52. Schoeller DA, Taylor PB. Precision of the doubly
labelled water method using the two-point calculation.
Hum Nutr Clin Nutr 1987; 41:215223.
53. National Health Interview Survey Electronic citation.
http://www.cdc.gov/nchs/nhishtm
54. Mokdad AH, Bowman BA, Ford ES, Vinicor F,
Marks JS, Loplan JP. The continuing epidemic of obesity and diabetes in the United States. JAMA 2001;
286(10):11951200.
55. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson
CL. Increasing prevalence of overweight among US
adults. JAMA 1994; 272:205211.
56. Levine JA, Weisell R, Chevassus S, Martinez CD,
Burlingam B, Coward WA. The work burden of women.
Science 2001; 294:812.
Hill et al.
57. Davey Smith G, Shipley MJ, Batty GD, Morris JN,
Marmot M. Physical activity and cause-specic mortality in the Whitehall study. Public Health 2000; 114:
308315.
58. Chave SP, Morris JN, Moss S, Semmence AM.
Vigorous exercise in leisure time and the death rate:
a study of male civil servants. J Epidemiol Commun
Health 1978; 32:239243.
59. Shetty PS, Henry CJ, Black AE, Prentice AM. Energy
requirements of adults: an update on basal metabolic
rates (BMRs) and physical activity levels (PALs). Eur
J Clin Nutr 1996; 50(suppl 1):S11S23.
60. Bouchard C, Deriaz O, Perusse L, Tremblay A.
Genetics of energy expenditure in humans. In: Bouchard C, ed. The Genetics of Obesity. Boca Raton:
CRC Press, 1994:135146.
61. Kaprio J, Koskenvuo M, Sarna S. Cigarette smoking,
use of alcohol, and leisure-time physical activity
among same sexed adult male twins. Prog Clin Biol
Res 1981; 69:3746.
62. Perusse L, Tremblay A, Leblanc C, Bouchard C.
Genetic and environmental inuences on level of
habitual physical activity and exercise participation.
Am J Epidiol 1989; 129:10121022.
63. Stephens T, Caspersen CJ. The demography of
physical activity. In: Bouchard C, Shephard RJ,
Stephens T, eds. Physical Activity, Fitness, and Health.
Champaign, IL: Human Kinetics Publishers, 1994:
203213.
64. Activity and Health Research. Allied Dunbar National Fitness Survey: Main Findings. London: Sports
Council and the Health Education Authority, 1992.
65. Caspersen CJ, Merritt RK. Trends in physical activity
patterns among older adults: the behavioral risk factor
surveillance system, 19861990. Med Sci Sports Exerc
1992; 24:S26.
66. Merritt RK, Caspersen CJ. Trends in physical activity
patterns among young adults: the behavioral risk
factor surveillance system, 19861990. Med Sci Sports
Exerc 1992; 24:S26.
67. Stephens T, Craig CL. The Well-Being of Canadians:
Highlights of the 1988 Campbells Survey. Ottawa: Canadian Fitness and Lifestyle Research Institute, 1990.
68. Risk Factor Prevalence Study Management Committee Risk Factor Prevalence Study: Survey No 3 1989.
Canberra: National Heart Foundation of Australia
and Australian Institute of Health, 1990.
69. Saris WHM, Elvers JWH, Vant Hof M, Binkhorst
RA. Changes in physical activity proles of children
aged 6 to 12 years. In: Rutenfranz J, ed. Children and
Exercise XII. Champaign, Il: Human Kinetics, 1986:
121130.
70. Matsushima M, Kriska A, Tajima N, LaPorte R. The
epidemiology of physical activity and childhood
obesity. Diabetes Res Clin Pract 1990; 10(suppl 1):
S95S102.
649
88.
650
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
Hill et al.
Bogardus C, Ravussin E. Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of
24-h RQ. Am J Physiol 1990; 259:E650E657.
Zurlo F, Nemeth PM, Choksi RM, Sesodia S, Ravussin E. Whole-body energy metabolism and skeletal
muscle biochemical characteristics. Metabolism 1994;
43:481486.
Blaak EE, Van Baak MA, Kemerink GJ, Pakbiers
MTW, Herdendal GAR, Saris WHM. h-Adrenergic
stimulation of energy expenditure and forearm skeletal
muscle metabolism in lean and obese men. Am J
Physiol 1994; 267:E316E322.
Chang S, Graham B, Yakubu F, Lin D, Peters JC, Hill
JO. Metabolic dierences between obesity-prone and
obesity-resistant rats. Am J Physiol 1990; 259:R1103
R1110.
Bouchard C, Tremblay A, Nadeau A, Despres JP,
Theriault G, Boulay MR, Lortie G, Leblanc C, Fournier G. Genetic eect in resting and exercise metabolic
rates. Metabolism 1989; 38:364370.
Villagra F, Cooke CB, McDonagh MJN. Metabolic
cost and eciency in two forms of squatting exercise in
children and adults. Eur J Appl Physiol 1993; 67:549
553.
Sharp TA, Reed GW, Sun M, Abumrad NN, Hill JO.
Relationship between aerobic tness level and daily
energy expenditure in weight-stable humans. Am J
Physiol 1992; 263:E121E128.
Costill DL. Inside Running: Basics of Sport Physiology. Indianapolis: Benchmark Press, 1986.
Holmer I. Physiology of swimming man. Acta Physiol
Scand 1974; 407:155.
Mulligan K, Buttereld GE. Discrepancies between
energy intake and expenditure in physically active
women. Br J Nutr 1990; 64:2336.
Dahlstrom M, Jansson E, Nordevang E, Kaijser L.
Discrepancy between estimated energy intake and
requirements in female dancers. Clin Physiol 1990; 10:
1125.
Jones PJ, Leitch CA. Validation of doubly labeled water for measurement of caloric expenditure in collegiate
swimmers. J Appl Physiol 1993; 74:29092914.
Schulz LO, Alger S, Harper I, Wilmore JH, Ravussin
E. Energy expenditure of elite female runners measured by respiratory chamber and doubly labeled
water. J Appl Physiol 1992; 72:2328.
Horton TJ, Drougas HJ, Sharp TA, Martinez LR,
Reed GW, Hill JO. Energy balance in endurancetrained female cyclists and untrained controls. J Appl
Physiol 1994; 76:19371945.
FAO. The State of Food Insecurity in the World 2000.
Rome: Food and Agriculture Organization of the United Nations, 2000.
Geeves MA. Stretching the lever-arm theory. Nature
2002; 415:129131.
Gollnick PD. Metabolism of substrates: energy sub-
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
651
by endurance training. Biochem Biophys Res Commun 1997; 231:463465.
151. Jansson E, Kaijser L. Substrate utilization and
enzymes in skeletal muscle of extremely endurancetrained men. J Appl Physiol 1987; 62:9991005.
152. Decombaz J, Schmitt B, Ith M, Decarli B, Biem P,
Kreis R, Hoppeler H, Boesch C. Postexercise fat
intake repletes intramyocellular lipids but no faster in
trained than in sedentary subjects. Am J Physiol Regul
Integr Comp Physiol 2001; 281:R760R769.
153. Saltin G. Metabolic fundamentals in exercise. Med Sci
Sports Exerc 1973; 5:137146.
154. Donovan CM, Brooks GA. Endurance training aects
lactate clearance not lactate production. Am J Physiol
1983; 244:E83E92.
155. Tarnopolsky LJ, MacDougall JD, Atkinson SA,
Tarnopolsky MA, Sutton JR. Gender dierences in
substrate for endurance exercise. J Appl Physiol 1990;
308:302308.
156. Blaak E. Gender dierence in fat metabolism. Curr
Opinion Clin Nutr Med Care 2001; 4:499502.
157. Toth MJ, Gardner AW, Arciero PJ, Calles-Escandon
J, Poehlman ET. Gender dierences in fat oxidation
and sympathetic nervous system activity at rest and
during submaximal exercise in older individuals. Clin
Sci 1998; 95:5966.
158. Horton TJ, Pagliassotti MJ, Hobbs K, Hill JO. Fuel
metabolism in men and women during short and longduration exercise. J Appl Physiol 1998; 85:18231832.
159. Carter SL, Rennie C, Tarnapolsky MA. Substrate
utilisation during endurance exercise in men and
women after endurance training. Am J Physiol 2001;
280:E898E907.
160. Tarnapolsky MA. Gender dierences in lipid metabolism during exercise and rest. In: Tarnapolsky MA,
ed. Gender Dierences in Metabolism Practical and
Nutritional Implication. Boca Raton: CRC Press,
1999:179199.
161. Burguera B, Proctor D, Dietz N, Guo Z, Joyner M,
Jensen MD. Leg free fatty acid kinetics during exercise
in men and women. Am J Physiol Endocrinol Metab
2000; 278:E113E117.
162. Perseghin G, Scifo P, Pagliato E. Gender factors aect
fatty acids induced insulin resistance in non obese
humans. Eects of oral steroidal contraception. J Clin
Endocrinol Metab 2001; 86:31883196.
163. Binnert C, Koistinen HA, Martin G, Andreelli F,
Ebeling P, Koivisto VA, Laville M, Auwerx J, Vidal
H. Fatty acid transport protein-1 mRNA expression
in skeletal muscle and in aclipose tissue in humans. J
Physiol 2000; 279:E1072E1079.
164. Nicklas BJ, Hackney AC, Sharp RL. The menstrual
cycle and exercise: performance, muscle glycogen, and
substrate responses. Int J Sports Med 1989; 10:264
269.
165. Hackney AC, McCracken-Compton MA, Ainsworth
652
B. Substrate responses to submaximal exercise in the
midfollicular and midluteal phases of the menstrual
cycle. Int J Sport Nutr 1994; 4:299308.
166. Calles-Escandon J, Arciero PJ, Gardner AW, Bauman
C, Poehlman ET. Basal fat oxidation decreases with
aging in women. J Appl Physiol 1995; 78:266271.
167. Blaak EE, Van Baak MA, Kemerink GJ, Pakbiers
MT, Heidendal GA, Saris WH. Beta adrenergic
stimulation of whole body energy expenditure and
skeletal muscle metabolism in lean and obese men. Am
J Physiol 1994; 267:306315.
168. Blaak EE, Saris WHM, Wolenbuttel B. Substrate
utilisation and thermogenic responses to beta adrenergic stimulation in obese subjects with NIDDM. Int
J Obes Relat Metab Disord 1999; 2:411418.
169. Blaak EE, Van Aggel-Leijssen DPC, Wagenmakers
AJ, Saris WH, Van Baak MA. Impaired oxidation of
plasma-derived fatty acids in NIDDM subjects during
moderate intensity exercise. Diabetes 2000; 49:2102
2107.
170. Jacobs DR Jr, Hahn LP, Folsom AR, Hannan PJ,
Sprafka JM, Burke GL. Time trends in leisure-time
physical activity in the upper Midwest 19571987:
University of Minnesota studies. Epidemiology 1991;
2:815.
171. Virkamaki A, Korsheninnikova E, Seppata-Lindroos
A, Vehkavaara S, Goto T, Halavaara J, Yki-Jarvinen
H. Intra-myocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake,
anti-lipolysis and early insulin signalling pathways in
human skeletal muscle. Diabetes 2001; 50:23372343.
172. Malenfant P, Tremblay A, Doucet E, Imbeault P,
Simoneau JA, Joanisse DR. Elevated intramyocellular
lipid concentrations in obese subjects is not reduced
after diet and exercise training. Am J Physiol Endocrinol Metab 2001; 280:E632639.
173. Malenfant P, Joanisse DR, Theriaulb R. Fat
content in individual muscle bers of lean and obese
subjects. Int J Obes Relat Metab Disord 2001; 25:
13161321.
174. Van Loon L, Greenha PL, Constantin-Teodosiu D,
Saris WH, Wagenmakers AJ. The eects of increasing
exercise intensity on muscle fuel utilisation in humans.
J Physiol 2001; 536:295304.
175. Schrauwen P, Van Aggel PPC, Wagenmakers AJM,
Van Baak MA, Saris WHM. Low intensity exercise
training increases non-plasma derived triglyceride
oxidation. Int J Obes 2000; 24:S181.
176. National Center for Health Statistics. Prevalence of
Overweight and Obesity Among Adults. Atlanta: National Center for Health Statistics, 1999. www.cdc.gov/
nchs.
177. MAFF. Household food consumption and energy
expenditure (annual reports). London: AMSO, 1940
1994.
178. DiPietro L. Physical activity, body weight and adipos-
Hill et al.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
653
207.
208.
209.
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
Wing RR, Hill JO. Successful weight loss maintenance. Annu Rev Nutr 2001; 21:323341.
Jakicic JM, Winters C, Lang W, Wing RR. Eects of
intermittent exercise and use of home exercise equipment on adherence, weight loss and tness in overweight women: a randomized trial. JAMA 1999; 282:
15541560.
Weinsier RL, Hunter GR, Desmond RA, Byrne NM,
Zuckerman PA, Darnell BE. Free-living activity
energy expenditure in women who are successful and
unsuccessful in maintaining a normal body weight.
Am J Clin Nutr 2002; 75:499504.
Tremblay A, Despres J-P, Leblanc C, Craig CL, Ferris
B, Stephens T, Bouchard C. Eect of intensity of
physical activity on body fatness and fat distribution.
Am J Clin Nutr 1990; 51:153157.
Broeder CE, Burrhus KA, Svanevik LS, Wilmore JH.
The eects of either high-intensity resistance or
endurance training on resting metabolic rate. Am J
Clin Nutr 1992; 55:802810.
Westerterp KR. Pattern and intensity of physical
activity. Nature 2001; 410:539.
Dunn AL, Marcus BH, Kampert JB, Garcia ME, Kohl
WH 3rd, Blair SN. Comparisons of lifestyle and
structured interventions to increase physical activity
and cardiorespiratory tness. JAMA 1999; 281(2):
327334.
Anderson RE, Wadden TA, Bartlett SJ, Zemel B,
Verde TJ, Franckowiak SC. Eects of lifestyle activity
vs structured aerobic exercise in obese women. JAMA
1999; 281:335339.
Fogelholm M, Kukkonen-Harjula K, Nenonen A,
Pasanen M. Eects of walking training on weight
maintenance after a very-low-energy diet in premenopausal obese women. Arch Intern Med 2000;
106: 21772184.
Hendelman D, Miller K, Baggette C, Debold E,
Freedson P. Validity of accelerometry for the
assessment of moderate intensity physical activity
in the eld. Med Sci Sports Exerc 2000; 32:S442
S449.
Welk GJ, Dierding JA, Thompson RW, Blair SN,
Dziura J, Hart P. The utility of the Digi-Walker step
counter to assess daily physical activity patterns. Med
Sci Sports Exerc 2000; 32:S481S488.
Westerterp KR. Assessment of physical activity level
in relation to obesity: current evidence and research
issues. Med Sci Sports Exerc 1999; S522S525.
Sallis JF, Bauman A, Pratt M. Environmental and
policy interventions to promote physical activity. Am J
Prev Med 1998; 15:379397.
Schrauwen P, Van Aggel-Leijssen DPC, Wagenmakers
AJM, Van Baak AM, Saris WHM. Low intensity
exercise training increases non plasma derived triglyceride oxidation. Int J Obes Relat Metab Disord 2000;
24:S181.
25
Endocrine Determinants of Obesity
Jonathan H. Pinkney
University of Liverpool, Liverpool, England
Peter G. Kopelman
Barts and the London Queen Marys School of Medicine and Dentistry, University of London, London, England
INTRODUCTION
II
655
656
Figure 1
III
Endocrine relationships among visceral obesity, insulin resistance, and steroid metabolism.
glucose uptake and oxidation in muscle (20) and insulinmediated suppression of hepatic glucose output (21). It
has been suggested that FA released by visceral fat play
a key role in the impairment of liver and muscle insulin
sensitivity (22). Recently, it has been suggested also that
FA accumulation in muscle may be a key event in the
impairment of insulin sensitivity (23).
Impaired glucose transport and insulin signaling
have attracted attention as possible explanations for
insulin resistance. In premenopausal women, insulinstimulated activity of the enzyme glycogen synthase
in quadriceps muscle declined with increasing obesity
and insulin resistance during a somatostatin-insulindextrose infusion (24). An inverse relationship was observed between insulin receptor numbers and a measure
of upper-body obesity, waist-to-hip ratio (WHR). Obesity was also associated with depletion of adipocyte
glucose transporters (GLUT4) (25). Severe insulin resistance in type 2 diabetic patients was associated with a
still greater fall in GLUT4 mRNA compared to simple
obesity that involved both plasma membrane and cytosolic compartments. In both patient groups, suppression of GLUT4 mRNA expression entirely accounted
for impaired insulin responsiveness in adipose tissue.
In contrast, no dierences were seen in skeletal muscle
GLUT4 content or mRNA from control subjects (26).
These studies support the concept of a primary defect in
GLUT4 in adipocytes but not in muscle.
More recently, it has been shown in animal models
that knockout of GLUT4 in adipose tissue leads to
insulin resistance in liver and muscle (27). The mechanism responsible for this remains to be determined
but FA are a leading candidate. Declining muscle
insulin sensitivity may also result from decreased functional activity of GLUT4 or impairment of insulinstimulated translocation of intracellular GLUT4 to the
cell surface. It has been demonstrated that chronic
exposure to high concentrations of glucose and insulin
reduces insulin-stimulated glucose transporter translocation (28). Thus hyperglycemia and/or hyperinsulinemia may contribute to insulin resistance.
Many other hormones and mediators are released by
adipose tissue (29), some aecting insulin secretion and/
or action. Leptin was found by some (30,31), but not all,
investigators to inhibit insulin signaling. However, leptin also inhibits insulin secretion (32), and this may
impair glucose tolerance. TNFa is also expressed in
adipocytes and may cause insulin resistance in obesity
(33). A comprehensive discussion of other factors is
beyond the scope of this chapter. These include prostanoids, angiotensinogen, IGF-1, IL-6, adiponectin, complement components and related molecules, and
657
resistin. It is clear that there are many potential mechanisms through which an increased adipose tissue mass
can inuence insulin secretion and action.
IV
ADRENOCORTICAL FUNCTION
IN OBESITY
Table 2
Obesity
658
VI
REGIONAL DISTRIBUTION
OF ADIPOSE TISSUE
VII
659
660
VIII
ESTROGEN METABOLISM
IN OBESITY
Excess body fat leads to changes in the hypothalamicpituitary-ovarian axis and ovarian function (72). The
production of estrogen and its precursors, including
androstenedione and testosterone, decreases with age
and after the menopause. In premenopausal women,
mean 24-hr plasma estrone and estradiol levels do not
dier in obese and lean women (73). However, obese
women have lower SHBG levels and increased free
estrogen. In postmenopausal obese women, serum
estrone and estradiol correlate with fat mass (74). SHBG
levels are also lower in older women, further elevating
free estradiol levels. Aromatization of androstenedione
to estrone occurs in adipose tissue of premenopausal
and postmenopausal women and is closely related to
body weight (75). Aromatization increases with age and
is two to four times higher in postmenopausal women
(76). Androstenedione is the major substrate for estrogen formation; although only a small amount of testosterone is aromatized, this may be of greater signicance.
Longcope and colleagues (77) have reported associations between body weight and the conversion of testosterone to estradiol. The interconversion of estrone to
estradiol is also greater in omental than subcutaneous
fat (78,79). Furthermore, adipose tissue 17-hydroxysteroid dehydrogenase activity, measured by the conversion of estrone to estradiol, is higher in premenopausal
than postmenopausal women, and women have higher
activity than men (78). Estrogens should not be considered as passive byproducts of obesity because they
positively promote preadipocyte proliferation, preservation, and further expansion of adipose tissue (79).
IX
661
662
XII
663
couples activity of the GH-IGF axis to signals that induce negative energy balance such as leptin and cytokines. The defence of lean body mass in the fasting
statean important function of the GH-IGF axis
would be more ecient if concurrent anorectic and
thermogenic signals could be shut down. However,
while ghrelin downregulation in the stomach may be
an appropriate adaptation to obesity, by potentiating
the central actions of signals that induce negative
energy balance, and reducing gastric acid secretion
and motility, it is also possible that low ghrelin secretion might have less desirable eects including contributing to the maladaptive reduction of GH secretion
characteristic of the obese state.
XIII
CONCLUSIONS
664
9.
10.
11.
12.
REFERENCES
13.
1.
2.
3.
4.
5.
6.
7.
8.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
665
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
666
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
667
treatment of obese women. Clin Endocrinol 1992;
36:105111.
101. Tanner JM, Whitehouse RH. The eect of human
growth hormone on subcutaneous fat thickness in
hyposomatrophic and hypopituitary dwarfs. J Endocrinol 1967; 39:263275.
102. Vahl N, Jorgensen JOL, Skjaerbaek C, Veldhuis JD,
Orskov H, Christiansen JS. Abdominal adiposity
rather than age and sex predicts mass and regularity
of GH secretion in healthy adults. Am J Physiol 1997;
272:E1108E1116.
103. Bengtsson BA, Eden S, Lonn L, et al. Treatment of
adults with growth hormone deciency with recombinant human GH. J Clin Endocrinol Metab 1994;
78:960967.
104. Jorgensen JO, Moller N, Wolthers T, et al. Fuel metabolism in growth hormonedecient adults. Metabolism 1995; 44:103107.
105. Maccario M, Grotolli S, Procopio M, et al. The GH/
IGF-1 axis in obesity: inuence of neuroendocrine and
metabolic factors. Int J Obes 2000; 24:S96S99.
106. Veldhuis J, Liem A, South S, et al. Dierential impact
of age, sex steroid hormones, and obesity on basal vs
pulsatile growth hormone secretion in men as assessed
in an ultrasensitivie chemiluminescence assay. J Clin
Endocrinol Metab 1995; 80:32093222.
107. Langendonk JG, Meinders AE, Burggraaf J. Inuence
of obesity and body fat distribution on growth
hormone kinetics in humans. Am J Physiol 1999;
277:E824E829.
108. Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ,
Johnson ML, Lizarralde G. Dual defects in pulsatile
growth hormone secretion and clearance subserve the
hyposomatotropism of obesity in man. J Clin Endocrinol Metab 1991; 72:5159.
109. Postel-Vinay MC, Saab C, Gourmelen M. Nutritional
status and growth hormone binding protein. Horm
Res 1995; 44:177181.
110. Fisker S, Vahl N, Jorgense JO, Christiansen JS,
Orskov H. Abdominal fat determines growth hormonebinding protein levels in healthy nonobese
adults. J Clin Endocrinol Metab 1997; 82:123128.
111. Maccarrio M, Arvat E, Procopio M, et al. Metabolic
modulation of growth hormonereleasing activity of
hexarelin in man. Metabolism 1995; 44:134138.
112. Alvarez CV, Mallo F, Burguera B, Caciedo L, Dieguez
C, Casanueva FF. Evidence for a direct pituitary
inhibition by free fatty acids of in vivo growth
hormone responses to growth hormone-releasing hormone in the rat. Neuroendocrinology 1991; 53:185
189.
113. Maccario M, Procopio M, Grotolli S, et al. In obesity
the somatotrope response to either growth hormone
releasing hormone or arginine is inhibited by somatostatin or pirenzepine but not by glucose. J Clin
Endocrinol Metab 1995; 80:37743778.
668
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
669
147.
148.
26
Endocrine Determinants of Fat Distribution
Renato Pasquali, Valentina Vicennati, and Uberto Pagotto
University of Bologna and S. Orsola-Malpighi General Hospital, Bologna, Italy
INTRODUCTION
III
A
672
Pasquali et al.
in the omental region, and the lipolysis rate is signicantly correlated to fat cell size regardless of either the
region of origin or gender, indicating that the regulation
of HSL activity is to a large extent dependent on fat cell
size (9). Antilipolytic parahormones such as adenosine
and prostaglandins, which are produced locally, are also
of importance for the regulation of lipolysis in humans.
IV
PHYSIOLOGY OF HORMONE
REGULATION OF BODY
FAT DISTRIBUTION
Insulin
673
Lipolysis
h1: z
h2: z
h3: z
Antilipolysis
Adenosine: =
a2: =
Insulin: #
Lipogenesis
LPL: #
Insulin: #
Subcutaneous fat
Obese
Nonobese
Lipolysis
h1: #
h2: #
h3: 0
Antilipolysis
Adenosine: =
a2: =
Insulin: z
Lipogenesis
LPL: z
Insulin: z
h1: =
h2: =
h3: zzz
Adenosine: =
a2: #
Insulin: ##
LPL: z
Insulin: ##
Obesec
h1: =
h2: #
h3: 0
Adenosine: =
a2: =
Insulin: #
LPL: z
z
Insulin: #
Catecholamines
Catecholamines may specically activate four adrenergic receptors: h1, h2, h3, and a2, all members of the
super family of G-protein-coupled receptors (24). There
are signicant species dierences in adrenergic receptors, and signicant dierences in anity of each receptor for the ligand. The order of anity of the adrenergic
receptors is a2>h1zh2>h3 for norepinephrine (25),
and a2>h2>h1>h3 for epinephrine (24). The biological signicance of the presence of three dierent
h-receptors in adipocytes is unclear but it has been
suggested that each receptor subtype might display a
dierent signaling role (26). All three h-receptors are
Gs coupled and all may activate adenylyl cyclase.
Only h3-receptors have been shown to also interact
with Gi in adipocyte membranes, suggesting a dierent
crosstalk of these receptors with inhibitory receptors
(26). h1-receptors, which are more sensitive to catecholamines and desensitize rapidly, may mediate acute
eects of low level catecholamine stimulation. On the
other hand, h3-receptors, which require higher levels of
catecholamines to be activated and are more resistant
to desensitization, deliver a more sustained signal (27,
28). The presence of the inhibitory a2-receptor provides
the cell with the opportunity of dual regulation of
cyclase activity. It has been demonstrated that gluteal
adipocytes isolated from females have more a2-receptors than adipocytes from males (29). Microdialysis
674
Pasquali et al.
Androgens
Glucocorticoids
Glucocorticoid receptors (GCRs), located at intracellular level, function as transcription factors by inducing
and/or repressing the expression of a host of target
genes. The GCRs are members of the steroid-thyroid
intracellular receptor superfamily. The ligand binding
to receptors is modulated by prereceptor metabolism (33). Recently, it has been demonstrated that
pre-receptor metabolism of GCs is an important determinant of tissue-specic responses. There is strong
evidence for such a role for 11h-hydroxysteroid-dehydrogenase (11hHSD) enzymes. In adipose tissue,
11hHSD isoform type 1 is involved in the conversion
of cortisone to cortisol. In human adipocyte culture,
11hHSD1 activity is higher in the omental than in the
subcutaneous fat (23) and GCRs show a regional
dierence in density, being higher in visceral fat depots
(23). In vitro studies have shown that cortisol induces
the LPL activity in human adipose tissue (34) and that
RU486, a glucocorticoid receptor antagonist, induces
an ecient inhibition of cortisol-induced LPL expression (35,36). The cortisol eects on LPL in human
adipose tissue are dependent on insulin. LPL is eciently expressed in a dose-dependent manner, and
675
of estradiol valerate and levonorgesterol to postmenopausal women signicantly increased the adipose tissue
LPL activity, but data about the eect of estrogens
alone were missing from that study. In contrast, Iverius
et al. (58) showed an inverse correlation between serum
E2 levels and adipose tissue LPL levels in obese women.
Adipose tissue is one of the main sites of E2 interconversion into estrone, particularly the gluteofemoral
region. Price et al. (59) showed that the eect of female
sex steroids is dierent depending on the menopause
status. In fact, in premenopausal women progesterone
is responsible for the stimulation of LPL activity, with
deposition of adipose tissue in the gluteofemoral area
rather than the abdominal region. On the contrary, in
postmenopausal women progesterone production
declined, and localized production of estrone predominates, with a decrease in LPL activity. Because estrone
production is higher in the gluteofemoral region, LPL
activity decreases in this area to a greater extent than
does activity in the abdominal region. Thus, this change
in activity is associated with abdominal deposition of
body fat. After all, the eects of estrogens partly
depend on those of androgens. However, to date, there
is very little information on the mechanisms by which
androgens and estrogens act separately and which
cellular and molecular mechanisms are involved in the
dierentiation of adipose tissue morphology and function between the sexes.
F
Thyroid Hormones
676
Pasquali et al.
GH
H
Growth hormone secretagogues (GHSs) are compounds able to stimulate GH release by parallel routes
to those used by GHRH (74). In 1996, a specic receptor
for these peptides was cloned and localized in dierent
central and peripheral organs (75), and a few years later
ghrelin, an endogenous ligand for this receptor, was
discovered (76). The most important source of production of ghrelin is the stomach, suggesting that this
peptide may act as an endocrine signal from gut to
hypothalamus. Recently, ghrelin has been shown to
play an important role in the development of obesity
(77). Interestingly, these data were anticipated by data
in which also GHSs were shown to enhance lean body
mass and bone mass (78). However, it was dicult to
discern whether the stimulatory eect of GHSs on food
intake or that on GH secretion prevailed in determining changes in body composition. In fact, chronic
stimulation of food intake by GHSs may result in increased body fat, whereas chronic stimulation of GH
may result in reduction of body fat, GH being a
lipolytic hormone. Recently, the usage of ghrelin in
GH-decient mice (lit/lit), has clearly conrmed that
ghrelin displays a GH-independent eect on body
weight increasing the fat mass (78). This adipogenic
eect is brilliantly mirrored by the simultaneous increased level of circulating leptin, whereas it is well
known that GH itself downregulates leptin levels. The
precise mechanisms by which ghrelin or GHSs induces
adiposity are still unclear, although it has been suggested that reduced levels of ghrelin may represent a
physiological adaptation to the positive energy balance
associated with obesity (79).
I
Leptin
IL-6
Similarly to leptin, IL-6 binds class I cytokine receptors, and in this way activates JAK and STATs. The
IL-6 receptor expression pattern in the dierent fat
depots localization is still unknown. IL-6 circulating
levels are positively correlated with body mass index
(86); this nding supports that notion that adipose
tissue has to be considered a main reservoir of this
cytokine. It has in fact been proposed that one-third of
circulating IL-6 derives from fat cells (87). IL-6 is
released from subcutaneous adipose tissue and threefold more from visceral depots (87,88). However, cells
other than adipocytes, such as broblasts, immune
cells, and vascular cells composing the whole architecture of adipose tissue, constitute the main source of
IL-6 (88), making it possible to speculate a mixed
autocrine and paracrine role of this cytokine. However, since the liver is the direct target of the venous
drainage from omental fat depots, the metabolic
impact of IL-6 produced by omental adipose tissue
677
might be of pathophysiological relevance for alterations in lipid synthesis and metabolism. IL-6 has been
shown to increase triglyceride secretion in rat liver
(89), so IL-6 secreted by omental depots may contribute to maintain hypertriglyceridemia associated with
abdominal obesity. IL-6 decreases adipose LPL activity (90) and increases lipolysis (91). These eects have
been correlated with the fat depletion occurring during
cachectic states characterized by high circulating IL-6
levels (90). IL-6 production from adipose tissue can be
stimulated by TNFa (92) and catecholamines (93),
whereas GCs downregulate its production (93). The
hyperactivation of hypothalamic-pituitary-adrenal
(HPA) axis and the increased cortisol turnover are
features of the visceral obese state (see below). IL-6 is
capable of directly activating this axis at all three levels
(94), so IL-6 produced by the adipose tissue may act
as a feedforward regulator of this axis, playing an
important role in contributing to modulate the dierential fat distribution that occurs in patients displaying
HPA hyperactivation.
K
TNFa
678
Pasquali et al.
Resistin
A new peptide named resistin has recently been identied in adipose tissue after a screening for genes
induced during adipocyte dierentiation. Resistin is
specically expressed in white adipose tissue, circulates
in the serum, and can be downregulated by thiazolidinediones. Increased resistin circulating levels have
been shown in mouse genetic and diet-induced forms
of obesity. Insulin-stimulated glucose uptake in adipocytes was increased by using neutralizing resistin anti-
Table 2
Hormones and Other Factors Involved in the Regulation of Body Fat Distribution and Their Mechanisms of Action
Androgens (testosterone)
Estrogens
Progesterone
GH and related peptides
Iodothyronines
Catecholamines
Leptin
IL-6
TNFa
Resistin
Cushings Syndrome
Cushings syndrome is characterized by a redistribution of adipose tissue from peripheral to central sites
of the body, mainly in the truncal region and visceral
depots. This may occur as a result of the dual eect
of GCs which on the one hand downregulate HPL
and increase lipolysis, and on the other hand favor
preadipocyte dierentiation and stimulate substrates
to gluconeogenesis and FFA to central fat. Centralization of visceral fat depots tends to be markedly
reduced in patients with Cushings syndrome after
eradication of causes of cortisol excess, and this process can be successfully completed within 12 years
after interventional surgical treatment at pituitary or
adrenal level.
B
Male Hypogonadism
679
particularly in the visceral depots, after long-term treatment with T, provided that physiological levels are
achieved and maintained over time.
C
Hyperandrogenism in Women
GH Deciency
Acromegaly
680
Pasquali et al.
PATHOPHYSIOLOGY OF DIFFERENT
OBESITY PHENOTYPES: THE ROLE
OF HORMONES
Sex Hormones in Women
Figure 1
681
Schematic representation of sex hormone alterations in obese women (left panel) and men (right panel).
with dierent obesity phenotypes (122), although estrogen production rates have been found to be particularly
increased in women with peripheral obesity. Together
with the aforementioned protective eects of estrogens
on visceral fat development, there is, however, evidence
that they play a key role in the regulation of subcutaneous adipocytes, particularly during pregnancy and
lactation (58). After menopause, a sudden decrease of
estrogens occurs, due to the physiological ovarian failure. Whether the occurrence of menopause alters body
weight and fat distribution remains controversial. In
fact, while many women claim an increase in body
weight during the transition period toward menopause
and after menopause, most but not all studies (123) have
shown that although the weight of postmenopausal
women is greater than before menopause, this dierence
tends to disappear after adjusting for age values, thus
suggesting that age and not the menopausal status per se
is probably responsible for weight increase.
Some discrepancies have also been found with
regard to the eects of menopause on fat distribution,
since there are studies reporting that postmenopausal
women had higher WHR values than premenopausal
women, whereas others did not observe any eect (123).
On the other hand, as discussed in a previous paragraph (see Sec. IV.E above), it should be taken into
account that the androgen/estrogen balance dierently
regulates the adipose tissue morphology and function
in the subcutaneous and visceral sites after menopause,
thereby potentially favoring some change in the phenotype pattern. The lack of detailed studies investigating the specic role of each class of hormones could
therefore explain the aforementioned discrepancies of
682
Pasquali et al.
683
684
Pasquali et al.
685
Figure 2 Schematic representation of the HPA axisnoradrenergic system alterations in the pathophysiology of abdominal
obesity and the metabolic syndrome. Exaggerated response to chronic stress factors and alterations in cortisol metabolism
(whose causative mechanisms are still unknown), with compensatory neuroendocrine activation, may cooperate in determining
HPA hyperactivation and cortisol hypersensitivity. Also shown is a schematic target cell, in which interconversion of cortisol and
cortisone by 11h-HSD dictates access of GCs to receptors and subsequent regulation of target genes, encoding those responsible
for negative feedback. Cortisol and cortisone circulate in similar free concentrations, although free cortisol is in equilibrium with
a pool of cortisol bound to CBG and albumin. Symbols in circles indicate increased or decreased activity. (From Refs. 68,150.)
obesity phenotype of both sexes. Both central and peripheral mechanisms responsible for altered HPA axis
activity in the abdominal obesity phenotype are represented in Figure 2.
VII
The recognition that adipose tissue has endocrine properties and represents a main target for hormone eects
has reinforced research in this direction, and over the
years new ndings have enormously increased our
knowledge on the main mechanisms of regulation of
some functions of the human body, including energy
balance and body composition, in both the physiological state and in diseases. Mechanisms of regulation of
the dierentiation and the lipogenetic/lipolytic balance
686
Pasquali et al.
8.
9.
10.
11.
12.
13.
14.
15.
16.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
Flier JS. Leptin expression and action: new experimental paradigms. Proc Natl Acad Sci USA 1997; 94:
42424245.
Kahn BB, Flier JS. Obesity and insulin resistance. J
Clin Invest 2000; 106:473481.
Cryer A. Tissue lipoprotein lipase activity and its action in lipoprotein metabolism. J Biochem 1981; 13:
525541.
Ailhaud G. Ladipocyte, cellule secretrice et endocrine.
Medecine/Sciences 1998; 14:858864.
Kern PA, High adipose tissue lipoprotein lipase
activity plays a causal role in the etiology of obesity.
In: Angel A, Anderson H, Bouchard C, Lau D, Leiter
L, Mendelson R, eds. Progress in Obesity Research:
Proceedings of the Seventh International Congress
on Obesity (Toronto, 1994). London: John Libbey &
Company, 7:8994.
Carey GB. Mechanisms regulating adipocyte lipolysis. In: Richter J, ed. Skeletal Muscle Metabolism in
Exercise and Diabetes New York: Plenum Press,
1998.
Bonadonna R, Bonora E. Glucose and free fatty acid
metabolism in human obesity. Relationships to insulin
resistance. Diabetes Rev 1997; 5:2151.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
687
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
688
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
Pasquali et al.
tication of estrogen receptor in human adipose tissue
and adipocytes. J Clin Endocrinol Metab 1994; 78:
950954.
Crandall DL, Busler DE, Novak TJ, Weber RV, Kral
JG. Identication of estrogen receptor beta RNA in
human breast and abdominal subcutaneous adipose
tissue. Biochem Biophys Res Commun 1998; 248:523
526.
Wade GN. Sex steroids and energy balance: sites and
mechanisms of action. Ann NY Acad Sci 1986; 474:
389399.
Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly
M, Rudling M, Lindberg MK, Warner M, Angelin B,
Gustafsson JA. Obesity and disturbed lipoprotein
prole in estrogen receptor-alpha-decient male mice.
Biochem Biophys Res Commun 2000; 278: 640645.
Heine PA, Taylor JA, Iwamoto GA, Lubahn DB,
Cooke PS. Increased adipose tissue in male and female
estrogen receptor-alpha knockout mice. Proc Natl
Acad Sci USA 2000; 97:1272912734.
Hamosh M, Hamosh P. The eect of estrogen on the
lipoprotein lipase activity of rat adipose tissue. J Clin
Invest 1975; 55:11321135.
Rebue-Scrive M, Basdevant A, Guy-Grand B. Eect
of local application of progesterone on human adipose
tissue lipoprotein lipase. Horm Metab Res 1983;
15:566.
Iverius PH, Brunzell JD. Relationship between lipoprotein lipase activity and plasma sex steroid level in
obese women. J Clin Invest 1988; 82:11061112.
Price TM, OBrien SN, Welter BH, George R,
Anandjiwala J, Kilgore M. Estrogen regulation of
adipose tissue lipoprotein lipasepossible mechanism
of body fat distribution. Am J Obstet Gynecol 1998;
178:101107.
Pucci E, Chiovato L, Pinchera A. Thyroid and lipid
metabolism. Int J Obes 2000; 24:S109S112.
Wahrenberg H, Wennlund A, Arner P. Adrenergic
regulation of lipolysis in fat cells from hyperthyroid
and hypothyroid patients. J Clin Endocrinol Metab
1994; 78:898903.
Richelsen B, Sorensen NS. a2- and h-adrenergic
receptor binding and action in gluteal adipocytes from
patients with hypothyroidism and hyperthyroidism.
Metabolism 1987; 36:10311039.
Lonn L, Stenlof K, Ottosson M, Lindroos AK,
Nystrom E, Sjostrom L. Body weight and body composition changes after treatment of hyperthyroidism.
J Clin Endocrinol Metab 1998; 83:42734296.
Lithell H, Vessby B, Dahlberg PA. High muscle
lipoprotein lipase activity in thyrotoxic patients. Acta
Endocrinol 1985; 109:227231.
Vikman K, Carlsson B, Billig H, Eden S. Expression
and regulation of growth hormone (GH) receptor
messenger ribonucleic acid (mRNA) in rat adipose
tissue, adipocytes, and adipocyte precursor cells: GH
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
689
L1 preadipocyte dierentiation by tumour necrosis
factor-alpha. J Mol Endocrinol 1992; 9:6172.
93. Papanicolaou DA, Petrides JS, Tsigos C, Bina S,
Kalogeras KT, Wilder R, Gold PW, Deuster PA,
Chrousos GP. Exercise stimulates interleukin-6 secretion: inhibition by glucocorticoids and correlation
with catecholamines. Am J Physiol 1996; 271:E601
E605.
94. Arzt E, Pereda MP, Castro CP, Pagotto U, Renner U,
Stalla GK. Pathophysiological role of the cytokine
network in the anterior pituitary gland. Front Neuroendocrinol 1999; 20:7195.
95. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct
role in obesity-linked insulin resistance. Science 1993;
259:8791.
96. Torti FM, Dieckmann B, Beutler B, Cerami A,
Ringold GM. A macrophage factor inhibits adipocyte
gene expression: an in vitro model of cachexia. Science
1985; 229:867869.
97. Grell M. Tumor necrosis factor (TNF) receptors in
cellular signaling of soluble and membrane-expressed
TNF. J Inamm 199596; 47:817.
98. Hube F, Birgel M, Lee YM, Hauner H. Expression
pattern of tumour necrosis factor receptors in subcutaneous and omental human adipose tissue: role of
obesity and non-insulin-dependent diabetes mellitus.
Eur J Clin Invest 1999; 29:672678.
99. Hotamisligil GS, Arner P, Atkinson RL, Spiegelman
BM. Dierential regulation of the p80 tumor necrosis
factor receptor in human obesity and insulin resistance. Diabetes 1997; 46:451455.
100. Hube F, Hauner H. The role of TNF-alpha in human
adipose tissue: prevention of weight gain at the
expense of insulin resistance? Horm Metab Res 1999;
31:626631.
101. Mohamed-Ali V, Goodrick S, Bulmer K, Holly JM,
Yudkin JS, Coppack SW. Production of soluble tumor
necrosis factor receptors by human subcutaneous adipose tissue in vivo. Am J Physiol 1999; 277:E971E975.
102. Hotamisligil GS, Arner P, Caro JF, Atkinson RL,
Spiegelman BM. Increased adipose tissue expression
of tumor necrosis factor-alpha in human obesity and
insulin resistance. J Clin Invest 1995; 95:24092415.
103. Garaulet M, Perex-Llamas F, Fuente T, Zamora S,
Tebar FJ. Anthropometric, computed tomography and
fat cell data in an obese population: relationship with
insulin, leptin, tumor necrosis factor-alpha, sex hormone-binding globulin and sex hormones. Eur J Endocrinol 2000; 143:657666.
104. Feingold KR, Grunfeld C. Role of cytokines in inducing hyperlipidemia. Diabetes 1992; 2:97101.
105. Yamaguchi M, Murakami T, Tomimatsu T, Nishio Y,
Mitsuda N, Kanzaki T, Kurachi H, Shima K, Aono T,
Murata Y. Autocrine inhibition of leptin production
by tumor necrosis factor-alpha (TNF-alpha) through
690
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
Pasquali et al.
TNF-alpha type-I receptor in vitro. Biochem Biophys
Res Commun 1998; 244:3034.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee
RR, Wright CM, Patel HR, Ahima SR, Lazar MA.
The hormone resistin links obesity to diabetes. Nature
2001; 409:307312.
Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee
RR, Dai CY, Enders GH, Silberg DG, Weu X, Wu
GD, Lazar MA. A family of tissue-specic resistin-like
molecules. Proc Natl Acad Sci USA 2001; 98:502506.
Fasshauer M, Klein J, Neumann S, Eszlinger M,
Paschke R. Isoproterenol inhibits resistin gene expression through a G(S)-protein-coupled pathway in
3T3-L1 adipocytes. FEBS Lett 2001; 500:6063.
Way JM, Gorgun CZ, Tong Q, Uysal KT, Brown KK,
Harrington WW, Oliver WR Jr, Wilson TM, Kliever
SA, Hotamisligil GS. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by
peroxisome proliferator-activated receptor gamma
agonists. J Biol Chem 2001; 276:2565125653.
Pasquali R, Vicennati V. Obesity and hormonal abnormalities. In: Bjorntorp P, ed. International Textbook of
Obesity Chichester: John Wiley & Sons, 2001:225239.
Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli R,
Rood JC, Greeson C, Partington C. Exogenous androgens inuence body composition and regional body
fat distribution in obese postmenopausal women
a clinical research center study. J Clin Endocrinol
Metab 1996; 81:21982203.
Bengtsson BA, Eden S, Lonn L, Kvist H, Stokland A,
Lindstedt G, Bosaeus I, Tolli J, Sjostrom L, Isaksson
OG. Treatment of adults with growth hormone (GH)
deciency with recombinant human GH. J Clin Endocrinol Metab 1993; 76:309317.
OSullivan AJ, Kelly JJ, Homan DM, Freund J, Ho
KK, Brummer RJ. Body composition and energy expenditure in acromegaly. J Clin Endocrinol Metab
1994; 78:381386.
Hansen TB, Gram J, Bjerre P, Hagen C, Bollerslev J.
Body composition in active acromegaly during treatment with octreotide: a double-blind, placebo-controlled cross-over study. Clin Endocrinol (Oxf) 1994;
41:323329.
Von Shoultz B, Carlstrom K. On the regulation of sexhormone-binding globulin. A challenge of old dogma
and outlines of an alternative mechanism. J Steroid
Biochem 1989; 32:327334.
Pasquali R, Casimirri F, Plate` L, Capelli M. Characterization of obese women with reduced sex hormonebinding globulin concentrations. Horm Metab Res
1990; 22:303306.
Samojlik E, Kirschner MA, Silber D, Schneider G,
Ertel NH. Elevated production and metabolic clearance rates of androgens in morbidly obese women.
J Clin Endocrinol Metab 1984; 59:949954.
Kirschner MA, Samojlik E, Drejka M, Szmal E,
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
691
ing hormone and GHRP-6: evidence for a marked
somatotroph secretory capability in obesity. J Clin
Endocrinol Metab 1993; 76:819823.
144. Frystyk J, Vestbo E, Skjaerbaek C, Mogensen CE,
rskov H. Free insulin-like growth factors in human
obesity. Metabolism 1995; 44(suppl):3744.
145. Rosembaum M, Gertner JM, Leibel R. Eects of
systemic growth hormone (GH) administration on
regional adipose tissue distribution and metabolism in
GH-decient children. J Clin Endocrinol Metab 1989;
69:12741281.
146. Solomon F, Cenco RC, Herp R, Sonksen PH. The
eects of treatment with recombinant human GH on
body composition and metabolism in adults with
GH deciency. N Engl J Med 1989; 321:17971803.
147. Hwu CM, Kwok CF, Lai TY, Shih KC, Lee TS, Hsiao
LC, Lee SH, Fang VS, Ho LT. Growth hormone (GH)
replacement reduces total body fat and normalize
insulin sensitivity in GH-decient adults: a report of
one-year clinical experience. J Clin Endocrinol Metab
1997; 82:32853292.
148. Skaggs SR, Crist DM. Exogenous human growth
hormone reduce body fat in obese women. Horm Res
1991; 35:1924.
149. Bjorntorp P. Visceral obesity: a civilization syndrome. Obes Res 1993; 1:206222.
150. Chalew S, Nagel H, Shore S. The hypothalamicpituitary-adrenal axis in obesity. Obes Res 1995; 3:
371382.
151. Pasquali R, Biscotti D, Spinucci G, Vicennati V,
Genazzani AD, Sgarbi L, Casimirri F. Pulsatile secretion of ACTH and cortisol in premenopausal
women: eect of obesity and body fat distribution.
Clin Endocrinol (Oxf) 1998; 48:603612.
152. Pasquali R, Vicennati V. The abdominal obesity
phenotype and insulin resistance are associated with
abnormalities of the hypothalamic-pituitary-adrenal
axis in humans. Horm Metab Res 2000; 32:521525.
153. Ljiung T, Andersoson B, Bengtsson BA, Bjorntorp P,
Marin P. Inhibition of cortisol secretion by dexamethasone in relation to body fat distribution: a doseresponse study. Obes Res 1996; 4:277282.
154. Pasquali R, Ambrosi B, Armanini D, Cavagnini F,
Degli Uberti E, Del Rio G, De Pergola G, Maccario
M, Mantero F, Marugo M, Rotella CM, Vettor R, on
the behalf of the Study Group on Obesity of the
Italian Society of Endocrinology. Cortisol and ACTH
response to oral dexamethasone in obesity and eects
of sex, body fat distribution and dexamethasone concentrations: a dose-response study. J Clin Endocrinol
Metab 2002; 87:166175.
155. Al-Damluji S. Adrenergic control of the secretion of
anterior pituitary hormones. Baillieres Clin Endocrinol Metab 1993; 7:355392.
156. Pasquali R, Vicennati V, Calzoni F, Gnudi U,
Gambineri A, Ceroni L, Cortelli P, Menozzi R, Sinisi
692
157.
158.
Pasquali et al.
R, Del Rio G. a2-Adrenoreceptor regulation of the
hypothalamic-pituitary-adrenocortical axis in obesity.
Clin Endocrinol (Oxf) 2000; 52:413421.
Strain GW, Zumo B, Kream J, Stain JJ, Levin J,
Fukushima D. Sex dierences in the inuence of obesity on the 24 hr mean plasma concentration of cortisol. Metabolism 1982; 31:209212.
Stewart PM, Boulton A, Kunar S, Clarck PMS.
Shackleton CHL Cortisol metabolism in human obesity: impaired cortisone-cortisol conversion in subjects
with central adiposity. J Clin Endocrinol Metab 1999;
84:10221027.
159. Rodin A, Thakkar H, Taylor N, Clayton R. Hyperandrogenism in polycystic ovary syndrome: evidence
for a dysregulation of 11h-hydroxysteroid dehydrogenase. N Engl J Med 1994; 330:460465.
160. Jamieson P, Chapman KE, Edwards CRW, Seckl JR.
11h-Hydroxysteroid dehydrogenase is an exclusive
11h-reductase in primary cultures of rat hepatocytes:
eect of physicochemical and hormonal manipulations. Endocrinology 1995; 136:47544761.
161. Andrew R, Phillips DIW, Walker BR. Obesity and
gender inuence cortisol secretion and metabolism in
man. J Clin Endocrinol Metab 1998; 83:18061809.
27
Sympathoadrenal System and Metabolism
Eric Ravussin
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
INTRODUCTION
The sympathetic nervous system (SNS) is an important component of the autonomic nervous system, and
thus plays a major role in the maintenance of body
homeostasis. The SNS is of particular importance in
the control of the cardiovascular system and of a
number of metabolic processes including energy
homeostasis. Alterations in SNS eects on metabolism
have been implicated in the development and maintenance of obesity, and the SNS is a potential therapeutic target in the treatment of obesity. This short
review provides an overview of the anatomical and
physiological aspects of the SNS, before considering
the evidence showing a role for the SNS in the development or treatment of obesity.
694
III
695
Figure 2 Summary of the metabolic eect of the sympathetic nervous system (SNS) and plasma adrenaline. Shaded boxes
represent plasma compartments for hormones or substrates, solid lines represent eect of adrenaline from the adrenal medulla, and
dashed lines represent activities mediated by sympathetic nerves. Other thin lines represent exchanges through the bloodstream.
696
IV
Nerve Activity
Neurotransmitter Release
697
VI
698
Figure 3 Components of daily energy expenditure, their major determinants and the methods by which they can be measured.
SPA, spontaneous physical activity; NEAT, nonexercise activity thermogenesis; SMR, sleeping metabolic rate; RMR, resting
metabolic rate; SNS, sympathetic nervous system.
weight gain. We here briey discuss how the sympathetic nervous system can inuence the dierent metabolic predictors of weight gain.
VII
A
699
Substrate Oxidation
The eects of the SNS on metabolism appear to inuence the relative amounts of substrate oxidized (41).
Accordingly, an inverse relationship was demonstrated
in white people between 24-hr RQ (measured in a
respiratory chamber) and basal muscle sympathetic
nerve activity (measured immediately after the stay in
the respiratory chamber) (51). The relationship between
RQ and SNS activity was independent of the percentage
of body fat and clearly indicates an association between
a low SNS activity and a low lipid oxidation. A possible
explanation for this observation is the stimulatory eect
of noradrenaline on intracellular lipolysis and on free
fatty acids uptake in the muscle, which seem impaired in
previously obese subjects (52).
E
700
in muscle. UCP3 mRNA expression increases in response to overfeeding and fasting (probably through
increased availability of NEFAs) and in response to
adrenergic stimulation. The UCP3 and UCP2 genes are
located adjacent to each other in a region implicated in
linkage studies as contributing to obesity (58), and a
polymorphism in the gene encoding for UCP3 has been
associated with reduced fat oxidation (59). However,
the potential uncoupling activity of UCP2 and UCP3 is
still debated (60) despite the fact that massive overexpression of human UCP3 in mice was associated with
increased metabolic rate (61).
VIII
IX
Because sympathetic activity is an important determinant of EE and plays a role in the propensity to weight
gain in some individuals, it is likely that constitutional
dierences in SNS activity may contribute to explain the
large variability in weight loss among obese individuals
on dietary treatment programs. Sympathetic activation
has also been associated with enhanced meal-induced
satiety (65), which suggests that the SNS exerts a dual
eect, i.e., working on both sides of the energy balance
equation. Pharmacological blockade of the SNS is
dicult to achieve, but a certain functional inhibition
occurs during chronic treatment with a number of
agents, such as h-adrenergic antagonists (1). Treatment
of hypertensive or other patients with h-antagonist
produces an average of 2- to 5-kg weight increase, which
can be entirely accounted for by fat gain (66). Even if
other unknown regulatory mechanisms may counteract
further weight gain (67), it is interesting that some
individuals experience a rather large weight gain during
inhibition of their SNS.
The habitual SNS activity may also play a role in
variability in weight loss during the treatment of obese
patients. Three studies have assessed the relationship
between pretreatment SNS activity of obese subjects
and weight loss outcome during hypoenergetic dieting.
In a study of obese females who underwent 36 weeks of
4.2-MJ d-1 diet, pretreatment levels of postprandial
plasma noradrenaline were positively associated with
the maximum achieved weight loss, and a low plasma
noradrenaline level was found to be a risk factor for a
small weight loss (68). Similarly, pretreatment levels of
both plasma noradrenaline and adrenaline were found
to be positively associated with fat loss in 63 obese
patients undergoing an 8-week, very low energy diet
(2.8 MJ d-1) (69). In a third study, Hellstrom et al. (70)
found that plasma noradrenaline and a2-adrenoceptor
sensitivity was associated with fat loss during 4 weeks on
a 1.6-MJ d-1 diet. These studies suggest that obese
patients with low SNS activity are less responsive to
diet-induced weight loss programs and that plasma
noradrenaline can be used as a prognostic marker of
weight loss.
701
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
REFERENCES
1.
2.
16.
17.
702
18.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
703
59. Argyropoulos G, Brown AM, Willi SM, Zhu J, He Y,
Reitman M, Gevao SM, Spruill I, Garvey WT. Eects
of mutations in the human uncoupling protein 3 gene
on the respiratory quotient and fat oxidation in severe
obesity and type 2 diabetes. J Clin Invest 1998; 102:
13451351.
60. Stuart JA, Harper JA, Brindle KM, Jekabsons MB,
Brand MD. Physiological levels of mammalian uncoupling protein 2 do not uncouple yeast mitochondria. J
Biol Chem 2001; 276:1863318639.
61. Clapham JC, Arch JR, Chapman H, Haynes A, Lister
C, Moore GB, Piercy V, Carter SA, Lehner I, Smith
SA, Beeley LJ, Godden RJ, Herrity N, Skehel M,
Changani KK, Hockings PD, Reid DG, Squires SM,
Hatcher J, Trail B, Latcham J, Rastan S, Harper AJ,
Cadenas S, Buckingham JA, Brand MD, Abuin A.
Mice overexpressing human uncoupling protein-3 in
skeletal muscle are hyperphagic and lean. Nature 2000;
406:415418.
62. Bray GA. Reciprocal relation of food intake and
sympathetic activity: experimental observations and
clinical implications. Int J Obes Relat Metab Disord
2000; 24(suppl 2):S8S17.
63. Young JB, Macdonald IA. Sympathoadrenal activity in
human obesity: heterogeneity of ndings since 1980. Int
J Obes Relat Metab Disord 1992; 16:959967.
64. Tataranni PA, Young JB, Bogardus C, Ravussin E.
A low sympathoadrenal activity is associated with
body weight gain and development of central adiposity in Pima Indian men. Obes Res 1997; 5:341
347.
65. Raben A, Holst JJ, Christensen NJ, Astrup A. Determinants of postprandial appetite sensations: macronutrient intake and glucose metabolism. Int J Obes
Relat Metab Disord 1996; 20:161169.
66. Astrup AV, Christensen NJ, Simonsen L, Bulow J.
Eects of nutrient intake on sympathoadrenal activity
and thermogenic mechanisms. J Neurosci Methods
1990; 34:187192.
67. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy
expenditure resulting from altered body weight. N Engl
J Med 1995; 332:621628.
68. Astrup A, Buemann B, Gluud C, Bennett P, Tjur T,
Christensen N. Prognostic markers for diet-induced
weight loss in obese women. Int J Obes Relat Metab
Disord 1995; 19:275278.
69. Kempen KPG. Predictors of fat loss during very-low
calorie diet in obese females. Maastricht, Holland:
University of Maastricht, 1996.
70. Hellstrom L, Rossner S, Hagstrom-Troft E, Reynisdottir S. Lipolytic catecholamine resistance linked to
alpha2-adrenoceptor sensitivitya metabolic predictor
of weight loss in obese subjects. Int J Obes 1995;
21:314320.
71. Astrup A, Toubro S, Raben A, Skov AR. The role of
low-fat diets and fat substitutes in body weight
704
72.
73.
28
Energy Expenditure and Substrate Oxidation
Jean-Pierre Flatt
University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A.
Angelo Tremblay
Laval University, Sainte-Foy, Quebec, Canada
It is dicult to assess the eciency of oxidative phosphorylation and the P:O ratio in intact cells, because the
ATP turnover due to the cells metabolic activities is not
readily measurable. Pahud et al. (2) were nevertheless
able to assess the eciency of oxidative phosphorylation in man by combining direct and indirect calorimetry measurements in young men pedaling on a bicycle
ergometer at dierent levels of work output. During
sustained aerobic work, the mechanical work performed was equivalent to 27% of the energy contained
in the increment in substrate oxidation elicited by pedaling. During the rst minutes of pedaling against a
suddenly increased resistance, the mechanical work produced (measured electrically with the bicycle ergometer) plus the energy appearing in the form of heat
(measured by direct calorimetry and from the increase
in the subjects body temperature) exceeded the energy
liberated by substrate oxidation (determined by indirect
calorimetry). This implies that preformed high-energy
bonds (ATP and creatine-phosphate) were utilized to
accomplish part of the mechanical work during this
705
706
RQ 1:00
4:99 kcal=L O2
C6H10O5 + 6 O2
Glucosyl-
RQ 1:00
5:05 kcal=L O2
4.5 C6H12O6 + 4 O2
Glucose
RQ 2:75
7:06 kcal=L O2
C16H32O2 + 23 O2
Palmitate
RQ 0:696
4:68 kcal=L O2
RQ 0:71
kcal=L O2
d
e
C57H107O6 + 78 O2
Triglyceride
a 4:69
RQ 0:40
liver
Protein
0.35 Gluc + 0.3 KB + 3.3 O2
RQ 1:0
periphery
C4.6H8.4O1.8N1.25 + 4.8 O2
g
Protein
RQ :835
O2
e 4:66kcal=L
707
Figure 1 ATP yields during oxidation of carbohydrate, fat, and protein. The numbers printed in brackets show moles of
substrate owing through various metabolic pathways, and, in parenthesis, the moles of ATP produced and expended per mole
substrate metabolized, assuming a P:O ratio of 3 for the reoxidation of mitochondrial NADH. (From Ref. 6.)
708
709
710
Several reactions in the fatty acidsynthesizing pathway require ATP, so conversion of glucose into fat requires a substantial energy investment. If the costs for
prior conversion of glucose into glycogen, as well as
for the transport of fatty acid synthesized in the liver
to adipose tissue are also included, the cost for conversion of dietary carbohydrate into fat may be assessed at f25% (7,33). In subjects consuming a
Western diet, fatty acid synthesis from glucose appears
to be of minor quantitative signicance (34,35), as even
the ingestion of an unusually large carbohydrate load
of 500 g is accommodated by expansion of the glycogen
reserves, without increases in body fat (36). Contrary to
still commonly held expectations, dissipation of dietary
energy by conversion of glucose into fat is therefore not
a reason that could explain why high-carbohydrate
diets are less conducive to obesity than high-fat diets.
Futile Cycles
711
Metabolic Eciency
712
(Fig. 2), and the reliability of such evaluations in characterizing potential dierences in metabolic eciencies is questionable.
Dierences in ATP dissipation through ion pumping, futile cycles, and protein turnover are all included
in the measured resting metabolic rates. These are closely correlated with the size of the fat-free mass and the fat
mass, and resting energy expenditures are thus higher
in obese than in lean subjects of the same heights (48),
though a certain degree of variability among individuals remains. The importance often attributed to such
dierences appears to be founded on the presumption
that changes in energy expenditure will not be oset
by changes in energy intake. Under conditions where
energy intake could be clamped at some particular
level, a 5% dierence in resting energy expenditure
would be oset by a dierence in body weight of 58 kg
Cold Exposure
There also seems to be a prevailing perception of increased hunger when subjects are exposed to a cold
environment, and of a tendency to gain fat during the
cold season.
II MEASUREMENT OF SUBSTRATE
OXIDATION AND ENERGY
EXPENDITURE
Changes in the bodys substrate content due to metabolism can be calculated from CO2 production, O2 consumption, and urinary nitrogen excretion data. This
experimental approach has provided a wealth of data on
human energy expenditure (28,29,56,57). The results of
this indirect calorimetry are consistent with data
obtained by direct measurement of heat production,
i.e., direct calorimetry but the former has the advantage of providing information on the relative amounts
of carbohydrate, fat, and protein used. Attention must
be given to careful calibrations to permit accurate
determinations of the respiratory quotient and hence
of the relative proportions of carbohydrate and fat
oxidized. When combined with precise assessment of
the amounts of nutrients consumed, indirect calorimetry can establish substrate or nutrient balances over
periods of 1 day or several days, which are far too small
to be established by body composition measurements
(27). In recent years, indirect calorimetry has been
complemented by the application of the doubly labeled
water (DLW) technique, which has allowed to determine energy expenditure (but not substrate balances) in
free-living subjects (48).
A
713
714
Diet-Induced Thermogenesis
Physical Activity
Figure 3 Variations in respiratory quotient during a lowand a high-intensity exercise. (From Ref. 83.)
715
Daily energy expenditures of subjects conned to a respiratory chamber are substantially lower than in freeliving subjects (91,92), and the spontaneous variations
in physical activity associated with free-living conditions cannot manifest themselves. On the other hand,
DLW measurements, which provide assessment of overall energy expenditure over periods of 710 days, do not
allow to dene variations in energy expenditure from
day to day. Future methodological developments may
permit us to assess substrate oxidation under free-living
conditions, a potential suggested by recent animal studies (93). These variations must be evaluated on the basis
of estimates calculated from activity logs. Many more
data are available on daily food intakes. The coecients
of variations for intraindividual daily food intake are
large, averaging F22% among adults (94), and ranging
from F15 to F33% in children (95). It seems to be
generally held that variations in food intake are substantially greater than variations in energy expenditure.
Deviations from the energy balance are thus probably
comparable in size to the variability in intakes. The
extent of daily variations in food intake and energy
expenditure, and the size of daily deviations from energy balance potentially inuence body weight maintenance, inasmuch as changes in food intake in response
to positive or negative energy balances may not occur
with the same accuracy (96,97).
III
FACTORS DETERMINING
SUBSTRATE OXIDATION RATES
Overall energy expenditure is determined by an individuals size and physical activity, and it is only modestly
Brain
Abdominal organs
Kidneys
Skin
Heart
Skeletal muscles
Other
Total
At rest
Light work
Heavy work
0.20
0.25
0.07
0.02
0.11
0.30
0.05
1.00
0.20
0.24
0.06
0.06
0.23
2.05
0.06
3.00
0.20
0.24
0.07
0.08
0.40
6.95
0.06
8.00
(whole body at rest = 1.00; actual value near 3.8 mL O2 min1 kg1)
Source: Ref. 16.
716
Some of the glucose utilized by various tissues is converted to lactate (Cori cycle) or to alanine (glucosealanine cycle), which are readily reconverted into glucose by the liver. Glucose turnover is thus substantially
greater than the rate of glucose oxidation. Carbohydrate oxidation determined by indirect calorimetry
describes the change in the bodys carbohydrate content. It should be noted at this point that the energy
content of glycogen (4.18 kcal/g) and of glucose (3.7
kcal/g) dier by 10% (because 1 mol of water is removed
when glucose is incorporated into the glycogen or
starch). It is thus important to be consistent and to
specify which of the two is being considered. During the
Starvation Ketosis
717
levels on their rates of utilization during the postprandial phase is enhanced by the release of insulin, which
promotes transport and storage of glucose, amino acids,
and fats while inhibiting the release of glucose from the
liver and of fatty acids from adipose tissue. The decline
in circulating FFA levels, brought about by the antilipolytic action of insulin complemented by the direct
and indirect eects of insulin in activating pyruvate
dehydrogenase (PDH) (111) lead to an increase in glucose oxidation and to a commensurate decrease in fatty
acid oxidation. The decline in insulin secretion when
glucose absorption from the gut is completed, complemented by the release of catecholamines and glucagon,
activates the mobilization of the bodys glycogen and
fat reserves to assure an adequate supply of glucose and
FFA in the circulation (112,113). These eects are
greatly enhanced when the demand for metabolic fuels
is magnied by physical eorts.
2
718
719
720
the items consumed (133). Inactive individuals reporting a high fat and alcohol intake are characterized by
increased subcutaneous adiposity, particularly in the
trunk area (122).
IV
SUBSTRATE BALANCES
AND WEIGHT MAINTENANCE
When the steady state of weight maintenance has become established, the concept of nutrient partitioning is rather meaningless, since over a period of a few
days all the nutrients consumed are oxidized, whereas
the type of nutrient retained preferentially varies from
day to day to compensate for short-term deviations from
equilibrated substrate balances. It is the nature of these
compensatory responses that needs to be examined to
understand what brings about body weight stability.
A
721
are slightly dierent for dierent diets does not deter the
fact that RQ/FQ ratios >1.0 imply positive energy
balances, whereas RQ/FQ ratios <1.0 indicate negative
energy balances. Weight maintenance, which depends
on protein, carbohydrate, and fat balances being all
close to zero, corresponds to the situation where the
respiratory quotient is equal, on average, to the diets
FQ (114).
The need to satisfy the RQ = FQ condition creates
constraints in the system, as it shows that a balance must
be reached between the inuences which the bodys
glycogen stores and the size of the adipose tissue exert
on the relative proportions of glucose and FFA being
oxidized (113,114). This creates a reason for a particular
degree of fatness to become established as long as an
individuals diet and lifestyle, as well as habitual glycogen levels, are constant (cf. Fig. 5). It is therefore not
necessary to postulate the existence of some mysterious
set-point to explain body weight stability.
C
Figure 7 Relationships among the RQ, the RQ/FQ ratio, and energy balance, assuming that carbohydrate balances are
equilibrated (solid lines) or that 20% of the energy imbalances are absorbed by gains or losses of glycogen (dotted lines). (From
Ref. 135.)
722
Impact of Hormones
723
Impact of Drugs
724
CONCLUSIONS
3.
4.
5.
6.
Astrand P-O, Rodahl K. Textbook of Work Physiology, 2nd ed. New York: McGraw-Hill, 1977.
Pahud P, Ravussin E, Jequier E. Energy expended
during oxygen decit period of submaximal exercise in
man. J Appl Physiol 1980; 48:770775.
Flatt JP, Pahud P, Ravussin E, Jequier E. An estimate
of the P:O ratio in man. TIBS 1984; 9:251255.
Brand MD, Couture P, Else PL, Withers KW, Hulbert
AJ. Evolution of energy metabolism. Proton permeability of the inner membrane of liver mitochondria is
greater in a mammal than in a reptile. Biochem J 1991;
275:8186.
Rolfe DFS, Brown GC. Cellular energy utilization and
molecular origen of standard metabolic rate in mammals. Physiol Rev 1997; 77(3):731758.
Flatt JP. Energy costs of ATP synthesis. In: Kinney JH,
Tucker H, eds. Energy Metabolism: Tissue Determinants and Cellular Corollaries. New York: Raven
Press, 1992:319342.
725
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
726
25. Thomas CD, Peters JC, Reed GW, Abumrad NN, Sun
M, Hill JO. Nutrient balance and energy expenditure
during ad libitum feeding of high fat and high
carbohydrate diets in humans. Am J Clin Nutr 1992;
55:934942.
26. Shetty PS, Prentice AM, Goldberg GR, Murgatroyd
PR, McKenna APM, Stubbs RJ, Volschenk PA.
Alterations in fuel selection and voluntary food intake
in response to isoenergetic manipulation of glycogen stores in humans. Am J Clin Nutr 1994; 60:534
543.
27. Stubbs RJ, Harbron CG, Murgatroyd PR, Prentice
AM. Covert manipulation of dietary fat and energy
density: eect on substrate ux and food intake in
men eating ad libitum. Am J Clin Nutr 1995; 62:316
329.
28. Kleiber M. The Fire of Life and Introduction to Animal Energetics. New York: Robert E. Krieger, 1975.
29. Lusk G. The Elements of the Science of Nutrition, 4th
ed. Philadelphia: W.B. Saunders, 1928.
30. Jungas RL, Halperin ML, Brosnan JT. Quantitative
analysis of amino acid oxidation and related gluconeogenesis in humans. Physiol Rev 1992; 72:419448.
31. Flat JP. The biochemistry of energy expenditure. Rec
Adv Obes Res 1978; 2:211228.
32. Shaw SN, Elwyn DH, Askanazi J, Iles M, Schwarz Y,
Kinney JM. Eects of increasing nitrogen intake on
nitrogen balance and energy expenditure in nutritionally depleted adult patients receiving parenteral nutrition. Am J Clin Nutr 1983; 37:930940.
33. Acheson KJ, Schutz, Y, Bessard T, Anantharaman K,
Flatt JP, Jequier E. Glycogen storage capacity and
de novo lipogenesis during massive carbohydrate overfeeding in man. Am J Clin Nutr 1988; 48:240247.
34. Hellerstein MK, Christiansen M, Kaempfer S, Kletke
C, Wu K, Reid JS, Mulligan K, Hellerstein NS,
Shackleton CHL. Measurement of de novo hepatic
lipogenesis in humans using stable isotopes. J Clin
Invest 1991; 87:18411852.
35. Guo ZK, Cella LK, Baum C, E R, Schoeller DA. De
novo lipogenesis in adipose tissue of lean and obese
women: application of deuterated water and isotope
ratio mass spectrometry. Int J Obes 2000; 24:932
937.
36. Acheson KJ, Schutz Y, Bessard T, Ravussin E, Jequier
E, Flatt JP. Nutritional inuences on lipogenesis and
thermogenesis after a carbohydrate meal. Am J Physiol
1984; 246:E62E70.
37. Owen OE, Holup JL, DAlessio DA, Craig ES,
Polansky M, Smalley KJ, Kavle EC, Bushman MC,
Owen LR, Mozzoli MA, Kendrick ZV, Boden GH. A
reappraisal of the caloric requirements of men. Am J
Clin Nutr 1987; 46:875885.
38. Ravussin E, Lillioja S, Anderson TE, Christin L,
Bogardus C. Determinants of 24-h energy expenditure
in man. J Clin Invest 1986; 78:15681578.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
727
68.
Elia M. Energy equivalents of CO2 and their importance in assessing energy expenditure when using tracer
techniques. Am J Physiol 1991; 260:E75E88.
69. Schoeller DA, Van Santen E. Measurement of energy
expenditure in humans by doubly labeled water
method. J Appl Physiol 1982; 53:955959.
70. Roberts SB, Dietz W, Sharp T, Dallal GE, Hill JO.
Multiple laboratory comparison of the doubly labeled
water technique. Obes Res 1995; 3:S3S13.
71. Prentice AM, Coward WA, Davies HL, Murgatroyd
PR, Black AE, Goldberg GR, Ashford J, Sawyer M,
Whitehead RG. Unexpectedly low levels of energy
expenditure in health women. Lancet 1985; i:1419
1422.
72. Heini A, Schutz Y, Diaz E, Prentice AM, Whitehead
RG, Jequier E. Free-living energy expenditure measured by two independent techniques in pregnant and
nonpregnant Gambian women. Am J Physiol 1991;
261:E9E17.
73. Tremblay A, Seale J, Almeras N, Conway J, Moe P.
Energy requirements of a postobese man reporting a
low intake at weight maintenance. Am J Clin Nutr
1991; 54:13.
74. Prentice AM, Black AE, Coward WA, Cole TJ.
Energy expenditure in overweight and obese adults in
auent societies: an analysis of 319 doubly-labelled
water measurements. Eur J Clin Nutr 1996; 50:93
97.
75. Westerterp KR, Saris WHM, Van Es M, Ten Hoor F.
Use of the doubly labelled water technique in humans
during heavy sustained exercise. J Appl Physiol 1986;
61:21622167.
76. Goran MI, Poehlman ET. Endurance training does
not enhance total energy expenditure in healthy elderly
persons. Am J Physiol 1992; 263:E950E957.
77. Heaton JM. The distribution of brown adipose tissue
in the human. J Anat 1972; 112:3539.
78. Astrup A, Bulow J, Madsen J, Christensen NJ. Contribution of brown adipose tissue and skletal muscle
to thermogenesis induced by ephedrine in man. Am J
Physiol 1985; 248:E507E515.
79. Norgan NG, Durnin JVGA. The eect of 6 weeks of
overfeeding on the body weight, body composition,
and energy metabolism of young men. Am J Clin Nutr
1980; 33:978988.
80. Ravussin E, Schutz Y, Acheson KJ, Dusmet M,
Bourquin L, Jequier E. Short-term, mixed-diet overfeeding in man: no evidence for Luxuskonsumption.
Am J Physiol 1985; 249:E470E477.
81. Diaz EO, Prentice AM, Goldberg GR, Murgatroyd
PR, Coward WA. Metabolic response to experimental
overfeeding in lean and overweight healthy volunteers.
Am J Clin Nutr 1992; 56:641655.
82. Tremblay A, Despres JP, Theriault G, Fournier G,
Bouchard C. Overfeeding and energy expenditure in
humans. Am J Clin Nutr 1992; 56:857862.
728
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
729
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
730
Terry RB, Wood PD. Dietary fat: carbohydrate ratio
and obesity in middle aged men. Am J Clin Nutr 1988;
47:9951000.
147. Romieu I, Willett WC, Stampfer MJ, Colditz GA,
Sampson L, Rosner B, Hennekens CH, Speizer FE.
Energy intake and other determinants of relative
weight. Am J Clin Nutr 1988; 47:406412.
148. Tremblay A, Despres J-P, Leblanc C, Craig CL, Ferris
B, Stephens T, Bouchard C. Eect of intensity of
physical activity on body fatness and fat distribution.
Am J Clin Nutr 1990; 51:153157.
149. Ewbank PP, Darga LL, Lucas CP. Physical activity as
a predictor of weight maintenance in previously obese
subjects. Obes Res 1995; 3:257264.
150. Rising R, Harper IT, Fontvielle AM, Ferraro RT,
Spraul M. Determinants of total daily energy expenditure: variability in physical activity. Am J Clin Nutr
1994; 59:800804.
151. Ballor DL, Keesey RE. A meta-analysis of the factors
aecting exercise-induced changes in body mass, fat
mass, and fat-free mass in males and females. Int J
Obes 1991; 15:717726.
152. Tremblay A, Almeras N, Boer J, Kranenbarg EK,
Despres JP. Diet composition and postexercise energy
balance. Am J Clin Nutr 1994; 59:975979.
153. King NA, Blundell JE. High-fat foods overcome the
energy expenditure induced by high-intensity cycling
or running. Eur J Clin Nutr 1995; 49:114123.
154. Schutz Y, Tremblay A, Weinsier RL, Nelson KM.
Role of fat oxidation in the long term stabilization of
body weight in obese women. Am J Clin Nutr 1992;
55:670674.
155. Smith SR, De Jonge L, Zachwieja JJ, Heli R, Nguyen
T, Rood JC, Windhauser MM, Bray GA. Fat and
carbohydrate balances during adaptation to a high-fat
diet. Am J Clin Nutr 2000; 71:450457.
156. Tappy L, Girardet K, Shwaller N, Vollenweider L,
Jequier E, Nicod P, Scherrer U. Metabolic eects of an
increase of sympathetic activity in healthy humans. Int
J Obes 1995; 19:419422.
157. Woods SC, Figlewicz Latteman DP, Schwartz MW,
Porte D. A re-assessment of the regulation of adiposity
and appetite by the brain insulin system. Int J Obes
1990; 14:6976.
158. Rowe JW, Young JB, Minaker KL, Steven AL,
Pallotta J, Lansberg L. Eect of insulin and glucose
infusions on sympathetic nervous system activity in
normal man. Diabetes 1981; 30:219225.
159. Berne C, Fagius J, Pollare T, Hemjdahl P. The
sympathetic response to euglycaemic hyperinsulinemia. Diabetologia 1992; 35:873879.
160. Vollenweider P, Randin D, Tappy L, Jequier E, Nicod
P, Scherrer U. Impaired insulin-induced sympathetic
neural activation and vasodilation in skeletal muscle
in obese humans. J Clin Invest 1994; 93:23652371.
161. Bray GA. Obesitya state of reduced sympathetic
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
activity and normal or high adrenal activity (the autonomic and adrenal hypothesis revisited). Int J Obes
1990; 14:7792.
Kaiyala KJ, Woods SC, Schwartz MW. New model
for the regulation of energy balance and adiposity by
the central nervous system. Am J Clin Nutr 1995; 62:
1123S1134S.
Schwartz MJ, Marks J, Sipols AJ, Baskin DG, Wood
SC, Kahn SE, Porte D. Central insulin administration reduces neuropeptide Y mRNA expression in the
arcuate nucleus of food-deprived lean (Fa/Fa) but
not obese (fa/fa) Zucker rats. Endocrinology 1991; 128:
26452647.
Williams G, McKibbin PE, McCarthy HD. Hypothalamic regulatory peptides and the regulation of
food intake and energy balance: signals or noise? Proc
Nutr Soc 1991; 50:527544.
Tremblay A, Sauve L, Despres JP, Nadeau A,
Theriault G, Bouchard C. Metabolic characteristics
of postobese individuals. Int J Obes 1989; 13: 357
366.
Tremblay A, Despres J-P, Maheux J, Pouliot MC,
Nadeau A, Moorjani PJ, Lupien PJ, Bouchard C.
Normalization of the metabolic prole in obese women by exercise and a low fat diet. Med Sci Sports
Exerc 1991; 23(12):13261331.
Saito M, Bray GA. Adrenalectomy and food restriction in the genetically obese (ob/ob) mouse. Am J
Physiol 1984; 246:R20R25.
Salomon F, Cuneo RC, Hesp R, Sonksen PH. The
eects of treatment with recombinant human growth
hormone on body composition and metabolism in
adults with growth hormone deciency. N Engl J Med
1989; 321:797803.
Simoneau JA, Bouchard C. Skeletal muscle metabolism and body fat content in men and women. Obes
Res 1995; 3:2329.
Colberg S, Simoneau J, Thaete F, Kelley D. Skeletal
muscle utilization of free fatty acids in women with
visceral obesity. J Clin Invest 1995; 95:18461853.
Lean MEJ, James WPT. Metabolic eects of isoenergetic nutrient exchange over 24 hours in relation
to obesity in women. Int J Obes 1988; 8:641648.
Buemann B, Astrup A, Madsen J, Christensen NJ. A
24-h energy expenditure study on reduced-obese and
nonobese women: eect of h-blockade. Am J Clin Nutr
1992; 56:662670.
Astrup A, Buemann B, Christensen NJ, Toubro S.
Failure to increase lipid oxidation in response to increasing dietary fat content in formerly obese women.
Am J Physiol 1994; 266:E592E599.
Raben A, Anderson HB, Christensen NJ, Madsen J,
Holst JJ, Astrup A. Evidence for an abnormal postprandial response to a high fat meal in women predisposed to obesity. Am J Physiol 1994; 267:E549
E559.
731
181.
182.
183.
Nadeau A, Bouchard C. Genotype dependency of dietary induced thermogenesis: its relation with hormonal
changes following overfeeding. Metabolism 1986; 35:
3036.
Poehlman ET, Tremblay A, Despres JP, Fontaine E,
Perusse L, Theriault G, Bouchard C. Genotype-controlled changes in body composition and morphology
following overfeeding in twins. Am J Clin Nutr 1986;
43:723731.
Bouchard C, Tremblay A, Despres JP, Nadeau A,
Lupien PJ, Theriault G, Dussault J, Moorjani S,
Pinault S, Fournier G. The response to long term
overfeeding in identical twins. N Engl J Med 1990; 322:
14771482.
Heitman BL, Lissner L, Srensen TIA, Bengtsson C.
Dietary fat intake and weight gain in women genetically predisposed for obesity. Am J Clin Nutr 1995; 61:
12131217.
29
Skeletal Muscle and Obesity
David E. Kelley
University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
Len Storlien
University of Wollongong, Wollongong, New South Wales, Australia, and AstraZeneca, Molndal, Sweden
INTRODUCTION
II
NONINVASIVE STUDIES OF
SKELETAL MUSCLE COMPOSITION
IN OBESITY
734
While quantitative muscle mass may be higher in obesity, a considerable body of literature has accumulated
that shows that qualitatively this muscle mass is quite
dierent in obesity with one of the features being different levels and localization of fats. Both computed
tomography and magnetic resonance imaging are appropriate and sensitive tools for investigations of such
issues (4).
1
Computed Tomography
735
Figure 1 Shown in the upper and lower panels are histograms of the distributions of skeletal muscle attenuation values, in Hounseld units, measured by computed tomography
imaging of the midthigh skeletal muscle. The dark shaded
bars for muscle from a lean subject represent the normal distribution (95% condence levels established in a group of
lean, healthy volunteers). In muscle from the obese subject, the
distribution of attenuation values is shifted to the left, and just
approximately half of the pixels are within the normal range.
736
MICROSCOPIC STUDIES OF
SKELETAL MUSCLE FIBERS
IN OBESITY
Lipid Content in Muscle Fibers
737
Figure 2 Skeletal muscle, biopsied from vastus lateralis muscle, is shown stained for ber type (ATPase), lipid content (Oil Red
O), oxidative enzyme capacity (SDH), and glycolytic enzyme activity (GPDH). A biopsy from a lean volunteer and one from an
obese volunteer are shown. The cryosections from muscle are stained in serial order so that these respective characteristics can be
assessed within single bers.
738
uncertain, though it might be speculated that a homeostatic balance between fuel stores and capacity for
oxidative metabolism is present in lean individuals. If
this is so, then the pattern in the muscle of individuals
with obesity and type 2 diabetes mellitus suggests that
lipid storage is increased out of proportion to the
capacity of these myocytes for substrate oxidation.
C
739
740
dria number or function, or both. Interestingly, following weight loss the subjects in the study by Simoneau
(48) did not have improvement in the capacity for fat
oxidation as measured by activities of CPT, CS, and
cytochrome C oxidase. In that same study, an increased
content of cytosolic fatty acid binding protein was
found in obesity, with an additional gender-related effect of higher concentrations in women. However, other
groups have found diminished content of cytosolic fatty
acidbinding protein in skeletal muscle in obese individuals with type 2 diabetes (49).
Another line of investigation into the capacity of
skeletal muscle for lipid oxidation concerns malonyl
CoA. Although skeletal muscle has a relatively limited
capacity for de novo lipogenesis, it does synthesize
malonyl CoA. Ruderman and colleagues (50) have
found that muscle content of malonyl CoA in rodents
increases in response to insulin and glucose, and can be
increased in insulin resistance and following denervation. Similar studies by Winder and colleagues (51)
indicate that increased muscle glucose metabolism in
skeletal muscle of the rat leads to an increased malonyl
CoA concentration. This is potentially germane to the
capacity for lipid oxidation because an increase in
malonyl CoA can inhibit CPT I, the muscle isoform of
which is particularly sensitive to inhibition by malonyl
CoA (52). Several groups have studied the regulation of
acetyl CoA carboxylase (ACC), the enzyme responsible
for synthesizing malonyl CoA from carbohydrate
(53,54). The thrust of this line of investigation is that
conditions may prevail in obesity and glucose intolerance, as well as inactivity, for accumulation of malonyl
CoA in skeletal muscle and thus lead to allosteric
inhibition of CPT I and, consequently, an inhibition
of lipid oxidation. Certainly, prolonged inhibition of
CPT1 has been shown to increase intramyocellular
triglyceride in studies on rodents (55). Then, excess
triglyceride or FFA in muscle might lead to increased
long chain acyl-CoA concentrations (5658), which in
turn might lead to further insulin resistance. We will
return to this issue.
Still another line of inquiry concerns uncoupling
proteins. Uncoupling proteins are postulated to inuence thermogenesis, as is well supported by the role of
UCP 1 in brown adipose tissue and suggested for homologs UCP 2 and 3. These ndings have potential
implications for the pathogenesis of obesity. Nordfors
et al. (59) reported decreased expression of UCP 2 in
skeletal muscle of human obese subjects. However,
Simoneau et al. (60) found increased protein content
UCP 2 in human skeletal muscle from obese individuals,
and examined the potential relation to energy expenditure and substrate oxidation, as well as to insulin
resistance, which is common in obesity. Skeletal muscle
UCP 2 content was signicantly higher in obesity and
was positively correlated with %FM (r=.60; P<.05).
However, UCP 2 content in muscle was not correlated
with basal energy expenditure (r=.03; P=.93), nor with
insulin stimulated rates of glucose metabolism Rd
(r=.21; P=.47) (60). There was a signicant correlation between muscle UCP 2 and patterns of macronutrient substrate oxidation within skeletal muscle,
such increased UCP 2 was associated with higher fasting
values of leg RQ (r=.57; P<.05), suggesting that UCP
2 may help to regulate nutrient partitioning within
muscle and favor carbohydrate oxidation. Several lines
of evidence suggest that UCP 3 expression is related to
fatty acid availability (61).
C
741
The indirect eects on energy balance via modulation of insulin action by lipid intermediates is likely to
involve a complex series of cellular metabolic interactions which, pleasingly, the data are now beginning
to clarify. Briey, saturated fatty acids like palmitate
specically inhibit PKB/Akt activation and, concomitantly, insulin-stimulated glucose uptake in primary
myocyte cultures (68). Equally, PKB activation has
been shown to inhibit insulin stimulation of glycogen
synthase kinase-3, thus impairing cellular capacity for
glycogen synthesis (69,70). Both of these observations
are likely to involve ceramide production; ceramide is
a sphingolipid derivative of palmitate, being the condensation product of serine and palmitoylCoA. Ceramides are on the synthetic pathway for, and are
also formed from the breakdown of, sphingomyelins.
Sphingomyelin concentrations in adipose tissue and
plasma have been shown to be positively related to
obesity (71,72). Cytokines like tumor necrosis factoralpha (TNF-a) increase breakdown of sphingomyelins.
Interestingly, salicylates (aspirin is acetylsalicylate)
inhibit sphingomyelin-generated ceramide production
and high doses have been shown to reduce obesity and
improve insulin action (73,74) although other mechanisms are also likely to be important in explaining this
observation.
Additional mechanisms of fatty acid modulation of
muscle lipid metabolism are likely to come via inuences on the sterol regulatory elementbinding proteins
(SREBPs). Activation particularly of SREBP1c induces
a number of enzymes in the pathways of de novo fatty
acid synthesis and through to triglyceride formation
(see 75). It has recently been shown that while palmitate
slightly induces SREBP1 expression in cell systems,
more unsaturated fatty acids are powerfully inhibitory
(76). Equally, it has been shown that diacylglycerol
(DAG) accumulation, from an increase in fatty acylCoA availability, specically from palmitate impairs
insulin-stimulated glucose uptake in primary myocyte
cultures (68). DAGs activate a number of isoforms of
protein kinase C (PKC), and it is likely that a mechanism linking DAG accumulation from palmitate to
impaired insulin action involves the known PKC inhibition of glucose transporter translocation. Palmitate is
the major end product of endogenous lipogenesis via
the fatty acid synthase cascade. In this regard it is
interesting that mice with absent or reduced fatty acid
synthase activity (knockout or cerulenin-treated) are
lean and resistant to high-fat feeding-induced obesity
(77). While the contribution of endogenous lipogenesis
to the total fatty acid pool in humans is a matter of
742
CLINICAL INVESTIGATIONS OF
FATTY ACID METABOLISM BY
SKELETAL MUSCLE IN OBESITY
743
744
Across the entire cohort, the amplitude of insulinstimulated change in leg RQ (D leg RQ: insulin-stimulated leg RQ fasting leg RQ) correlated signicantly
with insulin-stimulated increases in glucose metabolism
(r = .66, P<.001). This indicates responsiveness to
insulin in modulation of leg RQ is related to capacity
to respond to insulin stimulation of glucose uptake.
In obesity, the eect of insulin to suppress lipid oxidation was blunted, as has been previously reported (91,
92), and this clearly ts with the classic concept of fatty
acid induced insulin resistance (93). Not only was
incomplete suppression of lipid oxidation during insulin
stimulation observed among the obese volunteers in this
study, but rates of muscle lipid oxidation during insulin
infusion were correlated with the severity of insulinresistant glucose metabolism.
In summary, these observations do not indicate that
fatty acid oxidation within insulin-resistant muscle is
persistently increased. While insulin infusion did not
suppress muscle lipid oxidation in obesity (compared to
strong suppression in lean individuals), these rates of
fat oxidation were unchanged from fasting conditions.
During fasting conditions, rates of fat oxidation in skeletal muscle were lower in obese than in lean individuals.
745
VI
INSULIN-RESISTANT GLUCOSE
METABOLISM OF OBESITY
746
VII
In summary, the composition and biochemistry of skeletal muscle are altered in obese as compared to nonobese
individuals. These alterations dispose to a reduction in
the role of skeletal muscle in oxidation of lipid calories
and to a pattern of macronutrient partitioning that
increases lipid storage within skeletal muscle and systemically. Such a key role for skeletal muscle in the
pathogenesis of obesity is certainly consistent with the
capacity which skeletal muscle has to utilize both carbohydrate and lipid fuels and with the major role which
skeletal muscle can have in overall fuel balance. An
important morphological characteristic of skeletal
muscle in obesity is increased content of fat, particularly
the intramyocellular component. Accretion of fat within
muscle tissues appears to strongly correlate with insulin
resistance. This fat accretion within muscle of obese
individuals may not be simply a passive process, paralleling fat storage in other tissues. Instead, and of particular metabolic interest, is the emerging concept that
biochemical characteristics of skeletal muscle in obese
individuals dispose to fat accumulation in muscle and
may contribute substantially to the development and
maintenance of the obese state. These biochemical
characteristics of muscle in obese individuals have long
been recognized to include insulin resistance in pathways of glucose metabolism, and more recent studies
indicate as well a reduced capacity for the utilization of
fat calories. Again, it must be emphasized that a key
feature of skeletal muscle in obesity is a marked inexibility in modulation of fat utilization.
747
ACKNOWLEDGMENTS
The authors would like foremost to acknowledge and
remember the valuable contributions of Dr. Jean-Aime
Simoneau, who passed away in 1999. Dr. Simoneau
was an insightful investigator of obesity and the role of
skeletal muscle in the pathogenesis of obesity. This
chapter is dedicated to his memory. We would also like
to acknowledge the helpful comments of many
colleagues, and the cooperation of the many research
volunteers, without whom this knowledge could not
have been gained.
REFERENCES
1.
2.
748
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
749
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
750
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
751
tory quotient as a prognostic factor in weight-loss
rebound. Int J Obes 1997; 21:811817.
96. Friedman JE, Dohm L, Leggett-Frazier N, Elton CW,
Tapscott EB, Pories WP, Caro JF. Restoration of
insulin responsiveness in skeletal muscle of morbidly
obese patients after weight loss. J Clin Invest 1992;
89:701705.
97. Kempen KPG, Saris WHM, Kuipers H, Glatz JFC,
Van der Vusse GJ. Skeletal muscle metabolic characteristics before and after energy restriction in human
obesity: bre type, enzymatic h-oxidative capacity and
fatty acid bind protein content. Eur J Clin Invest 1998;
28:10301037.
98. Amatruda JM, Statt MC, Welle SL. Total and resting
energy expenditure in obese women reduced to ideal
body weight. J Clin Invest 1993; 92:12361242.
99. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy
expenditure resulting from altered body weight. N Engl
J Med 1995; 332:621628.
100. Ranneries C, Bulow J, Buemann B, Christensen NJ,
Madsen J, Astrup A. Fat metabolism in formerly obese
women. Am J Physiol 1998; 274:E155E161.
101. Turcotte LP, Richter EA, Kiens B. Increased plasma
FFA uptake and oxidation during prolonged exercise in
trained versus untrained humans. Am J Physiol 1992;
262:E791E799.
102. Olefsky JM, Farquhar JW, Reaven G. Relationship
between fasting plasma insulin level and resistance to
insulin-mediated glucose uptake in normal and diabetic
subjects. Diabetes 1973; 22:507513.
103. Olefsky JM. Decreased insulin binding to adipocytes
and monocytes from obese subjects. J Clin Invest 1976;
57:11651172.
104. Bogardus C, Lillioja S, Stone K, Mott D. Correlation
between muscle glycogen synthase activity and in vivo
insulin action in man. J Clin Invest 1984; 73:1185
1190.
105. Yki-Jarvinen H, Mott D, Young AA, Stone K,
Bogardus C. Regulation of glycogen synthase and
phosphorylase activities by glucose and insulin in
human skeletal muscle. J Clin Invest 1987; 80:95100.
106. Rothman DL, Shulman RG, Shulman GI. 31P nuclear
magnetic resonance measurements of muscle glucose-6phosphate: evidence for reduced insulin-dependent
muscle glucose transport or phosphorylation activity
in non-insulin-dependent diabetes mellitus. J Clin
Invest 1992; 89:10691075.
107. Roden M, Price TB, Perseghin G, Petersen KF,
Rothman DL, Cline GW, Shulman GI. Mechanism of
free fatty acid-induced insulin resistance in humans. J
Clin Invest 1996; 97:28592865.
108. Shulman GI, Rothman D, Jue T, Stein P, DeFronzo R,
Shulman R. Quantitation of muscle glycogen synthesis
in normal subjects and subjects with non-insulindependent diabetes by 13C nuclear magnetic resonance
spectroscopy. N Engl J Med 1990; 322:223228.
109. Saccomani MP, Bier DM, DeFronzo RA, Cobelli C. A
752
110.
111.
112.
113.
114.
115.
116.
30
Nutrient Partitioning
Samyah Shadid and Michael D. Jensen
Mayo Clinic, Rochester, Minnesota, U.S.A.
I
A
stimulate appetite. Other examples where nutrient partitioning relates to obesity and body fat content include
the stimulation of lean tissue synthesis at the expense
of fat calories by androgens and growth hormone, and
(presumably) the reverse of this process by deciencies
of these hormones.
A variety of physiological and cellular events play
key roles in determining nutrient partitioning. After a
general overview of these major determinants, the regulation of the major pathways of nutrient partitioning
will be reviewed, followed by specic hormonal inuences on each pathway. The net eects of the major nutrient partitioning hormones (insulin, growth hormone,
testosterone and cortisol) on lipid, protein, and carbohydrate metabolism are summarized in Figures 13.
INTRODUCTION
General Considerations on Nutrient
Partitioning
753
754
D
Figure 2 Endocrine control of glucose metabolism. Only
direct and noncontroversial eects are depicted. Cortisol and
growth hormone have additional eects to increase plasma
glucose concentrations by inducing insulin resistance.
Nutrient partitioning could be accompanied or exaggerated by changes in energy expenditure. Human energy
expenditure is usually broken down into three compo-
Nutrient Partitioning
II PROCESSING OF FUEL
The main sources of dietary energy are carbohydrates
(4 kcal/g), proteins (4 kcal/g), fat (9 kcal/g), and alcohol
(7 kcal/g). Alcohol will not be discussed. Fat, carbohydrates, and protein can serve functions in addition to
fuel provision and the ultimate fate of these molecules
depends on a variety of factors, among which hormonal
inuences are of importance.
A
Lipid Metabolism
755
Regulation of Lipolysis
Because of the importance of FFA availability in determining substrate oxidation, a brief overview of adipose tissue lipolysis will be provided. Under overnight
postabsorptive conditions, adipose tissue lipolysis is
restrained by the prevailing insulinemia; pharmacological inhibition of insulin secretion using somatostatin
results in an approximate doubling of FFA release rates.
Physiological hyperinsulinemia is capable of suppressing FFA release rates by 8090% from basal levels, and
FFA concentrations by >90%. Insulin-resistant obese
individuals display greater maximal release of FFA
during insulin withdrawal and lesser suppression of
FFA during hyperinsulinemia. Catecholamines are also
potent regulators of adipose tissue lipolysis. Epinephrine infusions can increase FFA release by three- to
fourfold. This is similar to the stimulation of lipolysis
that occurs during exercise. Catecholamines act through
the stimulation of h-adrenergic receptors via a classic
Gs-protein/cylic AMP mechanism that activates HSL
(2). Other hormonal regulators of lipolysis include
756
growth hormone and cortisol, although these are generally considered to be much less potent than insulin
and catecholamines.
B
Carbohydrate Metabolism
Protein Metabolism
Proteins include structural proteins, enzymes, nucleoproteins, oxygen-transporting proteins, contractile proteins, etc. The amino acids in these proteins are part of
an interchangeable pool. The daily turnover of amino
acids is substantially greater than the amount ingested
as dietary protein; only a minor fraction of amino acids
are oxidized or converted to glucose or fat.
Mechanical stimuli enhance skeletal muscle contractile protein synthesis, whereas hormonal and other
factors determine the synthesis rates of many types
of proteins. Given the tremendous variety of proteins
in the body, many of which have specic regulatory
pathways, this chapter will make only general reference to hormonal or metabolic regulation of protein
metabolism.
III
The eects of GH on fuel partitioning are directed toward the use of fat as the preferred oxidative substrate.
One of its main eects is, therefore, to increase FFA
availability to peripheral tissues. However, its metabolic
eects are biphasic: in the rst f90 min after secretion,
a transient insulinlike eect is observed, characterized
by accelerated glucose uptake and oxidation (6). Only
after this eect has dissipated, GH adopts lipolytic and
diabetogenic eects.
Nutrient Partitioning
757
758
Nutrient Partitioning
759
tions do tend to increase. Of interest, testosterone treatment in adolescents with delayed puberty causes insulin
stimulated oxidative and nonoxidative glucose disposal
rates to decline (18). These eects could well be temporary, as is the insulin resistance of puberty, and may be
related to increased competition from greater fatty acid
oxidation. In obese men, who are known to have lower
plasma testosterone levels, testosterone administration
increases insulin-stimulated glucose disposal rates (40).
Whether this is a direct or an indirect eect, perhaps
relating to changes in fat distribution or adipose tissue
function, is not clear.
During both acute and chronic hypercortisolemia, glucose levels are almost invariably reported to increase,
which is only partially attenuated by simultaneously
increasing insulin levels (28,45). This is a combined
eect of a decrease in insulin stimulated glucose uptake
and of glucose overproduction (14,28,33). The former
might be due to the increased circulating FFA, and, in
chronic corticosteroid exposure, perhaps also to
changes in muscle ber types (see below). As expected,
whole-body glucose oxidation diminishes (28,29). Glucose overproduction can be in part attributed to increased gluconeogenesis, which is induced by the increased supply of amino acids (especially alanine) and
glycerol, derived from protein and fat mobilization
(14,45,46).
It is likely that the combination of increased circulating glucose and peripheral insulin resistance, again, is a
reection of fuel redistribution: peripheral organs are
760
concentrations resulting from isolated hyperinsulinemia. Thus, partitioning of amino acids between skeletal
muscle and nonskeletal muscle sources is at least partially regulated by insulin.
2
Acute testosterone deciency, induced by GnRH analogs, has been shown to decrease whole-body protein
synthesis and proteolysis, resulting in a decrease in fatfree mass and muscle strength (19). Testosterone supplementation studies have conrmed these conclusions,
except for the eects on proteolysis, which was found to
decline under the inuence of testosterone.
These studies consistently reported that testosterone
administration or deciency did not change amino acid
oxidation rates or plasma amino acid concentrations.
This suggests that testosterone amplies muscle mass
by enhancing intracellular partitioning of amino acids
toward protein synthesis (especially in muscle) rather
than by increasing amino acid uptake. The latter has
been conrmed in amino acid tracer studies of testosterone administration in healthy young men (54). It
should be noted, however, that these studies are conducted in fasted states and that, under physiological
conditions, cellular amino acid availability and uptake
are expected to increase due to postprandial uctuations
in other hormones such as insulin and GH.
The well-established protein catabolic qualities of cortisol are far from random. Protein (but also fat and carbohydrate) supplies are mobilized, re-stored, and redirected according to their biological priority in stress
situations. Acute hypercortisolemia increases wholebody proteolysis (28,33,45) and concomitantly decreases whole-body protein synthesis (49). However,
the production of some proteins, such as some hepatic
proteins and some lymphocyte proteins, is selectively
stimulated (57). Overall amino acid oxidation increases
(28,58).
With chronic hypercortisolemia, whole-body protein
synthesis has also been shown to decrease, whereas the
eects on proteolysis are controversial (47,49). In addition, with prolonged hypercortisolemia, protein catabolism progressively outpaces protein synthesis (28,57),
leading to the evident protein wasting in the skeletal
Nutrient Partitioning
muscle and skin in Cushings syndrome, which accentuates the characteristic centripetal fat redistribution.
Furthermore, over time structural changes can be
observed in muscle. In addition to the above-mentioned
atrophy, one study found that muscles in Cushings syndrome may contain more type IIb (32% vs. 12%) than
type I bers (30% vs. 55%) compared to control subjects (59). Type IIb bers have a lower glycogen synthase activity and fewer mitochondria and are therefore thought to be more insulin resistant. Interestingly,
upper-body obese women display characteristics similar to those of women with Cushings syndrome.
IV
A
NUTRIENT PARTITIONING
IN OBESITY
General Considerations
761
762
Testosterone deciency leads to visceral fat accumulation; however, analogously to GH, visceral obesity as a
primary entity is also associated with lower free testosterone levels in men (62). As noted above, however, in
women visceral obesity is associated with increased
free testosterone (63). A satisfactory explanation for
this paradox has yet to be found; in neither case is it
clear whether this is based on a cause-and-eect relationship, or if so, whether the central fat accumulation
leads to changed testosterone levels or vice versa. In
both sexes, weight loss has been consistently found to
reverse the abnormalities in testosterone levels (6467).
Several theories have postulated hormones such as
leptin and GH to mediate the observed changes. However, neither is compatible with the changes in testosterone levels in women (68,69), and each theory is met
with many other counterarguments.
In conclusion, upper-body obesity is associated with
reversible high testosterone levels in women but low
levels in men. Though the latter relationship has been
intensively investigated, insight in the mechanism remains poor, theories varying from direct cause-andeect relationships to indirect eects involving leptin
and GH.
4
Visceral obesity shares many characteristics with Cushings syndrome. Both conditions are associated with
large abdominal subcutaneous fat cells with high lipolytic qualities, insulin resistance, hypertension, and
even buccal fat accumulation (70,71). In addition, the
changes in muscle bers described in women with Cushings syndrome were also found in upper-body obesity
(59).
As neither of these is typical of lower-body obesity, it
has been suggested that visceral adiposity might be associated with changes in the hypothalamus-pituitaryadrenal (HPA) axis or cortisol receptors. Indeed, one
glucocorticoid receptor polymorphism is associated
with visceral obesity (72), although it is unclear how
common or physiologically relevant these types of gene
polymorphisms are in upper body adiposity. The fact
that the HPA axis, on the other hand, is closely intertwined with food intake, makes a role in the development or sustaining of visceral obesity more plausible.
CRH is a potent anorexic peptide; the increased appetite, found in most types of hypercortisolemia, is
thought to be mediated by feedback inhibition of corticosteriods on CRH release. In rodent models, CRH
administration reduces the body weight threshold for
food hoarding behavior (73).
Therefore, obesity has been proposed to be a CRHdecient state. However, the changes in HPA axis found
in obesity, especially the abdominal type (74), are more
suggestive of a hyperactive HPA axis. Secretory rates of
cortisol are elevated in most, but not all, studies, even
when corrected for body surface area. Plasma cortisol
concentrations, however, remain normal or slightly lowered (74,75), which is thought to be a result of increased
plasma cortisol clearance. Indeed, many, but not all,
human studies report increased urinary cortisol excretion rates in obesity (71). In addition, the urinary excretion of 5a-reductase cortisol metabolites is positively
Nutrient Partitioning
763
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Flatt JP. Carbohydrate balance and food intake regulation. Am J Clin Nutr 1995; 62(1):155157.
Lafontan M, Berlan M. Fat cell a2-adrenoceptors: the
regulation of fat cell function and lipolysis. Endocr Rev
1995; 16(6):716738.
Meek S, Nair KS, Jensen MD. Insulin regulation of
regional free fatty acid metabolism. Diabetes 1999; 48:
1014.
Guo ZK, Hensrud DD, Johnson CM, Jensen MD. Regional postprandial fatty acid metabolism in dierent
obesity phenotypes. Diabetes 1999; 48:15861592.
Romanski SA, Nelson R, Jensen MD. Meal fatty acid
uptake in adipose tissue: gender eects in non-obese humans. Am J Physiol Endocrinol Metab 2000; 279:E455
E462.
Bengtsson B-A, Brummer R-JM, Eden S, Sjostrom L.
Eects of growth hormone on fat mass and fat distribution. Acta Paediatr 1992; 383:6265.
Mauras N, OBrien KO, Welch S, Rini A, Helgeson K,
Vieira NE, Yergey AL. Insulin-like growth factor I and
growth hormone (GH) treatment in GH-decient humans: dierential eects on protein, glucose, lipid, and
calcium metabolism. J Clin Endocrinol Metab 2000;
85(4):16861694.
Richelsen B, Pedersen SB, Kristensen K, Borglum JD,
Norrelund H, Christiansen JS, Jorgensen JO. Regulation of lipoprotein lipase and hormone-sensitive lipase
activity and gene expression in adipose and muscle tissue by growth hormone treatment during weight loss
in obese patients. Metabolism 2000; 49(7):906911.
Ottosson M, Vikman-Adolfsson K, Enerback S, Elander
A, Bjorntorp P, Eden S. Growth hormone inhibits lipoprotein lipase activity in human adipose tissue. J Clin
Endocrinol Metab 1995; 80(3):936941.
Richelsen B. Eect of growth hormone on adipose tissue and skeletal muscle lipoprotein lipase activity in
humans. J Endocrinol Invest 1999; 22(5 suppl):1015.
Oscarsson J, Ottosson M, Vikman-Adolfsson K, Frick
F, Enerback S, Lithell H, Eden S. GH but not IGF-I or
insulin increases lipoprotein lipase activity in muscle tissues of hypophysectomised rats. J Endocrinol 1999;
160(2):247255.
Slavin BG, Ong JM, Kern PA. Hormonal regulation of
hormone-sensitive lipase activity and mRNA levels in
isolated rat adipocytes. J Lipid Res 1994; 35(9):1535
1541.
Bjorgell P, Rosberg S, Isaksson O, Belfrage P. The antilipolytic, insulin-like eect of growth hormone is caused
by a net decrease of hormone-sensitive lipase phosphorylation. Endocrinology 1984; 115(3):11511156.
764
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
Nutrient Partitioning
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
765
55. Mauras N. Estrogens do not aect whole-body protein
metabolism in the prepubertal female. J Clin Endocrinol
Metab 1995; 80(10):28422845.
56. OSullivan AJ, Ho KK. A comparison of the eects of
oral and transdermal estrogen replacement on insulin
sensitivity in postmenopausal women. J Clin Endocrinol Metab 1995; 80(6):17831788.
57. Putignano P, Kaltsas GA, Korbonits M, Jenkins PJ,
Monson JP, Besser GM, Grossman AB. Alterations in
serum protein levels in patients with Cushings syndrome
before and after successful treatment. J Clin Endocrinol
Metab 2000; 85:33093312.
58. Haymond MW, Horber FF. The eects of human
growth hormone and prednisone on whole body estimates of protein metabolism. Horm Res 1992; 38(suppl
2):4446.
59. Rebue-Scrive M, Krotkiewski M, Elfverson J, Bjorntorp P. Muscle and adipose tissue morphology and
metabolism in Cushings syndrome. J Clin Endocrinol
Metab 1988; 67:11221128.
60. Eckel RH. Insulin resistance: an adaptation for weight
maintenance. Lancet 1992; 340(8833):14521453.
61. Scacchi M, Pincelli AI, Cavagnini F. Growth hormone in
obesity. Int J Obes Relat Metab Disord 1999; 23(3):260
271.
62. Couillard C, Gagnon J, Bergeron J, Leon AS, Rao DC,
Skinner JS, Wilmore JH, Despres JP, Bouchard C.
Contribution of body fatness and adipose tissue distribution to the age variation in plasma steroid hormone
concentrations in men: the HERITAGE Family Study. J
Clin Endocrinol Metab 2000; 85(3):10261031.
63. Jensen MD. Androgen eect on body composition and
fat metabolism. Mayo Clin Proc 2000; 75:S65S69.
64. Lima N, Cavaliere H, Knobel M, Halpern A, MedeirosNeto G. Decreased androgen levels in massively obese
men may be associated with impaired function of the
gonadostat. Int J Obes Relat Metab Disord 2000;
24(11):14331437.
65. Kraemer WJ, Volek JS, Clark KL, Gordon SE, Puhl
SM, Koziris LP, McBride JM, Triplett-McBride NT,
Putukian M, Newton RU, Hakkinen K, Bush JA,
Sebastianelli WJ. Inuence of exercise training on physiological and performance changes with weight loss in
men. Med Sci Sports Exerc 1999; 31(9):13201329.
66. Turcato E, Zamboni M, De Pergola G, Armellini F,
Zivelonghi A, Bergamo-Andreis IA, Giorgino R, Bosello
O. Interrelationships between weight loss, body fat distribution and sex hormones in pre- and postmenopausal
obese women. J Intern Med 1997; 241(5):363372.
67. Wabitsch M, Hauner H, Heinze E, Bockmann A, Benz
R, Mayer H, Teller W. Body fat distribution and steroid
hormone concentrations in obese adolescent girls before
and after weight reduction. J Clin Endocrinol Metab
1995; 80(12):34693475.
68. Isidori AM, Caprio M, Strollo F, Moretti C, Frajese G,
Isidori A, Fabbri A. Leptin and androgens in male obe-
766
sity: evidence for leptin contribution to reduced androgen levels. J Clin Endocrinol Metab 1999; 84(10):3673
3680.
69. Vermeulen A, Goemaere S, Kaufman JM. Testosterone, body composition and aging. J Endocrinol Invest
1999; 22(5 suppl):110116.
70. Levine JA. Relation between chubby cheeks and
visceral fat. N Engl J Med 1998; 339(26):19461947.
71. Pasquali R, Vicennati V. Activity of the hypothalamicpituitary-adrenal axis in dierent obesity phenotypes. Int
J Obes Relat Metab Disord 2000; 24(suppl 2):S47S49.
72. Buemann B, Vohl MC, Chagnon M, Chagnon YC,
Gagnon J, Perusse L, Dionne F, Despres JP, Tremblay
A, Nadeau A, Bouchard C. Abdominal visceral fat is
associated with a Bc1I restriction fragment length poly-
73.
74.
75.
76.
31
Obesity and Mortality Rates
Kevin R. Fontaine
Johns Hopkins University, Baltimore, Maryland, U.S.A.
David B. Allison
The University of Alabama at Birmingham, Birmingham, Alabama, U.S.A.
States and most of the Western world (24). As agricultural and industrial technologies spread into the
non-Western world, both the relative body weights
and rates of obesity are increasing in those populations as well (5). Given this, it is not surprising that
body weight is of considerable interest to the scientic community. Indeed, the problem of obesity has
become the subject of governmental policies, public
education campaigns, and insurance policies, and has
become a major target of the food and pharmaceutical
industries.
Despite eorts to address the rising rates of obesity,
the eect of variations in body weight on mortality remains a controversial topic (69). Some studies (1012)
suggest that the relationship between measures of relative body weight (e.g., body mass index [BMI]: kg/m2)
and longevity is decreasing, indicating essentially that
one can never be too thin. On the other hand, some
studies suggest that BMI has little important impact
on longevity (1315). Between these two extremes are
studies that suggest that the relationship between BMI
and mortality is U-shaped or J-shaped, indicating
higher mortalities at the extremes of the BMI distribution (1619). To complicate matters further, studies
suggest that the BMI/mortality relationship may vary
considerably as a function of demographic characteristics such as age, sex, and race (2022).
INTRODUCTION
A certain amount of overweight has been
looked upon with favor, our tendency being
to consider a certain degree of hyper-nutrition to be desirable.
O. H. Rogers (1901)
A sudden palpitation excited in the heart
of a fat man has often proved as fatal as a
bullet through the thorax.
W. Wadd (1829)
768
In this chapter, we review briey the literature pertaining to the association between BMI and mortality in
humans. We also examine what is known about the
eects of potential confounders of this association, most
notably smoking, preexisting disease, and physical inactivity. We also review briey studies that have investigated the potential moderating eect of variables such
as age and race, as well as the eect of weight loss on
mortality. Finally, we summarize the literature and provide recommendations for future research.
II
Methodologic Issues
Eect of Smoking
769
Authors
Fontaine et al.,
1998 (17)
Sempos et al.,
1998 (26)
Brenner et al.,
1997 (27)
Dorn et al.,
1997 (28)
Chyou et al.,
1997 (29)
Seidell et al.,
1996 (30)
Sample
1355 American women z50
from the Panel Study of
Income Dynamics
5209 Men and women from
the Framingham Heart
Study (2862 yrs at
baseline)
Cohort of 7812 male
German construction
workers (2564 yrs
at baseline)
1308 Men and women from
the Bualo Health Study
(2096 yrs at baseline)
8006 Japanese-American
men living in Hawaii
(4568 yrs at baseline)
48,287 Men & women
(3054 yrs at baseline)
Follow-up
(years)
Deaths
4.5
110
30
>1900
Covariates
Age, BMI, smoking,
education, 4 health
status variables
Age, illness, education,
smoking
Mean 4.5
167
29
576
22
2667
Mean 12
818
J-shaped relation
Age, cholesterol,
hypertension,
diabetes, smoking
Manson et al.,
1995 (12)
16
4726
Wienpahl et al.,
1990 (31)
15
676
Landi et al.,
2000 (32)
23
548
Visscher et al.,
2000 (19)
1530
3807
Yuan et al.,
1998 (33)
1198
Rissanen et al.,
1989 (34)
Median 12
Wannamethee
and Shaper
1989 (35)
Garrison et al.,
1983 (36)
Mean 9
660
26
679
Age, smoking
Results
Age, contraception,
hormone use, family
history of MI,
menopausal status,
smoking
Age, antecedent illness,
education, alcohol
use, smoking
Comorbidities, smoking,
alcohol use, cognitive
impairment
Age, study center
770
771
772
Figure 1 (A) Obesity causes low tness and low tness increases mortality rate. (B) Low tness causes obesity and obesity
increases mortality rate. (C) Obesity and low tness reciprocally cause each other and collectively they increase mortality rate.
(D) Obesity and low tness are correlated but only low tness increases mortality rate. (E) Obesity and low tness are
correlated but only obesity increases mortality rate.
773
774
Table 2 Studies Evaluating the Eects of Fat Mass (FM) and Fat-Free Mass (FFM) on Mortality Rate
Authors
Keys, 1989 (60)
Folsom et al.,
1993 (61)
Menotti et al.,
1993 (62)
Charles et al.,
2000 (63)
Baik et al.,
2000 (64)
Heitmann et al.,
2000 (65)
Lahmann et al.,
2000 (66)
Allison et al.
(submitted) (67)
Sample
Hydrodensitometry
Anthropometry
Anthropometry
Anthropometry
Anthropometry
Anthropometry
Bioimpedance
Anthropometry
Zhu et al.
(submitted) (68)
POTENTIAL MODERATORS
Age
775
Race
The majority of research on the eects of BMI on mortality has been conducted on samples of EuropeanAmericans (78). While it is clear that obesity in African-Americans, most notably women, is associated with
a number of risk factors (79,80), the relation between
obesity and mortality among African-Americans is not
as clear as it is in Caucasian individuals.
In a cohort of 2731 African-American women members of the Kaiser Foundation Health Plan who were
followed for 15 years, Wienpahl et al. (31) found an
essentially at BMI/mortality association across the
entire range of BMI. However, although the U-shaped
relation between BMI and all-cause mortality was not
signicant, Stevens et al. (81) found that, among African-American men, obesity was associated with increased risk of mortality from ischemic heart disease
(IHD). More recently, Stevens et al. (82) examined the
association of BMI to all-cause and CVD mortality
among 100,000 Caucasian and 8142 African-American
women from the American Cancer Society Prevention
Study I. At the 12-year follow-up, a signicant interaction was observed between ethnicity and BMI for
both all-cause and CVD mortality. Specically, among
white women, BMI was associated with all-cause mortality in all four groups (dened by smoking status and
educational attainment). In African-American women
with less than a high school education, there was no
signicant association between BMI and all-cause mortality. However, there was a signicant association
among high schooleducated African-American women. Models using the lowest BMI as the reference
group among never-smoking women with at least a
high school education indicated a 40% higher risk of
all-cause mortality at a BMI of 35.9 in the AfricanAmerican women versus 27.3 in the white women.
Stevens et al. (82) concluded that, although educational attainment appears to modify the impact of
BMI on mortality, BMI was a less potent risk factor
in the African-American women than in the Caucasian
women.
Two more recent relatively large and high-quality
studies have emerged with samples of African-Americans (83,84). These studies show that there clearly is a
deleterious eect of obesity on mortality rate among
African-Americans, though the BMIs associated with
minimum mortality rate may be slightly higher among
African-Americans (85). Other investigators (43,8689)
have obtained similar results, suggesting that the eect
of a given BMI increase on mortality rate may be less
776
777
Sample
Deaths
Follow-up
(years)
Williamson et al.
(1995) (100)
43,457 White
overweight
nonsmoking
women
4199
12
French et al.
(1999) (102)
1048
Williamson et al.
(1999) (103)
9360
1213
Pamuk et al.
(1993) (104)
533
1216
1282
5.5 mean
1441
12
380
67
1325
12
Not specied
20
539
Wee et al.
(2000) (105)
Williamson et al.,
2000 (101)
Higgins et al.,
1993 (108)
Diehr et al.,
1998 (70)
Results
In those with obesity-related comorbidities
intentional weight loss was associated with 20%
reduction in mortality rate. No association
between intentional weight loss and mortality rate
in women without obesity-related comorbidities.
Recent intentional weight loss of >20 lbs
associated with increased mortality rate.
Intentional weight loss of z20 lbs not associated
with higher CVD mortality risk. Unintentional
weight loss of z20 lbs associated with 2657%
higher total mortality risk and 51114% higher
CVD mortality risk.
Among those with no reported health problems,
intentional weight loss not associated with total,
CVD, or cancer mortality rate. Among men
with health problems, intentional weight loss
was not associated with total or CVD mortality
but with increased cancer mortality risk.
Weight loss of >5% maximum lifetime body
weight associated with increased death rates
even after excluding deaths within rst 58 years
after baseline.
Intentional weight loss of 510 lbs associated with
lower hazard of death compared to reference
group. Greater than 10-lb weight loss did not
signicantly increase longevity.
Both weight loss and weight gain of > 5 kg
signicantly increased all-cause and CHD
mortality.
Weight loss associated with increased risk of death
(range of relative risk = 1.043.42). Lowest
mortality in weight stable.
After adjusting for initial BMI, sociodemographic
factors, health status, and physical activity,
intentional weight loss was associated with 25%
reduction in total mortality and 28% reduction
in CVD and diabetes mortality.
Among men, weight loss associated with higher
20-year all-cause, cardiovascular, and CHD
mortality compared with weight-stable group.
Among overweight (BMIs 26.227.3) older adults
(aged 65100) a > 10-lb weight loss in the year
preceding the study had 5-yr mortality rates that
were similar to those who were weight stable in
the year prior to the study.
Clearly, the ideas put forward in this section are concepts for which we do not currently have supporting
data. Nevertheless, they are all quite consistent with existing knowledge, and we think it only a matter of time
before such more complex and individualized statements about optimal BMIs with respect to longevity
can be made.
778
ings such as these prompted Andres et al. (20) to conclude that no matter what population is studied, or how
the data are cleaned, treated, and analyzed, Evidence suggests that the highest mortality rates occur in
adults who either have lost weight or have gained excessive weight. The lowest mortality rates are generally
associated with modest weight gain (p 737).
This puzzling nding is the subject of considerable
inquiry (110). Among the important research challenges associated with investigating the eects of weight
change on mortality with current epidemiologic data
are: (1) the appropriateness of basing estimates of the
benets or risks of weight loss on self-reported intentionality; (2) the potential confounding eects of smoking and preexisting disease; (3) the diculty of assessing
and accurately taking account of weight regain after
weight loss; (4) assessing dietary changes during followup; and (5) the use of body mass index (BMI: kg/m2) as
a proxy for both fat mass and fat-free mass.
Another important issue to consider is the unknown
ecacy and safety of many weight loss practices. Methods for intentionally inducing weight loss include fad
diets, herbal supplements of untested safety (111), bulimia, and other potentially unsafe dietary practices.
Hence, it appears ill advised to estimate the eects of
weight loss achieved by medically recommended methods by studying weight loss that is merely reported to be
IV
A
The aforementioned methodological issues, most notably the use of BMI as a proxy for adiposity measures,
suggest strongly that the current epidemiologic data
may not provide us with the best estimates of the obesity/mortality association. Nonetheless, describing what
the available data show is relatively simple. When the
overall body of literature is reviewed, the data clearly
show that the association between BMI and mortality
is U- or J-shaped. Among nonelderly white males and
females, the nadirs of the curve tend to be around the
mid to high 20s for BMI. Though isolated studies may
occasionally show other results, these conclusions are
clearly supported by the overall body of data (18).
The relationship between BMI and mortality, however, appears to vary substantially by age and race, and
it is likely that other variables, not yet identied or fully
explored, may also moderate this relationship. It seems
ill advised, therefore, to generalize from studies in one
population (e.g., white middle-aged females) to other
779
780
sophisticated research designs and assessment techniques are required to tease out the independent eects
of obesity and tness on mortality. Indeed, recent randomized controlled clinical trials suggest that weight
loss appears to have a greater eect on CVD risk factors
than does improving cardiorespiratory tness, implying that obesity may play a more central role in morbidity and mortality than tness. Nonetheless, further
research is required to disentangle the independent
eects of obesity, a sedentary lifestyle, and poor tness
on health, morbidity, and mortality.
C
Intentional weight loss among persons with obesityrelated comorbidities such as diabetes appears to reduce
mortality rate. However, among apparently healthy
overweight/obese adults, intentional weight loss seems
to neither decrease nor increase mortality rate. Given
that these ndings were derived from observational
studies that relied on self-reported intentionality of the
weight loss, they should be interpreted with caution
(110). Nonetheless, the current data suggest that remaining weight stable or increasing body weight slightly
associates with lower mortality.
D
781
ACKNOWLEDGMENT
This work was supported in part by National Institutes of Health grants RO1DK51716, P30DK56336,
and R21AG17166.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
REFERENCES
17.
1.
782
18. Troiano RP, Frongillo EA Jr, Sobal J, Levitsky DA.
The relationship of body weight and mortality: a quantitative analysis of combined information from existing studies. Int J Obes Rel Metab Disord 1996; 20:63
75.
19. Visscher TLS, Seidell JC, Menotti A, Blackburn H,
Nissinen A, Feskens EJM, Kromhout D. Underweight
and overweight in relation to mortality among men
aged 4059 and 5069 years: The Seven Countries
Study. Am J Epidemiol 2000; 151:660666.
20. Andres R, Muller DC, Sorkin JD. Long-term eects of
change in body weight on all-cause mortality. A review.
Ann Intern Med 1993; 110:737743.
21. Stevens J, Cai J, Pamuk ER, Williamson DF, Thun MJ,
Wood JL. The eect of age on the association between
body-mass index and mortality. N Engl J Med 1998;
338:17.
22. Stevens J. Impact of age on associations between weight
and mortality. Nutr Rev 2000; 58:129137.
23. Kushner RF. Body weight and mortality. Nutr Rev
1993; 51:127136.
24. Michels KB, Greenland S, Rosner BA. Does body mass
index adequately capture the relation of body composition and body size to health outcomes? Am J Epidemiol 1998; 147:167172.
25. Allison DB, Heo M, Fontaine KR, Homan DJ. Body
weight, body composition, and longevity. In: Bjorntorp P, ed. International Textbook of Obesity Sussex:
John Wiley & Sons, 2001:3148.
26. Sempos CT, Durazo-Arvizu R, McGee DL, Cooper
RS, Prewitt TE. The inuence of cigarette smoking on
the association between body weight and mortality:
the Framingham Heart Study revisited. Ann Epidemiol 1998; 8:289300.
27. Brenner H, Arndt V, Rothenbacher D, Schuberth S,
Fraisse E, Fliedner TM. Body weight, pre-existing disease, and all-cause mortality in a cohort of male employees in the German construction industry. J Clin
Epidemiol 1997; 50:10991106.
28. Dorn JM, Schisterman EF, Winkelstein W Jr, Trevisan
M. Body mass index and mortality in a general population sample of men and women. The Bualo Health
Study. Am J Epidemiol 1997; 146:919931.
29. Chyou PH, Burchel CM, Yano K, Sharp DS,
Rodriguez BL, Curb JD, Nomura AM. Obesity, alcohol consumption, smoking, and mortality. Ann Epidemiol 1997; 7:311317.
30. Seidell JC, Verschuren WM, Van Leer EM, Kromhout
D. Overweight, underweight, and mortality: a prospective study of 48,287 men and women. Arch Intern Med
1996; 156:958963.
31. Wienpahl J, Ragland DR, Sidney S. Body mass index
and 15-year mortality in a cohort of black men and
women. J Clin Epidemiol 1990; 43:949960.
32. Landi F, Onder G, Gambassi G, Pedone C, Carbonin
P, Bernabei R. Body mass index and mortality among
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
783
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
784
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
103.
104.
105.
106.
107.
108.
109.
110.
111.
785
112.
32
Etiology of the Metabolic Syndrome
Per Bjorntorp
University of Goteborg, Goteborg, Sweden
determinant of most of the comorbidities, yet its statistical power is surprising. Possibly this measurement
contains unrecognized information beyond intra-abdominal fat mass, such as a muscle component included
in the hip circumference measurement. These issues are
an area for more research.
At the time of the rst edition, research on endocrine
perturbations focused on the disturbances of regulation
of the hypothalamic-pituitary-adrenal (HPA) axis and
its interference with the central gonadal and growth
hormone axes. Major advances have occurred with the
development of new techniques, which are sensitive and
discriminating enough to reveal minor regulatory errors
of daily life (24). Research has previously addressed the
peripheral consequences of the endocrine perturbations
(accumulation of intra-abdominal fat and insulin resistance) (5,6), perturbations in the capillary system and in
the synthesis of myosins (1). Much progress has been
made in these areas and in genetics since the previous
edition. The original Handbook examined the period up
to 19961997, so this chapter will focus on the following
years, including generally integrated and specic aspects
of these developments covered in several recent reviews
(29).
INTRODUCTION
II
A syndrome is a collection of symptoms typically occurring together. Such syndromes often originate from
787
Bjorntorp
788
errors not in a single organ or tissue, such as in myocardial infarction, liver cirrhosis, or brain tumors, but
from overriding systemic control of the function of several organs. Multiple consequences can result, causing
diculty in diagnosis. Such syndromes often begin as
basic symptomatic description, but if the basic etiology
becomes clearer, treatment shifts from symptomatic to
causal.
The metabolic syndrome is usually considered to include two major symptoms, insulin resistance and visceral obesity, with the addition of hypertension and
dyslipidemia in the form of elevated circulating concentrations of triglycerides and triglyceride-rich very low
density lipoprotein (VLDL) particles and low concentrations of high-density lipoprotein (HDL) particles.
The major question is whether these apparently divergent symptoms can be collected under one common
etiological mechanism.
The metabolic syndrome may arise from a component
of the syndrome, acting alone or in combination with
other factors. The list includes insulin resistance, visceral fat, endocrine dysregulation (cortisol, androgens,
insulin, growth hormone), obesity, and/or genetics. Let
us rst consider the possibility that a single symptom
causes the other components of the metabolic syndrome.
A
III
789
Eects of Cortisol
Cortisol is well known to cause peripheral insulin resistance, and the mechanisms have been claried (36).
Bjorntorp
790
IV
Environmental Stressors
791
Furthermore, sex steroid hormone secretions are diminished, a known consequence of long-term HPA axis
activation (45). This is followed by insulin resistance, impaired glucose tolerance, dyslipidemia, elevated blood
pressure, early coronary atherosclerosis, and visceral fat
accumulation (46,47). This mirrors the metabolic syndrome eects seen in our studies with humans subjected
to psychosocial stress.
Cross-sectional evidence indicates association between socioeconomic stress and the metabolic syndrome
(2,3,18,39). In the Whitehall studies, a socioeconomic
gradient is inversely associated with central obesity and
signs of the metabolic syndrome (48). In the men of our
studies, a similar socioeconomic-education gradient
shows the same associations and, in addition, signs of
increased stress-related cortisol secretion and a poor
dexamethasone suppression. Furthermore, these endocrine and somatic risk factor phenomena are proportional to time of exposure of socioeconomic handicaps
(49). These observations might be considered as prospective intervention studies and suggest that long-term
socioeconomic handicaps are followed by stress reactions along the HPA axis with subsequent generation of
the metabolic syndrome, which amplies the risk for
coronary artery disease and diabetes. This might be the
pathway via which social inequality leads to disease.
B
Psychological Traits
Stimulant Usage
Bjorntorp
792
fat depots (55). In severe cases of alcohol abuse, the socalled pseudo-Cushing syndrome may develop, which
mimics the eects of the true Cushings syndrome, and is
improved or cured by alcohol abstinence (56). Alcohol
consumption at moderately elevated levels has been
found to be associated with signs of the metabolic
syndrome (39). Alcohol may consequently be an additional factor in the generation of the metabolic syndrome through HPA activation.
Tobacco smoking is frequently found in metabolic
syndrome patients (11) and is known to be followed by
increased cortisol secretion (57). Smokers have an
increased visceral fat mass, diminishing with smoking
abstinence (58). Smoking also induces insulin resistance
(59) and consequently the major factors of the metabolic syndrome.
In summary, psychosocial and socioeconomic handicaps, depression and anxiety, alcohol, and smoking are
statistically associated with increased diurnal cortisol
secretion. These factors have been shown in separate
experiments to be followed by HPA axis activation,
increased cortisol secretion, and the metabolic syndrome. Several of these studies have an intervention
component, the results of which strengthen the argument for a cause-eect relationship. This suggests that
the statistical association of these factors with the
metabolic syndrome is caused by an elevated HPA axis
activity and cortisol secretion (See Fig. 4).
It is not possible to state which of these factors is the
most powerful in the individual case. It seems likely that
they are mixed and interrelated. One may, for example,
visualize a chain of events starting out with psychosocial
or socioeconomic misfortunes, followed by abuse of
stimulants and depressive symptoms. This chain might,
however, start with any of the separate factors as the
initial trigger.
PHYSIOLOGICAL ELEMENTS
Certain physiological events also correlate to the metabolic syndrome, including aging, cytokine exposure,
and the small-baby syndrome.
A
Aging
Cytokines
Small-Baby Syndrome
793
VI
A
Bjorntorp
794
VII
Figure 6 The risk ratio for development of type 2 diabetes mellitus in women in relation to sex hormone binding
(SHBG) quintiles. (From Ref. 80.)
and endometrial cancer, followed by premature mortality (11). In fact, the risk of developing diabetes increased
10- to 20-fold among the women with HA, irrespective
of menopausal state (80) (see Fig. 6). Calculations of
population attributable risk indicate that HA may
explain no less than 5067% of all development of type
2 diabetes in women. HA may thus be one of the most
powerful risk factors for serious disease in women. The
risk seems to aect the highest quartile of testosterone
values in women (17) and may therefore be considered
to be a common risk factor in the general population of
women. This risk factor has attracted surprisingly little
attention. Androgens showed consistent, strong statistical associations to anthropometric, metabolic, and
hemodynamic risk factors in women. This was particularly pronounced for free, active testosterone (T) but
was also seen for cortisol, androstenedione, and dihydroepiandrosterone sulfate (DHEAS), which are secreted mainly or exclusively from the adrenals.
Values for 17h-estradiol were low. The associations
to cortisol measurements were not as strong as in men,
and certainly not as strong as to androgens in the
women. Concentrations of the stronger androgens (T
and free T) correlated closely not only with weaker
androgens (androstenedione and 17-OH progesterone)
but also with hormones directly associated with the
activity of the HPA axis (ACTH, DHEAS, and cortisol
measurements) (17). It therefore seems likely that the
more powerful androgens are also at least partly of
adrenal origin.
795
796
Bjorntorp
Figure 8 Distribution of tetranucleotide repeats in the microsatellite of the fth intron of the CYP 450 aromatase gene in
women in the population. Obese, hyperandrogenic women
have a stretch of the tetranucleotide repeats corresponding to
168171 bps and lean, healthy women an average stretch of
187 bps. (From Refs. 17,88.)
quencevolume expansion with elevated blood pressuredoes not seem to have been conclusively shown
(90). Such a consequence seems rather unlikely, because
volume-regulating mechanisms should prevent it (91).
Furthermore, the concept of salt-induced pathogenesis
of primary hypertension has in general been received
with considerable doubt, at least within a normal range
of salt intake variation, although a possibility exists of
subgroups with genetically salt-sensitive individuals
(91). Thus, the argument for an insulin-mediated retention of salt in obesity and hypertension is weak.
Another mechanistic hypothesis is that insulin may
act via stimulation of the central sympathetic nervous
system (92). This hypothesis is hard to prove in humans
because of the diculties in measuring activity of the
sympathetic nervous system. For example, plasma concentrations or urinary outow of catecholamines are
measurements of the activity of the total sympathetic
nervous system, but a concentration sucient to regulate blood pressure might be too small to be detected.
Direct measurements of activity in sympathetic
nerves in relation to insulin levels during hyperinsulinemic clamp procedures do not provide long-term information (93). Patients with insulinoma and chronically
elevated insulin levels do not become hypertensive, and
successful surgery is not followed by changes in blood
pressure (94). A major diculty with this entire approach to the problem is, however, that primary hypertension in humans develops through several stages;
increased sympathetic nervous system activity is present
only in the early stages and is absent later (91). Meaningful studies therefore need to dene the stages of
development of hypertension. Most studies seem to
have been performed in established hypertension, where
increased sympathetic nervous system activity would
not have been expected to be present.
Primary hypertension develops through an initial
phase of hyperkinetic circulation, due to frequent activation of the sympathetic nervous system (95). Longterm follow-up studies indicate that this transitions into
a stage, which is dominated by a peripheral circulatory
resistance developed through adaptive processes (96).
The evidence for such a stage and the involvement of the
central sympathetic nervous system in early phases are
considerable, and this pathogenic pathway of hypertension seems to have reached a consensus in the eld of
hypertension research (97). These observations are
based on subjects with or without obesity, with varying
degrees of insulin resistance and hyperinsulinemia.
There is evidence that insulin activates the central
sympathetic nervous system (92). It may therefore be
presumed that a development towards hypertension
797
would be more likely to occur or to be more pronounced, if insulin amplies sympathetic nervous system activity in hyperinsulinemic conditions such as in
the metabolic syndrome.
There is, however, convincing evidence for other
primary events. Already Brod (98) in the 1950s could
show an increased stress sensitivity in early stages of
hypertension. Such observations are corroborated by
striking epidemiological observations. Nuns in a secluded cloister in northern Italy have been followed
through decades and do not see increased blood pressure with age, unlike women of similar ages living
outside the calm environmental conditions of the cloister. The dierence is apparent also after adjustments for
obesity, diet, alcohol intake, and childbirth (99). The
dierence in blood pressure development seems to be
best explained by the psychosocial environment.
Another similar example comes from the Kuna
Indian tribe, where individuals who moved into a large,
boisterous city developed hypertension, while those remaining in their ordinary habitat, or moving to a calm
environment outside the same city, remained normotensive. Salt intake does not appear to have played a
role because the salt intake is rather high in this tribe
and similar irrespective of habitat (100). Again these
observations support the detrimental inuence of a
stressful environment for the development of hypertension.
Direct prospective evidence is provided by studies in
the United States, where increase in blood pressure with
time, carefully measured continuously during ordinary
life conditions, is proportional to environmental stress
(101). Taken together, this evidence strongly suggests
inuence by environmental stress factors as an important pathogenic feature of primary hypertension. When
the metabolic syndrome with insulin resistance and
hyperinsulinemia is added, it seems likely that insulin
might amplify blood pressure elevation with insulin as
an active component (see Fig. 5).
These results allow a consideration of another important factor. As reviewed above, the metabolic syndrome
seems to have a background of HPA axis activation, due
to environmental factors, where perceived stress from
psychosocial and socioeconomic problems are important ingredients. In animals, there is a prole of dierent
stress reactions depending on the perception of a threatening challenge. With apparent possibilities to cope
with the challenge, the sympathetic nervous system is
activated with elevated blood pressurethe ght-ight
reaction. When the threat seems overwhelming, a
depressive, defeat reaction occurs with activation of
the HPA axis and a secondary inhibition of growth
798
Bjorntorp
IX
Visceral fat accumulation is part of the metabolic syndrome. This is, however, not the same as obesity, which
is dened as an increased body fat mass, irrespective of
localization. The question, then, is whether or not obesity is part of or associated with the metabolic syndrome.
Obesity of the gluteofemoral or peripheral type may
occur without the metabolic syndrome (108). Furthermore, elevated visceral fat accumulation may occur
without increase of total body fat such, as with aging
or smoking (11). These examples show that visceral fat
and obesity are two dierent entities. Nevertheless,
obesity and proportionally increased visceral fat accumulation frequently occur simultaneously (11). In fact,
in the statistical calculations of the Swedish population
samples (16,17), estimations of central waist circumference (WHR), visceral fat accumulation (abdominal sagittal diameter), and estimations of total body
fat (BMI) are not only closely statistically related to
each other but also to the components of the metabolic
syndrome, suggesting that obesity is indeed a part of this
syndrome.
Obesity is caused by a positive energy balance, by
either an increased energy intake or a diminished energy
output, or both. Both of these factors are regulated by a
large number of complicated mechanisms. With the
neuroendocrine-endocrine background of the metabolic syndrome, with the HPA axis and cortisol in a central
position, one may also ask if the associated obesity
might depend on similar factors.
Clinicians know that patients treated with glucocorticoids often become obese with a central localization of
excess fat. Such patients often report voracious hunger,
which can be objectively observed in clinical wards.
Direct experimental measurements in humans show
that with administration of glucocorticoids, leptin levels
increase (109,110), which would be expected to decrease
food intake by induction of satiety. Nevertheless, food
intake clearly increases after exposure to elevated glucocorticoid levels, shown recently in fully controlled
experiments with a food dispenser (111) or with automatic recording food-monitoring equipment (112).
Animal work shows that after adrenalectomy, food
intake is low, such as in the clinical entity of Addisonss
799
Bjorntorp
800
GENETICS
Genetic susceptibility to develop the metabolic syndrome might be localized to a large number of genes.
Since it has been considered unlikely that the components of the syndromevisceral obesity, insulin resistance, dyslipidemia, and hypertensioncan explain the
pathogenesis of the entire syndrome, genetic aberrations directly associated with these components will not
be discussed. Instead, since it appears that the origin of
the metabolic syndrome is found in central regulatory
errors, emphasis will be placed on genes involved in
such pathways.
A
Aromatase
Leptin
801
Figure 10 Factors regulating food intake. Pro-opiomelanocortin (POMC) induces ACTH and cortisol secretion,
regulates the secretion of melanocortin, active via melanocortin receptors (MCR 3 and 4), and h-endorphin.
Bjorntorp
802
testosterone, and perturbations in diurnal cortisol secretion, suggesting a hyperactivity of the HPA axis. In
addition, elevated abdominal sagittal diameter is an
indicator of increased visceral fat mass. This genetic
variant is also associated with behavioral characteristics
(Baghaei et al., unpublished). It may be speculated that
this genetic variation is of importance for the contents of
serotonin in nerve synapses, and that the short allele
therefore produces the combined eects of both a hyperactive HPA axis and visceral accumulation of body fat.
The homozygotes for the short-allele variant have a
frequency of f17%, while homozygotes for the long
allele are found in f33% of cases.
Further results of studies of the serotonin system
show in men associations to a genetic variant in the
5HTR 2A with a substitution of G to A at a position in
the promoter (1438). A/A homozygotes have a lower
BMI, WHR, and abdominal sagittal diameter, while the
G/A genotype shows a diminished suppressibility of
cortisol by dexamethasone. The frequencies of the A/A
and G/G homozygotes are 33% and 12% (142). It may
be speculated that this genetic variation is associated
with a product that promotes (G variant) or protects
from (A variant) the development of abdominal obesity
via serotonin inuence on the HPA axis.
Similar studies of the 5HTR 2C in women so far have
not revealed any associations of interest (unpublished).
E
Finally, along the HPA axis, the gene for corticotropinreleasing hormone (CRH) and the GR gene have been
examined. Nothing of interest seems to be present in the
CRH gene (Rosmond et al., unpublished), while the GR
gene shows several polymorphisms of potential interest.
A microsatellite in the rst coding exon, containing
trinucleotide repeats (CAG), seems preliminary to be
of normal length in subjects with the metabolic syndrome (143). A long allele (4.5 kb), obtained by the
restriction enzyme Bc1 I, cleaving the gene in the rst
intron, was found to be associated with abdominal
obesity, insulin resistance, and hypertension (144
146). We conrmed this and found in addition a poor
control of stimulated cortisol secretion (147), suggesting
more directly that this polymorphism might be of functional importance for the regulation of the HPA axis.
Thirteen percent of Swedish men are homozygotes for
this allele, and heterozygotes (45.1%) show similar
associations although less powerful. Another polymorphism in the promoter domain was found to be associated with basal cortisol secretion (148). A recent
report indicated that a Tsp 5091 polymorphism in the
803
Table 1 Frequency of Genetic Variants in Central Regulatory Genes Promoting or Protecting from Obesity
and the Metabolic Syndrome in Swedish Populations of Middle-Aged Men and Women
Gene locus
Aromatase
Leptin receptor
POMC
MCR 4
TPH
SERT
5-HTR 2A
GR
Protecting allele
Promoting allele
% Protecting allele
Long microsatellite
Several polymorphisms
Trinucleotide repeat
G!A
Short/short
Long/long
A/A
2.3 kb
Short microsatellite
Normal
No repeat
G/G
Long/long
Short/short
G/G
4.5 kb
5
1025
8
3
37
33
33
39
POMC, Pro-opiomelanocortin; MCR 4, melanocortin receptor 4; TPH, tryptophan hydroxylase; SERT, serotonin
transporter; 5HTR 2A, 5-hydroxytryptamine receptor 2A; GR, glucocorticoid receptor.
For explanation of alleles, see text.
XI
SUMMARY, SYNTHESIS,
AND CONCLUSIONS
804
contribute to the peripheral perturbations. The mechanisms for the peripheral eects of these endocrine and
autonomic perturbations at the tissue, cellular, and
molecular levels have been established. It seems somewhat surprising that these pathways have not been
studied more extensively to disclose the pathogenesis
of risk factors for cardiovascular disease and type 2
diabetes mellitus.
Recent ndings are the powerful eects of moderate
androgen elevations in women, probably at least partly
originating from the adrenals. This might be amplied
by a malfunction of the aromatase on a genetic basis.
The view on the associations between the anthropometric and metabolic parts of the metabolic syndrome
(visceral obesity, insulin resistance, and dyslipidemia)
with the hemodynamic part (hypertension) is another
new development. First, there is a statistical association
between symptoms of the neuroendocrine perturbations
and those of the sympathetic nervous system, suggesting
that both stress centers are activated in parallel. This is
independent of insulin, suggesting that insulin is not
involved primarily. The concomitant activation of the
HPA axis and the sympathetic nervous system is a wellknown phenomenon from stress research. A central
activation of the sympathetic nervous system is now
an established view on the pathogenesis of primary
hypertension. The elevated prevalence of hypertension
in the metabolic syndrome might be due to the apparent
dependence on leptin signals for blood pressure elevation. Insulin may well also be amplifying the central
activity of the sympathetic nervous system.
Our current view on the pathogenesis of hypertension in the metabolic syndrome is therefore that
a central activation of the sympathetic nervous system occurs parallel to the activation of the HPA axis,
generating respectively elevated blood pressure and
metabolic perturbations. The high prevalence of hypertension in the metabolic syndrome is probably due to
the additional, amplifying eects of leptin and insulin.
This view is strongly supported by similarities in environmental factors activating the HPA axis and the
central sympathetic nervous system and thus inducing
a frequent or chronic central arousal. With these considerations, the name metabolic syndrome may not
t as well, because it consists not only of metabolic
symptoms, but also of anthropometric symptoms (visceral obesity) and hemodynamic symptoms (hypertension). It might therefore be time to consider changing
the name of this cluster of symptoms to the central
arousal syndrome.
We have long been impressed by the statistical associations of the neuroendocrine, autonomic, and endo-
Bjorntorp
805
REFERENCES
1.
2.
3.
4.
5.
6.
Bjorntorp
806
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22. Pasquali R, Cantobelli S, Casimirri F. The hypothalamic-pituitary-adrenal axis in obese women with dierent patterns of body fat distribution. J Clin Endocrinol
Metab 1993; 77:341349.
23. Pasquali R, Anconetani B, Cattat R. Hypothalamicpituitary-adrenal axis acticity and its relationship to the
autonomic nervous system in women with visceral and
subcutaneous obesity: eects of corticotropin-releasing
factor/arginin-vasopressin test and of stress. Metabolism 1996; 45:531536.
24. Hautanen A, Adlercreutz H. Altered adrenocorticotropin and cortisol secretion in abdominal obesity:
implications for the insulin resistance syndrome. J
Intern Med 1993; 234:461469.
25. Pasquali R, Gagliardi L, Vicennati V. ACTH and
cortisol response to combined corticotropin releasing
hormone-arginine vasopressin stimulation in obese
males and its relationship to body weight, fat distribution and parameters of the metabolic syndrome. Int J
Obes Relat Metab Disord 1999; 23:419423.
26. Moyer A, Rodin J, Grilo C, Rebue-Scrive M. Stressinduced cortisol response and fat distribution in
women. Obes Res 1994; 2:255259.
27. Epel EE, Moyer AE, Martin CD, Rebue-Scrive M.
Stress-induced cortisol, mood, and fat distribution in
men. Obes Res 1999; 7:912.
28. Korbonitz M, Trainer PJ, Nelson ML. Dierential stimulation of cortisol and dehydroepiandrosterone levels
by food in obese and normal subjects: relation to body
fat distribution. Clin Endocrinol 1996; 45:699708.
29. Liu JH, Kazer RR, Rusnussen DD. Characterization of
the twenty-four hour secretion patterns of adrenocorticotropin and cortisol in normal women and patients
with Cushings disease. J Clin Endocrinol Metab 1987;
64:10271034.
30. Bungton CK, Givens JR, Kitabchi AE. Enhanced
adrenocortical activity as a contributing factor to diabetes in hyperandrogenic women. Metabolism 1994; 43:
584590.
31. Filipovsky J, Ducimetiere P, Eschwege E, Richard JL,
Rosselin G, Claude P. The relationship of blood
pressure with glucose, insulin, heart rate, fatty acids
and plasma cortisol levels according to degree of obesity
in middle-aged men. J Hypertens 1996; 14:229235.
32. Stolk RP, Lamberts SWJ, De Jong FH, Pols HAP,
Grobbee DE. Gender dierences in the associations
between cortisol and insulin sensitivity in healthy
subjects. J Endocrinol 1996; 149:313318.
33. Fraser R, Ingram MC, Anderson NH, Morrison C,
Davies E, Connell J. Cortisol eects on body mass,
blood pressure, and cholesterol in the general population. Hypertension 1999; 3:13741378.
34. Phillips DIW, Barker DJP, Fall CHD, Seckl JR,
Whorwood CB, Wood PJ, Walker BR. Elevated cortisol concentrations: a link between low birth weight
and the insulin resistance syndrome? J Clin Endocrinol
Metab 1998; 83:757760.
807
and risk for myocardial infarction. Prospective data
from the Baltimore ECA follow-up. Circulation 1996;
94: 31233129.
52. Eaton WW, Armenian H, Gallo J, Pratt L, Ford DE.
Depression and risk for onset of type II diabetes. A
prospective population-based study. Diabetes Care
1996; 19:10971102.
53. Thakore JH, Richards PJ, Reznek RH, Martin A,
Dinan T. Increased intra-abdominal fat deposition in
patients with major depressive illness as measured by
computed tomography. Biol Psychiatry 1997; 41:1140
1142.
54. Ahlberg C, Ljung T, Rosmond R, McEwen B, Holm G,
Bjorntorp P, Akesson HO. Depression and anxiety
symptoms in relation to anthropometry and metabolism in men. Psychiatr Res 2001; 112:101110.
55. Pettersson P, Ellsinger B-M, Sjoberg C, Bjorntorp P.
Fat distribution and steroid hormones in women with
alcohol abuse. J Intern Med 1990; 228:311316.
56. Smals AG, Kloppenborg PW, Njo KT. Alcohol induced cushingoid syndrome. Br Med J 1976; 2: 1928.
57. Gossain VV, Sherma NK, Srivastava L, Michelakis
AM, Rovner RV. Hormonal eects of smoking. II.
Eects on plasma cortisol, growth hormone, and
prolactin. Am J Med Sci 1986; 291:325327.
58. Shimokata H, Tobin HJD, Muller DC, Elahi D, Coon
PJ, Andres R. Studies in the distribution of body fat. I.
Eects of age, sex and obesity. J Gerontol 1989; 44:
M66M73.
59. Reaven GM. Pathophysiology of insulin resistance in
human disease. Physiol Rev 1995; 75:473486.
60. Sapolsky R, Krey L, McEwen B. The neuroendocrinology of stress and aging: the glucocorticoid cascade
hypothesis. Endocr Rev 1986; 7:289301.
61. Seeman TE, Robbins RJ. Aging and the hypothalamicpituitary-adrenal response to challenge in humans.
Endocr Rev 1994; 15:233260.
62. Bjorntorp P. Alterations in the ageing corticotropic
stress-response axis. In: Weldhuis J, ed. The Endocrinology of Ageing. London: Wellcome Trust, 2001:
4665.
63. Gabay C, Kushner I. Acute-phase proteins and other
systemic responses to inammation. N Engl J Med
1999; 340:448454.
64. Rohde LEP, Hennekens CH, Ridker PM. Survey of
C-reactive protein and cardiovascular risk factors in
apparently healthy men. Am J Cardiol 1999; 84:
10181022.
65. Tsigos C, Papanicolaou DA, Defensor R, Mitsiadis CS,
Kyrou I, Chrousos GP. Dose eects or recombinant
human interleukin-6 on pituitary hormone secretion
and energy expenditure. Neuroendocrinology 1997;
66:5462.
66. Bornstein SR, Chrousos GP. Adrenocorticotropin
(ACTH)- and non-ACTH-mediated regulation of the
adrenal cortex: neural and immune inputs. J Clin
Endocrinol Metab 1999; 84:17291736.
808
67. Barker DJP, Hales CN, Fall CHD, Osmond C,
Phipps K, Clark PMS. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidemia (syndrome X): relation to fetal growth.
Diabetologia 1993; 35:6267.
68. Reul JMHM, Stec I, Wiegers GJ, Labeur MS, Linthorst
ACE, Arzt E, Holsboer F. Prenatal immune challenge
alters the hypothalamic-pituitary-adrenocortical axis in
adult rats. J Clin Invest 1994; 93:26002607.
69. Dahlgren J, Nilsson C, Jennische E, Ho H-P, Eriksson
E, Niklasson A, Bjorntorp P, Albertsson K, Wikland A,
Holmang A. Prenatal cytokine exposure results in
obesity and gender-specic programming. Am J Physiol
Endocrinol Metab 2001; 281:E326E334.
70. Seckl J. Glucocorticoids, feto-placental 11 h-hydroxysteroid dehydrogenase type 2, and early life origins of
adults disease. Steroids 1997; 62:8994.
71. Nilsson C, Niklasson M, Eriksson E, Bjorntorp P,
Holmang A. Imprinting of female ospring with
testosterone results in insulin resistance and changes
in body fat distribution at adult age in rats. J Clin Invest
1998; 101:7477.
72. Nilsson C, Larsson B-M, Jennische E, Eriksson E,
Bjorntorp P, York DA, Holmang A. Maternal endotoxemia results in obesity and insulin resistance in
adult male ospring. Endocrinology 2001; 142:2622
2630.
73. Ravelli AC, Van der Meulen JH, Osmond C, Barker
DJ, Bleker OP. Obesity at the age of 50 y in men and
women exposed to famine prenatally. Am J Clin Nutr
1999; 70:811816.
74. Johannsson G, Marin P, Lonn L, Ottosson M, Stenlof
K, Bjorntorp P, Sjostrom L, Bengtsson BA. Growth
hormone treatment of abdominally obese men reduces
abdominal fat mass, improves glucose and lipoprotein
metabolism, and reduces diastolic blood pressure. J
Clin Endocrinol Metab 1997; 82:727734.
75. Seidell JC, Bjorntorp P, Sjostrom L, Kvist H, Sannerstedt R. Visceral fat accumulation in men is positively
associated with insulin, glucose and c-peptide levels, but
negatively with testosterone levels. Metabolism 1990;
39:897901.
76. Rosmond R, Bjorntorp P. The interactions between
hypothalamic-pituitary-adrenal axis activity, testosterone and insulin-like growth factor I and abdominal
obesity with metabolism in men. In J Obes Relat Metab
Disord 1998; 22:11841196.
77. Plotsky PM, Cunningham ETJr, Widmaier EP. Catecholaminergic modulation of corticotrophin-releasing
factor and adrenocorticotropin secretion. Endocr Rev
1989; 10:437458.
78. Kissebah AH, Krakower GR, Sonnenberg G, Hennes
MMI. Clinical manifestations of the metabolic syndrome. In: Bray GA, Bouchard C, James PCT, eds.
Handbook of Obesity. New York: Marcel Dekker,
1998:601636.
Bjorntorp
79. McEwen BS. Protective and damaging eects of stress
mediators. N Engl J Med 1998; 338:171179.
80. Lindstedt G, Lundberg PA, Lapidus L, Lundgren H,
Bengtsson C, Bjorntorp P. Low sex-hormone-binding
globuline concentration as independent risk factor for
development of NIDDM: 12-yr follow-up of population study of women in Gothenburg, Sweden. Diabetes
1991; 40:123128.
81. Lovejoy JC, Bray GA, Bourgeois MO, Macchiavelli R,
Rood JC, Greeson C, Partington C. Exogenous
androgens inuence on body composition and regional
fat distribution in obese menopausal women. A clinical
research center study. J Clin Endocrinol Metab 1996;
81:189203.
82. Elbers JM, Asscheman H, Seidell JC, Gooren LJ.
Eects of sex steroid hormones on regional fat deposits
as assessed by magnetic resonance imaging in transsexuals. Am J Physiol 1999; 276:E317E325.
83. Polderman KH, Gooren LJG, Aschermann H. Induction of insulin resistance by androgens and estrogens. J
Clin Endocrinol Metab 1994; 79:265271.
84. Holmang A, Svedberg J, Jennische E, Bjorntorp P.
Eects of testosterone on muscle insulin sensitivity and
morphology in female rats. Am J Physiol 1990; 258:
E555E560.
85. Rincon J, Holmang A, Odegaard-Wahlstrom E,
Lonnroth P, Bjorntorp P, Zierath JR, WallbergHenriksson H. Mechanisms behind insulin resistance
in rat skeletal muscle after oophorectomy and additional testosterone treatment. Diabetes 1996; 45:615
621.
86. Riggins GJ, Lokey LK, Chastain JL, Leiner HA,
Sherman SL, Wilkinson KD, Warren ST. Human genes
containing polymorphic trinucleotide repeats. Nat
Gene 1992; 2:186191.
87. Comings DE. Polygenic inheritance and micro/minisatellites. Mol Psychiatry 1998; 3:2131.
88. Baghaei F, Rosmond R, Westberg L, Hellstrand M,
Landen M, Eriksson E, Holm G, Bjorntorp P. The lean
woman. Obes Res 2002; 10:115121.
89. Jones MEE, Thorburn AW, Britt KL, Hewitt KN,
Wreford NG, Proietto J, Os OK, Leury BJ, Robertson
KM, Yao S, Simpson ER. Aromatase-decient (ArKO)
mice have a phenotype of increased adiposity. Proc Natl
Acad Sci USA 2000; 97:1273512740.
90. Rocchini AP. Obesity and blood pressure regulation.
In: Bray GA, Bouchard C, James WPT, eds. Handbook
of Obesity. New York: Marcel Dekker, 1998:677696.
91. Folkow B. Physiological aspects of primary hypertension. Physiol Rev 1982; 62:384504.
92. Landsberg L, Young JB. Insulin-mediated glucose
metabolism in the relation between dietary intake and
sympathetic nervous system activity. Int J Obes 1985;
9:6368.
93. Anderson EA, Homan RB, Baron TW, Sinkey CA,
Mark AL. Hyperinsulinemia produces both sympa-
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
809
109.
810
Bjorntorp
123.
Cheetham T, ORahilly S. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deciency. J Clin Invest 2000; 106:271
279.
Vaisse C, Clement K, Durand E, Hercberg S, GuyGrand B, Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogenous cause of morbid
obesity. J Clin Invest 2000; 106:253262.
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore
JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA,
Bostaon BA, Cone RD, Smith FJ, Campeld LA, Burn
P, Lee F. Targeted disruption of the melanocortin4 receptor results in obesity in mice. Cell 1997; 88:131
141.
Rosmond R, Chagnon M, Bouchard C, Bjorntorp P. A
missense mutation in the human melanocortin-4
receptor gene in relation to abdominal obesity and
salivary cortisol. Diabetologia 2002; 44:13351338.
Leibowitz SF, Alexander JT. Hypothalamic serotonin
in control of eating behavior, meal size, and body
weight. Biol Psychiatry 1998; 44:851864.
Nonogaki K, Strack AM, Dallman MF, Tecott LH.
Leptin-independent hyperphagia and type 2 diabetes in
mice with a mutated serotonin 5-HT2C receptor gene.
Nat Med 1998; 4:11521156.
Barnes NM, Sharp T. A review of central 5-HT
receptors and their function. Neuropharmacology
1999; 38:10381152.
Rosmond R, Bouchard C, Bjorntorp P. 5-HT2A
receptor gene promoter polymorphism in relation to
abdominal obesity and cortisol. Obes Res 2002; 10:585
589.
Ljung T, Ottosson M, Ahlberg A-C, Eden S, Oden B,
Okret S, Bronnegard M, Stierna P, Bjorntorp P.
Central and peripheral glucocorticoid receptor function
in abdominal obesity. Endocr Invest 2002; 25:229235.
Weaver JU, Hitman G, Kopelman PG. An association
between a Bcl I restriction fragment length polymorphism of the glucocorticoid receptor locus and hyperinsulinemia in obese women. J Mol Endocrinol 1992;
9:295300.
Watt GCM, Harrap SB, Foy CJW, Holton DW, Edwards HV, Davidson HR. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a
four corners approach to identication of genetic determinants of blood pressure. J Hypertens 1992; 10:473
482.
Buemann B, Vohl MC, Chagnon M, Chagnon YC,
Gagnon J, Perusse L, Dionne F, Despres JP, Tremblay
A, Nadeau A, Bouchard C. Abdominal visceral fat is
associated with a Bcl I restriction fragment length
polymorphism at the glucocorticoid receptor gene
locus. Obes Res 1997; 5:186192.
Rosmond R, Chagnon YC, Holm G, Chagnon M,
Perusse L, Lindell K, Carlsson B, Bouchard C,
Bjorntorp P. A glucocorticoid receptor gene marker is
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
811
151.
152.
153.
154.
155.
33
Obesity as a Risk Factor for Major Health Outcomes
JoAnn E. Manson
Harvard Medical School and Brigham & Womens Hospital, Boston, Massachusetts, U.S.A.
Patrick J. Skerrett
Brigham & Womens Hospital and Harvard Health Publications, Harvard Medical School, Boston,
Massachusetts, U.S.A.
Walter C. Willett
Harvard School of Public Health, Boston, Massachusetts, U.S.A.
INTRODUCTION
II
MORTALITY
While the precise shape of the body weight/mortality curve remains controversial, there is little question
that substantial excess adiposity increases mortality. A
reanalysis of 12-year follow-up data of the American
Cancer Societys Cancer Prevention Study I cohort that
excluded smokers and those with a history of cancer
or cardiovascular disease at baseline (8), as well as a
new analysis of a second Cancer Prevention cohort of
more than 1 million adults with 14 years of follow-up
(9), showed a clear pattern of increasing mortality with
increasing weight (Fig. 2). Among healthy people who
had never smoked, optimal mortality was found at a
BMI of 23.524.9 for men and 22.023.4 for women.
These data conrm similar observations from a 27-year
813
814
Manson et al.
Figure 1 Relation between body mass index up to 30 and the relative risks of type 2 diabetes, cholelithiasis, hypertension, and
coronary heart disease in the Nurses Health Study and the Health Professionals Follow-up Study. (From Ref. 13.)
815
Table 1 Prevalence Ratios and Relative Risks of Several Weight-Related Diseases in the Third
National Health and Nutrition Evaluation Survey (NHANES III),a the Nurses Health Study
(NHS),b and the Health Professionals Follow-up Study (HPFS)c
Obese
(BMI 30.034.9 kg/m2)
Very obese
(BMI z35.0 kg/m2)
1.01.3
1.4
1.5
1.11.7
1.5
2.0
2.23.0
1.5
2.2
1.11.6
1.7
1.7
1.23.2
2.1
2.7
1.45.5
2.3
3.0
1.21.9
1.1
1.3
1.11.7
0.9
1.2
0.91.7
0.7
1.3
1.83.8
4.6
3.5
2.510.1
10.0
11.2
3.518.1
17.0
23.4
1.31.9
1.9
1.4
1.84.1
2.5
2.3
2.521
3.0
2.9
Overweight
(BMI 25.029.9 kg/m2)
Coronary heart disease
NHANES III
NHS
HPFS
Hypertension
NHANES III
NHS
HPFS
Hypercholesterolemia
NHANES III
NHS
HPFS
Type 2 diabetes
NHANES III
NHS
HPFS
Gallbladder disease
NHANES III
NHS
HPFS
Values are prevalence ratios for men and women aged <55 years and z55 years compared with individuals
with BMIs of 18.024.9 kg/m2.
b
Values are relative risks compared with women with BMIs <25 kg/m2.
c
Values are relative risks compared with men with BMIs <25 kg/m2.
Sources: Refs. 5, 51.
a
III
CARDIOVASCULAR DISEASE
816
Manson et al.
Numerous observational studies, including many longterm prospective cohort studies (2232), have demonstrated a direct association between excess weight and
coronary heart disease, the most common cause of
death in the United States. The relationship appears
to be linear, and even individuals of average weight
(i.e., those with BMIs of 2426 kg/m2) at midlife are
at increased risk compared with leaner individuals. In
the Nurses Health Study, for example, even after controlling for age, smoking, menopausal status, use of
postmenopausal hormones, and parental history of
myocardial infarction, the relative risk of coronary
heart disease was 1.2 (95% CI, 0.971.44) for women
with BMIs of 2122.9 kg/m2, 1.46 (95% CI 1.201.77)
for BMIs of 2324.9 kg/m2, 2.06 (95% CI, 1.722.48)
for BMIs of 2528.9 kg/m2, and 3.56 (95% CI, 2.96
4.29) for BMIs of 29 kg/m2 or more, compared with
women whose BMIs were <21 kg/m2 (33). Weight gain
after age 18 was also associated in a dose-dependent
fashion with increased risk of coronary heart disease.
When women who had lost or gained less than 5 kg
were used as the referent, the risk of coronary heart
disease was 1.65 (95% CI, 1.332.05) among those who
gained 810.9 kg, 1.92 (95% CI, 1.612.29) among
those who gained 1119 kg, and 2.65 (95% CI, 2.17
3.22) among those who gained z20 kg (33). A 26-year
follow-up of more than 5000 men and women in the
Framingham Heart Study showed that relative weight
at baseline was positively associated with coronary
heart disease, coronary mortality, and congestive heart
failure independent of age, cholesterol level, systolic
Stroke
Venous Thromboembolism
Studies of the risk factors for venous thromboembolism, which have largely been conducted among populations of hospitalized patients, have generally
demonstrated an association between excess weight
and deep-vein thrombosis or pulmonary embolism
817
IV
818
Manson et al.
Figure 3 Prevalence of type 2 diabetes in the Third National Health and Nutrition Examination Survey by BMI categories.
(From Ref. 2.)
intake and increased exercise among 5000 obese individuals with type 2 diabetes (57). Results from this
trial should also oer important insights into the potential benecial eects of weight loss on risk of cardiovascular disease and other chronic conditions.
CANCER
Ever since the landmark American Cancer Society cohort study of 750,000 U.S. adults found a highly signicant age- and smoking-adjusted 33% increased risk
of cancer death among obese men and a 55% increase
among obese women (58), hundreds of other studies
have examined the association between weight and cancer in greater detail. Most, but not all, of these studies
suggest that excess weight is associated with increased
risks of endometrial (59), postmenopausal breast (59),
kidney (60), gallbladder (61), and colon (62) cancers.
A recent meta-analysis of overweight and cancer in
Europe suggests that excess weight accounts for 3.4%
of cancers in men and 6.4% in women, or a total of
VI
VII
OSTEOARTHRITIS
819
VIII
SLEEP APNEA
820
Manson et al.
Figure 4 Prevalence of osteoarthritis among women in the Third National Health and Nutrition Examination Survey by BMI
categories. (From Ref. 5.)
IX
REPRODUCTIVE HEALTH
Obesity during pregnancy is related to increased morbidity for both mother and child (see Chap. 43).
Maternal obesity is associated with a 10-fold increased
risk of hypertension and a threefold increased risk of
gestational diabetes (90,91), and is also strongly associated with the risk of pre-eclampsia (92,93). Women
who are overweight or obese are also more likely to
have other complications of pregnancy than women in
the healthy weight range. In an analysis of more than
96,000 births in Washington state, for example, overweight and obese women were signicantly more likely to have preterm deliveries, to deliver babies heavier
than 4000 g, or to require caesarean section, and infants
born to obese women had a twofold increased risk of
death within the rst year of life (94). Obesity also
increases the risks associated with anesthesia, possibly
due to the technical diculties in administration (95).
Excess weight may also interfere with the ability to
become pregnant. Among female nurses, BMI at age 18
was strongly associated with subsequent risk of ovula-
QUALITY OF LIFE
Another measure of the cumulative burden of weightrelated disorders is quality of life. In analyses from the
Nurses Health Study, both higher BMI and substantial
weight gain during adulthood were strongly associated
with reduced daily physical functioning and vitality, a
greater burden of physical pain, and diminished feelings of well-being. The average decline in physical
function experienced by a woman under age 65 years
who gained 9 kg or more over a 4-year period was approximately three times the magnitude of that associated with cigarette smoking over the same period
(99,100). In NHANES III, the proportion of participants reporting excellent health decreased in a linear
fashion with increasing BMI among whites, blacks, and
Hispanics, even in the absence of chronic disease conditions (101).
XI
CONCLUSION
REFERENCES
1.
821
2.
822
19. Duncan BB, Schmidt MI, Chambless LE, Folsom
AR, Carpenter M, Heiss G. Fibrinogen, other putative markers of inammation, and weight gain in middle-aged adultsthe ARIC study. Atherosclerosis
Risk in Communities. Obes Res 2000; 8:279286.
20. Visser M, Bouter LM, McQuillan GM, Wener MH,
Harris TB. Elevated C-reactive protein levels in overweight and obese adults. JAMA 1999; 282:21312135.
21. Stefanick ML. Exercise and weight loss. In: Hennekens CH, ed. Clinical Trials in Cardiovascular Disease:
A Companion Guide to Braunwalds Heart Disease.
Philadelphia: W.B. Saunders, 1999:375391.
22. Larsson B, Svardsudd K, Welin L, Wilhelmsen L,
Bjorntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease
and death: 13 year follow up of participants in the
study of men born in 1913. Br Med J (Clin Res Ed)
1984; 288:14011404.
23. Tuomilehto J, Salonen JT, Marti B, Jalkanen L, Puska
P, Nissinen A, Wolf E. Body weight and risk of
myocardial infarction and death in the adult population of eastern Finland. Br Med J (Clin Res Ed) 1987;
295:623627.
24. Fitzgerald AP, Jarrett RJ. Body weight and coronary
heart disease mortality: an analysis in relation to age
and smoking habit. 15 years follow-up data from the
Whitehall Study. Int J Obes Relat Metab Disord 1992;
16:119123.
25. Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH.
Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of
1922 to 1935. N Engl J Med 1992; 327:13501355.
26. Harris TB, Launer LJ, Madans J, Feldman JJ. Cohort
study of eect of being overweight and change in
weight on risk of coronary heart disease in old age.
BMJ 1997; 314:17911794.
27. Huang B, Rodreiguez BL, Burchel CM, Chyou PH,
Curb JD, Sharp DS. Association of adiposity with
prevalent coronary heart disease among elderly men:
the Honolulu Heart Program. Int J Obes Relat Metab
Disord 1997; 21:340348.
28. Lamarche B, Lemieux S, Dagenais GR, Despres
JP. Visceral obesity and the risk of ischaemic heart
disease: insights from the Quebec Cardiovascular
Study. Growth Horm IGF Res 1998; 8(suppl B):18.
29. Folsom AR, Stevens J, Schreiner PJ, McGovern PG.
Body mass index, waist/hip ratio, and coronary heart
disease incidence in African Americans and whites.
Atherosclerosis Risk in Communities study investigators. Am J Epidemiol 1998; 148:11871194.
30. Rosengren A, Wedel H, Wilhelmsen L. Body weight
and weight gain during adult life in men in relation to
coronary heart disease and mortality. A prospective
population study. Eur Heart J 1999; 20:269277.
31. Gray RS, Fabsitz RR, Cowan LD, Lee ET, Welty TK,
Jablonski KA, Howard BV. Relation of generalized
and central obesity to cardiovascular risk factors and
Manson et al.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
823
57. National Institute of Diabetes and Digestive and Kidney Diseases. Look AHEAD: Action for Health in
Diabetes. <http://www.niddk.nih.gov/patient/SHOW/
lookahead.htm> Accessed on 24 July 2001.
58. Lew EA, Garnkel L. Variations in mortality by weight
among 750,000 men and women. J Chronic Dis 1979;
32:563576.
59. Schindler AE. Obesity and cancer risk in women. Arch
Gynecol Obstet 1997; 261:2124.
60. Chow WH, Gridley G, Fraumeni JF Jr, Jarvholm B.
Obesity, hypertension, and the risk of kidney cancer in
men. N Engl J Med 2000; 343:13051311.
61. Lowenfels AB, Maisonneuve P, Boyle P, Zatonski
WA. Epidemiology of gallbladder cancer. Hepatogastroenterology 1999; 46:15291532.
62. Tomeo CA, Colditz GA, Willett WC, Giovannucci E,
Platz E, Rockhill B, Dart H, Hunter DJ. Harvard
Report on Cancer Prevention. Volume 3: prevention
of colon cancer in the United States. Cancer Causes
Control 1999; 10:167180.
63. Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO.
Overweight as an avoidable cause of cancer in Europe.
Int J Cancer 2001; 91:421430.
64. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of
risk factors. Hepatology 1990; 12:11061110.
65. Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997; 126:137145.
66. Maclure KM, Hayes KC, Colditz GA, Stampfer MJ,
Speizer FE, Willett WC. Weight, diet, and the risk of
symptomatic gallstones in middle-aged women. N
Engl J Med 1989; 321:563569.
67. Syngal S, Coakley EH, Willett WC, Byers T, Williamson DF, Colditz GA. Long-term weight patterns and
risk for cholecystectomy in women. Ann Intern Med
1999; 130:471477.
68. Prevalence of disabilities and associated health conditions among adultsUnited States, 1999. MMWR
2001; 50:120125.
69. Felson DT, Anderson JJ, Naimark A, Walker AM,
Meenan RF. Obesity and knee osteoarthritis. The
Framingham Study. Ann Intern Med 1988; 109:1824.
70. Hart DJ, Spector TD. The relationship of obesity, fat
distribution and osteoarthritis in women in the general
population: the Chingford Study. J Rheumatol 1993;
20:331335.
71. Hochberg MC, Lethbridge-Cejku M, Scott WW Jr,
Reichle R, Plato CC, Tobin JD. The association of
body weight, body fatness and body fat distribution
with osteoarthritis of the knee: data from the Baltimore Longitudinal Study of Aging. J Rheumatol 1995;
22:488493.
72. Sandmark H, Hogstedt C, Lewold S, Vingard E. Osteoarthrosis of the knee in men and women in association
with overweight, smoking, and hormone therapy. Ann
Rheum Dis 1999; 58:151155.
73. Sturmer T, Gunther KP, Brenner H. Obesity, over-
824
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
Manson et al.
weight and patterns of osteoarthritis: the Ulm Osteoarthritis Study. J Clin Epidemiol 2000; 53:307313.
Cicuttini FM, Baker JR, Spector TD. The association
of obesity with osteoarthritis of the hand and knee in
women: a twin study. J Rheumatol 1996; 23:1221
1226.
Sahyoun NR, Hochberg MC, Helmick CG, Harris T,
Pamuk ER. Body mass index, weight change, and
incidence of self-reported physician-diagnosed arthritis among women. Am J Public Health 1999; 89:391
394.
Heliovaara M, Makela M, Impivaara O, Knekt P,
Aromaa A, Sievers K. Association of overweight, trauma and workload with coxarthrosis. A health survey of
7,217 persons. Acta Orthop Scand 1993; 64:513518.
Tepper S, Hochberg MC. Factors associated with hip
osteoarthritis: data from the First National Health
and Nutrition Examination Survey (NHANES-I). Am
J Epidemiol 1993; 137:10811088.
Cooper C, Inskip H, Croft P, Campbell L, Smith G,
McLaren M, Coggon D. Individual risk factors for hip
osteoarthritis: obesity, hip injury, and physical activity. Am J Epidemiol 1998; 147:516522.
Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker
AM. Body weight, body mass index, and incident
symptomatic osteoarthritis of the hand, hip, and knee.
Epidemiology 1999; 10:161166.
Messier SP, Loeser RF, Mitchell MN, Valle G, Morgan
TP, Rejeski WJ, Ettinger WH. Exercise and weight loss
in obese older adults with knee osteoarthritis: a preliminary study. J Am Geriatr Soc 2000; 48:10621072.
Felson DT, Zhang Y, Anthony JM, Naimark A,
Anderson JJ. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham
Study. Ann Intern Med 1992; 116:535539.
Williams RA, Foulsham BM. Weight reduction in osteoarthritis using phentermine. Practitioner 1981; 225:
231232.
McGoey BV, Deitel M, Saplys RJ, Kliman ME. Eect
of weight loss on musculoskeletal pain in the morbidly
obese. J Bone Joint Surg Br 1990; 72:322323.
Grunstein R. Obstructive sleep apnoea as a risk factor
for hypertension. J Sleep Res 1995; 4:166170.
Strollo PJ Jr, Rogers RM. Obstructive sleep apnea. N
Engl J Med 1996; 334:99104.
Peppard PE, Young T, Palta M, Dempsey J, Skatrud
J. Longitudinal study of moderate weight change and
sleep-disordered breathing. JAMA 2000; 284:3015
3021.
Roux F, DAmbrosio C, Mohsenin V. Sleep-related
breathing disorders and cardiovascular disease. Am J
Med 2000; 108:396402.
Shahar E, Whitney CW, Redline S, Lee ET, Newman
AB, Javier Nieto F, OConnor GT, Boland LL,
Schwartz JE, Samet JM. Sleep-disordered breathing
and cardiovascular disease: cross-sectional results of
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
34
Effects of Obesity on the Cardiovascular System
Edward Saltzman
Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University
and TuftsNew England Medical Center, Boston, Massachusetts, U.S.A.
Peter N. Benotti
Valley Hospital, Ridgewood, New Jersey, U.S.A.
INTRODUCTION
II
826
increased stroke volume (6,911). The increase in cardiac output is generally in proportion to excess weight,
reecting the interrelationships among weight, blood
volume, stroke volume, and cardiac output (4,6,7,9,12).
Heart rate, the other determinant of cardiac output, remains essentially unchanged and does not signicantly
contribute to increased cardiac output in obesity (4,6,7,
10,11). While cardiac output is increased in absolute
terms, when normalized to body surface area, values
remain in the normal range (4,7). Arteriovenous oxygen
extraction, another mechanism that could increase oxygen delivery, is unchanged or only slightly increased in
obesity (5,9).
Reduced systemic vascular resistance accompanies
elevations in cardiac output that occur in nonhypertensive obesity (4,5,7). This reduction in peripheral resistance in part explains why hypertension is not observed
in all obese individuals who have elevated intravascular
volume and cardiac output. A limitation to this adaptive
mechanism clearly exists, however, since hypertension is
commonly associated with obesity.
The initial response to increased metabolic demand
and total blood volume is increased left ventricular
lling, leading to chamber dilatation and increased cardiac output. However, longer-term structural changes
accompany this hemodynamic adaptation. Left ventricular dilatation increases myocardial wall stress, which,
over time, stimulates left ventricular myocardial growth
and leads to elevated mass. In turn, wall stress is normalized, diminishing (at least in part) the stimulus for
further hypertrophy. In cross-sectional observations,
ventricular mass has been increased in proportion to
BMI, degree of overweight or fat mass (11,1317). In a
recent trial, left ventricular mass was associated with fat
mass, but was more strongly associated with fat-free
mass (18), perhaps reecting the greater relative contribution of fat-free mass than fat mass to oxygen consumption. In addition to degree of obesity, duration of
obesity also appears to be predictive of left ventricular
mass (15). Left ventricular mass has been directly associated with measures of central obesity, but the strengths
of these associations have varied considerably between
studies (11,14,18,19). Wikstrand et al. (11) have proposed that central obesity does not have an independent
eect on ventricular mass, but may promote adverse
loading conditions or elevated blood pressure. Metabolic factors associated with central obesity, such as
insulin resistance and hyperinsulinemia (20), have also
been proposed to contribute to left ventricular hypertrophy. Right ventricular dilatation and hypertrophy
also have been observed in extreme obesity (21), and the
presence of obstructive sleep apnea or obesity hypoventilation syndrome appears to increase risk for right as
well as left ventricular hypertrophy (22).
When left ventricular dilatation and hypertrophy
occur together, the usual relationship between left ventricular cavity radius and wall thickness is preserved and
eccentric hypertrophy results (Fig. 1). Hypertension
also promotes hypertrophy, reecting the increased wall
stress associated with elevations in systemic vascular
resistance. Essential hypertension in lean patients is, in
contrast to obese patients, typically characterized by
Figure 1 Eect of obesity and hypertension on cardiac structure. (Adapted from Ref. 238.)
827
828
Weight loss is accompanied by decreases in oxygen requirements, blood volume, and cardiac output (4547).
Reductions in blood pressure occur early in weight loss
and with modest amounts of lost weight (45,4850),
while greater degrees of weight loss have resulted in
amelioration or resolution of severe hypertension (51
53). Given trends toward normalization of blood volume and blood pressure, parallel changes in cardiac
function and structure might be expected. In mildly to
moderately obese persons, weight loss in the range of 4
10 kg has only inconsistently been associated with
decreased left ventricular dimension, loading conditions, and systolic function (5460). Despite the lack
of consistency in hemodynamic and functional parameters, reductions in left ventricular mass or wall thickness were observed in all but one (59) of these trials and
appeared to occur independent of reductions in blood
pressure (56,57). To dierentiate between the eects of
lost weight and reductions in blood pressure in over-
IV
A
ELECTROCARDIOGRAM, ARRHYTHMIAS,
AND SUDDEN DEATH
Eects on the Electrocardiogram
Considering that obesity is associated with hemodynamic and structural changes of the heart, as well as
with increased risk for sudden death, electrocardiographic (ECG) changes would not be unanticipated.
Frank et al. (66) examined ECG ndings in 1029 obese
subjects, which were then correlated with degree of
obesity, age, gender, and blood pressure. As obesity
increased, there was increased leftward QRS axis,
increased QRS voltage, and low QRS voltage was found
in 4%. The QT interval corrected for heart rate (QTc)
was abnormally prolonged in 28% and QTc prolongation correlated with degree of obesity. In trials where the
ECG in obese subjects has been compared to lean
controls, obese patients have had more leftward QRS
axis (although pathologic left axis deviation was rare),
lower QRS voltage, and more frequent T-wave attening in the inferior and lateral leads (6668). Alpert
(67) contrasted the ECGs of 100 obese subjects (BMI
48F2 kg/m2) with 100 lean controls and found that 11/
100 obese patients had low QRS voltage. None of these
11 subjects had elevated left ventricular mass/height
index, although in the entire population, left ventricular
mass index was elevated in 64/100. Alpert has proposed
829
830
Arrhythmia
(10%), ventricular tachycardia (6%), and supraventricular tachycardia (4%). In addition, changes suggestive
of cardiac ischemia during sleep occurred in 10% of
subjects.
C
Sudden Death
both. In all 11 patients who died under monitored conditions, ventricular arrhythmias were observed. Fisler
(98) compiled trials reporting sudden death or ECG
abnormalities in obese dieting patients prior to 1992,
and several subsequent reports have now been published
(72,99102). It appears that starvation lasting more than
several weeks, very low calorie diets with poor-quality
protein, and surgical weight loss without nutritional
monitoring were associated with QTc prolongation,
low QRS voltage, and sporadic arrhythmias (93
98,103). In contrast, very low calorie diets containing
sucient quantities of good quality protein and supplemented with micronutrients (72,98101,104107), and
starvation of brief (10 days) duration (102) have not
been associated with abnormalities of cardiac conduction, voltage, or rhythm.
Sudden death is now rarely reported in patients
undergoing surgical weight loss, suggesting that diet
quality, preoperative assessment, and postoperative
monitoring have improved. While no denitive underlying mechanism was found for sudden death during
prolonged starvation or very low calorie diets, a number
of factors have been proposed. Dietary factors include
consumption of inadequate or poor-quality protein,
electrolyte deciencies, and copper deciency (possibly
secondary to use of collagen, a protein source low in
copper) (93,98,108110). Other proposed factors include myocardial protein depletion and increased sensitivity to the sympathetic stimulation associated with
refeeding (93,98). Another proposed factor contributing
to sudden death is that there is a critical threshold for
loss of body weight or fat free mass. In a reanalysis in the
original 58 patients, Van Itallie and Yang (93) found a
direct relationship between initial BMI and months of
survival on a very low calorie diet. The authors suggest
that initially high levels of fat-free mass and fat might
confer a survival advantage by delaying loss to a critical
level of fat-free mass or myocardium.
V
ATHEROEMBOLIC DISEASE:
CORONARY HEART DISEASE
AND STROKE
831
plaque formation to plaque rupture and thrombus formation, and nally to brosis (112). Obesity and central
body fat distribution have been demonstrated to promote processes contributing to each of these stages
(Table 2). Traditional CHD risk factors, such as diabetes, hypertension, and dyslipidemia, are discussed
elsewhere in this volume. Several emerging nontraditional risk factors for CHD are associated with obesity,
including the role of chronic inammation, endothelial
dysfunction, and alterations in hemostasis and coagulation.
Coronary heart disease has recently been associated
with a state of chronic low-level inammation, a state
that may indicate underlying CHD, but also may contribute to pathogenesis (113115). Several circulating
markers of inammation, such as C-reactive protein
(CRP) and brinogen, have been identied as predictors
of CHD incidence and prognosis. CRP is an acute phase
protein that is elevated in response to inammation or
infection. CRP has been found to correlate directly with
degree of overweight, body fat, and central fat distribution; in addition, CRP has been associated with insulin
resistance, activation of coagulation, and subclinical
atherosclerosis (113,114,116121). In several trials,
CRP was a signicant predictor of new CHD events
and prognosis after CHD events, and use of CRP has
improved prediction of CHD events when combined
with blood lipids (119,122,123). CRP is produced in the
liver primarily under the control of interleukin-6 (IL-6),
a pro-inammatory cytokine produced in macrophages,
lymphocytes, and fat cells (124). IL-6 itself has been
associated with CHD (125), and also increases hepatic
832
Weight loss in overweight, moderately obese, and extremely obese subjects has been demonstrated to improve CHD risk factors such as blood pressure (49,186,
199,200), blood glucose and insulin concentrations
(201,202), and blood lipids (186,199,203). Hemostatic
imbalance appears to be normalized by weight loss, as
subjects who lost 814 kg demonstrated marked decreases in PAI-1, factor VIIc, and brinogen (186,203,
204). However, those who regain weight again revert
toward a pro-thrombotic state. Vasodilatory function
response to ischemia-induced forearm blood ow, an
indicator of endothelial vasodilatory function, was signicantly improved with weight losses of 57 kg (134).
833
VI
CARDIOVASCULAR EFFECTS
OF APPETITE SUPPRESSANTS
834
VII
CONCLUSION
Obesity is associated with substantial risk for cardiovascular morbidity and mortality. The obese state is
characterized by hemodynamic and structural adaptation, and promotes cardiovascular disease through traditional, newly described, or as yet undened risk
ACKNOWLEDGMENTS
Supported in part by the U.S. Department of Agriculture, Agricultural Research Service, under contract 533K06-5-10. Contents of this publication do not
necessarily reect the views or policies of the U.S. Department of Agriculture.
REFERENCES
1.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
835
dysfunction in cardiopathy of obesity. Chest 1987;
92:10421046.
26. Smith HL, Willius FA. Adiposity of the heart: a clinical
and pathologic study of one hundred and thirty-six
obese patients. Ann Intern Med 1933; 52:930931.
27. Carpenter HM. Myocardial fat inltration. Am Heart J
1962; 63:491496.
28. Amad KH, Brennan JC, Alexander JK. The cardiac
pathology of chronic exogenous obesity. Circulation
1965; 32:740745.
29. Koren MJ, Devereux RB, Casale PN, Savage DD,
Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114:345
352.
30. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli
WP. Left ventricular mass and incidence of coronary
heart disease in an elderly cohort. Ann Intern Med
1989; 110:101107.
31. Liao Y, Cooper RS, McGee DL, Mensah GA, Ghali
JK. The relative eects of left ventricular hypertrophy,
coronary artery disease, and ventricular dysfunction on
survival among black adults. JAMA 1995; 273:1592
1597.
32. Ghali JK, Liao Y, Simmons B, Castaner A, Cao G,
Cooper RS. The prognostic role of left ventricular
hypertrophy in patients with or without coronary artery
disease. Ann Intern Med 1992; 117:831836.
33. Casale PN, Devereux RB, Milner M, Zullo G, Harsheld GA. Value of echocardiographic measurement of
left ventricular mass in predicting cardiovascular
morbid events in hypertensive men. Ann Intern Med
1986; 105:173178.
34. Harjai KJ. Potential new cardiovascular risk factors:
left ventricular hypertrophy, homocysteine, lipoprotein(a), triglycerides, oxidative stress, and brinogen.
Ann Intern Med 1999; 131:376386.
35. Gardin JM, McClelland R, Kitzman D, Lima JA,
Bommer W, Klopfenstein HS, Wong ND, Smith VE,
Gottdiener J. M-mode echocardiographic predictors of
six- to seven-year incidence of coronary heart disease,
stroke, congestive heart failure, and mortality in an
elderly cohort (the Cardiovascular Health Study). Am J
Cardiol 2001; 87:10511057.
36. Chakko S, Mayor M, Allison MD, Kessler KM,
Materson BJ, Myerburg RJ. Abnormal left ventricular
diastolic lling in eccentric left ventricular hypertrophy
of obesity. Am J Cardiol 1991; 68:9598.
37. Ku CS, Lin SL, Wang DJ, Chang SK, Lee WJ. Left
ventricular lling in young normotensive obese adults.
Am J Cardiol 1994; 73:613615.
38. Crisostomo LL, Araujo LM, Camara E, Carvalho C,
Silva FA, Vieira M, Rabelo A Jr. Comparison of left
ventricular mass and function in obese versus nonobese
women <40 years of age. Am J Cardiol 1999;84:1127
1129, A1111.
836
39. Garavaglia GE, Messerli FH, Nunez BD, Schmieder
RE, Grossman E. Myocardial contractility and left
ventricular function in obese patients with essential
hypertension. Am J Cardiol 1988; 62:594597.
40. Hubert HB, Feinleib M, McNamara PM, Castelli WP.
Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the
Framingham Heart Study. Circulation 1983; 67:968
977.
41. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C,
Whelton PK. Risk factors for congestive heart failure in
US men and women: NHANES I epidemiologic followup study. Arch Intern Med 2001; 161:9961002.
42. Alpert MA, Terry BE, Mulekar M, Cohen MV, Massey
CV, Fan TM, Panayiotou H, Mukerji V. Cardiac
morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and eect of weight loss. Am J
Cardiol 1997; 80:736740.
43. Caruana L, Petrie MC, Davie AP, McMurray JJ. Do
patients with suspected heart failure and preserved left
ventricular systolic function suer from diastolic heart
failure or from misdiagnosis? A prospective descriptive study. BMJ 2000; 321:215218.
44. Kasper EK, Hruban RH, Baughman KL. Cardiomyopathy of obesity: a clinicopathologic evaluation of 43
obese patients with heart failure. Am J Cardiol 1992;
70:921924.
45. Reisin E, Frohlich ED, Messerli FH, Dreslinski GR,
Dunn FG, Jones MM, Batson HM Jr. Cardiovascular
changes after weight reduction in obesity hypertension.
Ann Intern Med 1983; 98:315319.
46. Beretta-Piccoli C. Blood volume changes after weight
reduction. Ann Intern Med 1983; 99:568569.
47. Alpert MA. Management of obesity cardiomyopathy.
Am J Med Sci 2001; 321:237241.
48. Stevens VJ, Corrigan SA, Obarzenek E. Weight loss
intervention in phase 1 of the trials of hypertension
prevention. Arch Intern Med 1993; 153:849858.
49. Blumenthal JA, Sherwood A, Gullette EC, Babyak M,
Waugh R, Georgiades A, Craighead LW, Tweedy D,
Feinglos M, Appelbaum M, Hayano J, Hinderliter A.
Exercise and weight loss reduce blood pressure in men
and women with mild hypertension: eects on cardiovascular, metabolic, and hemodynamic functioning.
Arch Intern Med 2000; 160:19471958.
50. Minami J, Kawano Y, Ishimitsu T, Matsuoka H,
Takishita S. Acute and chronic eects of a hypocaloric
diet on 24-hour blood pressure, heart rate and heartrate variability in mildly-to-moderately obese patients
with essential hypertension. Clin Exp Hypertens 1999;
21:14131427.
51. Benotti PN, Bistrian B, Benotti JR, Blackburn G, Forse
RA. Heart disease and hypertension in severe obesity:
the benets of weight reduction. Am J Clin Nutr 1992;
55:586S590S.
52. Foley E, Benotti P, Borlase B, et al. Impact of gastric
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
837
calcication: a study in type 1 diabetic patients and the
general population. Diabetes Care 2001; 24:11081114.
82. Zahorska-Markiewicz B, Kuagowska E, Kucio C, Klin
M. Heart rate variability in obesity. Int J Obes 1993;
17:2123.
83. Emdin M, Gastaldelli A, Muscelli E, Macerata A,
Natali A, Camastra S, Ferrannini E. Hyperinsulinemia
and autonomic nervous system dysfunction in obesity:
eects of weight loss. Circulation 2001; 103:513519.
84. Rissanen PF-KARA. Cardiac parasympathetic activity
is increased by weight loss in healthy obese women.
Obes Res 2001; 9:637643.
85. Hirsch J, Leibel RL, Mackintosh R, Aguirre A. Heart
rate variability as a measure of autonomic function
during weight change in humans. Am J Physiol 1991;
261:R1418R1423.
86. Koenig SM. Pulmonary complications of obesity. Am J
Med Sci 2001; 321:249279.
87. Koehler U, Becker HF, Grimm W, Heitmann J, Peter
JH, Schafer H. Relations among hypoxemia, sleep
stage, and bradyarrhythmia during obstructive sleep
apnea. Am Heart J 2000; 139:142148.
88. Valencia-Flores M, Orea A, Castano VA, Resendiz M,
Rosales M, Rebollar V, Santiago V, Gallegos J,
Campos RM, Gonzalez J, Oseguera J, Garcia-Ramos
G, Bliwise DL. Prevalence of sleep apnea and electrocardiographic disturbances in morbidly obese patients.
Obes Res 2000; 8:262269.
89. Chadwick J, Mann WN. The Medical Works of
Hippocrates. Oxford: Blackwell Scientic, 1950.
90. Kannel WB, Plehn JF, Cupples LA. Cardiac failure and
sudden death in the Framingham Study. Am Heart J
1988; 115:869875.
91. Drenick EJ, Fisler JS. Sudden cardiac arrest in
morbidly obese surgical patients unexplained after
autopsy. Am J Surg 1988; 155:720726.
92. Spooner PM, Albert C, Benjamin EJ, Boineau R,
Elston RC, George AL Jr, Jouven X, Kuller LH,
MacCluer JW, Marban E, Muller JE, Schwartz PJ,
Siscovick DS, Tracy RP, Zareba W, Zipes DP. Sudden
cardiac death, genes, and arrhythmogenesis: consideration of new population and mechanistic approaches
from a National Heart, Lung, and Blood Institute
workshop, part I. Circulation 2001; 103:23612364.
93. Van Itallie TB, Yang MU. Cardiac dysfunction in obese
dieters: a potentially lethal complication of rapid,
massive weight loss. Am J Clin Nutr 1984; 39:695702.
94. Brown JM, Yetter JF, Spicer MJ, Jones JD. Cardiac
complications of protein-sparing modied fasting.
JAMA 1978; 240:120122.
95. Singh BN, Gaarder TD, Kanegae T, Goldstein M,
Montgomerie JZ, Mills H. Liquid protein diets and
torsade de pointes. JAMA 1978; 240:115119.
96. Sours HE, Frattali VP, Brand CD, Feldman RA,
Forbes AL, Swanson RC, Paris AL. Sudden death
associated with very low calorie weight reduction
regimens. Am J Clin Nutr 1981; 34:453461.
838
97. Isner JM, Sours HE, Paris AL, Ferrans VJ, Roberts
WC. Sudden, unexpected death in avid dieters using the
liquid-protein-modied-fast diet. Observations in 17
patients and the role of the prolonged QT interval.
Circulation 1979; 60:14011412.
98. Fisler JS. Cardiac eects of starvation and semistarvation diets: safety and mechanisms of action. Am
J Clin Nutr 1992; 56:230S234S.
99. Seim HC, Mitchell JE, Pomeroy C, de Zwaan M.
Electrocardiographic ndings associated with very low
calorie dieting. Int J Obes 1995; 19:817819.
100. Doherty JU, Wadden TA, Zuk L, Letizia KA, Foster
GD, Day SC. Long-term evaluation of cardiac function
in obese patients treated with a very-low-calorie diet: a
controlled clinical study of patients without underlying
cardiac disease. Am J Clin Nutr 1991; 53:854858.
101. Pietrobelli A, Rothacker D, Gallagher D, Heymseld
SB. Electrocardiographic QTC interval: short-term
weight loss eects. Int J Obes 1997; 21:110114.
102. Zuckerman E, Yeshurun D, Goldhammer E, Shiran A.
24 h electrocardiographic monitoring in morbidly obese
patients during short-term zero calorie diet. Int J Obes
1993; 17:359361.
103. Pringle T, Scobie T, Murray R, Kesson C, Maccuish A.
Prolongation of the QT interval during therapeutic
starvation: a substrate for malignant arrhythmias. Int J
Obes 1983; 7:253261.
104. Weigle DS, Callahan DB, Fellows CL, Greene HL.
Preliminary assessment of very low calorie diets by
conventional and signal-averaged electrocardiography.
Int J Obes 1989; 13:691697.
105. Moyer CL, Holly RG, Amsterdam EA, Atkinson RL.
Eects of cardiac stress during a very-low-calorie diet
and exercise program in obese women. Am J Clin Nutr
1989; 50:13241327.
106. Linet OI, Butler D, Caswell K, Metzler C, Reele SB.
Absence of cardiac arrhythmias during a very-lowcalorie diet with high biological quality protein. Int J
Obes 1983; 7:313320.
107. Phinney SD, Bistrian BR, Kosinski E, Chan DP, Hoer
LJ, Rolla A, Schachtel B, Blackburn GL. Normal
cardiac rhythm during hypocaloric diets of varying
carbohydrate content. Arch Intern Med 1983;
143:22582261.
108. Lantigua RA, Amatruda JM, Biddle TL, Forbes GB,
Lockwood DH. Cardiac arrhythmias associated with a
liquid protein diet for the treatment of obesity. N Engl J
Med 1980; 303:735738.
109. Amatruda JM, Biddle TL, Patton ML, Lockwood DH.
Vigorous supplementation of a hypocaloric diet prevents cardiac arrhythmias and mineral depletion. Am J
Med 1983; 74:10161022.
110. Lowy SL, Fisler JS, Drenick EJ. Zinc and copper
nutriture in obese men receiving very low calorie diets of
soy or collagen protein. Am J Clin Nutr 1986; 43:272
287.
839
abrogates sex dierences in endothelial function in
premenopausal women. Circulation 2000; 101:2040
2046.
137. Abdu TA, Elhadd T, Pfeifer M, Clayton RN. Endothelial dysfunction in endocrine disease. Trends Endocrinol Metab 2001; 12:257265.
138. Al Suwaidi J, Higano ST, Holmes DR Jr, Lennon R,
Lerman A. Obesity is independently associated with
coronary endothelial dysfunction in patients with
normal or mildly diseased coronary arteries. J Am Coll
Cardiol 2001; 37:15231528.
139. Reed D, Yano K. Predictors of arteriographically
dened coronary stenosis in the Honolulu Heart
Program. Am J Epidemiol 1991; 134:111122.
140. Rimm EB, Stampfer MJ, Giovannucci E, Ascherio A,
Spiegelman D, Colditz GA, Willett WC. Body size and
fat distribution as predictors of coronary heart disease
among middle-aged and older US men. Am J Epidemiol
1995; 141:11171127.
141. Adams-Campbell LL, Peniston RL, Kim KS, Mensah
E. Body mass index and coronary artery disease in
African-Americans. Obes Res 1995; 3:215219.
142. Fitzgerald A, Jarrett R. Body weight and coronary
heart disease mortality: an analysis in relation to age
and smoking habit. 15 years follow-up data from the
Whitehall Study. Int J Obes Relat Metab Disord 1992;
16(2):119.
143. Kuhn FE, Rackley CE. Coronary artery disease in
women. Arch Intern Med 1993; 153:26262636.
144. Keys A, Aravanis C, Blackburn H, Van Buchem F,
Buzina R, Djordjevic B, Fidanza F, Karvonen M,
Menotti A, Puddu V, Taylor H. Coronary heart
disease: overweight and obesity as risk factors. Ann
Intern Med 1972; 77:1527.
145. Clark LT, Emerole O. Coronary heart disease in
African Americans: primary and secondary prevention.
Cleve Clin J Med 1995; 62:285292.
146. Caralis PV. Coronary heart disease in Hispanic
Americans: how does ethnic background aect risk
factors and mortality rates? Postgrad Med 1992;
91:179188.
147. Howard BV, Lee ET, Cowan LD, Fabsitz RR, Howard
WJ, Oopik AJ, Robbins DC, Savage PJ, Yeh JL, Welty
TK. Coronary heart disease prevalence and its relation
to risk factors in American Indians: the Strong Heart
Study. Am J Epidemiol 1995; 142:254268.
148. Robertson TL, Kato H, Rhoads GG. Epidemiologic
studies of coronary heart disease and stroke in Japanese
men living in Japan, Hawaii and California: incidence
of myocardial infarction and death from coronary heart
disease. Am J Cardiol 1977; 39:239243.
149. Wilson PWF. Established risk factors and coronary
artery disease: the Framingham Study. Am J Hypertens
1994; 7:7S12S.
150. Keil JE, Sutherland SE, Knapp RG, Lackland DT,
Gazes PC, Tyroler H. Mortality rates and risk factors
840
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
841
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
Relationship between fasting plasma glucose, atherosclerosis risk factors and carotid intima media thickness
in non-diabetic individuals. Diabetologia 1998; 41:706
712.
Mainard F, Auget JL, Vest P, Madec Y. Comparative
study of risk factors in patients undergoing coronary or
femoropopliteal artery bypass grafting. Br Heart J
1994; 72:542547.
Gon R, Kark JD, Friedlander Y, Lewis BS, Witt H,
Stein Y, Gotsman MS. Peripheral vascular disease in a
middle-aged population sample. The Jerusalem Lipid
Research Clinic Prevalence Study. Isr J Med Sci 1987;
23:157167.
Ness J, Aronow WS, Ahn C. Risk factors for symptomatic peripheral arterial disease in older persons in an
academic hospital-based geriatrics practice. J Am
Geriatr Soc 2000; 48:312314.
Giltay EJ, Lambert J, Elbers JM, Gooren LJ, Asscheman H, Stehouwer CD. Arterial compliance and
distensibility are modulated by body composition in
both men and women but by insulin sensitivity only in
women. Diabetologia 1999; 42:214221.
Gariepy J, Salomon J, Denarie N, Laskri F, Megnien
JL, Levenson J, Simon A. Sex and topographic dierences in associations between large-artery wall thickness and coronary risk prole in a French working
cohort: the AXA Study. Arterioscler Thromb Vasc Biol
1998; 18:584590.
Plavnik FL, Ajzen S, Kohlmann O Jr, Tavares A,
Zanella MT, Ribeiro AB, Ramos OL. Intima-media
thickness evaluation by B-mode ultrasound. Correlation with blood pressure levels and cardiac structures.
Brazil J Med Biol Res 2000; 33:5564.
MacMahon SW, Macdonald GJ, Bernstein L, Andrews
G, Blacket RB. A randomized controlled trial of weight
reduction and metoprolol in the treatment of hypertension in young overweight patients. Clin Exp
Pharmacol Physiol 1985; 12:267271.
Stevens VJ, Obarzanek E, Cook NR, Lee IM, Appel
LJ, Smith West D, Milas NC, Mattfeldt-Beman M,
Belden L, Bragg C, Millstone M, Raczynski J, Brewer
A, Singh B, Cohen J. Long-term weight loss and
changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med 2001;
134:111.
Kelley D. Eects of weight loss on glucose homeostasis
in NIDDM. Diabetes Rev 1995; 3:366377.
Letiexhe MR, Scheen AJ, Gerard PL, Desaive C,
Lefebvre PJ. Insulin secretion, clearance and action
before and after gastroplasty in severely obese subjects.
Int J Obes 1994; 18:295300.
Marckmann P, Toubro S, Astrup A. Sustained improvement in blood lipids, coagulation, and brinolysis
after major weight loss in obese subjects. Eur J Clin
Nutr 1998; 52:329333.
Rissanen P. Weight change and blood coagulability and
842
brinolysis in healthy obese women. Int J Obes 2001;
25:212218.
205. Heilbronn LK, Noakes M, Clifton PM. Energy restriction and weight loss on very-low-fat diets reduce C-reactive protein concentrations in obese, healthy women.
Arterioscler Thromb Vasc Biol 2001; 21:968970.
206. Williamson DF, Pamuk ER. The association between
weight loss and increased longevity. A review of the
evidence. Ann Intern Med 1993; 119:731736.
207. French SA, Folsom AR, Jeery RW, Williamson DF.
Prospective study of intentionality of weight loss and
mortality in older women: the Iowa Womens Health
Study. Am J Epidemiol 1999; 149:504514.
208. Williamson DF, Thompson TJ, Thun M, Flanders D,
Pamuk E, Byers T. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 2000; 23:14991504.
209. Kuller LH. Invited commentary on Prospective study
of intentionality of weight loss and mortality in older
women: the Iowa Womens Health Study and Prospective study of intentional weight loss and mortality
in overweight white men aged 4064 years. Am J
Epidemiol 1999; 149:515516.
210. Connolly HM, Crary JL, McGoon D, Hensrud DD,
Edwards BS, Scha HV. Valvular heart disease
associated with fenuramine-phentermine. N Engl J
Med 1997; 337:581588.
211. Graham DJ, Green L. Further cases of valvular heart
disease associated with fenuramine-phentermine. N
Engl J Med 1997; 337:635.
212. Cannistra LB, Davis SM, Bauman AG. Valvular heart
disease associated with dexfenuramine. N Engl J Med
1997; 337:636.
213. Cardiac valvulopathy associated with exposure to
fenuramine or dexfenuramine: U.S. Department of
Health and Human Services interim public health
recommendations, November 1997. MMWR 1997; 46:
10611066.
214. Weissman NJ, Tighe JF Jr, Gottdiener JS, Gwynne JT.
An assessment of heart-valve abnormalities in obese
patients taking dexfenuramine, sustained-release dexfenuramine, or placebo. Sustained-Release Dexfenuramine Study Group. N Engl J Med 1998; 339:725
732.
215. Davido R, McTiernan A, Constantine G, Davis KD,
Balady GJ, Mendes LA, Rudolph RE, Bowen DJ.
Echocardiographic examination of women previously
treated with fenuramine: long-term follow-up of a
randomized, double-blind, placebo-controlled trial.
Arch Intern Med 2001; 161:14291436.
216. Wee CC, Phillips RS, Aurigemma G, Erban S, Kriegel
G, Riley M, Douglas PS. Risk for valvular heart disease
among users of fenuramine and dexfenuramine who
underwent echocardiography before use of medication.
Ann Intern Med 1998; 129:870874.
217. Gardin JM, Schumacher D, Constantine G, Davis KD,
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
843
234.
235.
236.
237.
238.
35
Obesity and Lipoprotein Metabolism
Jean-Pierre Despres
Quebec Heart Institute, Laval Hospital Research Center, Laval University, Sainte-Foy, Quebec, Canada
Ronald M. Krauss
Childrens Hospital Oakland Research Institute, Oakland, Lawrence Berkeley National Laboratory,
and University of California, Berkeley, Berkeley, California, U.S.A.
DYSLIPIDEMIC PHENOTYPES
IN CORONARY HEART DISEASE:
BEYOND CHOLESTEROL
The measurement of plasma lipid levels is now commonly used to assess the risk of coronary heart disease
(CHD). Several epidemiological studies have shown
that there is a signicant positive relationship between
blood cholesterol levels and deaths associated with
CHD (13). In the Multiple Risk Factor Intervention
Trial (MRFIT), Stamler et al. (4) showed that in a sample of 356,222 male subjects, increased blood cholesterol
levels were associated with a progressive increase in
CHD mortality. However, despite the fact that numerous studies have shown this relationship, Genest et al.
(5) have reported that nearly 50% of patients having
ischemic heart disease (IHD) have plasma cholesterol
levels equal to or even lower than those of healthy
subjects.
Accordingly, Sniderman and Silberberg (6) emphasized that although the mean blood cholesterol concentration in CHD patients is generally signicantly higher
than that of healthy subjects, there is a considerable
overlap between CHD patients and healthy subjects.
Thus, the clinical value of total cholesterol measurement alone is of limited use in distinguishing CHD pa-
Numerous prospective studies that have measured cholesterol in the lipoprotein fractions (VLDL, LDL, and
HDL) have reported highly signicant associations
845
846
Figure 1 Simplied overview of lipoprotein metabolism. After hydrolysis of dietary triglycerides by intestinal lipase and their
secretion in the lymph as chylomicrons (containing dietary cholesterol, triglycerides, phospholipids, apolipoprotein [apo] B48, and
apo AI, AII, and AIV), these nascent particles acquire apo C and E in the circulation. The chylomicron binds to the enzyme
lipoprotein lipase located on the surface of the endothelial cells of several tissues, including adipose tissue and skeletal muscle. This
process allows the transfer of excess surface components (apo AI, AII, and AIV, of the C apolipoproteins and of phospholipids)
to HDL. The chylomicron remnant particle is then cleared from the circulation via the hepatic apo E (remnant) receptor. The rst
step of chylomicron catabolism which involves hydrolysis by endothelial lipoprotein lipase appears to be modulated by numerous
hormonal and metabolic factors. The second step, which involves the clearance of chylomicron remnants by hepatocytes, does not
seem to be under close hormonal or metabolic control. Endogenous lipids are secreted by the liver as VLDL particles. Availability of
lipids appears to determine the fate of constitutively synthesized apo B100 and will protect apo B against its degradation. Insulin
and cortisol also seem to be important modulators of VLDL secretion via indirect (substrate availability) and direct (apo B
synthesis) eects. Apo B is synthesized on ribosomes of the rough endoplasmic reticulum and associates with lipids in its smooth
surface end. The nascent VLDL particle is then transported to the Golgi. Particles are packed in secretion vesicles and then secreted.
VLDL particles will acquire additional apolipoproteins in the circulation. With the action of endothelial lipoprotein lipase, VLDL
will be hydrolyzed into VLDL remnants, intermediate-density lipoproteins (IDL) and nally, into LDL. About 50% of the particles
will be cleared as IDL by the apo B/E receptor; the others will be eliminated by extrahepatic and hepatic apo B/E receptors as LDL
particles. Nascent HDL particles have multiple origins (gut, liver, plasma). However, considerable evidence suggests that hydrolysis
of triglyceride-rich lipoproteins (chylomicrons and VLDL) is a major process by which excess surface components are transferred
from triglyceride-rich lipoproteins to nascent HDL particles. Thus, the more ecient the hydrolysis of triglyceride-rich lipoproteins, the higher the lipoprotein lipase activity in the postheparin plasma and the higher the plasma HDL concentrations, especially
the HDL2 subfraction.
847
848
to a decreased production of HDL precursors originating from the aggregation of an excessive number of surface components released by the hydrolysis of VLDL
and chylomicrons. In this regard, we further examined
the metabolic heterogeneity underlying low HDL cholesterol levels (32). We found that individuals with low
HDL cholesterol but normal TG levels did not show
elevated plasma insulin levels either in the fasting state
or in response to an oral glucose challenge. We also
found that isolated hypertriglyceridemia was not associated with increased plasma insulin levels. However,
the combination of low HDL cholesterol and of moderately elevated TG concentrations was associated with
a considerable and signicant increase in plasma insulin
concentrations measured in the fasting state and in response to the oral glucose load, suggesting that this
specic dyslipidemic state was particularly related to
hyperinsulinemia stemming from resistance of tissues
to insulin.
In the PROCAM Study conducted in Munster, Germany (27), and in the Helsinki Heart Study (26) the
combination of high TG and low HDL cholesterol levels was associated with a signicant increase in the risk
of CHD and a high percentage of coronary events were
specically related to this dyslipidemia. For instance,
infused in order to induce hyperinsulinemia to a predetermined level. Obviously, the rate at which blood sugar
levels drop varies if there is no simultaneous infusion
of glucose. The greater the sensitivity to insulin, the
faster the blood glucose levels fall, and the higher the
quantity of glucose needed to maintain euglycemia.
Consequently, the sensitivity to insulin, or the M value,
corresponds to the amount of glucose required to maintain a normal blood glucose level under a standardized
hyperinsulinemic state and this value is expressed in
milligrams of glucose infused per kilogram body weigh
per minute.
Reaven and colleagues (33) next subdivided the
group of 100 nondiabetic subjects according to fasting
insulin concentrations. The rst quartile comprised
individuals with the highest blood insulin levels; the
fourth, individuals with the lowest. Within these four
groups, considerable dierences were observed in terms
of in vivo sensitivity to insulin. Subjects of the lowest
insulin quartile were very sensitive to insulin (M value
>300), whereas subjects of the highest insulin quartile
were clearly insulin resistant (M value barely above
100). Two critically important observations were made.
Firstly, considerable dierences in terms of sensitivity
to insulin were found even among individuals with normal glucose tolerance. Furthermore, in 25% of normal
individuals, the magnitude of the insulin resistant state
was similar to that found among glucose-intolerant
individuals or type 2 diabetic patients. Consequently,
Reaven concluded that insulin resistance is prevalent in
our population since 25% of nondiabetic subjects seem
to have this characteristic.
There is considerable evidence indicating that insulin
resistance is associated with a pro-atherogenic dyslipidemic state (34,35). Considering the recently conrmed
high prevalence of insulin resistance for which the
cluster of metabolic abnormalities has been dened as
the metabolic syndrome in the recent National Cholesterol Education Program Adult Treatment Panel III
(NCEP-ATP III) guidelines (36), this condition is likely
to represent the most common cause of dyslipidemic
states found in CHD patients (37,38).
B Normal
849
850
II
C
The 5-year follow-up results of the Quebec Cardiovascular Study provided data supporting the concept that
the cluster of metabolic abnormalities which accompanies hyperinsulinemia (as a crude marker of insulin
resistance) was predictive of a substantially increased
risk of IHD (50). First, the 114 men who developed IHD
during the 5-year follow-up period were matched for
age, body mass index (BMI), smoking, and alcohol consumption with 114 men who remained healthy. We then
excluded diabetic and IHD patients who could not be
matched with controls because of extreme smoking
habits, and we were able to match 91 nondiabetic cases
and 105 controls (50). Fasting insulin concentrations
were initially 18% higher in men who then developed
IHD than in those who remained healthy. Furthermore,
851
852
III
853
Figure 4 Cross-sectional abdominal adipose tissue areas measured by CT at L4-L5 in a middle-aged man (B,D) and a young
man (A,C) with similar total body fat mass values. The visceral adipose tissue, delineated by drawing a line within the muscle wall
surrounding the abdominal cavity, is highlighted (C,D).
854
Figure 5 Plasma triglyceride and HDL cholesterol concentrations in nonobese subjects and in subgroups of obese subjects
matched for body composition but having either low or high levels of visceral adipose tissue (AT) determined by computed tomography. 1Signicantly dierent from nonobese subjects, P<.05. 2Signicantly dierent from obese subjects with low levels of
visceral adipose tissue, P<.05. (Adapted from Ref. 179.)
(Fig. 7) (110). Furthermore, we have studied the potential contribution of gender dierences in visceral adipose tissue accumulation to the sex dimorphism found
in CVD risk variables (111). After control for the gender dimorphism in visceral adipose tissue accumulation, it was found that most of the dierences observed
in indices of plasma glucose-insulin homeostasis and in
plasma lipoprotein-lipid prole were no longer signicantly dierent between men and women (111), suggesting that the greater CVD risk noted in men compared
to premenopausal women may be partly due to the preferential accumulation of visceral adipose tissue in male
subjects.
Finally, in an attempt to examine whether there
could be a threshold of visceral adipose tissue accumu-
855
Figure 6 Plasma glucose and insulin concentrations in fasting state (15 and 0 min) and during oral glucose tolerance
test in obese women with high (.) or low (o) levels of visceral
adipose tissue (n=10 subjects/group) and in a sample of lean
women (5) (n=25). 1Signicantly dierent from (5). 2Signicantly dierent from (o), P<.05. (Adapted from Ref. 109.)
lation above which complications may be found, several variables predictive of CVD and type 2 diabetes
were compared among samples of young adults and
premenopausal women who were divided into quintiles
formed on the basis of their cross-sectional visceral adipose tissue area measured by CT. Figure 8 shows that in
both men and women, a value <100 cm2 was associated
with a rather favorable risk prole (112). However, a
cross-sectional visceral adipose tissue area of 130 cm2
and above was associated with a substantial deterioration in the cardiovascular risk prole (112).
856
Figure 8 Relations of quintiles of abdominal visceral adipose tissue (AT) area to variables predictive of type 2 diabetes and CVD
risk in samples of 115 men and 72 women, respectively. This gure shows that visceral AT areas >100 cm2 are associated with
moderate but signicant metabolic changes, whereas visceral AT areas >135 cm2 in men and 128 cm2 in women are clearly
associated with further metabolic deteriorations that suggest an increased risk of type 2 diabetes and CVD. 1, 2, 3, or 4 signicantly
dierent from quintiles 1, 2, 3, and 4, respectively (P<.05). Apo: apolipoprotein; OGTT: oral glucose tolerance test. (From
Ref. 112.)
857
IV
858
Figure 10 Complex metabolic interactions that presumably occur with the insulin resistance/dyslipidemic phenotype. In this
case, insulin resistance is frequently accompanied by excess intra-abdominal (visceral) adipose tissue. The liver, via the portal
circulation, becomes exposed to high levels of free fatty acids (FFA) as the compensatory hyperinsulinemia poorly inhibits the
lipolysis of intra-abdominal fat cells. This phenomenon stimulates gluconeogenesis as well as VLDL synthesis and secretion.
Moreover, the catabolism of TG-rich lipoproteins appears to be slow, this being attributable to the fact that LPL activity is
reduced and the postprandial adipose tissue LPL response is inadequate. Impaired LPL activity may explain, at least to some
degree, the low HDL cholesterol levels of insulin-resistant individuals characterized by visceral obesity. The high activity of
another enzyme, hepatic lipase (HTGL), is a contributing factor in the further decrease of HDL cholesterol level. The high TG
levels resulting from the increased production and slower catabolism of VLDL promotes the transfer of TG to LDL and HDL in
exchange for their cholesteryl esters (CE). This phenomenon leads to an increase in VLDL CE, a process considered as
atherogenic. Moreover, the TG-enriched LDL and HDL fractions represent the substrate of choice for HTGL, this process
favoring the formation of dense LDL, the concentration of which is higher in coronary artery disease patients. These complex
metabolic interactions increase not only the risk of diabetes but also the risk of coronary heart disease in insulin resistant
individuals. CETP: cholesteryl ester transfer protein. GH: growth hormone; LCAT: lecithin-cholesterol acyl transferase; LPL,
lipoprotein lipase. (Adapted from Ref. 38.)
and decreased degradation (through reduced LPL activity) are associated with an increased transfer of TG
from VLDL to LDL or HDL particles (87,88) in exchange of LDL and HDL cholesteryl esters, leading to
the TG enrichment of LDL and HDL. Such TG enrichment is associated with a reduced cholesterol content
of HDL. Furthermore, TG-rich LDL and HDL particles represent good substrates for the enzyme HTGL,
ultimately generating an atherogenic dyslipidemic
phenotype including small, dense LDL and HDL particles (55,92). Thus, reciprocal changes in LPL and
HTGL activities are important correlates of dyslipidemias found in an insulin resistant state associated with
visceral obesity.
The mechanisms leading to in vivo insulin resistance
are not fully understood, and it is also known that impaired insulin action can be present in both obese and
nonobese subjects (33). These observations suggest that
insulin resistance is a heterogeneous condition and provide further evidence that some genetic factors are likely
to be involved. Studies conducted among insulin-resistant or type 2 diabetic subjects have shown that the presence of a familial history of diabetes may alter the
relationship of abdominal fat accumulation to indices
of plasma glucose-insulin homeostasis (146,147). We
have previously reported that in subjects with a similar
level of deterioration in plasma glucose-insulin homeostasis, those who displayed a positive familial history of diabetes had lower levels of abdominal fat than
subjects without a familial history of diabetes (147).
These results suggest that the presence of genetic susceptibility reduces the threshold of abdominal fat above
which metabolic alterations predictive of an increased
type 2 diabetes risk are observed. Thus, in abdominally
viscerally obese patients, high FFA concentrations (increased lipolysis of the visceral depot), decreased LPL
activity and reduced insulin sensitivity may lead to
metabolic changes that are ultimately involved in the
development of insulin resistance, glucose intolerance,
hyperinsulinemia, dyslipoproteinemia, type 2 diabetes,
and CVD.
In addition to the impaired FFA metabolism hypothesis briey reviewed above, it has been suggested that
abdominal obesity is associated with altered sex steroid
levels. Results that have crudely assessed body fat distribution by the WHR have reported low levels of sex
hormone binding globulin (SHBG) concentrations and
high levels of free testosterone in women with excess
abdominal fat (70,148151). Moreover, the altered sex
steroid concentrations observed in abdominally obese
women have also been associated with variations of in
vivo insulin sensitivity (70,150). Studies have also shown
859
860
results from complex metabolic and hormonal interactions that lead to insulin resistance and to an increased
CVD risk (Fig. 10).
From the evidence reviewed, the detection of the subgroup of obese patients at risk for complications associated with excess visceral adipose tissue is clinically
important. Thus, an adequate estimation of visceral
adipose tissue accumulation is of great relevance to better quantify the patients risk of CVD. Although CT is
very accurate and reliable, it is not accessible to most
clinicians, and it was relevant to develop approaches in
order to oer simple tools for the detection, prevention,
and treatment of visceral obesity.
A
Numerous studies have examined the correlations between anthropometric measurements and cross-sectional visceral adipose tissue areas measured by CT
(168,169,171). Until recently, the WHR had generally
been considered as the most relevant variable in the
assessment of visceral obesity (7685), this ratio being
often used in prospective and metabolic studies. Although the use of WHR has contributed to highlight the
importance of body fat distribution, we have reported
that visceral adipose tissue accumulation showed better
correlations with the waist circumference alone than
with the WHR (172). Figure 12 shows that the relation
of visceral adipose tissue area to the waist girth was
stronger than for the WHR, especially in women. Furthermore, the relationship between waist circumference
and visceral adipose tissue was found to be similar in
men and women. Moreover, waist circumference also
appears to be a good correlate of total body fatness and
therefore provides a better index of abdominal obesity
than the WHR alone, which is a weak correlate of total
adiposity (172).
For example, a nonobese woman with small hips may
have a WHR value which could be similar to an obese
woman with a large accumulation of abdominal fat but
with also a substantial deposition of fat at the hip level
(Fig. 12). Thus, despite similar WHR values in these two
subjects, the obese women would have a much greater
accumulation of visceral adipose tissue than the nonobese women despite the fact that their WHR are simi-
861
Figure 12 (A) Relation of waist-to-hip ratio (WHR) or waist circumference to abdominal visceral adipose tissue (AT) areas
measured by computed tomography in men and women. (B) Misleading evaluation provided by the WHR in two women with
markedly diering levels of total body fat and of visceral AT. This example illustrates the notion that the WHR is an index of the
relative accumulation of abdominal fat whereas waist circumference provides a better index of the absolute amount of abdominal
adipose tissue. BMI: body mass index. (Adapted from Refs. 172,178.)
tissue deposition (172). On that basis, the waist circumference has now been recognized as an index of abdominal fat in the NCEP-ATP III guidelines (36).
B
862
cially over time) than BMI, abdominally obese individuals remain a heterogeneous group of patients. We
were interested in the development of a simple screening approach to help physicians and health professionals identify high-risk abdominally obese patients with
the features of the insulin resistance/metabolic syndrome. In a recent study, we reported that waist circumference was the simplest and best correlate of plasma
insulin and apo B levels, whereas another simple parameter, fasting TG concentration, was the best predictor
of LDL size (40). Sensitivity and specicity analyses
revealed that the best discrimination of carriers/noncarriers of this atherogenic metabolic triad (elevated insulin
and apo B levels as well as small, dense LDL particles)
was obtained when using cuto points of 90 cm for waist
circumference and 2.0 mmol/L for TG in a sample of
middle-aged men (Fig. 13). For instance, middle-aged
men with a waist<90 cm and fasting TG levels <2.0
mmol/L had a low chance (10%) of being carriers of the
triad. However, >80% of men with a waist girth z90 cm
and TG levels z2.0 mmol/L had all features of the
metabolic triad (40). Thus, we believe that health professionals have access to a simple and inexpensive
screening test to identify a high-risk form of abdominal
obesity. As there are no prospective data available in
women to quantify the CHD risk associated with
the metabolic triad, there is an urgent need to validate
this approach in women. It should also be emphasized
that there are dierences in susceptibility to develop
visceral obesity and related complications (diabetes, hypertension, and CHD) among ethnic groups, and our
approach should only be considered as valid for Caucasian men. Specic cutos are likely to be obtained
for instance for our Native American population as
well as for the African-American and South Asian
populations.
Figure 13 Description of two phenotypes predictive of either a very low or a high risk of being characterized by the
atherothrombotic, inammatory prole of the metabolic
syndrome.
VI
From the epidemiological and metabolic evidence available, there is no doubt that abdominal obesity is an
important risk factor for the development of dyslipidemias and CVD. Several prospective studies have shown
that abdominal obesity is associated with an increased
mortality rate related to CVD (72,7678,173175).
However, it is also important to acknowledge the notion that no intervention study has shown that reducing
obesity and the amount of abdominal fat would lead to a
reduction in the incidence of CVD and related mortality.
To the best of our knowledge, the only ongoing project
on this issue is the study of Swedish Obese Subjects (SOS
study) (176), but these results will only apply to the
question of weight loss resulting from the surgical treatment of very obese patients. However, it must be
recognized that there is a considerable amount of literature that has indicated that reducing body weight and
lowering the amount of abdominal fat is associated with
major improvements in the CVD risk prole including
reduction in blood pressure, improvement in plasma
lipoprotein-lipid levels, and an increase in insulin sensitivity leading to a reduction in plasma insulin levels and
to an improvement of glucose tolerance (112).
As obesity is often associated with metabolic complications causing prejudice to health, it has been suggested that obesity should be considered as a disease.
However, because obesity is dened on the basis of the
BMI, some healthy individuals with BMI values z30 are
then classied as high-risk subjects (with a disease)
despite the presence of a normal metabolic risk prole.
This problem may explain the generally unimpressive
ndings reported with the pharmacotherapy of obesity,
as these studies have largely included low-risk, normolipidemic obese women with a normal metabolic risk
factor prole (177). Nevertheless, on the basis of the
substantial metabolic improvements that can be generated by a 510% weight loss (56,112), the importance
of targeting weight loss in high-risk viscerally obese
patients with an atherogenic dyslipidemic state and
identied by the hypertriglyceridemic waist phenotype
rather than by the BMI should be emphasized in clinical
practice (178). In this high-risk obesity phenotype, the
benets of pharmacotherapy may outweigh the potential hazards of drug therapya possibility that needs to
be urgently tested in randomized weight loss trials.
863
Figure 14 Potential benets of moderate (510%) weight loss in a high-risk patient with the cluster of atherothrombotic,
inammatory metabolic abnormalities associated with hypertriglyceridemic waist. Weight loss in abdominally obese patients is
associated with selective mobilization of diabetogenic and atherogenic visceral adipose tissue. Even a 510% weight loss is
associated with preferential mobilization of visceral adipose tissue, leading to simultaneous improvement in all metabolic markers
of coronary heart disease (CHD) risk. Thus, simultaneous metabolic improvements associated with mobilization of visceral adipose
tissue may contribute to substantially reducing the risk of an acute coronary event in high-risk patients. (Adapted from Ref. 178.)
864
4.
5.
6.
7.
8.
9.
ACKNOWLEDGMENTS
The work of the authors reviewed in this chapter has
been supported by the Canadian Institutes of Health
Research and by the Canadian Diabetes Association.
Jean-Pierre Despres is chair professor of human nutrition, lipidology and prevention of cardiovascular diseases, which is supported by Pzer, Provigo, and the
Foundation of the Quebec Heart Institute.
This work was supported by the National Institutes
of Health Program Project grant HL18574 from the
National Heart, Lung and Blood Institute, a grant
from the National Dairy Promotion and Research
Board, and administered in cooperation with the National Dairy Council, and was conducted at the Ernest
Orlando Lawrence Berkeley National Laboratory.
10.
11.
12.
13.
REFERENCES
14.
1.
2.
3.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
a broad range of initial cholesterol levels. The LongTerm Intervention with Pravastatin in Ischaemic
Disease (LIPID) Study Group. N Engl J Med 1998;
339(19):13491357.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a
randomised placebo-controlled trial. Lancet 2002; 360:
722.
Despres JP, Lemieux I, Dagenais GR, Cantin B,
Lamarche B. HDL-cholesterol as a marker of coronary
heart disease risk: the Quebec cardiovascular study.
Atherosclerosis 2000; 153(2):263272.
Superko HR. Beyond LDL cholesterol reduction. Circulation 1996; 94(10):23512354.
Gordon T, Castelli WP, Hjortland MC, Kannel WB,
Dawber TR. High density lipoprotein as a protective
factor against coronary heart disease: the Framingham
Study. Am J Med 1977; 62:707714.
Miller NE, Forde OH, Thelle DS, Mjos OD. The
Tromso Heart Study: high-density lipoprotein as a
protective factor against coronary heart disease: a prospective case-control study. Lancet 1977; 1:965967.
Castelli WP, Doyles JT, Gordon T. HDL-cholesterol
and other lipids in coronary heart disease: the cooperative lipoprotein phenotyping study. Circulation 1977;
55:767772.
Franceschini G. Epidemiologic evidence for highdensity lipoprotein cholesterol as a risk factor for
coronary artery disease. Am J Cardiol 2001; 88(12A):
9N13N.
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson
JW, Elam MB, Faas FH, Linares E, Schaefer EJ,
Schectman G, Wilt TJ, Wittes J. Gembrozil for the
secondary prevention of coronary heart disease in men
with low levels of high-density lipoprotein cholesterol.
Veterans Aairs High-Density Lipoprotein Cholesterol
Intervention Trial Study Group. N Engl J Med 1999;
341(6):410418.
Rubin EM, Krauss RM, Spangler E, Verstuyft S, Clift
S. Inhibition of early atherogenesis in transgenic mice
by human apolipoprotein A-I. Nature 1991; 353:265
267.
Austin MA. Plasma triglyceride and coronary heart
disease. Arterioscler Thromb 1991; 11:114.
Manninen V, Tenkanen L, Koskinen P, Huttunen JK,
Mantarri M, Heinonen OP, Frick MH. Joint eects of
serum triglyceride and LDL-cholesterol and HDL-cholesterol concentrations on coronary heart disease risk in
the Helsinki Heart Study. Implications for treatment.
Circulation 1992; 85:3745.
Jeppesen J, Hein HO, Suadicani P, Gyntelberg F.
Relation of high TG-low HDL cholesterol and LDL
cholesterol to the incidence of ischemic heart disease. An 8-year follow-up in the Copenhagen Male
Study. Arterioscler Thromb Vasc Biol 1997; 17(6):
11141120.
865
28.
Glomset JA. The plasma lecithin: cholesterol acyltransferase reaction. J Lipid Res 1968; 9:155167.
29. Trigatti B, Rigotti A, Krieger M. The role of the highdensity lipoprotein receptor SR-BI in cholesterol
metabolism. Curr Opin Lipidol 2000; 11(2):123131.
30. Oram JF, Vaughan AM. ABCA1-mediated transport
of cellular cholesterol and phospholipids to HDL apolipoproteins. Curr Opin Lipidol 2000; 11(3):253260.
31. Van Lenten BJ, Navab M, Shih D, Fogelman AM,
Lusis AJ. The role of high-density lipoproteins in
oxidation and inammation. Trends Cardiovasc Med
2001; 11(34):155161.
32. Lamarche B, Despres JP, Pouliot MC, Prudhomme
D, Moorjani S, Lupien PJ, Nadeau A, Tremblay A,
Bouchard C. Metabolic heterogeneity associated with
high plasma triglyceride or low HDL cholesterol levels
in men. Arterioscler Thromb 1993; 13(1):3340.
33. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37:15951607.
34. Laakso M, Sarlund H, Mykkanen L. Insulin resistance
is associated with lipid and lipoprotein abnormalities
in subjects with varying degrees of glucose tolerance.
Arteriosclerosis 1990; 10:223231.
35. Reaven GM, Ida-Chen YD, Jeppesen J, Maheux P,
Krauss RM. Insulin resistance and hyperinsulinemia
in individuals with small, dense, low density lipoprotein
particles. J Clin Invest 1993; 92:141146.
36. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment
Panel III). JAMA 2001; 285(19):24862497.
37. Despres JP. Visceral obesity: a component of the insulin
resistance-dyslipidemic syndrome. Can J Cardiol 1994;
10:17B22B.
38. Despres JP, Marette A. Relation of components of
insulin resistance syndrome to coronary disease risk.
Curr Opin Lipidol 1994; 5:274289.
39. Tchernof A, Lamarche B, Prudhomme D, Nadeau A,
Moorjani S, Labrie F, Lupien PJ, Despres JP. The
dense LDL phenotype. Association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in
men. Diabetes Care 1996; 19(6):629637.
40. Lemieux I, Pascot A, Couillard C, Lamarche B,
Tchernof A, Almeras N, Bergeron J, Gaudet D,
Tremblay G, Prudhomme D, Nadeau A, Despres JP.
Hypertriglyceridemic waist: a marker of the atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men? Circulation 2000;
102(2):179184.
41. Austin MA, King MC, Vranizan KM, Krauss RM.
Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease. Circulation 1990;
82:495506.
42. Ford ES, Giles WH, Dietz WH. Prevalence of the
metabolic syndrome among US adults: ndings from
866
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
867
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
868
97. Kannel WB, Gordon T, Castelli WP. Obesity, lipids
and glucose intolerance. The Framingham Study. Am
J Clin Nutr 1979; 32:12381245.
98. Borkan GA, Gerzof SG, Robbins AH, Hults DE,
Silbert CK, Silbert JE. Assessment of abdominal fat
content by computed tomography. Am J Clin Nutr
1982; 36:172177.
99. Tokunaga K, Matsuzawa Y, Ishikawa K, Tarui S. A
novel technique for the determination of body fat by
computed tomography. Int J Obes 1983; 7:437445.
100. Sjostrom L, Kvist H, Cederblad A, Tylen U, Sjostrom
L, Kvist H, Cederblad A, Tylen U. Determination of
total adipose tissue and body fat in women by computed tomography, 40K, and tritium. Am J Physiol
1986; 250:E736E745.
101. Kvist H, Chowdhury B, Grangard U, Tylen U,
Sjostrom L. Total and visceral adipose tissue volumes
derived from measurements with computed tomography in adult men and women: predictive equations.
Am J Clin Nutr 1988; 48:13511361.
102. Fujioka S, Matsuzawa Y, Tokunaga K, Tarui S.
Contribution of intra-abdominal fat accumulation to
the impairment of glucose and lipid metabolism in
human obesity. Metabolism 1987; 36:5459.
103. Fujioka S, Matsuzawa Y, Tokunaga K, Kano Y,
Kobatake T, Tarui S. Treatment of visceral obesity.
Int J Obes 1991; 15:5965.
104. Fujioka S, Matsuzawa Y, Tokunaga K, Kawamoto T,
Kobatake T, Keno Y, Kotani K, Yoshida S, Tarui S.
Improvement of glucose and lipid metabolism associated with selective reduction of intra-abdominal visceral fat in premenopausal women with visceral fat
obesity. Int J Obes 1991; 15:853859.
105. Sparrow D, Borkan GA, Gerzof SG, Wisniewski CK.
Relationship of body fat distribution to glucose tolerance. Results of computed tomography in male participants of the normative aging study. Diabetes 1986;
35:411415.
106. Peiris AN, Sothmann MS, Hennes MI, Lee MB,
Wilson CR, Gustafson AB, Kissebah AH. Relative
contribution of obesity and body fat distribution to
alterations in glucose insulin homeostasis: predictive
values of selected indices in premenopausal women.
Am J Clin Nutr 1989; 49:758764.
107. Despres JP, Nadeau A, Tremblay A, Ferland M,
Lupien PJ. Role of deep abdominal fat in the association between regional adipose tissue distribution and
glucose tolerance in obese women. Diabetes 1989; 38:
304309.
108. Pouliot MC, Despres JP, Nadeau A, Moorjani S,
Prudhomme D, Lupien PJ, Tremblay A, Bouchard C.
Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes
1992; 41:826834.
109. Despres JP. Visceral obesity, insulin resistance, and
related dyslipoproteinemias. In: Rifkin H, Colwell JA,
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
869
135.
870
Metabolic Complications of Human Obesities Amsterdam: Elsevier Science, 1985:115130.
151. Seidell JC, Bjorntorp P, Sjostrom L, Kvist H,
Sannerstedt R. Visceral fat accumulation is positively
associated with insulin, glucose and C-peptide levels,
but negatively with testosterone levels. Metabolism
1990; 39:897901.
152. Tchernof A, Despres JP, Belanger A, Dupont A,
Prudhomme D, Moorjani S, Lupien PJ, Labrie F.
Reduced testosterone and adrenal C19 steroid levels in
obese men. Metabolism 1994; 4:513519.
153. Tchernof A, Despres JP, Dupont A, Belanger A,
Nadeau A, Prudhomme D, Moorjani S, Lupien PJ,
Labrie F. Importance of body fatness and adipose
tissue distribution in the relation of steroid hormones
to glucose tolerance and plasma insulin levels in men.
Diabetes Care 1995; 18:292299.
154. Tchernof A, Despres JP. Sex steroid hormones, sex
hormone-binding globulin, and obesity in men and
women. Horm Metab Res 2000; 32(1112):526536.
155. Tchernof A, Labrie F, Belanger A, Prudhomme D,
Bouchard C, Tremblay A, Nadeau A, Despres JP.
Relationships between endogenous steroid hormone,
sex hormone-binding globulin and lipoprotein levels in
men: contribution of visceral obesity, insulin levels and
other metabolic variables. Atherosclerosis 1997; 133(2):
235244.
156. Tchernof A, Labrie F, Belanger A, Despres JP. Obesity
and metabolic complications: contribution of dehydroepiandrosterone and other steroid hormones. J Endocrinol 1996; 150(suppl):S155S164.
157. Brindley DN, Rolland Y. Possible connections between
stress, diabetes, obesity, hypertension, and altered metabolism that may result in atherosclerosis. Clin Sci
1989; 77:453461.
158. Brindley DN. Metabolic approaches to atherosclerosis:
eect of gliclazide. Metabolism 1992; 41(suppl 1):2024.
159. Brindley DN. Neuroendocrine regulation and obesity.
Int J Obes 1992; 16:S73S79.
160. Bjorntorp P. Visceral fat accumulation: the missing
link between psychosocial factors and cardiovascular
disease? J Intern Med 1991; 230:195201.
161. Rebue-Scrive M, Lundholm K, Bjorntorp P. Glucocorticoid binding of human adipose tissue. Eur J Clin
Invest 1985; 15:267271.
162. Pedersen SB, Jonler M, Richelsen B. Characterization
of regional and gender dierences in glucocorticoid
receptors and lipoprotein lipase activity in human adipose tissue. J Clin Endocrinol Metab 1994; 78:1354
1359.
163. Bengtsson BA, Eden S, Lonn L, Kvist H, Stokland A,
Lindstedt G, Bosaeus I, Tolli J, Sjostrom L, Isaksson
OG. Treatment of adults with growth hormone (GH)
deciency with recombinant human GH. J Clin Endocrinol Metab 1993; 76(2):309317.
164. Beshyah SA, Johnston DG. Cardiovascular disease
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
871
178.
179.
36
Obesity and Blood Pressure Regulation
Albert P. Rocchini
University of Michigan, Ann Arbor, Michigan, U.S.A.
INTRODUCTION
Obesity is an independent risk factor for the development of both hypertension and cardiovascular disease.
This chapter will summarize: techniques for measuring
blood pressure in obese individuals and the eect of
obesity on these measurements; the evidence that substantiates that obesity is an independent risk factor
for the development of hypertension; an explanation
of how obesity may result in the development of hypertension; a brief summary of other cardiovascular
abnormalities associated with obesity; and nally a brief
summary of how to manage the hypertensive obese
individual.
Cu Size
II MEASUREMENT OF BLOOD
PRESSURE IN OBESE INDIVIDUALS
For years, physicians believed that the high blood
pressure observed in many obese individuals was related
to a measurement error. The indirect method of measuring blood pressure usually results in an overestimation of both systolic and diastolic blood pressure. The
overestimation of blood pressure is due, in part, to the
fact that pressure measured by the cu and sphygmomanometer is not just the force required to occlude the
brachial artery but also includes the force required to
compress the soft tissues of the arm. In the case of
obesity, the increased subcutaneous fat present in the
873
874
Rocchini
Observer Errors
Figure 1
Physicians have taken reliable blood pressure measurements for nearly 90 years with a compression cu,
sphygmomanometer, and stethoscope. The major errors associated with the use sphygmomanometer and
stethoscope relate to calibration of the manometer,
position of the arm (if the arm is below heart level,
due to hydrostatic pressure, a falsely elevated blood
pressure will be recorded), and the experience and training of the observer.
In order to eliminate observer errors automated
blood pressure devices were developed. Most of these
devices use the oscillometric technique. The oscillometric technique involves analysis of arterial utter, the
lower-frequency oscillations that occur, with each
heartbeat, under an occluding cu between the systolic
Summary
Although the indirect method of blood pressure measurement may be imprecise in the obese individual, if
appropriate care is taken to use a trained observer, a
large enough blood pressure cu, and a calibrated measurement device, reliable measurements of blood pressure can be made even in extremely obese individuals.
III
A
Name of cu
Bladder
width (cm)
Bladder
length (cm)
Child
Small adult
Adult
Large adult
Thigh
8
11
13
17
20
13
17
24
32
42
Midpoint of arm is dened as half the distance from the acromion to the olecranon.
875
876
Rocchini
The denition of obesity also contributes to the controversy regarding the independence of obesity as an
etiological determinant of hypertension. Obesity is
dened not just as an increase in body weight but rather
as an increase in adipose tissue mass. Adipose tissue
mass can be estimated by multiple techniques such as:
skinfold thickness, body mass index ([weight in kg]/
[height in meters]2), hydrostatic weighing, bioelectrical
impedance, and water dilution methods. In most clinical
studies, body mass index is usually used as the index of
adiposity. Obesity is generally dened as a body mass
index >30 kg/m2. In 1956, Jean Vague (36) reported
that the cardiovascular and metabolic consequences of
obesity were greatest in individuals whose fat distribution pattern favored the upper-body segments. Since
that observation, several population-based studies have
demonstrated that upper-body obesity is a more important cardiovascular risk factor than body mass index
alone (3743). The Normative Aging Study (37) has
demonstrated that there is a signicant relationship between abdominal circumference and diastolic blood
pressure. In fact, the risk of developing hypertension
was better predicted by upper body fat distribution than
by either body weight or body mass index (Fig. 3). In
the Bogalusa Heart Study (38), blood pressure correlated strongly with upper-body fat pattern, but not with
measures of global obesity. Many investigators have
877
demonstrated that the association of obesity to increased cardiovascular risk is primarily related to upperbody adiposity (44,45). Therefore, since most published
studies investigating the role of obesity in hypertension
have used total body weight or body mass index, the
true role of adiposity in blood pressure regulation may
have been obscured.
E
The exact mechanism whereby obesity causes hypertension is still unknown. Obesity hypertension is complex and multifactorial. It appears to involve insulin
resistance, activation of the sympathetic nervous system, activation of the renin angiotensin system, abnor-
Insulin Resistance
878
Rocchini
a signicant linear relationship between insulin resistance, measured during a euglycemic insulin clamp
study, and blood pressure in a group of 143 hypertensive
and 51 normotensive subjects; however, f50% of the
hypertensive subjects had insulin-mediated glucose
uptake values that were within 1 standard deviation of
the normotensive group (that is, at least one half of the
hypertensive subject were not insulin resistant). No
correlation has been found between blood pressure
and plasma insulin or insulin sensitivity in Pima Indians (78) or obese Mexican-American women (44). Thus,
from all of these studies it is clear that not all hypertensive subjects are insulin resistant and that not all
insulin-resistant subjects are hypertensive.
Based on available data in the literature, it appears
that selective insulin resistance, not just hyperinsulinemia, is more likely the metabolic link that is responsible for the observed epidemiological relationship between obesity and hypertension. The term selective
insulin resistance implies that although an individual
or animal may have an impaired ability of insulin to
cause whole body glucose uptake, some of the other
physiological actions of insulin may be preserved. With
respect to hypertension, one of the potentially important actions of insulin is the ability to induce renal
sodium retention. Obese adolescents have selective
insulin resistance in that they are resistant with respect
to insulins ability to stimulate glucose uptake yet are
still sensitive to the renal sodium-retaining eects of
insulin (79) (Fig. 4). The spontaneously hypertensive
rat has also been documented to have impaired insulin
mediated whole-rat glucose uptake yet normal insulin
sensitivity to induce renal sodium retention (71). In
nonobese essential hypertensives, insulin resistance has
been demonstrated to involve glucose metabolism but
not lipid or potassium metabolism, and is limited to the
nonoxidative pathways of intracellular glucose disposal
(48,80).
Thus there is evidence to indicate that in obese
hypertensive subjects, insulin resistance is selective
(mostly involving glucose metabolism), tissue specic
(predominantly eecting skeletal muscle), and pathway
specic (insofar as only glycogen synthesis is usually
aected). Therefore, in any individual or animal the
degree to which insulin resistance is tissue and/or pathway specicity may determine whether hypertension
will develop. In addition to sodium retention, selective
insulin resistance may modulate the development of
hypertension through changes in vascular structure
and function, alterations in cation ux, activation of
the renin angiotensin aldosterone system, and activation of the sympathetic nervous system.
879
880
Rocchini
Figure 6 Rates of whole-body glucose uptake (M) determined during euglycemic clamp studies over a wide range of
steady-state insulin concentrations serially in four dogs fed a
high-fat diet. Weight gain resulted in a shift to right and a
decrease in maximal rate of M. P < .001. (From Ref. 90.)
881
minimum vascular resistance. These investigators demonstrated that the abnormal vascular responses to
ischemic exercise directly correlate with fasting insulin and whole-body glucose uptake, and that the vascular and metabolic abnormalities improve with weight
loss.
In the dog, euglycemic hyperinsulinemia increases
cardiac output in a dose-dependent fashion (90). However, feeding the high-fat diet resulted in right shift of
insulins eect to increase cardiac output. Compared to
the control fed dogs, the half-maximal response in the
insulin-induced increase in cardiac output (insulin ED50
dose) was 72% ( P < .05) higher at 1 week and 180%
( P < .01) higher at 6 weeks. Similarly, weight gain in the
dog blunts the vasodilator response to insulin in the
femoral artery. Steinberg et al. (99) demonstrated that
insulin enhances the release of endothelium-derived
nitric oxide. Baron et al. (100) demonstrated that insulin-resistant individuals exhibit blunted insulin-mediated vasodilatation and impaired endothelium-dependent vasodilatation. Others have also demonstrated
that salt-sensitive and insulin-resistant hypertensive
patients manifest impaired endothelium-dependent
relaxation mediated by nitric oxide (101,102).
In addition to insulin resistance possibly being associated with the development of vascular changes, there
also are data that suggest that abnormalities in skeletal
muscle vascular regulation may be a cause of insulin
resistance. In both the dog (97) and man (97) euglycemic
hyperinsulinemia has been documented to result in
vasodilatation, not vasoconstriction. Even though the
exact mechanism how insulin induces vasodilatation in
non-insulin-resistant individuals is unknown, some
investigators believe that this vasodilator response is
in part due to stimulation of endothelial-dependent relaxing factor (103,104). Type 2, but not type 1, diabetic
subjects respond abnormally to acetylcholine, which induces vasodilatation by stimulation of endothelial-dependent relaxing factor (105).
Insulin-mediated glucose uptake is determined both
by insulins ability to stimulate glucose extraction at the
level of tissues/cells and by the rate of glucose and
insulin delivery (blood ow). Thus, the relative contributions of tissue and blood ow actions of insulin will
determine the overall rate of glucose uptake (i.e., degree
of insulin resistance). In obese individuals with insulin
resistance, an attenuated limb vasodilator reponses to
hyperinsulinemia has been reported (106,107) (Fig. 7).
The lack of insulins ability to produce vasodilatation
has led Baron (108) to speculate that abnormalities of
skeletal muscle vascular regulation may be a cause, not
a result, of insulin resistance. This hypothesis is also
882
Rocchini
II bers tend to be better suited for anaerobic metabolism. Type IIa bers have the same capillary supply as
type I bers, whereas type IIb bers have a reduced
capillary supply. Lithell et al. (113) reported that muscle
ber diameter and capillary density correlate with fasting insulin levels. These investigators also demonstrated
that obese men have an increased ber diameter with no
increase in the number of capillaries per ber (i.e., a
reduced capillary density). Lillioja et al. (112) reported
similar results in a group of Pima Indians. Wade et al.
(105) and Staron et al. (114) reported a signicant
inverse correlation between the presence of type I bers
and body fatness. However, Simoneau and Bouchard
(121) found no relationship between percent body fat
and the percentage of type I bers in a group of 126
women and 213 men. The only signicant correlation
between body fatness and ber type observed in this
study was that obese men appeared to have an increase
percentage of type IIb bers with low aerobic enzyme
activities. Krotkiewski and Bjorntrop (122) observed
that upper-body obesity, increased waist-to-hip ratio,
was associated with an increased percentage of type II
bers. Based on these observations, it has been speculated that the hypertension and insulin resistance
observed in some obese individuals, especially those
with upper-body obesity, may be due to the high
percentage of type IIb muscle bers that have low
capillary density and reduced aerobic enzyme activities.
In support of this theory is the observation that endurance training in obese and nonobese individuals improves insulin resistance by increasing muscle oxidative
capacity and increasing capillary density (123,124).
Figure 7 Rates of leg blood ow (A) and rates of leg glucose
uptake (B) determined during euglycemic clamp studies over
a wide range of steady-state serum insulin concentrations in
lean (closed circles) and obese nondiabetic subjects (open circles) and patients with NIDDM (close triangles). Note the log
scale on the abscissa. To convert the insulin concentrations
from pmol/L divide by 7.175. (Adapted from Ref. 90.)
The fourth method by which obesity could cause hypertension is through alterations in cation transport. Insulin has been shown to aect sodium and calcium
transport, although controversy still exists regarding
the molecular mechanism of this eect. A direct eect of
insulin on sodium/hydrogen exchange has been demonstrated in vitro (125). Insulin has been reported to both
increase and decrease Na-K-ATPase activity (126).
Insulin has been linked to both Na-Li countertransport
and Na-K cotransport (126). In a study of leukocyte
sodium content and sodium pump activity in overweight and lean hypertensive subjects, it was observed
that overweight hypertensive subjects accumulated
intracellular sodium probable through abnormalities
of sodium pump activity (127). In obese hypertensive
men, the renin-angiotensin system and sympathetic
nervous system activity are reported to inuence the
regulation of erythrocyte sodium turnover during sodium and energy restriction (128). Thus, alteration in
intracellular sodium concentration could lead to an increased intracellular calcium, an increase in vascular
smooth muscle tone, and hypertension. Insulin alone
has also been demonstrated to elevate cytosolic free
calcium levels in adipocytes of normal subjects (129). In
addition, weight loss is obese individuals is reported to
be accompanied by a signicant decrease in platelet-free
calcium levels (130).
Insulin-mediated glucose transport is dependent on
an intracellular calcium concentration of between 40
and 375 nm/L (131). Thus, increased intracellular calcium concentration might lead to insulin resistance,
increased vascular resistance, and hypertension (50).
In hypertensive type II diabetics a decrease in calcium
adenosine-triphosphate activity is associated with
increased intracellular calcium concentration (132).
Insulin has also been shown to stimulate plasma membrane calcium adenosine-triphosphate activity (105)
and sodium-potassium adenosine-triphosphate activity
(126). Insulin resistance may blunt these pump functions and could lead to chronic increases in intracellular
calcium, increased peripheral vascular resistance, and
hypertension. Finally, reduced intracellular levels of
magnesium are also associated with increased vascular
resistance and insulin resistance (133). With the use of
magnetic resonance imaging to evaluate the aorta of
normal and hypertensive subjects. Resnick et al. (134)
found that increased abdominal visceral fat, decreased
intracellular magnesium, and advanced age were closely
associated with reduced aortic distensibility vessels.
Therefore, in obesity, alterations in either intracellular
calcium and/or magnesium could result in the development of both hypertension and insulin resistance.
E
883
884
Rocchini
The sixth way by which obesity could cause hypertension is through stimulation of the sympathetic nervous system. For over 20 years it has been recognized
that diet aects the sympathetic nervous system. Fasting suppresses sympathetic nervous system activity,
whereas overfeeding with either a high-carbohydrate
or high-fat diet simulates the sympathetic nervous
system (147150). Insulin is believed to be the signal
that networks dietary intake and nutritional status to
sympathetic activity. Glucose and insulin sensitive neurons in the ventromedial portion of the hypothalamus
have been demonstrated to alter the activity of inhibitory pathways between the hypothalamus and brainstem (151). It is believed that the physiological role of
strated that measurements of resting and 24-hr sympathoadrenal activity may dier in obese individuals. They
demonstrated that sympathic activity at rest as evaluated by forearm venous plasma norepinephrine levels
was increased in obese subjects. However, thrombocyte
norepinephrine and epinephrine levels, which likely reect 24-hr plasma catecholamine concentrates, were
reduced in obese subjects with a body fat percentage
above 40%. They speculate that the reduced thrombocyte catecholamine levels are probable due to a reduced
physical activity in these subjects.
Finally, there are also ethnic dierences in sympathetic tone. Weyer et al. (164) examined the relation
among heart rate, blood pressure, percent body fat,
fasting insulin, and muscle sympathetic nerve activity
in male normotensive whites and Pima Indians. These
investigators demonstrated that in both ethnic groups,
heart rate and blood pressure positively related to
percent body fat and muscle sympathetic nerve activity,
and both were independent determinants of heart rate
and blood pressure. However, muscle sympathetic
nerve activity was positively related to percent body
fat and fasting insulin concentration in whites but not in
Pima Indians. This study emphasizes that the roles of
hyperinsulinemia and increase sympathetic nervous
system activity as medicator for the relation between
obesity and hypertension can dier between among
ethnic groups. Weyers study (164) may explain why
the Pima Indians have a low prevalence of hypertension
in this population despite their high incidence of obesity
and insulin resistance.
Abnormalities in the sympathetic nervous system
may also play role in the actual pathogenesis of some
forms of obesity. The recent identication and cloning
of the h3-adrenergic receptor have spurred great interest
in the potential role of this receptor in the regulation of
energy expenditure and ultimately in the development
of obesity. The h3-adrenergic receptor is predominantly
expressed in omental fat tissue and gallbladder, at low
levels in ileum and colon, and absent in muscle, heart,
liver, lung, kidney, thyroid, and lymphocytes (165).
Mutations in the h3-adrenergic receptor gene have been
detected in Pima Indians and Mexican-Americans, two
populations with a high incidence of obesity and diabetes (166). Finally, preliminary studies in obese
humans have demonstrated that the administration of
an agent with high specicity for the h3-adrenergic
receptor results in increased energy expenditure that is
accompanied by a marked improvement in insulin
sensitivity and glucose tolerance (167).
Finally, there is evidence suggesting that alterations
in sympathetic activity can cause insulin resistance. The
885
Natriuretic Peptides
886
Rocchini
Figure 8 Rates of whole-body insulin-mediated glucose uptake (M) determined during euglycemic clamp studies over
a wide range of steady-state insulin concentrations (5, week
0; D, week 1 of fat diet; , week 6 of fat diet) in dogs fed a
high-fat diet with and without clonidine treatment. Weight
gain resulted in a shift to the right and a decrease in the
maximal rate of M ( P<.001) in dogs not treated with clonidine; however, if the dogs were treated with clonidine,
weight gain did not alter the dose-response relation. (From
Ref. 173.)
Leptin
Leptin is a 167amino acid hormone that is secreted exclusively by adipocytes. By binding to the leptin receptor in the hypothalamus and by activating multiple
neuropeptide pathways, leptin decreases appetite and
increases energy expenditure, thereby decreasing adipose tissue mass and body weight. Serum leptin level is
low in lean individuals and is elevated in most obese
Summary
OBESITY AS A CARDIOVASCULAR
RISK FACTOR
887
888
Rocchini
depressed myocardial contractility, and diastolic dysfunction can predispose individuals to excessive ventricular ectopy. Messerli et al. (212) reported that the
prevalence of premature ventricular contractions was 30
times higher in obese individuals with eccentric left
ventricular hypertrophy than in lean individuals.
The cardiovascular response to stress is thought to
relate to cardiovascular risk. Rockstroh and associates
(213) demonstrated that obese hypertensive individuals
respond abnormally to stress. In their study, they
evaluated the hemodynamic responses to mental and
isometric stress in obese and nonobese hypertensive
individuals. They observed that obese hypertensive
individuals responded to mental stress with vasoconstriction and to isometric stress with an exaggerated
increase in arterial pressure.
Finally, as with hypertension, insulin resistance may
be related to both the cardiac hypertrophy and abnormal cardiac function that is observed in many obese
individuals. Nakajima et al. (214) reported that there is a
direct relationship between intraabdominal fat accumulation and the cardiac abnormalities associated with
obesity. Since increased upper-body and intra-abdominal fat accumulation relates to the presence of insulin
resistance even without signicant overall obesity, these
investigators speculated that the cardiac dysfunction
observed in obese individuals may be related to insulin
resistance.
A
Summary
VI
Weight loss is the cornerstone of hypertensive management in the obese individual. Weight loss in both
adolescents and adults improves all of the cardiovascular abnormalities associated with obesity, including
hypertension, dyslipemia, sodium retention, structural
abnormalities in resistant vessels, and left ventricular
hypertrophy and dysfunction. It is also important to
realize that the method by which weight loss is accomplished is important. Although weight loss in general
889
VII
SUMMARY
890
Rocchini
ACKNOWLEDGMENTS
Supported in part by grants 1RO1 HL 52205, HL-18575, 2RO1-HL-35743, 2P60 AM 20572, and 2P01HL1857524 from the National Institutes of Health.
15.
16.
REFERENCES
17.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
891
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
892
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
Rocchini
hypertensive patients during somatostatin infusion. J
Hypertens 1989; 7(suppl 6):S196S197.
Reaven GM, Ho H, Homan BB. Somatostatin inhibition of fructose-induced hypertension. Hypertension 1989; 14:117120.
Krotkorwski M, Mandroukas K, Sjostrom L, Sullivan
L, Wetterquist H, Bjorntrop P. Eect of long-term
physical training on body fat, metabolism and blood
pressure in obesity. Metabolism 1979; 28:650658.
Zavaroni I, Sander S, Scott S, Reaven GM. Eect of
fructose feeding of insulin secretion and insulin action
in the rat. Metabolism 1980; 29:970973.
Hwang IS, Ho H, Homan BB, Reaven GM. Fructoseinduced insulin and hypertension in rats. Hypertension
1987; 10:512516.
Reaven GM, Ho H, Homan BB. Attenuation of fructose-induces hypertension in rats by exercise drainage.
Hypertension 1988; 12:129132.
Reaven GM, Ho H, Homan BB. Somatostatin inhibition of fructose-induced hypertension. Hypertension 1989; 14:117120.
Kurtz TW, Morris RC, Pershadsingh HA. The Zucker
fatty rat as a genetic model of obesity and hypertension. Hypertension 1989; 13(6 pt 2):896901.
Mondon CE, Reaven GM. Evidence of abnormalities
of insulin-stimulated glucose uptake in adipocytes isolates from spontaneously hypertensive rats with
spontaneous hypertension. Metabolism 1988; 37:303
305.
Reaven GM, Chang H, Homan BB, Azhar S. Resistance to insulin-stimulated glucose uptake in adipocytes isolates from spontaneously hypertensive rats.
Diabetes 1989; 38:11551160.
Finch D, Davis G, Bower J, Kirchner K. Eect of insulin on renal sodium handling in hypertensive rats.
Hypertension 1990; 15:514518.
Brands MW, Hildebrandt DA, Mizell HL, et al. Sustained hyperinsulinemia increases arterial pressure in
conscious rats. Am J Physiol 1991; 260:R764R768.
Meehan WP, Buchanan TA, Hsueh WA. Chronic insulin administration elevates blood pressure in rats.
Hypertension 1994; 23(pt 2):10121017.
Julius S, Jamerson K, Media A, et al. The association
of borderline hypertension with target organ changes
and higher coronary risk. Tecumseh Blood Pressure
Study. JAMA 1990; 264:354358.
Ferrari P, Weidmann P, Shaw S, et al. Altered insulin
sensitivity, hyperinsulinemia, and dyslipidemia in
individuals with a hypertensive parent. Am J Med
1991; 91:589596.
Grugni G, Ardizzi A, Dubini A, Guzzaloni G, Sartorio
A, Morabito F. No correlation between insulin levels
and high blood pressure in obese subjects. Horm
Metab Res 1990; 22(2):124125.
Hall JE, Brands MW, Kivlighn SD, Mizelle HL,
Hidebrandt DA, Gaillard CA. Chronic hyperinsulin-
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
emia and blood pressure: interaction with catecholamines? Hypertension 1990; 15:519527.
Brechtold P, Jorgens V, Finke C, et al. Epidemiology
and hypertension. Int J Obes 1981; 5(suppl 1):17.
Rocchini AP, Katch V, Kveselis D, Moorehead C,
Martin M, Lampman R, Gregory M. Insulin and renal
retention in obese adolescents. Hypertension 1989;
14:367374.
DeFronzo RA, Tobin JD, Andres R. Glucose clamp
technique: a method for quantifying insulin secretion
and resistance. Am J Physiol 1979; D214D223; 237:
839.
DeFronzo RA, Cooke CR, Andres R, Fabona GR,
Davis PJ. The eect of insulin on renal handling of
sodium, potassium, calcium and phosphate in man. J
Clin Invest 1975; 55:845855.
Baum M. Insulin stimulates volume absorption in the
proximal convoluted tubule. J Clin Invest 1987; 79:
11041109.
Vierhapper H, Waldhausl W, Nowontny P. The eect
of insulin on the rise in blood pressure and plasma
aldosterone after angiotensin II in normal man. Clin
Sci 1983; 64:383386.
Rocchini AP, Moorehead C, DeRemer S, Goodfriend
TL, Ball DL. Hyperinsulinemia and the aldosterone
and pressor responses to angiotensin II. Hypertension
1990; 15:861866.
Finta KM, Rocchini AP, Moorehead C, Key J, Katch
V. Sodium retention in response to an oral glucose
tolerance test in obese and nonobese adolescents.
Pediatrics 1992; 90:442446.
Rocchini AP. Insulin resistance, obesity, and hypertension. J Nutr 1995; 125(suppl 6):1718S1724S.
Sharma AM, Spies KP, Ruland K, Distler A. Hyperinsulinemia response to oral glucose in normotensive
salt-sensitive subjects. Am J Hypertens 1991; 4:13A.
Hall JE, Granger JP, Hester RL, Montani JP. Mechanisms of sodium balance in hypertension: role of pressure natriuresis. J Hypertens 1986; 4(suppl 4): S57S65.
Ter Maaten JC, Bakker SJ, Serne EH, Ter Wee PM,
Donker AJ, Gans RO. Insulins acute eects on glomerular ltration rate correlate with insulin sensitivity
whereas insulins acute eects on proximal tubular sodium reabsorption correlate with salt sensitivity in normal subjects. Nephrol Dial Transplant 1999; 14:2357
2363.
Rocchini A, Marker P, Cervenka T. Time course of
insulin resistance associated with weight gain in the
dog: relationship to the development of hypertension.
Am J Physiol 1996; 272:E147E154.
Laakso M, Edelman SV, Brechtel G, Baron AD.
Impaired insulin-mediated skeletal muscle blood ow
in patients with NIDDM. Diabetes 1992; 41:1076
1083.
Kolterman O, Insel J, Saekow M, Olefsky J. Mechanisms of insulin resistance in human obesity: evidence
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
893
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
894
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
Rocchini
Krotkiewski M, Bjorntorp P. Muscle tissue in obesity
with dierent distribution of adipose tissue: eects of
physical training. Int J Obes 1986; 10:331341.
Anderson P, Henriksson J. Capillary supply of the
quadriceps femoris muscle of man: adaptive response
to exercise. J Physiol 1977; 270:677690.
Chi MMY, Hintz CS, Henriksson J. Chronic stimulation of mammalian muscle: enzyme changes in
individual bers. Am J Physiol 1986; 251:c633c642.
Lagadie-Grossman D, Chesnais JM, Fewray D. Intracellular pH regulation in papillary muscle cells from
streptozotocin diabetic rats: an ion-sensitive microelectrode study. Pugers Arch 1988; 412:613617.
Tedde R, Sechi LA, Marigliano A, Scano L, Pala A. In
vitro action of insulin on erythrocyte sodium transport
mechanisms: its possible role in the pathogenesis of
arterial hypertension. Clin Exp Hypertens 1988; 10:
545559.
Ng LL, Harker M, Abel ED. Leucocyte sodium content and sodium pump activity in overweight and lean
hypertensives. Clin Endocrinol (Oxf) 1989; 30(2): 191
200.
Herlitz H, Fagerberg B, Jonsson O, Hedner T, Andersson OK, Aurell M. Eects of sodium restriction
and energy reduction on erythrocyte sodium transport
in obese hypertensive men. Ann Clin Res 1988; 20
(suppl 48):6165.
Draznin B, Kao M, Sussman KE. Insulin and glyburide
increase in cytosolic free calcium concentration in
isolated rat adipocytes. Diabetes 1987; 36:174178.
Jacobs DD, Sowers JR, Hmeidan A, Niyogi T, Simpson
L, Standley PR. Eects of weight reduction on cellular
cation metabolism and vascular resistance. Hypertension 1993; 21:308314.
Dranzin B, Sussman K, Koa M, et al. The existence of
an optimal range of cystolic free calcium for insulinstimulated glucose transport in rat adipocytes. J Biol
Chem 1987; 262:14851488.
Shaefer W, Prieben J, Mannhold R, et al. Ca2+-Mg2+ATPase activity of human red blood cells in healthy
and diabetic volunteers. Klin Wochenschr 1987; 65:
1721.
Resnick LM, Gupta RK, Gruenspan H, et al. Intracellular free magnesium in hypertension: relation to
peripheral insulin resistance. J Hypertens 1988; 6:
S199S201.
Resnick LM, Militianu D, Cummings AJ, Pipe JG,
Evelhoch JL, Soulen RL. Direct magnetic resonance
determination of aortic distensibility in essential
hypertension, relation to age, abdominal visceral fat,
and in situ intracellular free magnesium. Hypertension
1997; 30:654659.
Rocchini AP, Katch VL, Grekin R, Moorehead C,
Anderson J. Role for aldosterone in blood pressure
regulation of obese adolescents. Am J Cardiol 1986;
57:613618.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
895
ments. Int J Obes Relat Metab Disord 1999; 23:810
815.
164. Weyer C, Pratley RE, Snitker S, Spraul M, Ravussin
E, Tataranni A. Ethnic dierences in insulinemia and
sympathetic tone as links between obesity and blood
pressure. Hypertension 2000; 36:531542.
165. Krief S, Lonnquest F, Raimbault S. Tissue distribution of B3-adrenergic receptor RNA in man. J Clin
Invest 1993; 91:344349.
166. Walston J, Silver K, Bogardus C, Knowler WC, Celi
FS, Austin S, Manning B, Strosberg AD, Stern MP,
Raben N. Time of onset of non-insulin-dependent
diabetes mellitus and genetic variation in the beta 3adrenergic-receptor gene. N Engl J Med 1995; 333(6):
343347.
167. Wheeldon NM, McDevett DG, McFarlene LC,
Lipworth BJ. B-adrenoceptor subtypes me dietary
the metabolic eects of BRL 35135 in man. Clin Sci
1994; 86:331337.
168. Lager I, Attrall S, Eriksson BM. Studies on the insulinantagonistic eect of catecholamines in normal man:
evidence for the importance of b2-receptor. Diabetologia 1986; 29:409416.
169. Diebert DC, DeFronzo RA. Epinephrine-induced insulin resistance in man. J Clin Invest 1980; 65:717
721.
170. Jamerson K, Julius S, Gudbrandsson T, Andersson O,
Brant D. Reex sympathetic activation induces acute
insulin resistance in the human forearm. Hypertension
1993; 21:618623.
171. Rosen P, Ohly P, Gleochman. Experimental benet of
moxonidine on glucose metabolism and insulin secretion in the fructose-fed rat. J Hypertens 1997; 15(suppl
I):S31S38.
172. Ernsberger P, Friedman JE, Kooletsky RJ. The 11imidazoline receptor: from binding site to therapeutic
target in cardiovascular disease. J Hypertens 1997;
15(suppl I):S9S23.
173. Rocchini AP, Mao HZ, Babu K, Marker P, Rocchini
AJ. Clonidine prevents insulin resistance and hypertension in obese dogs. Hypertension 1999; 33(pt II):
548553.
174. Licata G, Volpe M, Scanglione R, Rubattu S. Saltregulating hormones in your normotensive obese
subjects. Eect of saline load. Hypertension 1994;
3(suppl I):120124.
175. Maoz E, Shamiss A, Peleg E, Salzberg M, Rosenthal
T. The role of atrial natriuretic peptide in the natriuresis of fasting. J Hypertens 1992; 10:10411044.
176. Dessi-Fulgheri P, Sarzani R, Tamburrini P, Moraca
A, Espinosa E, Cola G, Giantomassi L, Rappelle A.
Plasma atrial natriuretic peptide and natriuretic
peptide receptor gene expression in adipose tissue of
normotensive and hypertensive obese patients. J
Hypertens 1997; 15:16951699.
177. Golden P, MacCagnan TJ, Pardridge WM. Human
896
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
Rocchini
blood brain barrier leptin receptor binding and
endocytosis in isolated human brain microvessels. J
Clin Invest 1997; 99:1418.
Considine RV, Sinha MK, Heiman ML, Kriauciunas
A, Stephens TW. Serum immunoreactive leptin concentrations in normal-weight and obese humans. N
Engl J Med 1996; 334:292295.
Collins S, Kuhn CM, Petro AE, Swick AG, Chrunyk
BA, Surwit RS. Role of leptin in fat regulation. Nature
1996; 380:667.
Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz
WI. Receptor mediated regional sympathetic nerve
activation by leptin. J Clin Invest 1997; 100:270278.
Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension 1998;
31:409414.
Ogawa Y, Masuzaki H, Aizawa M, Yura S, Satoh N,
Iwai H, Hosada K, Nakao K. Blood pressure elevation
in transgenic mice over-expressing leptin, the obe gene
product. J Hypertens (abstract) 1989; 16:S7.
Haynes WG, Morgan DA, Walsh SA, Sivitz W, Mark
AL. Cardiovascular consequences of obesity: role of
leptin. Clin Exp Pharmacol Physiol 1998; 25652569.
Bjorntorp P, Rosmond R. Neuroendocrine abnormalities in visceral obesity. Int J Obes Relat Metab Disord
2000; 24(suppl 2):S80S85.
Strain GW, Zumo B, Strain JL. Cortisol production
in obesity. Metabolism 1980; 29:980985.
Rosmond R, Dallman MF, Bjorntorp P. Stress-related
cortisol secretion in men: relationships with abdominal
obesity and endocrine, metabolic and hemodynamic
abnormalities. J Clin Endocrinol Metab 1998; 83: 1853
1859.
Kvist H, Chowdhury B, Grangard U, Tylen U, Sjostrom. Total and visceral adipose tissue volumes derived from measurements with computed tomography
in adult men and women: predicative equations. Am J
Clin Nutr 1988; 48:13511361.
Rosmond R, Bjorntorp P. The interactions between
hypothalamic-pituitary-adrenal axis activity, testosterone, insulin-like growth factor I and abdominal obesity with metabolism and blood pressure in man. Int J
Obes Relat Metab Disord 1998; 22:11841196.
Zahrezewska KE, Cusin J, Sainbury A, Pohner F,
Jeanrenaud FR, Jeanrenaud B. Glucocorticoids are
counterregulatory hormones to leptin. Towards an
understanding of leptin resistance. Diabetes 1997;
46:717719.
Rosmond R, Holm G, Bjorntorp P. Food-induced
cortisol secretion relation to anthropometric, metabolic and hemodynamic variables in men. Int J Obes
Relat Metab Disord 2000; 24:95105.
Rosmond R, Chagnon YC, Holm G, Changon M,
Perusse L, Lindell K, Carlsson B, Bouchard C,
Bjorntorp P. A glucocorticoid receptor gene marker
is associated with abdominal obesity, leptin, and
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
897
220.
221.
222.
223.
224.
225.
226.
227.
228.
229.
230.
231.
232.
233.
234.
37
Obesity and Diabetes
Jeanine Albu and F. Xavier Pi-Sunyer
Columbia University College of Physicians and Surgeons and St. Lukes-Roosevelt Hospital Center,
New York, New York, U.S.A.
that siblings of diabetics had a threefold higher prevalence of diabetes, but those with the highest prevalence
were the obese siblings of nonobese diabetic propositi.
More recently, Knowler et al. (8) have shown that in the
Pima Indian population, the likelihood of developing
diabetes rises steeply with increasing fatness (Fig. 1).
Finally, the seriousness of the present status in the
United States, with regard to the increase in prevalence
of type 2 diabetes mellitus, is reected in the data from
the NHANES (National Health Examination Survey)
III data (19881994). Type 2 diabetes mellitus showed a
strong increase in prevalence with increasing degree of
overweight among both younger and older subjects. The
prevalence was a staggering ve times higher for men
and 8.3 times higher for women in the most obese group
compared to normal-weight individuals. As opposed to
earlier studies, the prevalence ratio associated with
elevated weight was three- to fourfold greater among
younger overweight men and women (Fig. 2) (59).
There have been prospective studies in a number of
countries, including the United States (10), Norway
(11), Sweden (12), and Israel (13) which have shown
that increasing weight increases the risk of diabetes. In
the Nurses Health Study, which has followed 114,824
women for 14 years, it has also been found that the risk
of developing diabetes increases as body mass index
(BMI) increases (14,15). Weight gain of even 7.010.9
kg after the age of 18 years was associated with a
twofold increase in the risk for diabetes. It is important
900
III
The possibility of a relationship between the distribution of body fat and diabetes was rst raised by Jean
Vague (30), who clinically observed and reported in
1947 the occurrence of two kinds of obesities: the
android, apple shape or predominantly upper-body
distribution of the adipose tissue, and the gynoid,
pear shape or predominantly lower-body distribution of the adipose tissue. Subsequent cross-sectional
and prospective studies have linked diabetes mellitus,
dyslipidemia, and other cardiovascular risk factors to
the distribution of body fat.
Feldman et al. (31), studying a group of more than
7000 people at multiple sites, found that those with
diabetes were fatter and also had a more central distribution of their fat. They suggested that in diabetes there
is an abnormality in hormone balance that causes
women to be more like men in central fat distribution
and exaggerates this eect in men. A study of more than
15,000 American women showed that clinical diabetes
was related directly not only to increasing obesity but
also to increasing central obesity. Women with both
upper-body fat predominance and severe obesity had a
relative risk of diabetes 10.3 times as great as nonobese
subjects with lower-body fat predominance (32).
Distribution of body fat has been measured anthropometrically by four methods: (1) the ratio of the waist
901
902
IV
INSULIN RECEPTORS
INSULIN RESISTANCE
VI
POSTRECEPTOR EFFECTS
After insulin binds to its receptor, the autophosphorylation results in activation of the tyrosine kinase
activity causing a conformational change that allows
ATP and receptor substrates to reach the catalytic site
(57,58). The activated insulin receptor kinase results in
phosphorylated IRS proteins (insulin receptor substrate
proteins) on tyrosine residues. These phosphorylated
IRS proteins serve as docking sites for downstream
eectors (postreceptor events). Such an eector is phosphatidyl inositol 3-kinase (PI 3-kinase). This mediates
most metabolic responses to insulin, i.e., protein and
glycogen synthesis, antilipolysis, and antiapoptosis, as
well as glucose transport, which leads to the utilization
of glucose, both oxidation and storage (58,59).
While the insulin receptor is downregulated in human
obesity, there is no further decrease in its activity in liver
and muscle of patients with type 2 diabetes, suggesting
that the more severe insulin resistance in these patients,
when present, is primarily of postreceptor nature
(53,60). Insulin receptor phosphorylation, IRS-1 phosphorylation, and PI 3-kinase activity are decreased in
intact skeletal muscle strips from obese subjects (61).
Some investigators have shown that, overall, the muscle
is as equally and severely resistant to the action of
insulin in those obese patients without diabetes as in
those with diabetes (60). Others have shown that the PI
3-kinase is more severely reduced in patients with type 2
diabetes (61). Furthermore, adipose tissue is more insulin resistant in type 2 DM than it is in obesity (60),
primarily owing to decreased insulin receptor tyrosine
kinase activity in the tissue of patients with type 2
diabetes (62). Present working hypotheses for obesitylinked kinase activity inhibition are elevation in tyrosine
phosphatase activity or enhanced Ser/Thr phosphorylation of the receptor that impairs its tyrosine kinase
activity (58,59).
Glucose transport in insulin-sensitive cells is greatly
enhanced by insulin. This occurs by translocation of glucose transporters from the intracellular pool to the plasma membrane (63). A PI 3-kinasedependent pathway
facilitates the translocation of the insulin-dependent glucose transporter 4 (Glut 4) (59). In obesity and diabetes,
glucose transporters in adipose tissue are decreased due
to pretranslational suppression of Glut 4 transporter
gene (64). However, in muscle tissue there is impaired
Glut 4 function and/or translocation to the cell membrane surface and not transporter depletion (65).
Glucose disposal is impaired in obese persons (55,
66). Use of indirect calorimetry during insulin clamp
studies has allowed measurement of glucose uptake in
human subjects. The dierence between glucose oxidation and glucose disposal, that is, the nonoxidative
glucose disposal, is used to measure glucose storage as
glycogen (66,67), since there is little net glucose conversion to lipid and little of the glucose that is taken up
by muscle is released as lactate. Both glucose oxidation
and glucose storage are impaired in obesity, and more
so in diabetes. However, the major defect of glucose
metabolism is in glucose storage, since oxidation is
less impaired (68). This is shown in Figure 4 taken from
one of our studies (69).
Defects in glycogen synthase activity (70,71), hexokinase II (72,73), and glucose transport (72,74,75) have all
903
Figure 4 Total glucose disposal during euglycemic hyperinsulinemic clamp. Values are means F SE partitioned into
glucose oxidation (determined by indirect calorimetry) and
nonoxidative glucose disposal (storage). P<.001 for glucose
oxidation, glucose storage, and total glucose disposal: lean
> obese > diabetic men. (From Ref. 69.)
904
IX
INSULIN SECRETION
905
for insulin secretion. It became apparent that the prevalence of insulin hypersecretion was greater than the
prevalence of insulin resistance in each category of BMI
(Fig. 5) (132). In Pima Indians, there is an upper limit to
this relation between adiposity and insulin secretory
response. There is increasing insulin resistance as the
percent of fat in the body increases up to about 3540%;
after that, insulin resistance does not increase further
and insulin levels no longer rise (134).
The documented aberrations in insulin secretion in
obese individuals, coupled with other hormonal abnormalities such as poor response to growth hormone and
glucagon stimulation, made it unclear whether the hormonal defects seen in obesity were primary or a consequence of the obesity. The hormonal abnormalities
are thought to be a consequence of the obesity since they
revert to normal with eective weight loss and are found
to appear after prolonged overfeeding of normal volunteers to an obese state (135). However, it is not known
whether insulin hypersecretion is an earlier event at the
very origin of weight gain, reecting perhaps a central
nervous system derangement. For example, hyperinsulinism may be a result, at least in part, of dietary factors
rather than exclusively a consequence of insulin antagonism. Excess calories (136) and excess carbohydrate
(137) may enhance insulin secretory response.
In those obese individuals who begin to develop
abnormal glucose metabolism, the postprandial increase of insulin over basal values is actually decreased
in comparison to normal subjects. This impairment is
rst observed as patients move from normal to impaired
Figure 5 Prevalence of insulin resistance and insulin hypersecretion as a function of body mass index in nondiabetic,
normotensive Caucasian subjects. (From Ref. 132.)
906
XI
EFFECT OF EXERCISE
XII
907
XIII
908
One has to be careful of the eectiveness of weightreducing programs for obese patients with type 2 diabetes treated with large doses of insulin. In such instances,
the danger of hypoglycemia must be recognized, and
there is a need for close monitoring of blood glucose
with frequent decreases in insulin as necessary. Some
of the postulated reasons for weight gain with insulin
therapy are decreased thermogenesis (199,200) and increased appetite (201); thus, it may be impossible to
achieve weight loss with caloric restriction unless insulin (or oral agents that increase insulin levels) are
being adequately adjusted to the lower-calorie diet
prescribed.
Various classes of hypoglycemic agents, including
metformin and acarbose, have been identied that,
when used to normalize blood glucose, do not produce
weight gain, hypoglycemia, or hyperinsulinemia (202
204). In the United Kingdom Prospective Diabetes
Study (UKPDS), a randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in
patients with newly diagnosed type 2 DM that could not
be controlled with diet therapy, intensive blood glucose
control with insulin or sulfonylurea therapy signicantly decreased progression of microvascular disease. Patients allocated to insulin gained more weight and had
more hypoglycemic events than did patients allocated
to sulfonylurea. Obese patients allocated to metformin
gained least weight and had the fewest hypoglycemic
attacks (203,204).
A new class of antidiabetic agents, the thiazolidinediones (glitazones), reduce hepatic output of glucose
and increase peripheral uptake of glucose, thus enhancing insulin sensitivity and reducing the amount of
exogenous insulin needed (205,206). In studies comparing insulin-glitazone treatment with insulin alone, the
combination therapy resulted in better glycemic control
but was associated with greater weight gain. The signicance of weight gain from glitazones is dicult to
assess. Despite the weight gain, the glitazones may be
benecial in that they redistribute fat from visceral to
subcutaneous areas. In addition, some of the weight
gain is due to peripheral edema and to an increase in
extracellular uid (207).
It is our opinion that hypoglycemic agents that are
not likely to produce weight gain should be used in
the obese diabetic patient whenever possiblethat is,
when endogenous insulin secretion is adequate. If insulin secretagogues or exogenous insulin need to be used,
it would be very benecial to combine them with an
insulin-sensitizing agent like metformin to minimize
weight gain and the amount of insulin needed to achieve
glycemic control.
909
910
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
911
41.
912
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
913
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
914
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
915
158.
916
nemia as an independent risk factor for ischemic heart
disease. N Engl J Med 1996; 334:952957.
174. Steinberg D, Parthasarathy S, Carew TE, Khoo JC,
Witztum JL. Beyond cholesterol. Modications of low
density lipoprotein that increase its atherogenicity. N
Engl J Med 1989; 320:915924.
175. UKPDS Group. U.K. Prospective Diabetes Study 7
response of fasting plasma glucose to diet therapy in
newly presenting type II diabetic patients. Metabolism
1990; 146:17491753.
176. Zavaroni I, Bonora E, Pagliara M, et al. Risk factors
for coronary artery disease in healthy persons with
hyperinsulinemia and normal glucose tolerance. N
Engl J Med 1989; 320:702706.
177. Pyorala K, Savolainen E, Kaukola S, Haapakoski J.
Plasma insulin as coronary heart disease risk factor;
relationship to other risk factors and predictive value
during 9-year follow-up of the Helsinki Policemen
Study population. Acta Med Scand 1985; 701:(suppl)
3852.
178. Fontbonne AM, Eschwege EM. Insulin and cardiovascular disease: Paris Prospective Study. Diabetes
Care 1991; 14:461469.
179. Welbom TA, Wearne K. Coronary heart disease
incidence and cardiovascular disease mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979; 2:154160.
180. Stout RW. Insulin and atheroma: a 20-yr perspective.
Diabetes Care 1990; 13:631654.
181. Vague P, Juhan-Vague I, Aillaud MF, et al. Correlation between blood brinolytic activity, plasminogen
activator inhibitor level, plasma insulin level, and relative body weight in normal and obese subjects. Metabolism 1986; 2:250253.
182. Vague P, Juhan-Vague I, Chabert V, Alessi MC, Atlan
C. Fat distribution and plasminogen activator inhibitor
activity in nondiabetic obese women. Metabolism 1989;
38:913915.
183. Galloway JA. Treatment of NIDDM with insulin
agonists or substitutes. Diabetes Care 1990; 13:1209
1239.
184. Genuth JF. Insulin use in NIDDM. Diabetes Care
1990; 13:12401246.
185. Diabetes Control and Complications Trial Research
Group. The eect of intensive treatment of diabetes on
the development and progression of long-term complications in insulin-dependent diabetes mellitus. N
Engl J Med 1993; 329:977986.
186. Brownlee M. Glycation products and the pathogenesis
of diabetic complications. Diabetes Care 1992; 15:
18351843.
187. American Diabetes Association. Clinical practice
recommendations, American Diabetes Association
19921993. Diabetes Care 1993; 16(suppl 2):1118.
188. Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
917
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
229.
Mannucci E, Ognibene A, Cremasco F, et al. Glucagon-like peptide (GLP)-1 and leptin concentrations in
obese patients with type 2 diabetes mellitus. Diabetic
Med 2000; 17:713719.
Ritzel R, Schulte M, Prksen N, et al. Glucagon-like
peptide 1 increases secretory burst mass of pulsatile
insulin secretion in patients with type 2 diabetes and
impaired glucose tolerance. Diabetes 2001; 50:776
784.
Toft-Nielsen MB, Madsbad S, Holst JJ. Determinants
of the eectiveness of glucagon-like peptide-1 in type
2 diabetes. J Clin Endocrinol Metab 2001; 86:3853
386.
Gutzwiller JP, Drewe J, Goke B, et al. Glucagon-like
peptide-1 promotes satiety and reduces food intake in
patients with diabetes mellitus type 2. Am J Physiol
1999; 276:R1541R1544.
Naslund E, Gutniak M, Skogar S, Rossner S, Hellstrom PM. Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying
in obese men. Am J Clin Nutr 1998; 68:525530.
Flint A, Raben A, Rehfeld JF, Holst JJ, Astrup A.
The eect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans. Int J
Obes Relat Metab Disord 2000; 24:288298.
Davis HR Jr, Mullins DE, Pines JM, et al. Eect of
chronic central administration of glucagon-like peptide-1 (736) amide on food consumption and body
weight in normal and obese rats. Obes Res 1998; 6:147
156.
Van Dijk G, Thiele TE. Glucagon-like-peptide-1 (7
36) amide: a central regulator of satiety and interoceptive stress. Neuropeptides 1999; 33:406414.
Drucker DJ. Minireview: the glucagon-like peptides.
Endocrinology 2001; 142:521527.
Larsen J, Hylleberg B, Ng K, Damsbo P. Glucagonlike peptide-1 infusion must be maintained for 24h/day
to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulfonylurea treatment. Diabetes Care 2001; 24:14161421.
Doyle ME, Egan JM. Glucagon-like-peptide-1. Rec
Prog Horm Res 2001; 56:377399.
Balsiger BM, Murr MM, Poggio JL, Sarr MG. Bariatric surgery. Surgery for weight control in patients
with morbid obesity. Med Clin North Am 2000; 84:
477489.
Bloomgarden ZT. European Association for the Study
of Diabetes Annual Meeting, 2000. Diabetes Care
2001; 24:11151119.
38
Obesity and Gallbladder Disease
Cynthia W. Ko and Sum P. Lee
University of Washington, Seattle, Washington, U.S.A.
INTRODUCTION
Gallstones are a common problem in the general population, and have an even higher prevalence in the
obese and in those losing weight. Complications of
gallstones include biliary colic, acute and chronic
cholecystitis, and pancreatitis. Three conditions are
necessary for cholesterol gallstone formation: supersaturation of bile with cholesterol, nucleation of
cholesterol crystals, and gallbladder stasis. In obese
subjects, these pathogenetic mechanisms may be modied, leading to a predisposition to gallstone formation.
This chapter will review the pathogenesis of cholesterol
gallstones, and the eects of obesity and weight loss on
gallbladder disease.
Cholesterol
The liver is the site of primary site of cholesterol synthesis and lipoprotein metabolism in the body. Free
cholesterol is synthesized in the hepatocyte endoplasmic
reticulum. The rate-limiting enzyme in cholesterol synthesis is HMG-CoA reductase (2). Each day, several
grams of cholesterol derived from lipoproteins are taken
up by the liver. Cholesterol enters the liver in esteried
form, is transported to the lysosomes, and is then
converted into its free form. It is then transported to
the endoplasmic reticulum and reesteried for storage.
Cholesterol esters in the endoplasmic reticulum are
continually undergoing hydrolysis, providing a constant supply of free cholesterol. This free cholesterol is
the substrate pool for bile acid and lipoprotein synthesis
and for secretion into bile. The rate of biliary excretion
from this pool varies with the rate of bile salt and
lipoprotein synthesis. Biliary cholesterol secretion is
quantitatively correlated with bile salt secretion (2).
However, the ratio of cholesterol to bile salts secreted
increases as bile salt secretion decreases, in part explaining the nding of more saturated bile (higher cholesterol-to-bile salt ratio) at low bile ow rates. Cholesterol
is believed to be secreted from the liver in the form of
phospholipid-cholesterol vesicles (3). Leptin levels inuence the amount of cholesterol secreted into bile in
animal models (4), and gallstone prevalence is corre-
II PATHOGENESIS OF CHOLESTEROL
GALLSTONES
Bile is a complex substance composed of lipids, proteins, electrolytes, and water. There are three principal
biliary lipids: cholesterol, bile acids, and phospholipids
(primarily phosphatidylcholine). Many species of proteins are present, and they are derived from serum
proteins as well as hepatocyte, bile duct, and gallbladder
epithelial secretion. Gallstone formation is determined
by the physical-chemical interactions of all of these
components present in bile (1).
919
920
Ko and Lee
Bile Acids
Proteins
Phospholipids
Biliary cholesterol transport can be transported in unilamellar vesicles, which are 4070 nm in diameter and
consist of a bilayer of phospholipids interdigitated with
cholesterol (3,1317). Vesicles contain very little or no
bile acids. In bile with a higher concentration of bile
acids, such as gallbladder bile, these vesicles may fuse
and form larger, multilamellar vesicles up to 5001000
nm in diameter (1517). Vesicles are believed to be less
thermodynamically stable than mixed micelles, and
cholesterol in these vesicles may coalesce to form a
metastable state (3,13,1820). Cholesterol in vesicles is
felt to be more prone to nucleate and precipitate (20
23), and gallstone patients may have a larger proportion of cholesterol transported in this form (22).
Motor Function
Gallbladder motility is commonly assessed by measuring fasting volume, contracted or residual volume, and
fractional emptying. Maximal contraction is seen after
meals. Between meals, the gallbladder may undergo
partial emptying and lling. During periods of fasting,
gallbladder contraction is weak, and bile accumulates in
the gallbladder, with sequestration of the circulating
bile acid pool. With the resulting fall in bile acid secretion rates, bile becomes progressively more saturated,
and cholesterol crystallization or stone formation may
occur. Contractile function of the gallbladder is important to empty any saturated bile, sludge, or small stones
before larger stones can form (26). Gallbladder contractility is controlled through the endocrine and nervous systems. The most important hormone regulating
gallbladder contractility is cholecystokinin (CCK). This
hormone is released by the duodenum after meals, and
causes gallbladder contraction and sphincter of Oddi
relaxation (26). Neural control is mediated through
both the vagus nerve and the sympathetic nervous
system. Vagal activity enhances gallbladder contrac-
921
Mucosal Function
Cholesterol crystal nucleation is the rst step in gallstone formation. Nucleation begins with aggregation
and fusion of unilamellar vesicles to multilamellar
vesicles, with subsequent aggregation of cholesterol
molecules to form crystals. This initial aggregation is
922
Ko and Lee
EFFECTS OF OBESITY
sity has direct eects on bile composition and gallbladder motility. This section will review the epidemiology
of gallbladder disease and the eects of obesity on bile
composition and gallbladder motility that predispose to
gallstone formation.
A
923
Many studies have shown that obese women are predisposed to gallbladder disease (Table 1). The incidence
of gallstones in obese women has been estimated at 2.6
per 100 person-years, with approximately two-thirds
of these stones being asymptomatic (95). The relative risk seems to increase as body weight increases
(73,74,78,85,86,93,9699). Thus, the risk of gallstones
relative to nonobese women is increased two times in
women with a body mass index (BMI) >30 kg/m2 and
seven times in women with a BMI >45 kg/m2 (86).
However, there is not a dened threshhold eect, as the
relative risk of gallstones increases with BMI, even in
women with a BMI <25 kg/m2. Obesity seems to confer a greater relative risk in younger populations
(98,100,101). In one study of obese adolescents, 55%
of adolescent females undergoing cholecystectomy were
obese, compared to 23% of adolescent females undergoing nongallbladder surgery, a relative risk of 4.2
(101). This relationship between obesity and gallstones
is less striking in men, but several studies have also
shown an increased risk of gallstones in men with
increasing BMI (79,99,102,103). Up to 43% of men
and women undergoing bariatric surgery have gallbladder disease, dened as prior cholecystectomy or gallstones (104,105).
Study population
Diagnostic criteria
Normal
population
78
85
Screening by US
Screening by US
BMI <22.5
BMI <21.65
86
Previous cholecystectomy
or symptoms
BMI <24
93
US if symptomatic
BMI <22
94
Obese prior to
bariatric surgery
Previous cholecystectomy
and intraoperative US
BMI <20
US, ultrasound.
Obese
population
BMI
BMI
BMI
BMI
BMI
BMI
BMI
BMI
BMI
BMI
BMI
BMI
BMI
BMI
>25
21.623.8
23.825.8
>25.8
3035
3540
4045
>45
2224.9
2531.9
>32
3540
4050
5060
Relative risk
1.9
1.1
1.4
1.8
3.69
4.72
5.11
7.36
1.6
3.3
6.3
5
7
8
924
Ko and Lee
Figure 1 Hepatic cholesterol metabolism. In the liver, cholesterol may be derived from circulating lipid particles or synthesized de novo from acetate via the HMG CoA reductase
pathway. Export pathways of cholesterol include incorporation into circulating VLDL particles, esterication via the
ACAT enzyme, conversion to bile acids, or secretion into bile.
LDL = low-density lipoprotein; HDL = high density lipoprotein; CM = chylomicron; CMR = chylomicron receptor;
VLDL = very low density lipoprotein; ACAT = acetyl CoA
cholesterol acyl transferase.
925
IV
Gallbladder stasis is an important factor that predisposes to formation of gallstones. Obesity in itself is
associated with gallbladder hypomotility and stasis,
with many studies showing increased fasting volumes,
increased residual volumes, and decreased fractional
emptying (3032,125,126). Multiple mechanisms may
predispose to alterations in gallbladder motility in the
obese. Alterations in peripheral CCK levels have been
Incidence
135
US, ultrasound.
Study population
Obese undergoing
bariatric surgery
Obese undergoing
bariatric surgery
Obese undergoing
bariatric surgery
Obese on low-calorie diet
Obese undergoing
bariatric surgery
Obese on low-calorie diet
Obese on low-calorie diet
Obese undergoing
bariatric surgery
Obese undergoing
bariatric surgery
Method of
weight loss
Diagnostic test
Follow-up
period
Percent with
gallstones
Jejunoileal bypass
US if symptomatic
24 months
Jejunoileal bypass
Oral cholecystogram
36 months
male 10%
female 9%
10.3%
Jejunoileal bypass
US if symptomatic
60 months
20%
540-kcal diet
US screening
Gastric bypass
US screening
4 weeks
8 weeks
6 months
7.8%
25.5%
36%
520-kcal diet
605-kcal diet
Gastric bypass
US screening
US if symptomatic
US screening
Gastric bypass
US screening
16
6
6
12
18
3
weeks
months
months
months
months
months
10.9%
11%
37%
37%
37%
43%
926
Ko and Lee
Risk Factors
927
Figure 2 Schematic of cholesterol nucleation. In bile, cholesterol exists in two soluble formsvesicles and mixed micelles. They
are in dynamic equilibrium (1), depending on total bile salt concentration and lipid density. With concentration, the vesicles may
be depleted with phospholipid and enriched with cholesterol, resulting in a tendency for the vesicles to aggregate and fuse (2).
Pro-nucleators may aid vesicular fusion. The fused vesicles are transitional forms and lead to formation of multilamellar
liposomes or liquid crystals (3). Cholesterol separates from the liquid to solid crystalline forms during nucleation (4). It is unclear
whether fused vesicles can nucleate into solid cholesterol crystals. (From Ref. 168.)
Prevention
Prophylactic Cholecystectomy
Some authors have advocated prophylactic cholecystectomy at the time of bariatric surgery because of
the >30% incidence of gallstones in the initial period
of rapid weight loss. From 10% to 25% of patients who
have not had a prior cholecystectomy will already have
gallstones at the time of surgery, and 95% of patients
undergoing cholecystectomy at bariatric surgery will
have pathologic evidence of gallbladder disease (104,
928
Ko and Lee
105). Cholecystectomy adds only minimally to procedure time (3045 min), and patients undergoing prophylactic cholecystectomy have not had a higher incidence
of perioperative complications or a longer hospital stay.
Many centers have moved to routinely performing cholecystectomy at the time of gastric bypass surgery (104,
105). Prophylactic cholecystectomy before initiating
weight reduction diets has not been advocated.
3
Bile acid supplementation has been used as a nonsurgical treatment for gallstones. Certain bile acids, CDCA
and ursodeoxycholic acid (UDCA), contribute to cholesterol solubilization and can decrease bile lithogenicity. Bile acid supplementation is generally well tolerated
and without signicant adverse eects.
In the nonobese, treatment with CDCA desaturates
bile and prolongs nucleation times (20,156). However,
this eect is not seen consistently in the obese, even with
the same doses per kilogram being administered
(17,18,157160). Biliary cholesterol concentrations
and saturation indices reliably decrease to unsaturated
ranges only with high dose therapy (157160). HMG
CoA reductase activity is reduced during CDCA therapy, with subsequent reduction in hepatic cholesterol
synthesis and secretion (122). However, CDCA is a
potent inhibitor of cholesterol 7a-hydroxylase, and thus
decreases cholesterol catabolism. With oral therapy,
this bile acid can increase the total bile acid pool and
the rate of bile acid secretion, and in fact, becomes the
predominant circulating bile acid. Although it has
benecial eects on bile composition, CDCA may
increase gallbladder mucin secretion, and potentially
enhance cholesterol crystal nucleation (4951).
Currently, the use of UDCA has superseded that of
CDCA. UDCA is safe and eective. Treatment with
UDCA prolongs nucleation times and decreases the
concentration of cholesterol and phospholipid present
in the vesicular phase (20,135,157161). Gallbladder
bile from patients treated with UDCA contains only a
trace of cholesterol in vesicles, the more lithogenic form
of transport (162). Similar to CDCA, UDCA decreases
biliary cholesterol concentration by decreasing activity
of hepatic HMG CoA reductase (122). It has no eect
on the activity of cholesterol 7a-hydroxylase. The
molar percentage of bile acids is unchanged to slightly
increased with UDCA, and UDCA becomes the predominant bile acid during therapy (122,135,161). In
addition to its eects on bile composition, UDCA may
SUMMARY
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Scharschmidt BF. Bilirubin metabolism, bile formation, and gallbladder and bile duct function. In:
Sleisenger MH, Fordtran JS, eds. Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Philadelphia: W.B. Saunders, 1993:17301746.
Cooper AD. Epidemiology, pathogenesis, natural history, and medical therapy of gallstones. In: Sleisinger
MH, Fordtran JS, eds. Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. Philadelphia:
W.B. Saunders, 1993:17881804.
Somjen GJ, Gilat T. A non-micellar mode of cholesterol transport in human bile. FEBS Lett 1983; 156:265
268.
Cohen DE, Ranginani N, Vanpatten S, Rossetti L.
Leptin regulates coupling of biliary cholesterol to bile
salt secretion in Zucker rats [abstract]. Hepatology
1999; 30:429A.
Duggirala R, Mitchell BD, Blangero J, Stern MP.
Genetic determinants of variation in gallbladder disease
in the Mexican-American population. Genet Epidemiol
1999; 16(2):191204.
Reuben A. Bile formation: sites and mechanisms.
Hepatology 1984; 4(suppl 5):15S24S.
Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK,
Wagenaar E, Van Deemter L, Mol CA. Homozygous
disruption of the murine mdr2 P-glycoprotein gene
leads to a complete absence of phospholipid from bile
and to liver disease. Cell 1993; 75(3):451462.
Smith AJ, Timmermans-Hereijgers JL, Roelofsen B,
Wirtz KW, Van Blitterswijk WJ, Smit JJ, Schinkel AH.
The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma
membrane of broblasts from transgenic mice. FEBS
Lett 1994; 354(3):263266.
Reuben A. Biliary proteins. Hepatology 1984; 4(suppl
5):46S50S.
Small DM, Rapo S. Source of abnormal bile in patients
with cholesterol gallstones. N Engl J Med 1970; 283:53
57.
Admirand WH, Small DM. The physico-chemical basis
of cholesterol gallstone formation in man. J Clin Invest
1968; 47:10431052.
Carey MC, Small DM. The physical-chemistry of cholesterol solubility in bile: relationship to gallstone formation and dissolution in man. J Clin Invest 1978; 61:
9981026.
Lee SP. The mechanism of mucus secretion by the
gallbladder epithelium. Br J Exp Pathol 1980; 61:117
119.
Lee SP, Park HZ, Madani H, et al. Partial character-
929
ization of a non-micellar system of cholesterol solubilization in bile. Am J Physiol 1987; 252:G374G383.
15. Halpern Z, Dudley MA, Kibe A, Lynn MP, Breuer AC,
Holzbach RT. Rapid vesicle formation and aggregation
in abnormal human biles. A time-lapse video-enhanced
contrast microscopy study. Gastroenterology 1986; 90:
875885.
16. Kibe A, Dudley MA, Halpern Z, et al. Factors aecting cholesterol monohydrate crystal nucleation time in
model systems of supersaturated bile. J Lipid Res 1985;
26: 11021111.
17. Halpern Z, Dudley MA, Lynn MP, et al. Vesicle aggregation in model systems of bile: relation to crytal nucleation and lipid composition of the vesicular phase.
J Lipid Res 1986; 27:295306.
18. Somjen GJ, Marikovsky Y, Lelkes P, Gilat T. Cholesterol-phospholipid vesicles in human bile: an ultrastructural study. Biochim Biophys Acta 1986; 879:14
21.
19. Carey MC, Cohen DE. Biliary transport of cholesterol
in vesicles, micelles, and liquid crystals. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile Acids and the Liver.
Lancaster: MTP Press, 1987:287300.
20. Hirota I, Chijiiwa K, Noshiro J, Makayama F. Eect of
chenodeoxycholate and ursodeoxycholate on nucleation time in human gallbladder bile. Gastroenterology
1992; 102:16681674.
21. Zhao XT, Schoenel LJ, Bonorris GG, Van de Velde
RL, Marks JS. Increased cholesterol in vesicles is associated with rapid nucleation of human gallbladder bile.
Hepatology 1994; 20:117A. Abstract.
22. Holzbach RT. Recent progress in understanding
cholesterol crystal nucleation as a precursor to human
gallstone formation. Hepatology 1986; 6:14031406.
23. Holzbach RT, Halpern Z, Dudley MA, et al. Biliary
vesicle aggregation and cholesterol crystal nucleation:
evidence for a coupled relationship. In: Paumgartner G,
Stiehl A, Berok W, eds. Bile Acids and the Liver. Lancaster: MTP, 1987:301316.
24. Little TE, Lee SP, Madani H, Kaler EW, Chinn K.
Interconversions of lipid aggregates in rat and model
bile. Am J Physiol 1991; 23:G70G79.
25. Pattinson NR, Chapman BA. Distribution of biliary
cholesterol between mixed micelles and nonmicelles in
relation to fasting and feeding in humans. Gastroenterology 1986; 91:697702.
26. Tierney S, Pitt HA, Lillemoe KD. Physiology and
pathophysiology of gallbladder motility. Surg Clin
North Am 1993; 73(6):12671290.
27. Fridhandler TM, Davison JS, Shaer EA. Defective
gallbladder contractility in the ground squirrel and
prairie dog during the early stages of cholesterol gallstone formation. Gastroenterology 1983; 85(4):830
836.
28. Behar J, Lee KY, Thompson WR, Biancani P. Gallbladder contraction in patients with pigment and cho-
930
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
Ko and Lee
lesterol stones. Gastroenterology 1989; 97(6):1479
1484.
Pomeranz IS, Shaer EA. Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology 1985; 88(3):787791.
Palasciano G, Serio G, Portincasa P, Palmieri V, Fanelli
M, Velardi A, Calo Gabrieli B. Gallbladder volume in
adults, and relationship to age, sex, body mass index,
and gallstones: a sonographic population study. Am J
Gastroenterol 1992; 87(4):493497.
Kucio C, Besser P, Jonderko K. Gallbladder motor
function in obese versus lean females. Eur J Clin Nutr
1988; 42(2):121124.
Marzio L, Capone F, Neri M, Mezzetti A, De Angelis
C, Cuccurullo F. Gallbladder kinetics in obese patients.
Eect of a regular meal and low-calorie meal. Dig Dis
Sci 1988; 33(1):49.
Vezina WC, Paradis RL, Grace DM, Zimmer RA,
Lamont DD, Rycroft KM, King ME. Increased volume
and decreased emptying of the gallbladder in large
(morbidly obese, tall normal, and muscular normal)
people. Gastroenterology 1990; 98(4):10001007.
Glasbrenner B, Dominguez-Munoz JE, Nelson DK,
Pieramico O, Holzwarth C, Riepl RL, Malfertheiner
P. Postprandial release of cholecystokinin and pancreatic polypeptide in health and in gallstone disease: relationships with gallbladder contraction [see comments].
Am J Gastroenterol 1994; 89(3):404410.
Cano N, Cicero F, Ranieri F, Martin J, di-Costanzo J.
Ultrasonographic study of gallbladder motility during
total parental nutrition. Gastroenterology 1986; 91:
313317.
Messing B, Bories C, Kuntslinger F, Benier JJ. Does
total parenteral nutrition induce gallbladder sludge formation and lithiasis? Gastroenterology 1983; 84: 1012
1019.
Fisher RS, Koch E, Levin G. Eects of somatostatin on
gallbladder emptying. Gastroenterology 1987; 92:88
90.
Johansson C, Kollberg B, Efendic S, Uvnaswallenstein
K. Eects of graded dose of somatostain on gallbladder
emptying and pancreatic enzyme output after oral glucose in man. Digestion 1981; 22:2431.
Diamond JM. Transport of salt and water in rabbit and
guinea pig gallbladder. J Gen Physiol 1964; 48:114.
Dietschy JM. Water and electrolyte movement across
the wall of the everted rabbit gallbladder. Gastroenterology 1964; 47:395408.
Wood JR, Svanvik J. Gall-bladder water and electrolyte transport and its regulation. Gut 1983; 24(6):579
593.
Shiman ML, Sugerman HJ, Moore EW. Human gallbladder mucosal function: eect of concentration and
acidication of bile on cholesterol and calcium solubility. Gastroenterology 1990; 99:14521459.
Van Erpecum KJ, Van Berge Henegouwen GP,
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
931
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
932
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
Ko and Lee
aged men. A 25-year follow-up study (the Zutphen
Study). Ann Epidemiol 1994; 4(3):248254.
Attili AF, Scafato E, Marchioli R, Marsi RM, Festi D.
Diet and gallstones in Italy: the cross-sectional MICOL
results. Hepatology 1998; 27(6):14921498.
Misciagna G, Centonze S, Leoci C, Guerra V,
Cisternino AM, Ceo R, Trevisan M. Diet, physical activity, and gallstonesa population-based, case-control study in southern Italy. Am J Clin Nutr 1999;
69(1):120126.
Leitzmann MF, Giovannucci EL, Rimm EB, Stampfer
MJ, Spiegelman D, Wing AL, Willett WC. The relation
of physical activity to risk for symptomatic gallstone
disease in men. Ann Intern Med 1998; 128:417425.
Leitzmann MF, Rimm EB, Willett WC, Spiegelman D,
Grodstein F, Stampfer MJ, Colditz GA. Recreational
physical activity and the risk of cholecystectomy in women [see comments]. N Engl J Med 1999; 341(11):777
784.
Utter AC, Whitcomb DC, Nieman DC, Butterworth
DE, Vermillion SS. Eects of exercise training on gallbladder function in an obese female population. Med
Sci Sports Exerc 2000; 32(1):4145.
Maclure KM, Hayes KC, Colditz GA, Stampfer MJ,
Speizer FE, Willet WC. Weight, diet, and the risk of
symptomatic gallstones in middle-aged women. N Engl
J Med 1989; 321:563569.
Shiman ML, Sugerman HJ, Kellum JH, Brewer WH,
Moore EW. Gallstones in patients with morbid obesity.
Relationship to body weight, weight loss and gallbladder bile cholesterol solubility. Int J Obes Relat Metab
Disord 1993; 17(3):153158.
Acalovschi MV, Blendea D, Pascu M, Georoceanu A,
Badea RI, Prelipceanu M. Risk of asymptomatic and
symptomatic gallstones in moderately obese women: a
longitudinal follow-up study. Am J Gastroenterol 1997;
92(1):127131.
Tucker LE, Tangedahl TN, Newmark SR. Prevalence
of gallstones in obese Caucasian American women.
Int J Obes 1982; 6(3):247251.
Thijs C, Knipschild P, Leers P. Is gallstone disease
caused by obesity or by dieting? Am J Epidemiol 1992;
135(3):274280.
Palasciano G, Portincasa P, Vinciguerra V, Velardi A,
Tardi S, Baldassarre G, Albano O. Gallstone prevalence and gallbladder volume in children and adolescents: an epidemiological ultrasonographic survey and
relationship to body mass index. Am J Gastroenterol
1989; 84(11):13781382.
Must A, Spadano J, Coakley EH, Field AE, Colditz G,
Dietz WH. The disease burden associated with overweight and obesity. JAMA 1999; 282(16):15231529.
Petitti DB, Sidney S. Obesity and cholecystectomy
among women: implications for prevention. Am J Prev
Med 1988; 4(6):327330.
Honore LH. Cholesterol cholelithiasis in adolescent
females: its connection with obesity, parity, and oral
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
933
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
934
Eect of obesity and weight reduction on biliary cholesterol saturation and the response to chenodeoxycholic acid. Eur J Clin Invest 1985; 16:133142.
149. Schlierf G, Schellenberg B, Stiehl A, Czygan P, Oster P.
Biliary cholesterol saturation and weight reduction
eects of fasting and low calorie diet. Digestion 1981;
21:4449.
150. Soorensen TIA, Brussgaard A, Pederson LR, Krag E.
Lithogenic index of bile after jejunoileal bypass operation for obesity. Scand J Gastroenterol 1977; 12:449
451.
151. Shiman ML, Sugerman JH, Kellum JM, et al.
Changes in gallbladder bile composition following gallstone formation and weight reduction. Gastroenterology 1992; 103:214.
152. Shiman ML, Shamburek RD, Schwartz CC, Sugerman HJ, Kellum JM, Moore EW. Gallbladder mucin,
arachidonic acid, and bile lipids in patients who develop
gallstones during weight reduction. Gastroenterology
1993; 105(4):12001208.
153. Freeman JB, Meyer PD, Printen KJ, Mason EE,
DenBesten L. Analysis of gallbladder bile in morbid
obesity. Am J Surg 1975; 129:163166.
154. Inoue K, Fuchigama A, Higashide S, Sumi S, Kogire
M, Suzuki T, Tobe T. Gallbladder sludge and stone
formation in relation to contractile function after gastrectomy. Ann Surg 1992; 215:1926.
155. Festi D, Colecchia A, Orsini M, Sangermano A, Sottili
S, Simoni P, Mazzella G. Gallbladder motility and
gallstone formation in obese patients following very
low calorie diets. Use it (fat) to lose it (well). Int J Obes
Relat Metab Disord 1998; 22(6):592600.
156. Danzinger RG, Hofmann AF, Thistle JL, et al. Eect of
oral chenodeoxycholic acid on bile acid kinetics and
biliary lipid composition in women with cholelithiasis.
J Clin Invest 1972; 52:2809.
157. Mazzella G, Bazzoli F, Festi D, Ronchi M, Aldini R,
Roda A, Grigolo B. Comparative evaluation of chenodeoxycholic and ursodeoxycholic acids in obese patients. Eects on biliary lipid metabolism during weight
maintenance and weight reduction. Gastroenterology
1991; 101(2):490496.
158. Iser JH, Maton PN, Murphy GM, Dowling RH. Resistance to chenodeoxycholic acid (CDCA) treatment
in obese patients with gall stones. BMJ 1978; 1(6126):
15091512.
159. Maton PN, Murphy GM, Dowling RH. Lack of re-
Ko and Lee
160.
161.
162.
163.
164.
165.
166.
167.
168.
sponse to chenodeoxycholic acid in obese and nonobese patients. Role of cholesterol synthesis and possible response to ursodeoxycholic acid. Gut 1980; 21
(12):10821086.
Whiting MJ, Hall JC, Iannos J, Roberts HG, Watts JM.
The cholesterol saturation of bile and its reduction by
chenodeoxycholic acid in massively obese patients. Int J
Obes 1984; 8(6):681688.
Zuin M, Petroni ML, Grandinetti G, Crosignani A,
Bertolini E, Battezzati PM, Podda M. Comparison of
eects of chenodeoxycholic and ursodeoxycholic acid
and their combination on biliary lipids in obese patients
with gallstones. Scand J Gastroenterol 1991; 26(3):257
262.
Okamoto S, Nakano K, Kosahara K, Kishinaka M,
Oda H, Ichimiya H, Chijiiwa K. Eects of pravastatin
and ursodeoxycholic acid on cholesterol and bile acid
metabolism in patients with cholesterol gallstones. J
Gastroenterol 1994; 29(1):4755.
Marks JW, Bonorris GG, Schoeneld LJ. Eects of
ursodiol or ibuprofen on contraction of gallbladder and
bile among obese patients during weight loss. Dig Dis
Sci 1996; 41(2):242249.
Shiman ML, Kaplan GD, Brinkman-Kaplan V,
Vickers FF. Prophylaxis against gallstone formation
with ursodeoxycholic acid in patients participating in a
very-low-calorie diet program. Ann Intern Med 1995;
122:899905.
Sugerman HJ, Brewer WH, Shiman ML, Brolin RE,
Fobi MA, Linner JH, MacDonald KG. A multicenter,
placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention
of gallstone formation following gastric-bypass-induced rapid weight loss. Am J Surg 1995; 169(1):91
96. Discussion 9697.
Shoheiber O, Biskupiak JE, Nash DB. Estimation of
the cost savings resulting from the use of ursodiol for
the prevention of gallstones in obese patients undergoing rapid weight reduction. Int J Obes Relat Metab
Disord 1997; 21(11):10381045.
Broomeld PH, Chopra R, Scheinbaum RC, Bonorris
GG, Silverman A, Schoeneld LJ, Marks JW. Eects of
ursodeoxycholic acid and aspirin on the formation of
lithogenic bile and gallstones during loss of weight. N
Engl J Med 1988; 319:567572.
Yamada T, ed. Atlas of Gastroenterology. 2d ed.
Philadelphia: Lippincott Williams and Wilkins, 1999.
39
Obesity and Pulmonary Function
Shyam Subramanian and Kingman P. Strohl
Case Western Reserve University School of Medicine, Cleveland, Ohio, U.S.A.
(males) or >28 (females). The literature is too heterogeneous to combine studies or to examine the relationship of obesity to respiratory function using continuous
variables for each condition. Therefore, we will discuss
studies that examined categorical eects (obese vs. nonobese subjects).
Respiratory compliance is a measure that relates to
the pressure changes that are required to increase lung
volume and can be inuenced by the mechanical properties of both the lungs and the chest wall (1416). One
major problem in obesity is that increased weight pressing on the thoracic cage and abdomen makes the chest
wall sti and noncompliant (14,15). In addition to increased adiposity around the thoracic cage, chest wall
compliance may be decreased because the decreased
total thoracic and pulmonary volume may pull the chest
wall below its resting level to a atter portion of its pressure-volume curve. In a study on sedated, paralyzed,
postoperative morbidly obese patients, functional residual capacity (FRC) was seen to be markedly low compared to normals, and respiratory compliance was
found to be low owing to signicant decrease in both
lung and chest wall compliance (17).
Total respiratory system resistance was also markedly increased, primarily owing to an increase in lung
resistance. Oxygenation was impaired and correlated
with total respiratory system compliance. PaCO2 was
not dierent between obese and lean subjects and did
not relate to compliance, resistance, or FRC. The same
group later compared respiratory mechanics during
INTRODUCTION
936
general anesthesia among groups of normals, overweight subjects, and obese subjects (BMI 2540) and
subjects with morbid obesity (BMI >40) (18). Increasing BMI was correlated to an exponential increase in
FRC. Compliance of both the total respiratory system
and the lungs decreased; in contrast, the compliance of
the chest wall was only minimally aected, and the
resistance of the lung and of the total respiratory system
increased. Chest wall compliance falls more in obese
than lean subjects in moving from the sitting to the
supine or even prone position (14,19). In obese patients,
prone positioning has been shown to improve pulmonary function, by increasing FRC and lung compliance
during general anesthesia (20).
There is a relationship between chest wall compliance
and CO2 retention, independent of body fat. In those
obese individuals with an increase in arterial PaCO2 and
therefore alveolar hypoventilation, chest wall compliance was one-third of normal, whereas in equally obese
but eucapnic subjects, chest wall compliance was in the
normal range (16). The mechanism for the dierences in
chest wall compliance in the two groups was not studied;
the interpretation of the results centered on the role of
chest wall compliance in CO2 retention.
The lung itself may be indirectly aected by chest
wall mass loading, as lung compliance in addition to
chest wall compliance is decreased in some obese individuals (14,21,22). Mechanisms for increased lung stiness include a large pulmonary blood volume and/or
dependent airways, greater collapse of alveolar units
and/or intrinsic alterations of the elastic characteristics
of lung tissues with surface lining lm modications.
Another factor would be the imposition of abdominal
fat, producing a cephalad-displaced diaphragm, and
restricting lung ination and promoting recoil in expiration. Experimental mass loading of the chest wall
produces dependent bronchioalveolar units with atelectasis which increases further the work of breathing (23).
With both an increased lung and chest wall stiness, in
an obese individual there is an increased mechanical
work of breathing as well as an oxygen cost of breathing
(24,25). Work of breathing can be increased two- to
threefold even in obese eucapnic individuals. Another
factor contributing to this increased work of breathing
is the marked increase in lung and consequently respiratory resistance (18,26).
B
A common complaint in the obese individual is dyspnea, a sense of shortness of breath on exertion or at rest
(49,50). In a recent study, 60% of patients with a BMI
>28 and no comorbid conditions reported some dyspnea at rest (51). Factors that appear to correlate with
increased shortness of breath include the decrease in
chest wall compliance and the ineciency of the respiratory control system (see above). The moderately obese
individual, though, can sustain a level of ventilation to
maintain normal levels of arterial PCO2 and increase
ventilation appropriately with exercise (52). This indicates that the metaboreceptor response to exercise can
be intact, at least in moderately obese individuals.
There are three somewhat unique aspects of exercise
related to obesity. The rst relates to the increased
ventilatory demands imposed by the increased weight
of the individual. This eect is seen clearly in that
ventilation for a given work load on treadmill testing is
much greater than that on bicycle testing (15,5254) and
is explained by the weight borne while walking. A second
eect relates to the observation that while ventilation is
usually increased in relationship to oxygen consumption, in the moderately obese subject studied both at rest
and with exercise, arterial oxygen levels increase on
exercise with little change in PaO2. This response is
attributed to improved ventilation-perfusion matching
937
III
CATEGORIES OF RESPIRATORY
COMPROMISE IN OBESITY
938
syndrome (both reviewed below). Patients in this category exhibit an inherent predisposition to pulmonary
embolism (61,62). Pulmonary hypertension, which can
be present in these patients during light exercise, may
predispose these patients to inactivity, to dependent
edema, and to subsequent risk for venous thrombosis
(61). The eects of pulmonary emboli on the lung of an
obese individual will be compounded by abnormalities
in respiratory function imposed by increased weight
alone (62) (see section on OHS). Another confounding
factor in this classication is the relationship of respiratory morbidity to the circulatory physiology and pathophysiology of obesity (61,63).
IV
SLEEP-DISORDERED BREATHING
AND OBESITY
Obstructive sleep apnea (OSA) syndrome is characterized by loud snoring, episodic partial or complete
obstruction of the upper airway during sleep, and consequent sleep fragmentation leading to excessive daytime sleepiness. In addition to the morbidity associated
with chronic sleepiness, patients with OSA are at increased risk for hypertension, myocardial infarction,
and stroke (10). The diagnosis and treatment of OSA
have been reviewed elsewhere (10,6466), although a
few key points are mentioned here. When OSA is
suspected clinically, the diagnosis is conventionally
conrmed via polysomnography, a test in which multiple physiological variables including the electroencephalogram, electrocardiogram, and several measures
of respiratory function are recorded during sleep. The
most common measure of OSA severity determined in
this manner is the total number of apneas (cessation of
airow of 10 sec) and hypopneas (partial obstructions)
per hour of sleep (apnea + hypopnea index; AHI).
However, other features in the presentation may indicate the need for a therapeutic intervention.
Population studies in the United States and several
other countries suggest that the syndrome of obstructive
sleep apnea, daytime sleepiness, and cardiovascular
disease is present in f14% of working men and women
(10,67). There are pockets of higher prevalence, for
instance in minority populations and children with
tonsillar hypertrophy; however, one of the best-characterized associations is between obesity and OSA. The
correlation between body weight and sleep apnea was so
strong as to dominate recognition strategies for almost
two decades and link sleep apnea almost exclusively
with obesity hypoventilation or Pickwickian syndrome
(64,66,68); however, in community studies the associa-
939
tion of OSA with obesity is not as strong as in clinicbased case collections or reviews from referral centers
(10,68). A brief review of this association follows, as
does a more thorough account of the literature regarding mechanisms and the eect of weight reduction.
A
940
OBESITY HYPOVENTILATION
SYNDROME
941
PCO2
PO2
Complications
Mild
Moderate
Severe
4550
>70
Absent
5060
6070
Absent
>60
<60
Present
942
MANAGEMENT STRATEGIES
FOR OSA AND OHS
Clinical Studies of Weight Loss
Anorexiant Drugs
943
944
Noninvasive Ventilation
Medications
a.
Tracheotomy
Indications include failure of/inability to tolerate medical measures and severe cor pulmonale or serious
nocturnal arrhythmias (129). The morbidities, including
risks of tracheal stenosis, infection and psychosocial
problems, preclude its widespread use. Because these
patients have large necks, special tracheotomy techniques are reported, including several skin-ap methods
(148) that allow improved and easier stoma care.
4
Supplemental Oxygen
VII
Epidemiological Studies
Studies in Adults
945
Multiple population-based studies across dierent continents have found a strong association between selfreported asthma and obesity in the pediatric population
(156159). This association seems to be stronger among
girls (156158). In a study looking at ED visits in
children aged 49 years seen with asthma, Belamarich
946
Mechanisms
947
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
948
14. Sharp JT, Barrocas M, Chokroverty S. The cardiorespiratory eects of obesity. Clin Chest Med 1980; 1(1):
103118.
15. Ray CS, et al. Eects of obesity on respiratory function.
Am Rev Respir Dis 1983; 128(3):501506.
16. Naimark A, CR. Compliance of the respiratory system in health and obesity. J Appl Physiol 1960; 15:377
382.
17. Pelosi P, et al. Total respiratory system, lung, and chest
wall mechanics in sedated-paralyzed postoperative
morbidly obese patients. Chest 1996; 109(1):144151.
18. Pelosi P, et al. The eects of body mass on lung volumes, respiratory mechanics, and gas exchange during general anesthesia. Anesth Analg 1998; 87(3):654
660.
19. Suratt PM, et al. Compliance of chest wall in obese
subjects. J Appl Physiol 1984; 57(2):403407.
20. Pelosi P, et al. Prone positioning improves pulmonary
function in obese patients during general anesthesia.
Anesth Analg 1996; 83(3):578583.
21. Douglas FG, Chong PY. Inuence of obesity on peripheral airways patency. J Appl Physiol 1972; 33(5):
559563.
22. Rochester DF, Enson Y. Current concepts in the
pathogenesis of the obesity-hypoventilation syndrome.
Mechanical and circulatory factors. Am J Med 1974;
57(3):402420.
23. Sharp JT, HJ, Sweany SK, Meadows WR, Pietras RJ.
Eects of mass loading the respiratory system in man.
J Appl Physiol 1964; 19:959966.
24. Dempsey JA, et al. Work capacity determinants and
physiologic cost of weight-supported work in obesity.
J Appl Physiol 1966; 21(6):18151820.
25. Sharp JT, HJ, Sweany SK, Meadows WR, Pietras RJ.
The total work of breathing in normal and obese men.
J Clin Invest 1964; 43:728739.
26. Zerah F, et al. Eects of obesity on respiratory resistance. Chest 1993; 103(5):14701476.
27. Sharp J. The chest wall and respiratory muscles in
obesity, pregnancy and ascites. In: Roussos C, Macklem PT, eds. The Thorax. New York: Marcel Dekker,
1985:9991021.
28. Barlett HL, Buskirk ER. Body composition and the
expiratory reserve volume in lean and obese men and
women. Int J Obes 1983; 7(4):339343.
29. Jacobsen E, Dano P, Skovsted P. Respiratory function before and after weight loss following intestinal
shunt operation for obesity. Scand J Respir Dis 1974;
55(6):332339.
30. Reichel G. Lung volumes, mechanics of breathing and
changes in arterial blood gases in obese patients and
in Pickwickian syndrome. Bull Physiopathol Respir
(Nancy) 1972; 8(5):10111020.
31. Stalnecker MC, Suratt PM, Chandler JG. Changes in
respiratory function following small bowel bypass for
obesity. Surgery 1980; 87(6):645651.
949
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
950
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
951
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
952
158.
159.
160.
161.
162.
163.
164. Kaplan TA, Montana E. Exercise-induced bronchospasm in nonasthmatic obese children. Clin Pediatr
(Phila) 1993; 32(4):220225.
165. Fredberg JJ, et al. Airway smooth muscle, tidal stretches,
and dynamically determined contractile states. Am J
Respir Crit Care Med 1997; 156(6):17521759.
166. Hakala K, Stenius-Aarniala B, Sovijarvi A. Eects of
weight loss on peak ow variability, airways obstruction, and lung volumes in obese patients with asthma.
Chest 2000; 118(5):13151321.
167. Dhabuwala A, Cannan RJ, Stubbs RS. Improvement in
co-morbidities following weight loss from gastric
bypass surgery. Obes Surg 2000; 10(5):428435.
168. Murr MM, Siadati MR, Sarr MG. Results of bariatric
surgery for morbid obesity in patients older than 50
years. Obes Surg 1995; 5(4):399402.
169. Stenius-Aarniala B, et al. Immediate and long term
eects of weight reduction in obese people with asthma:
randomised controlled study. BMJ 2000; 320(7238):
827832.
40
Obesity, Arthritis, and Gout
Anita Wluka and Flavia M. Cicuttini
Monash University, Melbourne, Victoria, Australia
Tim D. Spector
Guys and St. Thomas Hospital NHS Trust, London, England
INTRODUCTION
Cross-sectional epidemiological studies have consistently shown a relationship between obesity and knee
OA, which has generally been stronger in women than
in men. The reported increased risks have ranged from
two- to seven-fold for women in the top tertile of BMI
compared to women in the bottom tertile (814)
(Table 1). The earliest survey to mention this link
954
Wluka et al.
Table 1 Evidence of Association Between Knee OA and Obesity from Some Recent Cross-Sectional and Longitudinal
Population-Based Studies
Study
Cross-sectional
Felson et al., 1988 (12)
Davis et al., 1990 (14)
Hart et al., 1993 (16)
Longitudinal
Anderson, 1988 (13)
among the dierent knee compartments. A recent population based case control study examined whether risk
factors for OA dier between the dierent knee compartments (20). This study did not show a signicant
eect of obesity on the patellofemoral joint but showed
an eect at the tibiofemoral joint. This case control
study, based on small numbers, was the rst to consider
the possibility that OA in dierent compartments may
have dierent etiologies and that previously described
risk factors such as obesity may have dierential eects
in the dierent compartments. In contrast, data from a
population-based cross-sectional study of middle-aged
women showed it to be an important risk factor for both
medial tibiofemoral and patellofemoral joint disease
(21). This is an area where further work will be needed
to clarify the role of obesity as a risk factor in OA in
the dierent compartments of the knee. This is likely
to have important implications for preventive strategies in OA of the knee and for our understanding of the
pathogenesis of OA.
C
Longitudinal studies have consistently shown an association of obesity with knee OA (Table 1). The Framingham Study examined the association between obesity
and knee OA in a longitudinal study. At the time of that
study, the group had been followed up for 35 years (22).
955
A further method for examining the association between obesity and osteoarthritis is via twin studies,
which have been used to estimate the magnitude of the
weight dierence associated with the development of
OA (21). Twin studies provide a special research methodology that, as well as assessing the relative contributions of genetic and environmental factors to a disease,
may also be used to examine environmental risk factors
in twin pairs discordant for that disease trait. The twin
model used in this study enabled close matching of the
diseased and nondiseased twin for genetic similarity and
many known or unknown environmental factors, thus
providing a useful tool to quantify the magnitude of the
dierence in obesity between the twin with disease and
their cotwin with no disease.
The twin study conrmed that obesity is a strong risk
factor for OA of the knee, with twins with OA of the
tibiofemoral and patellofemoral joints of the knee tending, on average, to be 35 kg heavier than their cotwin
(Fig. 1). This weight dierence was also observed in
asymptomatic women, again suggesting that obesity is a
cause of OA rather than the converse. After adjusting
for other potential risk factors, the results showed that
for every kg increase in weight, a twin had a 14%
increased risk of developing tibiofemoral osteophytes
and a 32% increased risk of developing patellofemoral
osteophytes compared to their cotwin. These results
were consistent with a previous population study, in a
similar age group of women, that showed that the risk of
knee OA increased by 35% for every 5 kg of weight gain
(16). This suggests that in middle-aged women even
small increases in body weight are associated with
signicant increases in risk of developing OA. Risks in
men, however, cannot be extrapolated from these
results, and separate studies are needed.
E
956
Wluka et al.
OA is a disease of cartilage in which cartilage breakdown and erosion are accompanied by bony changes
such as osteophytes, subchondral sclerosis, and bony
cysts. Although the mechanisms by which obesity may
lead to OA are unknown, three hypotheses have been
proposed (14,15,37): (1) obesity increases the load
across the knee joint resulting in increased or abnormal
stress and resultant deterioration of the joint structures;
(2) obesity acts indirectly by metabolic changes associated with increased fatness such as glucose intolerance,
hyperlipidemia, hyperestrogenemia, or changes in bone
density; and (3) elements of the diet that result in
obesity, such as high fat content and adversely aect
bone, cartilage, or other joint structures (Table 2).
Obesity may initiate cartilage breakdown or may
promote joint destruction after the initial incipient
lesion. Biomechanical characteristics may be accentuated by obesity. In a study of 300 subjects, most of the
eect of BMI on the severity of OA in medial tibiofemoral osteoarthritis was explained by varus malalignment of the joint (38). Furthermore, this study showed
that obese subjects with valgus malalignment had
hardly any increase in OA prevalence. These results
suggest that a major mechanical inuence of obesity is
modied by alignment. Whether obesity inuences
957
a. Hypertension
On analysis of the data from the 1960s survey in
Leigh and Wensleydale, Lawrence found that hypertension was associated with generalize OA in men and
with knee OA in hypertensive, nonobese females (40).
The relationship was between diastolic blood pressure
and knee OA in both obese and nonobese females, and
this association remained in each 5-year age group from
45 to 69. The association between hypertension and OA
was also observed in the Chingford population study
which showed that ever treated hypertension was
associated with the development of OA and that this
association was strongest for those with bilateral knee
disease (41).
However, other studies have failed to conrm an
association between OA and blood pressure. No association was found in a study of 70-year-old people in
Goteborg (29). In univariate analysis of NHANES 1
data, an increase in recorded diastolic and systolic
blood pressure was found in females with knee OA,
but this association disappeared after adjusting for
weight (42). Similarly, in the Baltimore Longitudinal
Study of Aging (43), men and women with knee OA
had higher unadjusted blood pressure than those with
normal radiographs. However, after adjustment for age
and weight, the eect was lost in men. Although women
with knee OA had higher systolic pressure than those
with normal knees, the mean pressure was within the
normal range.
958
b.
Wluka et al.
Cholesterol
959
Most nonfatal chronic conditions are strongly age related (53), their prevalence rising with increasing age of
the population. Thus, as the total population continues
to age owing to the decrease in birth rate and to recent
declines in mortality in the older age groups, the burden
of nonfatal diseases and impairments will continue to
increase. This has highlighted the need to examine
prognostic factors for disability. Using the 1984 Supplement on Aging conducted by the National Center for
Health Statistics, the risk factors for disability among
U.S. adults aged 55+ who had arthritis were compared
to those who did not have arthritis (54). This study
showed that obesity was strongly implicated in disability once arthritis was present. Thus, not only obesity is a
risk factor for developing OA, but it also contributes to
the disability once it occurs. The contribution of obesity
to symptom development in individuals who already
have the pathological changes of OA is unclear. Studies
that have assessed whether obese subjects with concurrent radiographic OA are more likely to have symptoms
have yielded conicting results (11,55).
Summary
960
Wluka et al.
receive a controlled calorie weight loss diet and Manzidol (an appetite suppressant, Sanorex, Sandoz), and
18 to receive advice only. All were given ongoing
NSAID therapy (Rantudil) and advised to walk for up
to 30 min continuously per day during the 6-week trial.
Three in the control group forgot to wear pedometers
for several days and were excluded from the study. The
treatment group lost more weight and was more active
than the control group. Nineteen of 22 (86.4%) in the
treatment group improved symptomatically, compared
to 4 of 15 (26.7%) in the advice-only group. In the
treatment group, symptomatic relief of knee OA was
most strongly associated with reduction in body fat
(2.4%, SD 2.6) and physical activity (7.5, SD 1.7
103 steps per day). Physical activity and reduction in
body fat percent were related.
M
III
A large body of evidence exists to support an association between gout and obesity. The New Haven survey
showed that certain metabolic conditions, including
hyperuricemia, were associated with obesity (10). In a
cross-sectional study of 73,000 women aged 3049,
obesity was shown to be signicantly associated with
gout ( P < .001) (61). In 460 apparently healthy Dutch
men and women aged 6579 years, serum uric acid
level was found to be positively associated with body
weight, body mass index, body fatness, and lean body
mass in men but not in women (62). In a study of 7735
middle-aged men in 24 British towns, a positive association was observed between BMI and gout (63).
The association between obesity and hyperuricemia
has also been observed in other ethnic groups. A survey
of 115 Maori men of working age showed a strong
relationship between hyperuricemia and obesity (64). In
Melanesian and Asian Indians in Fiji, BMI was shown
to have a signicant and independent association with
plasma uric acid levels in both nondiabetic and diabetic
men and women (65). However, the most extreme
example of an association between gout and obesity
was seen in sumo wrestlers, who do not appear to have
any underlying genetic predisposition to gout (66). In a
study of 96 sumo wrestlers in Japan, mean serum levels
of uric acid were signicantly higher than those obtained in 89 age-matched healthy males. Weight correlated signicantly with uric acid.
Some recent data have suggested that body fat and
the distribution pattern of fat may be more important
than total weight as a risk factor for gout (67). The
association between fat distribution and gout was examined in 95 overweight adult men and 210 overweight
adult women (67). It was found that, adjusted for age
and body mas index, a high waist-thigh circumference
ratio was a risk factor for gout, particularly in women.
The association of waist-hip circumference ratio with
gout was less pronounced in men. Visceral fat (estimated from abdominal CT scans) was shown to be
961
Diet
962
Wluka et al.
Alcohol
Many studies with dierent study designs and in dierent populations have now shown a relationship between
alcohol consumption and gout (8591). For example, in
a population-based study in Denmark, 5249 males aged
between 40 and 59 were interviewed to identify a history
963
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
IV
SUMMARY
13.
14.
ACKNOWLEDGMENTS
We would like to thank Dr. Nisha Manek for her
helpful comments.
15.
REFERENCES
16.
1.
17.
964
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Wluka et al.
asessment of the knee joint in osteoarthritis. Br J Rheum
1992; 51:8082.
McAlindon TE, Snow S, Cooper C, Dieppe PA. Radiographic patterns of knee osteoarhtitis in the community: the importance of the patellofemoral joint. Ann
Rheum Dis 1993; 51:844849.
Leadingham J, Regan M, Jones A, Doherty M. Radiographic patterns and associations of osteoarthritis of
the knee in patients referred to hospital. Ann Rheum Dis
1993; 52:520526.
Cooper C, McAlindon T, Snow S, Vines K, Young P,
Kirwan J. Mechanical and constitutional risk factors for
symptomatic knee osteoarthritis: dierences between
medial tibiofemoral and patellofemoral disease. J
Rheumatol 1994; 21(2):307313.
Cicuttini FM, Spector T, Baker J. Risk factors for
osteoarthritis in the tibiofemoral and patellofemoral
joints of the knee. J Rheumatol 1997; 24(6):11641167.
Felson DT. Obesity and osteoarthritis of the knee. Bull
Rheum Dis 1992; 41(2):67.
Gelber AC, Hochberg MC, Mead LA, Wang NY,
Wigley FM, Klag MJ. Body mass index in young men
and the risk of subsequent knee and hip osteoarthritis.
Am J Med 1999; 107(6):542548.
Hart DJ, Doyle DV, Spector TD. Incidence and risk
factors for radiographic knee osteoarthritis in middleaged women: the Chingford Study. Arthritis Rheum
1999; 42(1):1724.
Hochberg MC, Lawrence RC, Everett DF, CornoniHuntley J. Epidemiologic associations of pain in osteoarthritis of the knee: data from the National Health and
Nutrition Examination Survey and the National Health
and Nutrion Examination-I Epidemiologic Follow-up
Survey. Semin Arthritis Rheum 1989; 18(4 suppl 2):49.
Acheson RM, Kelsey JL, Ginsburg GN. The New Haven
survey of joint diseases. XVI. Impairment, disability and
arthritis. Br J Prev Med 1974; 27:168176.
Van Saase JL, Van denbroucke JP, Van Romunde LK,
Valkenburg HA. Osteoarthritis and obesity in the general population. A relationship calling for an explanation. J Rheumatol 1988; 15(7):11521158.
Davis MA, Neuhaus JM, Ettinger WH, Mueller WH.
Body fat distribution and osteoarthritis. Am J Epidemiol
1990; 132(4):701707.
Bagge E, Bjelle A, Eden S, Svanborg A. Factors associated with radiographic osteoarthritis: results from the
population study 70-year-old people in Goteborg. J
Rheumatol 1991; 18:12181222.
Oliveria SA, Felson DT, Cirillo PA, Reed JI, Walker
AM. Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee.
Epidemiology 1999; 10(2):161166.
Sowers MF, Zobel D, Weissfeld L, Hawthorne VM,
Carman W. Progression of osteoarthritis of the hand and
metacarpal bone loss: a twenty-year followup of incident
cases. Arthritis Rheum 1991; 34:3642.
Hochberg MC, Lethbridge-Cejku M, Plato CC, Wigley
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
965
64. Gibson T, Waterworth R, Hateld P, Robinson G,
Bremner K. Hyperuricaemia, gout and kidney function
in New Zealand Maori men. Br J Rheum 1984; 23:276
282.
65. Tuomilehto J, Zimmet P, Wolf E, Taylor R, Ram P,
King H. Plasma uric acid level and its association with
diabetes mellitus and some biologic parameters in a biracial population of Fiji. Am J Epidemiol 1988; 127:321
336.
66. Nishizawa T, Akaoka I, Nishida Y, Kawaguchi Y,
Hayashi E. Some factors related to obesity in the Japanese sumo wrestler. Am J Clin Nutr 1976; 29:1167
1174.
67. Seidell JC, Bakx JC, De Boer E, Deurenberg P, Hautvast
JG. Fat distribution of overweight persons in relation to
morbidity and subjective health. Int J Obes 1985; 9:363
374.
68. Takahashi S, Yamamoto T, Tsutsumi Z, Moriwaki Y,
Yamakita J, Higashino K. Close correlation between
visceral fat accumulation and uric acid metabolism in
healthy men. Metabolism 1997; 46(10):11621165.
69. Roubeno R, Klag MJ, Mead LA, Liang KY, Seidler
AJ, Hochberg MCJ. Incidence and risk factors for gout
in white men. JAMA 1991; 266:30043007.
70. Must A, Jacques PF, Dallal GE, Bajema CJ, Dietz WH.
Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of
1922 to 1935. N Engl J Med 1992; 327:13501355.
71. Lin K-C, Lin H-Y, Chou P. The interaction between uric
acid level and other risk factors on the development of
gout among asymptomatic hyperuricemic men in a
prospective study. J Rheumatol 2000; 27:15011505.
72. Cigolini M, Targher G, Tonoli M, Manara F, Muggeo
M, De Sandre G. Hyperuricaemia: relationships to body
fat distribution and other components of the insulin
resistance syndrome in 38-year-old healthy men and
women. Int J Obes Relat Metab Disord 1995; 19:92
96.
73. Facchini F, Chen YD, Hollenbeck CB, Reaven GM.
Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric
acid concentration. JAMA 1995; 66:30083011.
74. Wannamethee SG, Shaper AG, Whincup PH. Serum
urate and the risk of major coronary heart disease events.
Heart 1997; 78:147153.
75. Culleton BF, Larson MG, Kannel WB, Levy D. Serum
uric acid and risk for cardiovascular disease and death:
the Framingham Heart Study. Ann Intern Med 1999;
131:713.
76. Emmerson BT. Alteration of uric acid metabolism by
weight reduction. Aust NZ J Med 1973; 3:410412.
77. Brauer GW, Prior IAM. A prospective study of gout
in New Zealand Maoris. Ann Rheum Dis 1978; 37:466
472.
78. Scott JT. Obesity and uricaemia. Clin Rheum Dis 1977;
3:2535.
79. Zollner NB. Consequences of malnutrition in prosper-
966
ous countries. Zentralbl Bakteriol Orig 1976; 163:111
117.
80. Maistruk PN, Priputina LS, Rudenko AK, Smoliar VI.
Nutrition and the state of health of the population of the
UkrSSR. Vopr Pitan 1976; 1:1317.
81. Chou P, Soong LN, Lin HY. Community-based epidemiological study on hyperuricemia in Pu-Li, Taiwan. J
Formos Med Assoc 1993; 92:597602.
82. Torralba TP, Bayani Sioson PS. The Filipino and gout.
Semin Arthritis Rheum 1975; 4:307320.
83. Brule D, Sarwar G, Savoie L. Changes in serum and
urinary uric acid levels in normal human subjects fed
purine-rich foods containing dierent amounts of adenine and hypoxanthine. J Am Coll Nutr 1992; 11:353
358.
84. Dessein PH, Shipton EA, Stanwix AE, Joe BI,
Ramokgadi I. Benecial eects of weight loss associated
with moderate calorie/carbohydrate restriction, and
increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a
pilot study. Ann Rheum Dis 2000; 59(7):539553.
85. Takahashi S, Yamamoto T, Moriwaki Y, Tsutsumi Z,
Higashino K. Impaired lipoprotein metabolism in patients with primary goutinuence of alcohol intake
and body weight. Br J Rheumatol 1994; 33:731734.
86. Lutalo SK, Mabonga N. A clinical assessment of the
consequences of alcohol consumption in communal
drinkers in the Zimbabwean Midlands. Cent Afr J Med
1992; 38:380384.
87. al Jarallah KF, Shehab DK, Buchanan WW. Rheumatic
complications of alcohol abuse. Semin Arthritis Rheum
1992; 22:162171.
88. Cook DG, Shaper AG, Thelle DS, Whitehead TP. Serum
Wluka et al.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
41
Obesity, Pregnancy, and Infertility
Stephan Rossner
Huddinge University Hospital, Huddinge, Sweden
II
Rossner
968
III
WEIGHT DEVELOPMENT
AND PREGNANCY
parity, multiple pregnancies, ethnic origin, various aspects of socioeconomic status, drug abuse, and physical
activity levels.
A
Mean body weight and the prevalence of obesity increase with pregnancy. Rookus et al. (18) reviewed the
older literature on this issue (16,1926) and concluded
that (1) the cohort sizes varied from 49 to 35,556 deliveries; (2) age correction was seldom carried out; (3)
prepregnancy weight was generally not well measured;
and (4) the timing of the postpartum weight measurement varied from 4 to 24 months.
In a later extensive review by Harris (27), the general
outcome of this literature was summarized as follows:
90% of all studies reviewed found a body weight greater
after pregnancy than before (by 0.2-10.6 kg). However,
only 3/71 studies in her review (18,28,29) complied with
the following quality criteria:
1. Accurate measurements of body weight from
conception and onwards must be obtained.
2. Sucient time for weight lost after delivery must
be allowed.
3. The parallel eect of ageing during pregnancy
and follow-up must be accounted for.
In this subgroup (18,28,29) the average cost of a
pregnancy was 0.9-3.3 kg. These dierences in weight
gain became slightly smaller (0.4-3.0 kg) after control
for several sociobehavioral confounders. Thus in the
literature it is generally rare that factors such as age,
height, education, parity, giving up work, smoking
habits, prepregnant weight and activity, alcohol consumption, marital status, morbidity, and dieting behavior obviously of importance in evaluating the role of
physical activity, are accounted for (27). This evaluation
is further complicated by the fact that changes of these
confounders may take place in dierent ways and during various phases of the entire pregnancy period.
Since body weight also increases with age in the fertile age groups, it has been necessary to analyze weight
increase, parity, and age separately. Such studies demonstrate that the weight increase associated with pregnancy is age independent. The relationship between
body weight development and parity can be illustrated
by Figure 1, derived from a Finnish study (30).
Body weight increases with age, whether women have
children or not. Figure 2, based on a representative
sample of the entire Swedish adult female population, is
a cross-sectional example of the increase in BMI with
age, more pronounced in women than in men. It should
969
Fetus
Placenta
Amniotic uid
Uterus
Mammary glands
Blood
Extracellular uid
Other tissues (mainly fat)
Total
Source: Ref. 31.
Weight (g)
Fluid
weight (g)
3300
650
800
900
400
1300
1200
3950
12,500
2340
540
790
740
300
1100
1200
1000
8010
Rossner
970
A marked weight increase occurs at the time of menopause. However, it is not clear whether this is related to
the loss of the regular menstruations or aging in itself
has these eects on body weight development. Weight
increase to the degree of overweight and even obesity at
the time of menopause may have important health
implications, since this is a part of the risk factor pattern
associated with atherosclerotic manifestations. It has
been demonstrated that with menopause there is an
increase in the atherogenic lipoprotein prole (33,34).
In an analysis of the Healthy Womens Study (35),
weight changes and the eect of weight change on
coronary heart disease risk factors were analyzed prospectively. Four hundred eighty ve women were
studied when they were premenopausal and aged 4250 years and then restudied 3 years later. During this
time period the average weight gain was 2.3 F 4.2 kg,
but there were no signicant dierences in weight gain
of women who remained premenopausal and those who
had a natural menopause. The weight gain observed was
signicantly associated with increases in conventional
risk factors for coronary heart disease. However, it was
not possible to predict who would gain weight based on
the variables at entry to the study.
During the perimenopausal transition there is not
only an increase in body weight but also a redistribution of adipose tissue with an increase in waist circumference and upper-body fat (36). This shift is also
related to the change in carbohydrate metabolism (35).
The data from the Healthy Womens Study underscore the fact that much more information is needed
concerning the eects of menopause on body weight
development. Of particular interest for the future development are studies that are longitudinal and include
various populations, since most previous work has
almost exclusively been done in whites. It is of interest
to note that a prospective study of Pima Indian women
at the time of menopause found no changes in body
weight with menopause and also no changes in lipoprotein levels (37).
C
certain weight level. Excessive weight gain during pregnancy is a clear risk for future development of obesity,
and high weight gain during pregnancy is furthermore a
risk factor associated with toxemia although it is likely
that the toxemia of pregnancy in this case is rather the
cause than the eect.
The body weight increase of the pregnant woman
constitutes the sum of several tissues (31). To determine
the true energy costs of a pregnancy, longitudinal
studies are essential, since interindividual variations
are marked. During recent years several such longitudinal studies have been published. In general they
describe a similar pattern: in developing countries the
energy costs of the pregnancy are low but increases in
countries in the Western world. In all studies, however,
the observed changes in energy intake over the entire
pregnancy seem insucient to meet the energy costs of
the total pregnancy. This has led several researchers to
speculate that substantial energy savings must occur
during pregnancy.
The weakening of the relationship between gestational weight gain and birth weight with increasing body
mass index of the woman suggests that in heavy women
the energy supplies are generally sucient, whereas in
undernourished women the development of the fetus is
more dependent on the state of the maternal nutrition.
Thus dierent recommendations for suggested weight
increase throughout a pregnancy may be appropriate in
thin women. Energy balance is less of a problem in
overweight women, and recommendations in this group
would be adjusted accordingly.
D
971
Rossner
972
IV
The mean weight increase 1 year after delivery compared to the reported weight at the time of conception
was 1.5 kg (Fig. 3). When we corrected for the estimated
underreporting of the weight at conception from our
parallel studies (0.8 kg plus the estimated mean weight
increase with time 0.2 kg), the net mean weight increase
induced by a pregnancy was calculated at 0.5 kg. However, the range was very wide: 1.5% of the women had
a mean weight retention of at least 10 kg, and 13%
had a weight retention between 5 and 10 kg. The majority (56%) had a weight retention of up to 5 kg. Thirty
percent of the women lost weight. The wide weight
change distribution one year after delivery is shown in
Figure 4.
Table 2 summarizes characteristics of weight development after delivery. The correlations of established
behaviors at baseline and changes in behavior with
weight change overall exhibited very low r values.
Women with >5 kg weight retention diered from the
other women in several respects. Whereas women with a
small net increase in weight lost a mean of 2.3 kg
between 2.5 and 12 months after delivery, women with
larger weight retention increased 0.4 kg during the same
time period. Those who retained more weight:
1.
2.
3.
4.
973
P<.05,
P<.01,
c
P<.001.
Source: Ref. 25.
b
974
Rossner
Figure 5 Dierent trend patterns in physical activity and eects on postpartum body weight development. (From Ref. 41.)
Figure 6 The Stockholm Pregnancy and Weight Development Study. Weight loss in kg from 2.5 to 12 months postpartum in groups with dierent lactation scores. Statistically
signicant dierences from score 09 and 1019 shown as
*P<.05 and **P<.01. (From Ref. 25.)
975
Rossner
976
Smoking aects body weight. Generally, smoking increases the basal metabolic rate by f10% (60), and
smokers are relatively lean (61,62). The weight development pattern in pregnancy is confounded by the fact
that many smoking women give up this habit when they
learn of their pregnancy.
Smoking mothers seem to gain f13% less per week
than nonsmokers (63). In this study from Australia,
reformed smokers, who decided to quit when they
learned of their pregnancy, had the highest weekly
weight gain of all groups. Our Stockholm data show
similar results, both with a high pregnancy weight gain
and also with higher weight retention than in those who
never smoked or who continued (25). However, these
results are not in agreement with all other studies. In the
large Ontario Perinatal Mortality Study of 31,788
women smoking habits were unrelated to maternal
weight gain distribution (64).
VII
IX
A moderate degree of overweight may aect the reproductive capacity signicantly. In a case control study
of body mass index and ovulatory infertility, 597 white
infertile women with ovulatory dysfunction were compared with 1695 primiparous control women (77). The
study demonstrated an increased risk for primary ovulatory infertility already in women with a body mass
index of 27 kg/m2 or greater. At BMI above 25 kg/m2,
the risk of ovulatory infertility had almost doubled.
Women admitted to an in vitro fertilization unit
provide a unique opportunity to study determinants of
fecundity while controlling for several other confounders related to conception. In a Dutch study the probability of conception after insemination was studied in
500 women (78). The main reasons for articial insemination were infertility or subfertility of the partner with
azoospermia or oligospermia, respectively. The youngest woman was 20 years old; only a few women were
above age 40. Two hundred sixty women reported regular smoking habits. As expected, the women were less
likely to conceive with higher ages (P<.05). The study
demonstrated that a 0.1-unit increase in waist-hip ratio
was associated with a 30% decrease in probability of
977
Physical activity is obviously an important determinator of weight development, even in pregnancy (82). A
retrospective analysis of the literature, mainly based on
an extended Medline search and the Pregnancy and
Rossner
978
XI
XII
WEIGHT DEVELOPMENT
IN PREGNANT ADOLESCENTS
Since maternal weight gain is an important and manageable determinant of infant birth weight among adolescents, some studies have addressed factors related to
weight gain in young women. Generally, the women
studied have been poor and with numerous psychosocial problems including drug abuse. Stevens-Simon 141
studied pregnant black teenager (87). The group was
divided into three dierent weight gain subgroups. Slow
weight gain was associated with a lower quality of food
intake. Teenagers who gained more weight during their
pregnancies were more compliant with prenatal visits,
but also reported more depressive symptoms and more
alcohol consumption. An important nding was the
substantial variability in the amount of weight gain,
ranging from 1.8 to 27.9 kg with a mean weight increase
of 14.3 F 6.0 kg (SD). This study suggests that proper
nutritional care in this group of young women may be
an eective method to promote optimal gestational
weight gain. In the analysis of the 99 pregnant young
women (88), most were poor but with an ethnic variability. The authors had anticipated that negative attitudes toward pregnancy weight gain would be more
common among these young women and that such
attitudes would adversely aect an optimal adolescent
maternal weight gain. These teenagers were studies by
means of a weight gain attitude scale as well as several
other determinants of nutritional status, dietary and
health habits, and social history. Surprisingly enough,
the authors demonstrated that these young women were
not more concerned about staying slim than older
pregnant adolescents and adults. Negative weight gain
attitudes were more commonly found among heavy and
depressed adolescents and those who did not have a
family support.
The examples of weight gainrelated factors in adolescents given above relate to the problems in the United
States. It is reasonable to believe that the situation will
be quite dierent in other cultures, where pregnancy
early in the life of a young woman might be considered a
normal life event or in societies where the attitude to
abortion in pregnant teenagers is dierent. For this
979
REFERENCES
1.
Rossner
980
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30. Heliovaara M, Aromaa A. Parity and obesity. J Epidemiol Community Health 1981; 35:197199.
31. Hytten FE, Leitch I. The Physiology of Human Pregnancy Oxford: Blackwell Scientic, 1971.
32. Ash S, Fischer CC, Truswell AS, Allen JR, Irwing L.
Maternal weight gain, smoking, and other factors in
pregnancy as predictors of infant birth-weight in Sydney women. Aust NZ J Obstet Gynaecol 1989; 29:212
219.
33. Hjortland MC, McNamara, Kannel WB. Some atherogenic concomitants of menopause: the Framingham
Study. Am J Epidemiol 1976; 103:304311.
34. Lindquist O, Bengtsson C. Serum lipids, arterial blood
pressure and body weight in relation to the menopause:
results from a population study of women in Goteborg,
Sweden. Scand J Clin Lab Invest 1980; 40:629636.
35. Wing RR, Matthews KA, Kuller LH, Meilahn EN,
Plantinga PL. Weight gain at the time of menopause.
Arch Intern Med 1991; 151:97102.
36. Kuller LH, Meilahn EN, Cauley JA, Gutai JP, Matthews
KA. Epidemiologic studies of menopause: changes in
risk factors and disease. Exp Gerontol 1994; 29:495509.
37. Hamman RF, Bennett PH, Miller M. The eect of menopause on serum cholesterol in American (Pima) Indian
women. Am J Epidemiol 1975; 102:164169.
38. Chevrier J, Dewailly E, Ayotte P, Mauriege P, Despres
JP, Trembley A. Body weight loss increases plasma and
adipose tissue concentrations of potentially toxic pollutants in obese individuals. Int J Obes Relat Disord 2000;
24:12721278.
39. Rebue-Scrive M, Enk L, Crona P, et al. Fat cell
metabolism in dierent regions in women. Eects of menstrual cycle, pregnancy and lactation. J Clin Invest 1985;
75:19731976.
40. Illingworth PJ, Jung RT, Howie PW, Isles TE. Reduction in postprandial energy expenditure during lactation.
BMJ 1987; 294:15731576.
41. Ohlin A, Rossner S. Trends in eating patterns, physical
activity and sociodemographic factors in relation to
postpartum body weight development. Br J Nutr 1994;
71:457470.
42. Prentice AM, Prentice A. Energy cost of lactation. Annu
Rev Nutr 1988; 8:6379.
43. Spaaij CJK, Van Raaij JMA, Van der Heijden LJM, et
al. No substantial reduction of the thermic eect of a
meal in pregnancy in well-nourished Dutch women. Br J
Nutr 1994; 71:335344.
44. Spaaij CJK, Van Raaij JMA, Van der Heijden LJM, de
Groot CPGM, Boekholt HA, Hautvast JGAJ. No
changes during pregnancy in the net cost of cycling
exercise. Eur J Clin Nutr 1994; 48:513521.
45. Spaaij CJK, Van Raaij JMA, de Groot CPGM, Van der
Heijden LJM, Boekholt HA, Hautvast JGAJ. Eect of
lactation of resting metabolic rate and on diet- and workinduced thermogenesis. Am J Clin Nutr 1994; 59:4247.
46. Forsum E, Sadurskis A. Estimation of body fat in
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
981
65. Gross T, Sokol RJ, King K. Obesity in pregnancy: risks
and outcome. Obstet Gynecol 1980; 56:446450.
66. Garbaciak JA Jr, Richter M, Miller S, Barton JJ.
Maternal weight and pregnancy complications. Am J
Obstet Gynecol 1985; 152:238245.
67. Johnson SR, Kolberg BH, Warner MW, Railsback LD.
Maternal obesity and pregnancy. Surg Gynecol Obstet
1987; 164:431437.
68. Mitchell MC, Lerner E. A comparison of pregnancy
outcome in overweight and normal weight women. J Am
Coll Nutr 1989; 8:617624.
69. Naeye RL. Maternal body weight and pregnancy
outcome. Am J Cin Nutr 1990; 52:273279.
70. Tilton Z, Hodgson MI, Donoso E, Arteaga A, Rosso P.
Complications and outcome of pregnancy in obese
women. Nutrition 1989; 5:9599.
71. Perlow JH, Morgan MA, Montgomery D, Towers CV,
Porto M. Perinatal outcome in pregnancy complicated
by massive obesity. Am J Obstet Gynecol 1992; 167:958
962.
72. Gross TL. Operative considerations in the obese
pregnant patient. Clin Perinatol 1983; 10:411421.
73. Reaven GM. Role of insulin resistance in human disease
[Banting Lecture 1988]. Diabetes 1988; 37:593607.
74. Kissebah AH, Vydelingum N, Murray R. Relation of
body fat distribution to metabolic complications of
obesity. J Clin Endocrinol Metab 1982; 54:254260.
75. Landon MB, Osei K, Platt M, OVDorisio T, Samuels P,
Gabbe SG. The dierential eects of body fat distribution on insulin and glucose metabolism during pregnancy. Am J Obstet Gynecol 1994; 171:875884.
76. Hartz AJ, Rupley DC, Rimm AA. The association of
girth measurements with disease in 32,856 women. Am J
Epidemiol 1984; 119:7180.
77. Grodstein F, Goldman MB, Cramer DW. Body mass
index and ovulatory infertility. Epidemiology 1994;
5:247250.
78. Zaadstra BM, Seidell JC, Van Noord PAH, et al. Fat and
femal fecundity: prospective study of eect of body fat
distribution on conception rates. BMJ 1993; 306:484
487.
79. Grenman S, Ronnema T, Irisia K, Kaihola HL, Gross
M. Sex steroid, gonadotrophin, cortisol and prolaction
levels in healthy, massively obese women: correlation
with abdominal fat cell size and eect of weight
reduction. J Clin Endocrinol Metab 1986; 63:1257.
80. Charles MA, Pettitt DJ, MCance DR, Hanson RL,
Bennett PH, Knowler WC. Gravidity, obesity and noninsulin-dependent diabetes among Pima Indian women.
Am J Med 1994; 97:250255.
81. Edman CD, MacDonald PC. Eect of obesity on
conversion of plasma androstenedione to estrone in
ovulatory and anovulatory young women. Am J Obstet
Gynecol 1978; 130:456461.
82. Bell R, OVNeill M. Exercise and pregnancy: a review.
Birth 1994; 21:8595.
Rossner
982
83.
84.
85.
86.
87.
88.
89.
90.
Rossner S. Physical activity and prevention and treatment of weight gain associated with pregnancy: current
evidence and research issues. Med Sci Sports Exerc 1999;
31:S560S563.
Clapp JF III, Little KD. Eect of recreational exercise on
pregnancy weight gain and subcutaneous fat deposition.
Med Sci Sports Exerc 1995; 27:170177.
Kahn HS, Williamson DF, Stevens JA. Race and weight
change in US women: the roles of socioeconomic and
marital status. Am J Public Health 1991; 81:319323.
Parker JD, Abrams B. Dierences in postpartum weight
retention between black and white mothers. Obstet
Gynecol 1993; 81:768774.
Stevens-Simon C, McAnarney ER. Determinants of
weight gain in pregnant adolescents. J Am Diet Assoc
1992; 92:13481351.
Stevens-Simon C, Nakashima I, Andrews D. Weight
gain attitudes among pregnant adolescents. J Adolesc
Health 1993; 14:369372.
Pederson AL, Worthington-Roberts B, Hickok DE.
Weight gain patterns during twin gestation. J Am Diet
Assoc 1989; 89:642646.
Leermakers EA, Anglin K, Wing RR. Reducing post-
91.
92.
93.
94.
95.
96.
42
Physical Activity, Obesity, and Health Outcomes
William J. Wilkinson and Steven N. Blair
The Cooper Institute, Dallas, Texas, U.S.A.
INTRODUCTION
984
part of a comprehensive weight loss program is consistent with the above summary statement and is based on
an evidence-based review of the scientic literature (1).
The purpose of this chapter is to review the current
scientic evidence on the interrelationships among
physical activity, obesity, and health outcomes. We will
give particular attention to recent evidence-based consensus statements on physical activity and obesity. We
also will review prospective observational studies from
the Aerobics Center Longitudinal Study cohort and
other investigations that stratify health outcomes based
on both markers of body habitus and measures of
cardiorespiratory tness or physical activity. We will
review evidence from randomized controlled trials
(RCT) on the inuence of exercise intervention on
obesity-related disease risk factors and conclude the
chapter with recommendations in the areas of research,
public health, and clinical practice.
II
III
A large body of scientic evidence and consensus opinion conrms that low levels of physical activity and
cardiorespiratory tness are associated with high rates
of all-cause and cause-specic mortality across diverse
population groups (8,1618,31,32). Regular physical
activity and moderate to high levels of cardiorespiratory
tness are associated with more favorable disease risk
proles and lower all-cause and CVD mortality (8,16,
3335). The inverse association between physical activity or cardiorespiratory tness and premature mortality
is independent of changes in disease risk factors and
other potentially confounding variables (36,37).
Based on a review of 42 prospective cohort studies,
Lee and Skerrett concluded that there is clear evidence
of an inverse dose-response relation between volume of
physical activity (or level of physical tness) and allcause mortality rates (34). These studies suggest that
physical activity resulting in an energy expenditure of
f1000 kcal/wk is associated with a signicant 2030%
reduction in risk of all-cause mortality (33,34). Evidence-based review also supports an inverse doseresponse relation between physical activity and incidence and mortality rates from cardiovascular and
coronary heart disease (CHD) (33,35). Available data
indicate a benecial eect of physical activity on incidence of colon cancer; however, the evidence is less
conclusive for a reduction in risk for other types of
cancer, such as cancers of the breast and prostate
(33,38).
Physical activity and higher levels of cardiorespiratory tness are associated with lower risk for type 2
diabetes, hypertension, weight gain, and functional limitations that often occur with aging (33,3942). Activity
and tness are also associated with improvements in the
plasma lipid prole and favorable alterations in coagu-
985
IV
986
Figure 1 Adjusted relative risk estimates and 95% CI for all-cause mortality for losing weight, lowering blood pressure,
reducing cholesterol, stopping smoking, and improving tness in men at risk for each of these risk factors at the rst of two
preventive medical examinations. Cuto points for at-risk categories are in parentheses below each risk factor. Analyses were
adjusted for age, family history of coronary heart disease, health status, baseline values, changes for all variables in the gure,
and interval in years between examinations. (Adapted from Ref. 46.)
987
Source of
evidence
Randomized controlled
trials (rich body of data)
Randomized controlled
trials (limited body of data)
Nonrandomized trials
Observational studies
Panel consensus judgment
Denition
Evidence is from endpoints of well-designed RCTs
(or trials that depart only minimally from
randomization) that provide a consistent pattern
of ndings in the population for which the
recommendation is made. Category A therefore
requires substantial numbers of studies involving
substantial numbers of participants.
Evidence is from endpoints of intervention studies
that include only a limited number of RCTs,
post-hoc, or subgroup analysis of RCTs, or
meta-analysis of RCTs. In general, category
B pertains when few randomized trials exist,
they are small in size, and the trial results are
somewhat inconsistent, or the trials were
undertaken in a population that diers from the
target population of the recommendation.
Evidence is from outcomes of uncontrolled or
nonrandomized trials or from observational studies.
None of the evidence statements on tness and health
outcomes were placed in this category.
Source: Ref. 1.
Cardiorespiratory Fitness
The NIH report includes an evidence statement conrming the ability of physical activity to increase cardiorespiratory tness in overweight and obese individuals
independent of weight loss (1). Based on a review of 11
RCTs meeting acceptance criteria, the NIH panel
placed the evidence in category A. All 11 studies showed
that physical activity increased maximal oxygen uptake
in men and women in the exercise groups by an average
of 1418%. Even in studies with modest weight loss
(<2%), physical activity increased tness by an average
of 1216%.
In a more recent RCT, Ross et al. (49) reported on the
eects of diet- or exercise-induced weight loss or exercise
988
Table 2 Evidence Statements for the Inuence of Physical Activity and Cardiorespiratory Fitness on Obesity-Related Health
Outcomes
NIH evidence
statements
Evidence
category
ACSM consensus
statements
Evidence
category
1. Cardiorespiratory tness
Physical activity in overweight
and obese adults increases
cardiorespiratory tness
independent of weight loss.
2. Morbidity and mortality
C
C
3. Cardiovascular disease
Physical activity independently
reduces CVD risk factors.
Physical activity independently
reduces risk for cardiovascular
disease.
4. Insulin resistance and glucose tolerance
RCTs provide strong evidence that physical activity can reduce blood
pressure in obese subjects and that the reduction is independent of
weight loss or changes in body composition. The response does not go
beyond the blood pressure reduction obtained by diet alone.
Observational studies support the concept that physical activity reduces
the risk for developing hypertension, independent of its eects on body
size or body composition.
Physical activity of a volume that results in at least 4.5 kg weight loss will
raise HDL-cholesterol and lower triglycerides in men and postmenopausal women.
The addition of physical activity to a low-energy, low-fat diet will reverse
the HDL-lowering eect of the low-fat diet in overweight men
and women.
In men and postmenopausal women with atherogenic dyslipidemia, the
addition of physical activity to a modestly reducing, low-fat diet
signicantly enhances the LDL-lowering eect of the diet.
7. Cancer
Evidence not reviewed.
989
All-Cause Mortality
Figure 2 The association between BMI and the prevalence of low cardiorespiratory tness (dark area of the gure) in 6840
women (panel A) and 23,190 men (panel B) from the Aerobics Center Longitudinal Study cohort who were free of CHD, cancer,
and abnormal ECG. The number of individuals across the BMI strata of 18.524.9, 25.029.9, 30.034.9, 35.039.9, and z40
were 5499, 959, 262, 83, and 37 for women, and 9838, 10,544, 2308, 361, and 139 for men.
990
Figure 3 Relative risks for all-cause (panel A) and cardiovascular disease (CVD) (panel B) mortality by BMI and other CVD risk
factors in 25,714 men followed for 258,781 man-years of observation (1025 deaths, 439 from CVD). Relative risks were adjusted
for age and examination year. The referent group in each of the ve analyses was normal-weight men (BMI 18.524.9) who did not
have the CVD risk factor examined in the specic analysis. Overweight men were those with a BMI of 25.029.9, and obese men
were those with BMI z30.0. (Adapted from Ref. 53.)
weight men who were unt. The highest death rate was
observed in the unt obese men (62.1/10,000 man-years
of observation).
Extending the observations of Barlow and colleagues, Lee et al. (56) performed a more detailed
analysis on the relation of cardiorespiratory tness to
mortality in overweight men in 21,856 men from the
ACLS cohort. In this study, men with previous myocardial infarction, stroke, and cancer at baseline were
excluded, and the analyses were adjusted for smoking
habit and alcohol intake. The men were stratied by
BMI and cardiorespiratory tness. Normal-weight men
were classied as a BMI from 19.0 to <25, mild-overweight from 25.0 to <27.8, and overweight z27.8 kg/
m2. The investigators used two categories for cardiorespiratory tness: (1) unt (bottom 20th centile based
on age and treadmill time) and (2) t (the remaining
80%). Fit normal-weight men were used as the reference group in the analysis. Unt men had a higher risk
of all-cause mortality than their t counterparts in all
three BMI categories. In this study, men who were unt
and overweight had the highest risk for all-cause
mortality at follow-up. However, t and overweight
991
Figure 4 Body mass index and relative risks of all-cause (panel A) and cardiovascular disease (CVD) (panel B) mortality by
cardiorespiratory tness level in 21,856 men from the Aerobics Center Longitudinal Study cohort followed for 176,189 years of
observation (427 deaths: 144 CVD, 143 cancer, 140 other). Adjusted for age, examination year, smoking habit, and alcohol
intake. Unt men (black bars) were the least t 20% in each age group, and all other men were classied as t. (Adapted from
Ref. 56.)
992
Figure 5 Relative risks for all-cause (panel A) and cardiovascular disease (CVD) (panel B) mortality by percent body fat and
cardiorespiratory tness level in 21,925 men followed for 176,742 man-years of observation (428 deaths: 144 CVD, 143 cancer,
141 other). Relative risks are adjusted for age, examination year, smoking status, alcohol intake, and parental history of coronary
heart disease. Unt men (black bars) were the least t 20% in each age group, and all other men were classied as t. (Adapted
from Ref. 57.)
ceived physical tness with the risk of all-cause mortality (59). The study population was 2212 middle-aged
and elderly Finnish men and women followed for 16
years. In this study, low levels of leisure-time physical
activity (LTPA) seemed to predict and low perceived
physical tness predicted an increased risk of all-cause
mortality among both men and women. However, in
contrast to the hypothesis, obesity was not an independent predictor of mortality in this population, and
no interaction eect was found between BMI and
LTPA or perceived tness and the relative risk of death.
The authors concluded that the benecial eects of
LTPA and tness are similar among obese and nonobese men and women.
2
Cardiovascular disease
993
Both obesity and physical inactivity are major independent predictors for CHD (1,8,25). In the United
States, CHD is responsible for >450,000 deaths each
year and is the single leading killer of men and women
(60). Neither of the evidence reports makes a specic
statement on CHD; however, the review by Blair and
Brodney (54) provides a summary of seven prospective
observational studies that included the exposure variables of body habitus and physical activity as predictors
of fatal and nonfatal CHD. In general, these studies
demonstrate a protective eect of physical activity
against CHD in men regardless of BMI. In a study from
Salonen et al. (62), overweight men (BMI z27 kg/m2)
who were active at work and in their leisure time had a
CHD death rate of 7.4/1000 men compared with a rate
of 25.9/1000 in sedentary men with a BMI <27 kg/m2.
Morris et al. (63) reported a heart attack rate of 7.3/1000
man-years in sedentary overweight (BMI z27 kg/m2)
men and only 1.3/1000 man-years in the most active
men in the same BMI category. The rate in sedentary
normal-weight (BMI <24 kg/m2) men was 5.5/1000
man-years and 1.9/1000 man-years in regular vigorous
exercisers. The lower rate of CHD events in these two
studies suggests that physically active overweight men
may have lower CHD mortality compared with normalweight but inactive men.
Unfortunately, none of the studies reviewed by Blair
and Brodney (54) were designed to specically investigate the inuence of physical activity on CHD in
overweight and obese individuals. Typically, the highest
BMI stratum in these studies had a lower bound in the
mild-overweight category, so we cannot be certain that
the results apply to obese individuals. Only one study
included data for women. There are no studies examining CHD as the outcome variable and BMI and cardiorespiratory tness as exposure variables.
Two more recent studies evaluated the relation of
physical activity to CHD mortality in both men and
women. In the study by Dorn et al. (58), physical activity
was only associated with a decreased risk of CHD
mortality in nonobese men. In the study by Haapanen-Niemi and colleagues (59), BMI was not associated
with increased risk of CHD mortality in men or women;
therefore, no interaction eect was found between physical activity or perceived tness and BMI for CHD
994
Cancer
Comorbidities
995
996
were not dierent among the three treatments. In summary, while clinical trial data provide evidence that
physical activity independently improves insulin action
and glucose tolerance independent of weight loss, the
combination of exercise plus dietary intervention to
induce weight loss appears to produce more favorable
changes in glucose homeostasis.
A recent study from the ACLS cohort suggests that
physical activity and cardiorespiratory tness may provide protection against premature mortality in men with
type 2 diabetes. In this study, Wei et al. (84) reported on
1263 men with type 2 diabetes followed prospectively
for all-cause mortality. During an average follow-up of
12 years there were 180 deaths. After adjusting for
multiple inuencing factors, men in the low-tness
group (bottom 20th centile based on age and treadmill
time) had a risk for all-cause mortality of 2.1 (95% CI,
1.52.9) compared with t men (remaining 80%). Men
who reported being physically inactive at baseline had
an adjusted risk for mortality of 1.7 (95% CI, 1.22.3)
compared with physically active men. In this study,
tness had the same protective eect in normal-weight
(BMI <25 kg/m2) and overweight men (BMI z25 kg/
m2). Hu et al. (85) reported on the inuence of physical
activity on CVD in 5125 female nurses with type 2
diabetes over 14 years of follow-up. In this study,
greater leisure-time physical activity was associated
with a reduced risk of CHD and stroke, and the inverse
association persisted in a subgroup analysis stratied by
BMI. The results of these two studies suggest that
physical activity and cardiorespiratory tness have
strong and independent eects on morbidity and mortality in individuals with type 2 diabetes and that the
protective eect extends to both normal weight and
overweight individuals.
2
997
998
RECOMMENDATIONS
Research
Public Health
Clinical Practice
999
1000
2.
3.
4.
VI
CONCLUSIONS
ACKNOWLEDGMENTS
We thank Melba Morrow and Ginny Shead for editorial
review and assistance with manuscript preparation. We
thank Dr. Kenneth H. Cooper and the sta of the
Cooper Aerobics Center for making this work possible.
The work reported here is supported in part by National
Institutes of Health grants AG06945 and HL48597.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
REFERENCES
1.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
1001
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
1002
48. American College of Sports Medicine. American College of Sports Medicine roundtable: physical activity in
the prevention and treatment of obesity and its comorbidities. Med Sci Sports Exerc 1999; 31(11)(suppl):
S497S667.
49. Ross R, Dagnone D, Jones PJH, et al. Reduction in
obesity and related comorbid conditions after dietinduced weight loss or exercise-induced weight loss in
men: a randomized, controlled trial. Ann Intern Med
2000; 133:92103.
50. American College of Sports Medicine. The recommended quantity and quality of exercise for developing
and maintaining cardiorespiratory and muscular tness in healthy adults. Med Sci Sports Exerc 1998; 30:
975991.
51. Cooper KH, Pollock ML, Martin RP, et al. Physical
tness levels vs selected coronary risk factors: a crosssectional study. JAMA 1976; 236:166169.
52. Gibbons LW, Blair SN, Cooper KH, et al. Association
between CHD risk factors and physical tness in
healthy adult women. Circulation 1983; 67:977983.
53. Wei M, Kampert JB, Barlow CE, et al. Relationship
between low cardiorespiratory tness and mortality in
normal-weight, overweight, and obese men. JAMA
1999; 282:15471553.
54. Blair SN, Brodney S. Eects of physical inactivity and
obesity on morbidity and mortality: current evidence
and research issues. Med Sci Sports Exerc 1999;
31:S646S662.
55. Barlow CE, Kohl HW III, Gibbons LW, et al. Physical
tness, mortality and obesity. Int J Obes Relat Metab
Disord 1995; 19:S41S44.
56. Lee CD, Jackson AS, Blair SN. US weight guidelines: Is
it also important to consider cardiorespiratory tness?
Int J Obes Relat Metab Disord 1998; 22:S2S7.
57. Lee CD, Blair SN, Jackson AS. Cardiorespiratory tness, body composition, and all-cause and cardiovascular disease mortality in men. Am J Clin Nutr 1999;
69:373380.
58. Dorn JP, Cerny FJ, Epstein LH, et al. Work and leisure
time physical activity and mortality in men and women
form a general population sample. Ann Epidemiol
1999; 9:366373.
59. Haapanen-Niemi N, Miilunpalo S, Pasanen M, et al.
Body mass index, physical inactivity and low level of
physical tness as determinants of all-cause and cardiovascular disease mortality16y follow-up of middleaged and elderly men and women. Int J Obes 2000;
24:14651474.
60. American Heart Association. 2001 Heart and Stroke
Statistical Update. Dallas: American Heart Association, 2000.
61. Sesso HD, Paenbarger RS, Ha T, et al. Physical
activity and cardiovascular disease risk in middle-aged
and older women. Am J Epidemiol 1999; 150: 408416.
62. Salonen JT, Slater JS, Tuomilehto J, et al. Leisure time
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
1003
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
1004
108.
109.
43
Obesity and Quality of Life
Donald A. Williamson
Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, U.S.A.
Patrick M. ONeil
Medical University of South Carolina, Charleston, South Carolina, U.S.A.
1006
Psychological Functioning
1007
Figure 1 Hypothetical positive events foregone to reach weight goal. aTreatment-seeking obese participants dier from nontreatment-seeking obese participants. bNon-treatment-seeking obese participants dier from nonobese participants ( P < .01).
(From Ref. 15.)
1008
Figure 2 Hypothetical negative events to be incurred to reach weight goal. aTreatment-seeking obese participants dier from
nontreatment-seeking obese participants ( P < .01). (From Ref. 14.)
1009
It is noteworthy that Bruch challenged only the accuracy of the popular stereotypes, not the underlying assumption that there was a common set of personality
characteristics that captured the behavioral and psychological functioning of obese adults or children. Personality traits represent psychological and/or behavioral dimensions which vary broadly across members of
the normal population, but on which a particular person is generally consistent across time and situations.
For example, extraversion/introversion, rigidity/exibility, masculinity/femininity, dominance/submission,
and obsessive-compulsive tendencies may all be considered personality traits. There is little consistent evidence that obese people dier from the nonobese on
such general dispositional traits, and little evidence that
there are signicant personality characteristics that are
unique to obese persons (47,48).
In contrast to personality traits, personality type can
be thought of as the relative conguration of various
individual traits. In order to demonstrate that there is
an obese personality, there should be evidence that
the obese population has personality types that are generally homogeneous within that group and generally
dierent from those types seen in the nonobese population. Neither type of evidence has been reported. One
cluster analysis of Minnesota Multiphasic Personality
Inventory proles of 170 women applying for obesity
surgery found that there were ve derived cluster proles that were similar to those found in other populations. Further, these ve nonunique prototypes described barely more than half the subjects (49). It is
unlikely that the broader and much more diverse population of obese persons is any more homogeneous or
dierent from nonobese people than was this group
of surgery applicants. Given the sheer numbers of the
obese population, it is improbable that so many individuals could be described by a very small number of
personality types.
C
1010
obese, there are some people who experience signicant psychological and behavioral disturbances (32) or
may live in poverty, and these people may be at risk for
chronic obesity and may be less likely to lose weight
in structured weight loss trials (58,79). This perspective
suggests that there may be certain risk or protective factors for adverse psychological correlates of obesity. The
following sections describe some of these factors.
B
Gender
Ethnicity
Minority adults (especially women) tend to be less concerned about overweight status and are less motivated
to lose body weight than white adults (7982). As noted
earlier, African-American men and women have lower
levels of body size dissatisfaction (56). Therefore, minorities may be at lower risk for developing mood or
self-esteem problems associated with obesity, yet may
also be less motivated to lose weight.
1011
Severity of Obesity
In general, higher levels of obesity are negatively correlated with quality of life. For example, morbidly obese
adults who seek obesity surgery report extremely negative reactions to their obesity. Furthermore, a national
survey (90) found that obese women with a BMI z 36
were more likely to report histories of rape, sexual
molestation, or posttraumatic stress disorder than less
overweight women. These data suggest that a history of
trauma and/or binge eating may be associated with
morbid obesity, signicant mood disturbances, and a
very low quality of life, but these cross-sectional studies
do not inform us about the causes of lower quality of life
that is correlated with obesity.
III
D Binge Eating
Research has consistently found that obese binge eaters
experience more psychological disturbances than obese
people who do not frequently engage in binge eating
(18,83,84). There has been considerable controversy
about the distinction between a psychiatric syndrome
called Binge Eating Disorder (BED) and binge eating as
a behavioral correlate of obesity (85). Recent research
studies that have used very strict denitions and have
used structured interview methods for assessing BED
have found that the syndrome as dened by the American Psychiatric Association (16) is actually quite rare
(13%) even in obese people seeking treatment (86).
However, binge eating as a symptom of obesity is much
more common; signicant binge eating is observed in
715% of obese adults (85). Men are slightly less likely
to report binge eating than women, and most ethnic
groups report comparable rates of binge eating. Binge
eating and BED are associated with higher rates of depression (85). A recent study reported by Womble et al.
(87) found that binge eating was highly correlated with
obesity and that the combined inuences of negative
1012
Mood
1013
Figure 3 Relationships between weight change and changes in SF-36 subscale scores over a 4-year period in women younger
than 65 years. (From Ref. 96.) Asterisk indicates P<.01; dagger, P<.05; double dagger, P<.001; and 5F-36, Medical Outcomes
Study Short-Form 36 Health Status Survey. A decrease in the bodily pain score indicates a decrease in functioning due to bodily
pain.
sion (102). Nonoverweight volunteers undergoing a 3week low-calorie diet (103) had indications of reduced
availability of tryptophan for serotonin synthesis (lowered total plasma tryptophan, lowered ratiol of tryptophan to competing amino acids). Whether this applies
to overweight dieters remains to be seen.
Given the temporary nature of most weight losses,
the possible impact of weight regain on mood deserves
consideration. It has been asserted (68) that weight cycling may be associated with adverse psychological outcomes. However, there is little evidence in support of
this position. Several cross-sectional comparisons of cyclers and noncyclers among clinical samples have failed
to reveal consistent dierences in psychological functioning (78). Foster et al. (104) used a prospective design
to assess mood and eating-related variables among a
1014
direction) on well-being or depression, but 1-year gainers and losers both reported having experienced more
life change events than did 1-year maintainers. Subjects
who denied historical patterns of losing and regaining
reported greater well-being and control of eating compared to those who described their weight as typically
uctuating.
A related issue is whether weight gain per se, rather
than weight gain following a weight loss, may have psychological eects. Analysis of psychological well-being
scores for a subset of women in an NHANES I followup sample showed that those who had gained weight
recently (at least 4.5 kg in the previous 6 months) had
lower well-being scores than women who had maintained stable weights (106). This nding was seen in
nonoverweight, overweight, and obese women. This
study did not distinguish intentional from unintentional
weight changes, or gain from regain; however, in this
nationally representative sample there is no reason to
believe that regain of previously intentionally lost
weight accounted for more than a small minority of
the cases of weight gain.
C
Hunger
nding suggests that long-term maintenance of substantially lowered body weight is not accomplished at the
cost of chronic hunger.
D
Body Image
As noted earlier, dissatisfaction with body size is a common problem associated with obesity, and body size
dissatisfaction generally worsens with increased adiposity (56). The association of body size dissatisfaction and
BMI has been observed in men and women, but it is less
pronounced in African-Americans than in whites (56).
Based on these ndings, one would hypothesize that
weight loss would be associated with improvement of
body image. In general, this hypothesis has been supported for persons who lose weight through lifestyle
behavior modication and obesity surgery (2,14,19,38,
111). However, many other factors are also associated
with improved body image that accompanies weight
loss. An important variable is the persons weight loss
goals. Foster et al. (112) found that most participants in
weight loss trials do not achieve weight losses that meet
even minimally acceptable weight goals. These ndings
suggest that improvement of body image may not be a
direct product of weight loss, but instead may be caused
by a complex interaction of changes in body weight,
ideal body size goals, and personality characteristics
related to the importance of thinness and physical
appearance for self-esteem.
IV
A
or her functioning in eight areas: Health, Social/Interpersonal, Work, Mobility, Self-Esteem, Sexual Life,
Activities of Daily Living, and Comfort with Food
(2,4). Recently, a shorter (31-item) version has been
developed (114).
The 36-item Medical Outcomes Study Short Form
(SF-36) (113) is a very widely used self-report index
of health status and medical outcomes as related to a
variety of medical conditions and treatments. It produces scores on eight scales measuring physical and
emotional functioning and general health perceptions.
As previously described, both the Impact of Weight
on Quality of Life Scale and the SF-36 have shown the
ability to detect dierences associated with dierences
in body weight. Further, these measures have been
found to be sensitive to changes in body weight and
can be used as indices for benets of weight loss upon
health and well-being.
There are a number of brief surveys and questionnaires that have been developed as measures of quality
of life (115). Most of these questionnaires assess very
general happiness with life (116) and/or family relationships (117). These measures have not received widespread use, in comparison to the SF-36 and Impact of
Weight on Quality of Life.
C
1015
1016
1017
objectively large amounts of food (134). Also as mentioned, the IDED-IV (135) structured interview has
been validated as an objective method for dening
binge-eating disorder (86).
REFERENCES
Body Image
Until recently, questionnaires have been most frequently used in studies of body image, body dissatisfaction, and obesity. Two of the more frequently used
questionnaires are the body dissatisfaction scale of the
EDI-2 (138) and the Body Shape Questionnaire (150).
Recently, two nonquestionnaire measures of body
image associated with obesity have been developed.
Williamson et al. (56) validated the Body Image Assessment for Obesity (BIA-O). The BIA-O measures estimates of current, ideal, and reasonable body size, using
pictures of body silhouettes that vary in terms of body
size and shape (from very thin to very obese). The discrepancy between current and ideal body size estimates
was validated as a measure of body size dissatisfaction.
The BIA-O has been validated for use with Caucasian men and women and African-American men and
women. Stewart et al. (65) validated a computerized
body image assessment procedure called the Body
Morph Assessment (BMA). The BMA also measures
estimates of current, ideal, and reasonable body size and
these estimates were validated against the BIA-O. Thus
far, the BMA has only been studied with Caucasian
women, which limits its use with a diverse population.
1.
2.
3.
4.
5.
6.
7.
8.
CONCLUSIONS
9.
10.
11.
12.
13.
Testa MA, Simonson DC. Assessment of quality-oflife outcomes. N Engl J Med 1996; 334:835840.
Kolotkin RL, Head S, Hamilton M, Tse C-KJ. Assessing impact of weight on quality of life. Obes Res 1995;
3:4956.
Ware JE Jr, Gandek B. Overview of the SF-36 Health
Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 1998; 51:903
912.
Kolotkin RL, Head S, Brookhart A. Construct validity
of the Impact of Weight on Quality of Life Questionnaire. Obes Res 1997; 5:434441.
Fontaine KR, Cheskin LJ, Barofsky I. Health-related
quality of life in obese persons seeking treatment. J
Fam Pract 1996; 43:265270.
Fontaine KR, Barlett SJ, Barofsky I. Health-related
quality of life among obese persons seeking and not
currently seeking treatment. Int J Eating Disord 2000;
27:101105.
Fontaine KR, Barofsky I, Cheskin LJ. Predictors of
quality of life for obese persons. J Nerv Ment Dis 1997;
185:120122.
Sullivan M, Karlsson J, Sjostrom L, Backman L,
Bengtsson C, Bouchard C, Dahlgren S, Jonsson E,
Larsson B, Lindstedt S, Naslund I, Olbe L, Wedel H.
Swedish Obese Subjects (SOS)an intervention study
of obesity. Baseline evaluation of health and psychosocial functioning in the rst 1743 subjects examined.
Int J Obes 1993; 17:503512.
Doll HA, Petersen SE, Stewart-Brown SL. Obesity and
physical and emotional well-being: associations between body mass index, chronic illness, and the physical
and mental components of the SF-36 questionnaire.
Obes Res 2000; 8(2):160170.
Brown WJ, Mishra G, Kenardy J, Dobson A. Relationships between body mass index and well-being in young
Australian women. Int J Obes Relat Metab Disord
2000; 24:13601368.
Gortmaker SL, Must A, Perrin JM, Sobol AM, Dietz
WH. Social and economic consequences of overweight
in adolescence and young adulthood. N Engl J Med
1993; 329:10081012.
Sargent JD, Blanchower DG. Obesity and stature in
adolescence and earnings in young adulthood. Analysis of a British birth cohort. Arch Pediatr Adolesc
Med 1994; 148:681687.
Garn SM, Sullivan TV, Hawthorne VM. Educational
level, fatness, and fatness dierences between husbands
and wives. Am J Clin Nutr 1989; 50:740745.
1018
14. Rand CSW, MacGregor AMC. Successful weight loss
following obesity surgery and the perceived liability of
morbid obesity. Int J Obes 1991; 15:577579.
15. ONeil PM, Smith CF, Foster GD, Anderson DA. The
perceived relative worth of reaching and maintaining
goal weight. Int J Obes Relat Metab Disord 2000;
24:10691076.
16. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington: American Psychiatric Association, 1994.
17. Fitzgibbon ML, Stolley MR, Kirschenbaum DS. Obese
people who seek treatment have dierent characteristics than those who do not seek treatment. Health
Psychol 1993; 12:342345.
18. ONeil PM, Jarrell MP. Psychological aspects of obesity and dieting. In: Wadden TA, Van Itallie TB, eds.
Treatment of the Seriously Obese Patient. New York:
Guilford Press, 1992:342.
19. Stunkard AJ, Wadden TA. Psychological aspects of
severe obesity. Am J Clin Nutr 1992; 55:524S532S.
20. Wadden TA, Stunkard JJ. Social and psychological
consequences of obesity. Ann Intern Med 1985; 103:
10621067.
21. Berman WH, Berman ER, Heymsfeld S, Fauci M,
Acherman S. The eect of psychiatric disorders on
weight loss in obesity clinic patients. Behav Med 1993;
18:162167.
22. Goldsmith SJ, Anger-Friedfeld K, Beren S, Rudolph
D, Boeck M, Aronne L. Psychiatric illness in patients
presenting for obesity treatment. Int J Eating Disord
1992; 12:6371.
23. Halmi KA, Long M, Stunkard AJ, Mason E. Psychiatric diagnosis of morbidly obese gastric bypass patients. Am J Psychiatry 1980; 137:470472.
24. Robins LN, Helzer JE, Weissman MM, Orvaschel H,
Gurenberg E, Burke JD, Regier DA. Lifetime prevalence of specic psychiatric disorders in three sites.
Arch Gen Psychiatry 1984; 41:949958.
25. Prather RC, Williamson DA. Psychopathology associated with bulimia, binge eating, and obesity. Int J
Eating Disord 1988; 7:177184.
26. Britz B, Siegfried W, Ziegler A, Lamertz C, HerpertzDahlmann BM, Remschmidt H, Wittchen HU, Hebebrand J. Rates of psychiatric disorders in a clinical study
group of adolescents with extreme obesity and in obese
adolescents ascertained via a population based study.
Int J Obes Relat Metab Disord 2000; 24:17071714.
27. Palinkas LA, Wingard DL, Barrett-Connor E. Depressive symptoms in overweight and obese older adults: a
test of the jolly fat hypothesis. J Psychosom Res
1996; 40:5966.
28. Poston WSC, Goodrick GK, Foreyt JP. The Rosenberg Self-Esteem Scale. In: St. Jeor ST, ed. Obesity Assessment: Tools, Methods, Interpretations. New York:
Chapman & Hall, 1997:59.
29. French SA, Story M, Perry CL. Self-esteem and obesity
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
1019
Eating disorder symptoms and concerns about body
dier as a function of gender and sexual orientation.
J Social Clin Psychol 2000; 19:240255.
60. Collins JK. Methodology for the objective measurement of body image. Int J Eating Disord 1987; 6:393
399.
61. Colins JK, Beaumont PJV, Touyz SW, Krass J,
Thompson P, Philips T. Variability in body shape perception in anorexic, bulimic, obese, and control subjects. Int J Eating Disord 1987; 6:633638.
62. Counts CR, Adams HE. Body image in bulimic, dieting, and normal females. J Psychopathol Behav Assess
1985; 72897300.
63. Davis CJ, Williamson DA, Goreczny AJ, Bennett SM.
Body image disturbances and bulimia nervosa: an empirical analysis of recent revisions of DSM-III. J Psychopathol Behav Assess 1989; 11:6169.
64. Williamson DA, Prather RC, McKenzie SJ, Blouin
DC. Behavioral assessment procedures can dierentiate bulimia nervosa, compulsive overeater, obese, and
normal subjects. Behav Assess 1990; 12:239252.
65. Stewart TM, Williamson DA, Smeets MAM, Greenway FL. The Body Morph Assessment: development of
a computerized measure of body image. Obes Res 2001;
9:4350.
66. Polivy J, Herman CP. Dieting and bingeing: a causal
analysis. Am Psychol 1985; 40:193201.
67. Brownell KD, Greenwood MRC, Stellar E, Shrager
EE. The eects of repeated cycles of weight loss and
regain in rats. Physiol Behav 1986; 38:459464.
68. Brownell KD, Rodin J. Medical, metabolic and psychological eects on weight cycling. Arch Intern Med
1994; 154:13251330.
69. Yanovski SZ, Atkinson RL, Dietz WH, et al. National
Task Force on the Prevention and Treatment of Obesity. Weight cycling. JAMA 1994; 272:11961202.
70. Herman PC, Polivy J. Anxiety, restraint, and eating
behavior. J Abnorm Psychol 1975; 84:666672.
71. Polivy J, Herman CP. Etiology of binge eating: psychological mechanisms. In: Fairburn CG, Wilson GT,
eds. Binge Eating: Nature, Assessment and Treatment.
New York: Guilford Press, 1993:173205.
72. Lawson OJ, Williamson DA, Champagne CM, DeLany JP, Brooks ER, Howat PM, Wozniak PJ, Bray
GA, Ryan DH. The association of body weight, dietary
intake, and energy expenditure with dietary restraint
and disinhibition. Obes Res 1995; 3:433439.
73. Westenhoefer J. Dietary restraint and disinhibition: is
restraint a homogeneous construct? Appetite 1991; 16:
4555.
74. Williamson DA, Lawson OJ, Brooks ER, Wozniak PJ,
Ryan DH, Bray GA, Duchmann EG. Association of
body mass with dietary restraint and disinhibition.
Appetite 1995; 25:3141.
75. Lowe MR. The eects of dieting on eating behavior: a
three-factor model. Psychol Bull 1993; 114:100121.
1020
76. Stunkard AJ, Messick S. The Three-Factor Eating
Questionnaire to measure dietary restraint, disinhibition, and hunger. J Psychosom Res 1985; 29:7183.
77. Smith CF, Williamson DA, Bray GA, Ryan DH. Flexible vs. rigid dieting strategies: relationship with adverse
behavioral outcomes. Appetite 1999; 32:295305.
78. National Task Force on the Prevention and Treatment
of Obesity. Dieting and the development of eating disorders in overweight and obese adults. Arch Intern Med
2000; 160:25812589.
79. Kumanyika S. Obesity in black women. Epidemiol Rev
1987; 9:3150.
80. Stevens J, Kumanyika SK, Keil JE. Attitudes toward
body size and dieting: dierences between elderly black
and white women. Am J Public Health 1994; 84:1322
1325.
81. Kumanyika S, Wilson JF, Guilford-Davenport M.
Weight-related attitudes and behaviors of black women. J Am Diet Assoc 1993; 93:416422.
82. Powell AD, Kahn AS. Racial dierences in womens
desires to be thin. Int J Eating Disord 1995; 17:191195.
83. Kolotkin RL, Revis ES, Kirkley B, Janick L. Binge
eating in obesity: associated MMPI characteristics.
J Consult Clin Psychol 1987; 55:872876.
84. Yanovski SZ, Nelson JE, Dubbert BK, Spitzer RL.
Association of binge eating disorder and psychiatric
comorbidity in obese subjects. Am J Psychiatry 1993;
150:14721479.
85. Williamson DA, Martin CK. Binge eating disorder: a
review of the literature after publication of DSM-IV.
Eating Weight Disord 1999; 4:103114.
86. Varnado PJ, Williamson DA, Bentz BG, Ryan DH,
Rhodes SK, ONeil PM, Sebastian SB, Barker SE.
Prevalence of binge eating disorder in obese adults
seeking weight loss treatment. Eating Weight Disord
1998; 2:117124.
87. Womble LG, Williamson DA, Martin CK, Zucker NL,
Thaw JM, Netemeyer R, Lovejoy JC, Greenway FL,
Psychosocial variables associated with binge eating in
obese males and females. Int J Eating Disord 2001;
30:217221.
88. Stice E, Akutagawa D, Gaggar A, Agras WS. Negative aect moderates the relation between dieting and
binge eating. Int J Eating Disord 2000; 27:218229.
89. Telch CF, Agras WS, Rossiter EM. Binge eating increases with increasing adiposity. Int J Eating Disord
1988; 7:115119.
90. Danksy BS, ONeil PM, Brewerton TD, Kilpatrick
DG. The nature of the relationship between obesity
and victimization in a national sample of US women
[abstr]. Ann Behav Med 1993; 15:S67.
91. Fontaine KR, Barofsky I, Andersen RE, Bartlett SJ,
Wiersema L, Cheskin LJ, Franckowiak SC. Impact of
weight loss on health-related quality of life. Quality
Life Res 1999; 8(3):275277.
92. McMahon FG, Fujioka K, Singh BN, Mendel CM,
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
1021
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
1022
nation: a semi-structured interview for the assessment
of the specic psychopathology of eating disorders. Int
J Eating Disord 1987; 6:18.
135. Kutlesic V, Williamson DA, Gleaves DH, Barbin JM,
Murphy-Eberenz KP. The Interview for the Diagnosis of Eating Disorders IV: application to DSM-IV
diagnostic criteria. Psychol Assess 1998; 10:4148.
136. ONeil PM, Currey HS, Hirsh AA, Malcom FJ,
Sexauer JD, Riddle FE, Tayor CT. Development and
validation of the Eating Behavior Inventory. J Behav
Assess 1979; 1(suppl 2):123132.
137. Currey HS, ONeil PM, Malcolm R, Riddle FE. Factor analysis of the eating behavior inventory. Fourth
International Congress on Obesity, New York, October 1983 .
138. Garner DM. Eating Disorder Inventory-2 Manual.
Odessa, FL: Psychological Assessment Resources,
1991.
139. Smith CF, Williamson DA, Womble LG, Johnson J,
Burke LE. Psychometric development of a multidimensional measure of weight-related attitudes and behaviors. Eating Weight Disord 2000; 5:7386.
140. Anderson DA, Williamson DA, Duchmann EG,
Gleaves DH, Barbin JM. Development and validation
of a multifactorial treatment outcome measure for eating disorders. Assessment 1999; 6:720.
141. Herman CP, Mack D. Restrained and unrestrained
eating. J Personal 1975; 43:647660.
142. Polivy J, Herman PH, Howard KI. Restraint scale:
assessment of dieting. In: Hersen M, Bellack AS, eds.
143.
144.
145.
146.
147.
148.
149.
150.
Index
Adipocyte apoptosis
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 566
Adipocyte binding protein (aP2), 264
Adipocyte dierentiation
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 563565
Adipocyte dierentiation related protein (ADRP), 494
Adipocyte secretory products
visceral adipose tissue (VAT), 600
Adipocyte-specic genes
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 566567
Adipogenesis
cellular models, 492494
molecular mechanisms, 499504
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 561563
genetic studies, 571572
receptor equipment, 494496
sequential events, 494496
transcriptional activators and repressors, 499504
Adiponectin, 287
visceral adipose tissue (VAT), 599
Adipose cell
dierentiation, 495
plasticity
cellular models, 492494
Adipose tissue
abdomen
imaging, 5658
Abdomen
adipose tissue imaging, 5658
circumference and diastolic blood pressure,
877
computed tomography, 57
visceral fat, 167168
Abdominal obesity and diabetes mellitus, 283
Acarbose and diabetes, 908
Acc2, 264
Accelerometers, 633
Accuracy, 6566
predictive body composition methods, 8386
Acetazolamide, 944
Acetylcholine and feeding-related circuits,
336337
Acetyl CoA carboxylase 2 (Acc2), 264
Acidic broblast growth factor (alphaFGF), 331
ACLS, 985
Acomys caharinus, 268
Acromegaly and body fat distribution, 679680
ACTH, 301
Activity logs, 634
Activity recall, 633
Activity thermogenesis
quantifying, 634635
total daily energy expenditure, 640
Acupuncture, 5
Acylation-stimulation protein (ASP), 266
visceral adipose tissue (VAT), 595596
Acyl COA, 264
Adenylyl cyclase regulation, 518
1023
1024
[Adipose tissue]
anatomic distribution, 38
development in early life, 483
dierentiation, 482
distribution, 6061
as endocrine organ, 671
growth, 484485
hormonal eects, 485486
lipogenesis, 671672
lipolysis, 672
malignancies, 492
nutrients, 487488
ontogeny, 482483
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 569571
phylogeny, 482483
precursor cells, 484
regional distribution, 658659
regional growth, 489
secretions, 284
in vitro development, 492499
in vivo regulation, 482490
Adipose tissue cellularity, 490491
diet, 490491
physiology, 483489
weight change, 490491
Adiposity
age changes, 123124
atomic level, 3435
cellular level, 36
measurement
body mass index, 773774
monkeys, 282283
molecular level, 3436
tissue organ level, 3638
whole-body level, 38
Adolescents
overweight
secular trends, 122
ADP, 4647
ADRB3 gene, 213
Adrenal steroid hormones, 308309
Adrenal steroids, 225
Aerobics Center Longitudinal Study (ACLS), 985
Aerent receptors
stomach, 382
Africa, obesity in women, 94
African-Americans
fat distribution, 137
hypertension
prevalence, 877
major genes, 162
mortality rate, 775
quality of life, 1011
subcutaneous fat, 84
total body fat
Index
[African-Americans]
multicomponent measurement, 49
visceral adipose tissue (VAT), 593
Age
anthropometry
Mexican-Americans, 69
non-Hispanic blacks, 68
non-Hispanic whites, 67
exercise, 636
exercising individual, 643
food, thermic eect, 622
mortality rate, 774775
pregnancy weight, 968969
work eciency, 639
Age changes
adiposity, 123124
Aging
lipid mobilization, 521
metabolic syndrome, 792
Aging-associated obesity
primates, 281292
Agouti gene, 14, 261
Agouti gene-related peptide (AGRP), 212, 213, 303, 314315,
543, 662663
modier, 213
NPY, 213214
regulation, 212213
Agouti locus
structure, 212
Agouti protein, 543
Agouti-Yellow, 202215
identication, 202203
modiers, 203, 212
normal action, 203
pigmentation phenocopies, 203
AGRP (see Agouti gene-related peptide (AGRP))
AHO, 233234
AIDS
visceral adipose tissue (VAT), 600
Air displacement plethysmography (ADP), 4647
Albright hereditary osteodystrophy (AHO), 233234
Alcohol
gout, 962963
hypothalamic-pituitary-adrenal axis dysregulation,
791792
Alcohol intake
oxidation, 720
All-cause mortality
physical activity, 989993
Alpha blockers
hypertension
obesity, 889
AlphaFGF, 331
Alpha-glycerol dehydrogenase (alphaGPDH), 265
Alpha-melanocyte stimulating hormone (alpha-MSH),
303, 543
Index
Altered leptin pathway
experimental obesity models,
465466
Alveolar-to-arterial gradient, 937
Amandamide, 318
Amino acids
feeding-related circuits, 337338
substrate oxidation, 717718
Aminostatic theory, 405
Amitriptyline, 17
Amphetamine, 15
Amylin, 262, 391
Anatomy, historical development of, 6
Androgen receptors
adipose tissue, 487
Androgens
body fat distribution, 674675
Android obesity, 162163, 851, 901
Androstenedione, 659
Anesthesia, introduction, 15
Angiopoietin-1, 483
Angiotensin-converting enzyme inhibitors
hypertension
obesity, 889
Angiotensin II, 499
Aniline, 15
Animal models
new peptide regulators, 410412
Anorexia, 322, 393
Anorexiant drugs, 943
ANP, 519520
Anthropometry, 5960
age
Mexican-Americans, 69
non-Hispanic blacks, 68
non-Hispanic whites, 67
Mexican-Americans, 69
Antiadipogenic factors, 499
Antidiabetic drugs, 17
Anxiety, 1007, 1012
AP2, 264
Apo A-IV, 326327, 392
ApoE, 600
Apolipoprotein A-IV (apo A-IV), 326327, 392
Apolipoprotein E (ApoE), 600
Apoptosis, 481
adipocyte
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 566
white adipose tissue (WAT), 491492
Appetite
anatomy, 432
food inuences, 441
research, 428429
Appetite control systems
compartments, 435440
1025
Appetite suppressants
cardiovascular eects, 833834
Appetite system
behavior, 431433
nature, 431435
physiology, 431
Arabic medicine, 6
Arachidonic acid, 498
ARC, 305
Arcuate nucleus (ARC), 305
Arginine vasopressin (AVP), 303
Aromatase, 265
metabolic syndrome, 800801
Aromatase-decient mice, 264
Arrhythmia, 830
Asian-Americans
visceral adipose tissue (VAT), 593
Asian Indians
gout, 960
Asians, 103
body composition, 83
cardiovascular morbidity, 88
ASIP gene, 204
ASP, 266
visceral adipose tissue (VAT), 595596
Aspirin
weight reduction
gallstones, 928
Associations, 23
Association studies, 169
Asthma
obesity, 945946
weight loss, 946
Atherogenic dyslipidemias
waist girth, 862864
Atherogenic metabolic prole
visceral adipose tissue (VAT), 857
Atherosclerosis, 283, 907
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 572
weight loss, 833
Atrial natriuretic peptides
hypertension, 885
Atrial natriuretic peptides (ANP), 519520
Australian aborigines
non-insulin-dependent diabetes mellitus (type 2), 900
Autonomic nervous system
food, thermic eect, 623
Avicenna medicine, 18
AVP, 303
Ayurveda, 5
A-ZIP/F, 267
7B2, 265
Bantings cure, 19
Bardet Biedl syndrome, 234
1026
Bariatric gastric surgery
glucose tolerance, 910
Basal lipolysis
visceral adipose tissue (VAT), 594
Basal metabolic rate (BMR), 341, 618621, 631632
nutrient partitioning, 755
Basophilic adenomas
pituitary gland, 17
BAT (see Brown adipose tissue (BAT))
BDI, 1008, 1015
Beacon, 320
Beaumont, William, 12
Beck Depression Inventory (BDI), 1008, 1015
Behavior
brain, 338340
food intake, 427428
Behavioral neuroscience, 301343
Behavior generator system, 338
Behavior inhibition system, 338339
Behavior modication, 20
Behavior reinforcement system, 338339
hypothalamic control, 339
Berardinelli-Seip congenital lipodystrophy syndrome,
237
Beta3-adrenergic receptor gene, 885
Beta3-agonists
diabetes, 909
Beta3-AR knockout mice, 263
Beta blockers
hypertension and obesity, 889
Beta-casomorphin, 392
BFLS, 234235
BIA, 6465
Biguandines
hypertension and obesity, 889
Bile, 919
composition of in gallbladder disease, 924925
Bile acids, 920
Bile acid supplementation
weight loss, 928
Biliary lipids
physical chemistry, 920921
synthesis and secretion, 919920
Binge eaters, 340, 1011, 10161017
Binge Eating Questionnaire, 1016
Binge Eating Scale, 1016
Biochemistry, 13
Biogenic amines
eating, 331336
Bioimpedance analysis (BIA), 6465
Biological chemistry, 1314
Birth body size, 109110
Birth weight
maternal body weight, 975
Blacks (see African-Americans)
Blood, circulation, 12
Index
Blood ow
visceral adipose tissue (VAT), 597
Blood pressure
body fat distribution, 876877
body mass index, 876877
cu (see Compression cu)
measurement, 873874
equipment, 874
physical activity, 996997
regulation, 873890
weight gain, 875
weight loss, 875876
BMI (see Body mass index (BMI))
B-mode imaging ultrasound, 59
BMR (see Basal metabolic rate (BMR))
BNP, 519520
BOD POD Body Composition System, 46
Body builders
body mass index, 85
Body composition, 13, 34
adiposity-related components, 71
age-related changes, 135136
versus body mass index, 780
ethnic and geographic inuences, 8190
exercise, 636
exercising individual, 643
fetal nutrition, 110112
food
thermic eect, 622
monographs, 7071
physical activity energy cost, 638
resting metabolic rate (RMR), 619
substrate oxidation, 717, 722723
Body fat, 409
determination, 82
distribution, 8889
diabetes, 903904
genetic epidemiology, 161162
physical activity, 644
Body fat distribution
blood pressure, 876877
conception, 977
dyslipidemia, 850852
lipid mobilization, 521
non-insulin-dependent diabetes mellitus (type 2),
901902
osteoarthritis, 958959
Body fat percent, 83, 86
Body image, 1017
obesity, 10091010
quality of life, 1014
Body mass
fetal growth, 113114
genetic epidemiology, 161162
Body mass index (BMI), 39, 85, 120
adiposity measures, 773774
Index
[Body mass index (BMI)]
blood pressure, 876877
versus body composition, 780
cardiorespiratory tness, 989
cuto points, 8688
inheritance, 15
major gene, 162
mortality, 986
optimal mortality, 813815
predictive value, 158
versus total body fat, 70
Body size
birth, 109110
Body weight
dopamine, 335
measurement, 3840
physical activity energy cost, 638
Body weight loss, 322
Bombesin, 262263, 329, 389
Borjeson-Forssman-Lehmann syndrome (BFLS), 234235
Boyle, Robert, 13
Brain and behavior, 338340
Brain areas, 305306
Brain insulin
energy balance, 469470
Brain insulin hypothesis, 462
Brain natriuretic peptides (BNP), 519520
Brain pathways
peripheral signals, 466
Brain transport
leptin, 473475
Brazil, 97
Breast cancer, 796, 818
Breastfeeding and pediatric obesity, 125
Brown adipose tissue (BAT), 258
apoptosis, 481
in white fat depots, 541542
BRS3 gene, 204
Bulimia, 340, 10151016
Burnout
cortisol, 793794
1-butyrylglycerol, 483
Calcium blockers
hypertension and obesity, 889
Calipers, 59
Callipyge locus, 204
Caloric partitioning
leptin deciency, 216217
Caloric restriction
diabetes, 908
Calorie intake in elderly, 138
CAMP-elevating agents, 497
Canada, 95
Canadians
non-insulin-dependent diabetes mellitus (type 2), 900
1027
Cancer, 818819
physical activity, 994
Candidate genes, 15
linkages, 176
markers, 170171
primates, 284
Carbacyclin, 497
Carbohydrate, 443445
satiety, 439
Carbohydrate intake
glucose oxidation, 718
Carbohydrate metabolism, 264265
endocrine control, 758759
nutrient partitioning, 756
Carbon, 34
Carboxypeptidase E, 225226, 258259
Carboxypeptidase H, 258259
Cardiac output
euglycemic hyperinsulinemia, 881882
Cardiac structure and function, 825827
weight loss, 828829
Cardiorespiratory tness, 987989
Cardiovascular disease, 815817, 984
physical activity, 993
Cardiovascular risk factors, 88, 887888
Cardiovascular system, 825834
CART, 323324
Casomorphin, 392
Catecholamines, 523525
body fat distribution, 673674
CCAAT enhancer-binding proteins (CEBP), 267
CCK (see Cholecystokinin (CCK))
CCKAR gene, 204
CEBP, 267
CEBP gene, 204
Cell surface receptors, 496
CETP, 600
Chaucer, 18
Chemical carcass analyses, 81
Chemistry, 13
Children
feeding practice in pediatric obesity, 125
overweight, secular trends, 122
total body fat, multicomponent measurement, 49
type 2 diabetes mellitus, 117
Chinese, 102103
bioelectrical impedance, 85
medicine, 45
body composition, 83
non-insulin-dependent diabetes mellitus (type 2), 900
pharmacopeia, 5
Cholecystokinin (CCK), 227228, 262, 303, 310, 328329, 388,
396, 473
receptors, 227228, 436437
Cholelithiasis
body mass index, 814
1028
Cholesterol, 919920
mortality, 986
nucleation, 921922
osteoarthritis, 958
Cholesterol crystals
growth into stones, 922
Cholesterol ester transfer protein (CETP), 600
Cholesterol gallstones
pathogenesis, 919922
Ciliary neurotropic factor (CNTF), 322, 393
Cinchona bark (quinine), 5
Cinephotography, 633
Circulating factors, 437
Circulating glucocorticoid
leptin, 471473
Circulation, blood, 12
Circumference measurement, 59
Circumference ratios, problems, 61
Clinical medicine, 16
Clinical practice
physical activity, 9991000
CNTF, 322, 393
Cocaine-and amphetamine-regulated transcript (CART),
323324
Cognitive behavioral therapy
OSA, 942943
Cold exposure and energy expenditure, 712713
Cold intolerance and leptin deciency, 216
Colipase, 392
Colon cancer, 818
Component eld measurement
total body fat, 5965
Component reference methods, 4059
Compression cu, 874
bladder dimensions, 874
blood pressure measurement, 873874
Computed tomography, 4952
Conception, body fat distribution, 977
Confounding deaths, 768
Congenital disorder of glycosylation type 1a, 235
Congenital malformations, 820
Congestive heart failure, 827828
Congresses, 23
Conicity index, 61
Continuous crossed-circulated rats, 394
Converting enzymes, 265266
Copernicus, 6
Coronary artery disease, 907
Coronary heart disease, 816817, 831833
body mass index, 814
deaths, 112
dyslipidemic phenotypes, 845850
growth, 112
insulin resistance/metabolic syndrome, 850
physical activity, 993994
relative risks, 815
Index
[Coronary heart disease]
visceral adipose tissue (VAT), 860864
weight loss, 833
Corpulency, 22
CORT (see Corticosterone (CORT))
Corticoids, 225
Corticosterone (CORT), 301
hypothalamic peptides, 309
insulin, 309
leptin, 309
Corticotropin-releasing factor (CRF), 487
Corticotropin-releasing hormone (CRH), 301, 324325
Cortisol, 657
burnout, 793794
metabolic syndrome, 789791
stress, 799
visceral adipose tissue (VAT), 597598
Cortisone-cortisol interconversion
visceral adipose tissue (VAT), 599600
CPE
secretory pathway, 226
CPEfat mutation, 225
CPE gene, 204
Creoles
non-insulin-dependent diabetes mellitus (type 2),
900
CRF, 487
CRH, 301, 324325
CRH/urocortin-glucocorticoid system, 262
Crossed-circulated rats
challenges, 394
gut nerve sections, 393397
interpretation diculties, 395
results, 396
Crossed-intestines experiments
limitation, 386
Cuba, 97
Cu, blood pressure (see Compression cu )
Culture
obesity prevalence, 105106
Cushings syndrome, 17, 487, 658, 790
body fat distribution, 679
visceral adipose tissue (VAT), 597598
Cyclo(His-Pro), 331
Cyproheptadine, 17
Cytokines, 263, 322323
food intake, 393
metabolic syndrome, 792
DAG, 741
DALY, 149
DBH gene, 205
Deep vein thrombosis, 817
Dehydroepiandrosterone (DHEA), 658
elderly, 142143
2-deoxyglucose (2-DG), 407
Index
Depression, 10071008, 1012
hypothalamic-pituitary-adrenal axis dysregulation,
791
Dexamethasone suppression, 793
Dexfenuramine, 833834
Dextroamphetamine, 15
2-DG, 407
Dgat, 264
DGAT gene, 205
DHEA, 658
elderly, 142143
DHT, 680
Diabetes
daily food intake in rats, 391
exercise, 906
free fatty acids, 903
gallbladder disease, 922
infertility and weight, 977
insulin resistance, 902
leptin, 909
macrovascular disease risk, 906907
obesity, 899910
management, 907910
Pima Indians, 905906
pregnancy, 976977
severity in rodents, 258
visceral adipose tissue (VAT), 903904
Diabetes allele
identication, 221
Diabetes mellitus
abdominal obesity, 283
sex hormone-binding globulin (SHBG)
women, 795
Diacylglycerol (DAG), 741
Diacylglycerol acyl transferase (Dgat), 264
Diaphragm, stretched, 937
Diastolic blood pressure, abdominal circumference, 877
Diazoxide, 682
Diet, 1718, 18
adipose tissue cellularity, 490491
composition
feeding behavior, 440451
exercise
visceral adipose tissue (VAT), 602603
gout, 961962
resting metabolic rate (RMR), 619620
18th century, 18
Dietary composition
food, thermic eect of, 621622
Dietary factors in gallbladder disease, 923
Dietary fat
substrate oxidation, 722
thermic eect, 622
Dietary intake, misreporting of, 430
Dietary practice
pediatric obesity, 125
1029
Dietary restraint, 10161017
Dietary Restraint Scale, 1016
Dietary weight loss studies in the elderly, 141
Diet composition and food intake, 427454
Diet-induced obesity, 450
Diet-induced thermogenesis, 714
Dieting, 1010
Digestion, 12
Digit preference, 874
Dihydrotestosterone (DHT), 680
Dilution techniques, 82
Dinitrophenol, 15
Dionysius, 5
Direct calorimetry, 615
Direct costs, 150
cost centers, 154
Disability-adjusted life years (DALY), 149
Disinhibited eating, 1010, 1016
Disturbed eating, 10151016
Divine Farmer, 5
Dopamine, 205, 263, 304, 333336
body weight, 335
hypothalamus, 334
mesolimbic system, 334335
neurotransmitter release, 335336
taste reactions, 335
Dorsomedial nucleus (DMN), 305
Doubly labeled water technique, 615616, 634635
Douglas bags, 633634
Dual-energy X-ray absorptiometry (DXA), 4749
Dutch Eating Behavior Questionnaire, 1016
DXA, 4749
Dyslipidemia
body fat distribution, 850852
elderly, 139
spontaneous obesity, 283
visceral adipose tissue (VAT), 852857, 860864
cause-eect relationship, 857860
Dyslipidemic phenotypes
coronary heart disease, 845850
Dyslipoproteinemias
physical activity, 997998
Dyspnea, 937
Eastern Mediterranean, 101102
Eating
biogenic amines, 331336
disturbed patterns, 1010
hormones, 306311
peptides, 311321
Eating behavior, 10151016
Eating Behavior Inventory (EBI), 1016
Eating behavior or fuel intake
food intake, 428429
Eating Disorder Examination, 10151016
Eating Inventory, 1016
1030
Eating reduction
peptides, 321331
Ebers papyrus, 4
EBI, 1016
Ebsteins diet, 1920
Economic costs, 149155
study requirements, 154155
study comparisons, 152154
types, 150
Education and exercise, 636
Edwin Smith papyrus, 4
EGF, 499
Egyptian medicine, 4
Elderly, total body fat, multicomponent measurement, 49
Electrocardiogram, 829
Endocrine obesity, 269
Endometrial cancer, 796, 818
Endurance training in the elderly, 142
Energy monitoring, 437
Energy balance, 631
brain insulin, 469470
fuel composition, 720721
regulation, 409, 464
RQ/FQ, 721
vagotomy, 396
Energy density, 444
macronutrients, 446
Energy exchange, 34
Energy expenditure, 13, 341
components, 631634
control, 464465
daily variability, 715
elderly, 138
measurement, 615618, 616618, 713715
nutrient partitioning, 754755
physical activity, 631646, 714715
primates, 287288
substrate oxidation, 713725
sympathetic nervous systems, 698700
uncoupling protein 1 (UCP1), 539540, 620621
weight loss, 625626
weight maintenance, 721722
Energy intake, 34, 447
food, thermic eect of, 621622
tonic control, 440
Energy metabolism
lactation, 970973
pregnancy, 970
Energy turnover
free-living subjects, 713714
Enterostatin, 325, 392
Environmental associations
pediatric obesity, 125128
Environmental stressors
hypothalamic-pituitary-adrenal axis dysregulation, 791
Ephedra, 834
Index
Epidemic, explanation of, 103106
Epidemiology, 768774
Epidermal growth factor (EGF), 499
Epinephrine and resting metabolic rate (RMR),
620
Esophageal stula, 378380
Estimation errors, 6566
Estradiol, 301
Estradiol alpha-receptor, 264
Estrogen, 264, 680
body fat distribution, 675
glucose metabolism, 759
lipid metabolism, 757
metabolism, 660
protein metabolism, 760
Estrogen receptors in adipose tissue, 487
Estrogen replacement therapy and adipose tissue, 487
Ethanol, thermic eect of, 622
Ethnicity
body composition, 88
body mass index, 88
fat distribution, 137
pediatric obesity, 121
pregnancy
weight gain, 978
quality of life, 1011
sympathetic nervous systems, 885
Euglycemic clamp studies
whole-body glucose uptake, 880
Euglycemic hyperinsulinemia
cardiac output, 881882
glucose uptake, 879
Euglycemic insulin infusion
systolic blood pressure, 884885
Europe, 98101, 99
Exercise, 1718, 413, 632
age, 636
amount performed, 635
body composition, 636
diabetes, 906
duration, 641642
education, 636
energy cost, 633634
gender, 636
genetics, 636
hypertension
obesity, 889
intensity, 641
intraabdominal fat mass, 142
lipid mobilization, 521
metabolic cost, 637
nature and duration quantication, 632635
nutrient partitioning, 753754
retrospective survey, 632633
visceral adipose tissue (VAT), 601602
Exercise tolerance, 938
Index
Exercise training
elderly, 141142
work eciency, 639
Exercising individual
age, 643
body composition, 643
characteristics, 642643
gender, 642643
Experimental science, 2122
Extracellular matrix, 499
Extraordinary obesity, 1617
Factorial method, 634
Familial partial lipodystrophy dunnigan (FPLD), 237238
Family history and body mass index, 776777
Famine, 110
Fascia lata, 736
Fasting and Agouti gene-related peptide, 212213
Fat, 445446, 452
mimetics, 452
oxidation
inhibition, 412
satiety, 439
Fat balance, control of, 465
Fat deposits, 590
neck, 940
Fat distribution
classication, 9394
endocrine determinants, 671686
racial/ethnic characteristics, 137
Fat-free mass (FFM), 81
age-related changes, 136
hydration, 3536
mortality rate, 774
Fat intake
fat oxidation, 718719
Fat mass (FM), 81
mortality rate, 774
Fat mouse, 258259
Fat mutation, 225226
defective neuropeptide processing, 226
Fat oxidation
elderly, 138
fat intake, 718719
Fat paradox, 446
Fat-sugar seesaw, 445
Fatty acid metabolism in skeletal muscle, 742745
Fatty acids, 498
selective mobilization, 517518
visceral adipose tissue (VAT), 596
Fatty mutation, 223224
Fatty oxidation in skeletal muscle, 740741
Feeding behavior, 432
diet composition, 440451
physiology, 431
uncoupling protein1 (UCP1), 543544
1031
Feeding-related circuits
acetylcholine, 336337
amino acids, 337338
Female hypogonadism and body fat distribution,
679
Fenuramine, 15, 833834, 943
Fertility, 682
Fetal growth
adult body mass, 113114
obesity-related disease, 112113
Fetal nutrition and body composition, 110112
FFM (see Fat-free mass (FFM))
FGF, 331, 499
FGF13 gene, 205
Fibrinolysis and visceral adipose tissue (VAT),
600
Fibroblast growth factor (FGF), 499
Filipinos, diet and gout, 962
Finnish families, 174
Fluoxetene, 834
FM, 81
mortality rate, 774
Food
gastrointestinal components, 436437
orosensory components, 436
Food addiction models, 339340
Food consumption, 428429
Food delivery in the small intestine, 385
Food inuences, appetite, 441
Food intake
behavior, 427428
control, 464465
cytokines, 393
diet composition, 427454
eating behavior or fuel intake, 428429
experimental studies, 373413
gastrointestinal tracts, 381
hibernating rodents, 375
hormones, 387390
inammatory peptides, 393
internal signals, 373376
liver, 400404
obesity, 412413
palatability factors, 451
pancreatic hormones, 390392
studies
demand characteristics, 430
methodological approaches, 429431
po2er, sensitivity, eect, 430
power, sensitivity and eect size, 430
precision vs. naturalness, 429430
regulation, 431
relevant questions, 430431
weight maintenance, 721722
FPLD, 237238
FRC, 935936
1032
Free fatty acids in diabetes, 903
Free-living subjects, energy turnover, 713714
Fuel composition
energy balance, 720721
substrate oxidation, 717
Functional residual capacity (FRC), 935936
GABA, 263264
GAL, 303, 313314
Galanin (GAL), 303, 313314
Galaninlike peptide, 313314
Galectin-12, 290
Galen, 56, 18
Gallbladder
motility alterations, 925
motor function, 921
mucosal function, 921
Gallbladder cancer, 818
Gallbladder disease, 819
epidemiology, 922925
obesity, 919929
relative risks, 815
risk factors, 922923
weight loss, 925926
Gallstones, 819
incidence, 925926
obesity, 923924
prevention, 927928
prophylactic cholecystectomy, 927928
risk factors, 926
during weight loss
pathophysiology, 926927
Gamma-aminobutyric acid (GABA), 263264
Gas exchange, 936937
Gastric bypass surgery, OSA, 943
Gastric emptying, 380
rats, 381
Gastric stula, 378380
Gastric inhibitory peptide (GIP), 387, 388, 390
Gastric theory, limitation of, 383
Gastroesophageal reux disease, 946
Gastrointestinal tracts
food intake, 381
signals, 377378
GDF8 gene, 208
Gender
exercise, 636
exercising individual, 642643
food, thermic eect of, 622
quality of life, 1011
visceral adipose tissue (VAT), 592593, 854
work eciency, 639640
Gene-environment, 176181
Gene-gene interactions, 176181
Gene-gene interations, 162
Gene knockout models, 254256, 260267
Index
Genes
location, 183185
symbols, 183185
Genetic epidemiological model-tting, 181
Genetic epidemiology, 159168
ndings, 161168
methods, 160170
combined models, 161
major gene, 161
multifactorial, 160161
Genetics, 1415, 157170
environmental interactions, 724725
exercise, 636
lipolysis, 525526
metabolic syndrome, 800803
primates, 284287
resting metabolic rate (RMR), 620
visceral adipose tissue (VAT), 598
work eciency, 639
Genetic susceptibility, 176
Genome scans
studies, 172173
Genomewide explorations, 181182
Genomewide scans
linkages, 171175
Genotype-environment interactions, 176181
ndings, 179181
method, 176179
recommendations, 181183
Geriatric obesity, 135143
causes, 137138
consequences, 138140
functional, 139140
metabolic, 138139
prevalence, 135137
treatment, 140143
drug, 142143
Gestational diabetes, 820
GFAT, 265
Ghrelin, 319320, 382, 662663
body fat distribution, 676
GHRH (see Growth hormone-releasing hormone (GHRH)
GHRP, 319
GHS and body fat distribution, 676
GIP, 387, 388, 390
Gi-protein-coupled receptors, 518519
Glargine and diabetes, 908909
Glitazones and diabetes, 908
GLP-1 (see Glucagonlike peptide 1 (GLP-1))
GLP-2, 398
Glucagon, 327, 390
Glucagonlike peptide 1 (GLP-1), 327328, 387, 389, 390, 398
diabetes, 909
Glucocorticoid receptor
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 565566
Index
Glucocorticoids, 497
adipose tissue, 486487
body fat distribution, 674
fat distribution, 684685
glucose metabolism, 759
lipid metabolism, 757758
nutrient partitioning, 762763
obesity, 799
protein metabolism, 760761
Glucose and osteoarthritis, 958
Glucose-induced thermogenesis, 622
Glucose intolerance
gallbladder disease, 922
leptin deciency, 216
Glucose metabolism
estrogen, 759
glucocorticoids, 759
growth hormone, 758
insulin, 758
testosterone, 758759
Glucose oxidation and carbohydrate intake, 718
Glucose tolerance and physical activity, 994995
Glucose transporters, 264265, 310311
Glucose uptake
euglycemic hyperinsulinemia, 879
visceral adipose tissue (VAT), 595
Glucostatic theory, 404405
Glucuronic acid, 682
GLUT4, 488, 657
Glut4, 264265
Glutamine: fructose-6-phosphate amidotransferase (GFAT),
265
Glycerol, 408
Glycerol dehydrogenase (GPDH), 265
Glycogen, 42
Glycolytic enzyme proles of skeletal muscle, 739740
GNAS1 gene, 205
GnRH, 310311
Go-coupled receptors, tubby mutation, 227
Gonadal steroid hormones, 310
Gonadotrophin-releasing hormone (GnRH), 310311
Gout and obesity, 960963
longitudinal studies, 961
GPC3 gene, 205
GPC4 gene, 205
GPDH, 265
G protein alpha subunit, 266
G-protein-coupled receptors, 518
Greco-Roman medicine, 56
Growth and coronary heart disease, 112
Growth hormone, 263, 498, 520, 661662
adipose tissue, 486
body fat distribution, 676
elderly, 142
fat distribution, 683
glucose metabolism, 758
1033
[Growth hormone]
lipid metabolism, 756757
nutrient partitioning, 761762
protein metabolism, 760
visceral adipose tissue (VAT), 597
Growth hormone deciency and body fat distribution,
679
Growth hormone-releasing hormone (GHRH), 310311,
318319, 382
gene, 206
Growth hormone-releasing peptides (GHRP), 319
Growth hormone secretagogues (GHS) and body fat
distribution, 676
Gs-protein-coupled receptors, 518
Gut nerve sections in crossed-circulated rats, 393397
Gut-related peptide hormones, 392393
Gynoid obesity, 168, 851, 901
Hand, osteoarthritis of and obesity, 955956
Harvey, William, 12
HDL, 283
Health outcomes
obesity, 984
physical activity, 984985
Heart rate
high-fat diet, 875
24-hour energy expenditure, 713
Hepatic vagotomy, 404
Herbal weight loss aids, 834
HERITAGE family study, 174175
Hibernating rodents and food intake, 375
High blood pressure (see Hypertension)
High-carbohydrate foods, 444
High fat content, 413
overeating, 412
High-fat diet, 875
with sedentary lifestyle
substrate oxidation, 722723
High sympathetic tone, 341
Hip, osteoarthritis of and obesity, 956957
Hispanics, fat distribution, 137
Histamine, 263, 304, 336
Histology, 6
Hmgic, 267
HMGIC gene, 206
Holland, diet and gout, 961
Hormones, 260264, 301303, 680685
abbreviations, 302
eating, 306311
food intake, 387390
metabolic syndrome, 788789
substrate oxidation, 723
visceral adipose tissue (VAT), 597598
Hormone-sensitive lipase (HSL), 264, 515, 517, 672
dierences, 522523
gene expression, 518
1034
24-hour energy expenditure
heart rate, 713
metabolic chambers, 713
HPA (see Hypothalamic-pituitary-adrenal (HPA) axis)
HSL (see Hormone-sensitive lipase (HSL))
5HT, metabolic syndrome, 801803
Human genetic obesities without mouse homologs,
233238
Humans, leptin, biological activity of, 467468
Human single-gene obesities, 228233
Hunger and quality of life, 1014
Hunger state, 434435
Hydrodensitometry plethysmography, 4546
Hydrometry, 4345
Hydrotherapy, 15
3-hydroxybutyrate, 407
Hyperandrogenicity in women, 794796
Hypercapnia, 940
Hypercholesterolemia, relative risks of, 815
Hypercortisolemia, 886887
Hyperglycemia in mice, 224225
Hyperinsulinemia, 877878, 906907
chronic sodium retention, 879880
Hyperphagia, 15, 215216, 444, 656
Hypertension, 826827
atrial natriuretic peptides, 885
body mass index, 814
elderly, 139
leptin, 886
metabolic syndrome, 796799
obesity, 874877
epidemiological studies, 874875
hypothalamic origins, 886887
ion transport, 882883
management, 888889
mechanism, 877887
vascular structure and function, 881882
osteoarthritis, 957
physical activity, 996997
pregnancy, 820
prevalence, 877
relative risks, 815
skeletal muscle, 882
sympathetic nervous systems, 884885
Hyperthyroidism, 620
Hypertriglyceridemic waist, 861864
Hyperuricemia, 960, 961
Hypothalamic control, reinforcement system, 339
Hypothalamic hypogonadism and leptin deciency,
217
Hypothalamic obesity, 268269
Hypothalamic peptides
corticosterone (CORT), 309
Hypothalamic-pituitary-adrenal (HPA) axis, 487
fat distribution, 684685
metabolic syndrome, 790792, 802803
Index
Hypothalamus
dopamine, 334
lesions, 374
Hypothyroidism, 485
Hypoxia, 940
ICAM-1, 267
IDED-IV, 1016
IFN-alpha, 393
IGF (see Insulinlike growth factor (IGF))
IL-1, 322, 393
IL-6 (see Interleukin (IL)-6)
IL-1b, 393
converting enzyme, 265
Imaging, 4956
Imhotep, 4
Impact of weight on quality of life, 1005
Inactivity in the elderly, 138
Incas, 5
Indapaminde, hypertension and obesity, 889
India
non-insulin-dependent diabetes mellitus (type 2), 900
Indian medicine, 5
Indian Ocean islanders
non-insulin-dependent diabetes mellitus (type 2), 900
Indirect calorimetry, 615, 616618, 633634, 713
Indirect costs, 150
Indonesians
bioelectrical impedance, 85
Infant feeding and obesity, 111112
Infants, adipose tissue in, 485
Infertility
leptin deciency, 217
weight, 977
Inammatory peptides and food intake, 393
Innervation and visceral adipose tissue (VAT), 597
Institute of Medicine (IOM) pregnancy recommendations,
975976
Insulin, 306, 391, 464465, 473, 497498
adipose tissue, 486
body fat distribution, 521, 672673
brain transport, 466
corticosterone (CORT), 309
glucose metabolism, 758
hypertension
metabolic syndrome, 798
interaction, 470471
lipid metabolism, 756
lipid oxidation, 744
Na-K-ATPase, 882883
nutrient partitioning, 761
obesity, 656657
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 569571
protein metabolism, 759760
renin-angiotensin system, 883884
Index
[Insulin]
resistance, 283
substrate oxidation, 717, 723
visceral adipose tissue (VAT), 594595
Insulin-dependent diabetes mellitus (type1), 899
Insulinlike growth factor (IGF), 262, 483, 497498,
661662
adipose tissue, 486
fat distribution, 683
Insulin-mediated glucose transport, 883
Insulinoma, 797
Insulinopenia in mice, 224225
Insulin receptors, 290, 902
Insulin resistance
chronic sodium retention, 879880
diabetes, 902
elderly, 138
hypertension
obesity, 877878
metabolic syndrome, 788
physical activity, 994995
skeletal muscle, 881882
tumor necrosis factor-alpha (TNF-alpha), 904905
Insulin resistance/metabolic syndrome
coronary heart disease, 850
Insulin resistance syndrome, 848849
Insulin-resistant glucose metabolism, 745747
Insulin secretion
diabetes, 905906
Insulin-suppressed fatty acids in type 2 diabetes, 747
Intangible costs, 150
Interferon-alpha (IFN-alpha), 393
Interleukin (IL)-1, 322, 393
Interleukin (IL)-6, 322
body fat distribution, 677
metabolic syndrome, 792
visceral adipose tissue (VAT), 599600
Interleukin (IL)-1b, 393
converting enzyme, 265
Internal signals
food intake, 373376
types, 376377
International Diabetes Institute, 103
International Journal of Obesity, 23
Interpersonal consequences
obesity, 10081009
Interview for Diagnosis of Eating Disorders, fourth version
(IDED-IV), 1016
Intestines
meal termination, 386
signals, 384387
stomach emptying, 381
Intra-abdominal fat mass and exercise, 142
Intracellular adhesion molecule 1 (ICAM-1), 267
In vivo lipolysis and visceral adipose tissue (VAT), 595
IOM pregnancy recommendations, 975976
1035
Japanese-Americans
fat distribution, 137
gallbladder disease, 923
visceral adipose tissue (VAT), 904
Japanese school children, 119
JDCA
weight loss, 928
Jejunoileal bypass surgery, 397
Journals, 23
Kidney cancer, 818
Kinematic measurements, 633
KK mice, 260
Klinefelter syndrome, 682
Knee, osteoarthritis of and obesity, 953955
Korotko sounds, 874
Lactation
energy metabolism, 970973
lifestyle trends, 973975
Laxatives, 15
LDL, 283, 907
LDL cholesterol, 845849
Left ventricular hypertrophy, 827
Leg respiratory quotient, fasting values, 743
Leisure time physical activity (LTPA)
secular trends, 644645
LEP Arg105Trp C, 229230
LEP G398, 228229
LEP gene, 206
LEP mutations, 229
LEPR (see Leptin receptor (LEPR))
Leptin, 14, 215220, 284287, 306308, 383, 410411, 440,
461463, 464465, 473, 657
Agouti gene-related peptide, 212213
biological activity, 466467
body fat distribution, 676677
brain transport, 466, 473475
cardiovascular eects, 886
cells mediating, 224
circulating, 218
circulating glucocorticoid, 471473
corticosterone (CORT), 309
deciency, 215216
diabetes, 909
expression, 218
gene, 411412
human biological activity, 467468
hypertension, 886
metabolic syndrome, 798
interaction, 470471
melanocortin, 472473
metabolic syndrome, 801
mice, 217
neuroendocrine system interaction, 473
NPY, 471
1036
[Leptin]
outside brain, 219220
reduced brain responsiveness, 469
regulation, 217218
resistance, 269
resting energy expenditure, 621
rodent biological activity, 466467
visceral adipose tissue (VAT), 598
Leptin receptor (LEPR), 220225, 222, 230, 468469
alleles, 222223
extinct mutations, 223224
gene, 207
genomic structure, 221
isoforms, 221222
Leukemia inhibitory factor (LIF), 497
Level gene, 178
LH, 301
LHRH, 301
LIF, 497
Lifestyle changes, 103105
Lifestyle physical activity (LSPA)
secular trends, 644645
Linkage phenotypes, 177
Linkage studies, 171
Lipectomy, 488489
Lipid, 311
dened, 35
physical activity, 997998
Lipid metabolism
endocrine control, 756758
estrogen, 757
genes, 264267
glucocorticoids, 757758
growth hormone, 756757
insulin, 756
nutrient partitioning, 755756
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 572
skeletal muscle in weight loss, 745
testosterone, 757
Lipid mobilization, 515527
body fat distribution, 521
Lipid-mobilizing factor (LMF), 520
Lipid oxidation and insulin, 744
Lipid signaling in skeletal muscle, 741742
Lipin, 266
Lipodystrophies
visceral adipose tissue (VAT), 600
Lipodystrophy syndromes with single-gene basis, 237
Lipogenesis in adipose tissue, 671672
Lipolysis, 515527
adipose tissue, 672
basal rate, 522
control, 516
dysregulation, 522525
genetics, 525526
Index
[Lipolysis]
hormonal control, 518520
regulation, 755756
in vivo regulation, 520522
Lipolytic agonists
visceral adipose tissue (VAT), 594
Lipoprotein lipase (LPL), 409, 494, 671
visceral adipose tissue (VAT), 596
Lipoprotein metabolism, 845864
overview, 846
Lipostatic hypothesis, 412
Lipostatic regulation, 438
Lipostatic theory, 408
Liver, 437
food intake, 400404
signals, 400404
Liver disease, 819
LMF, 520
Long-chain fatty acids
adipose tissue, 487488
Longitudinal assessment, 160
Long-term energy balance feedback
nutrient stores, 438440
Low-birth weight, 110
Low energy expenditure, 697698
Lower body fat, 168
Lower gut signals, 397400
Low parasympathetic tone, 341
Low sympathetic tone, 341342
LPL (see Lipoprotein lipase (LPL))
LSPA, secular trends, 644645
LTPA, secular trends, 644645
Lung volume, 940
Luteinizing hormone (LH), 301
Luteinizing hormone-releasing hormone (LHRH), 301
Lysophosphatidic acid, 497498
Macaca, 281
Macaca fascicularis, 283
Macaca mulatta, 284
Macaca nemestrina, 284
Macronutrients, 441447, 449541
energy density, 446
Macrophage colony-stimulating factor (MCSF)
adipose tissue, 485
Magas, 5
Magnetic resonance imaging, 5256
protocol, 55
reliability studies, 54
software, 53
validation studies, 54
Mahoganoid, 203
Mahoganoid gene, 261
Mahogany, 203
Mahogany gene, 261
Major gene, 161
Index
Male hypogonadism and body fat distribution, 679
Males, sex hormones, 682683
Malignancies and adipose tissue, 492
Malnourished children, 442
M amylin, 329330
Maori and gout, 960
Massively obesity, 1617
Maternal body weight and birth weight, 975
Mayans, 5
Mayers glucostatic theory, 341
MCH, 262, 316317
MCH gene, 207
MC3R, 215
MC4R, 215, 230231
MC4R gene, 207, 213
MCSF and adipose tissue, 485
Meal termination in intestines, 386
Mean arterial pressure related to high-fat diet, 875
Medial hypothalamus, 305
Medial preoptic area (MPO), 305
Medical Outcomes Study Short-Form Health Survey (SF-36),
10051006
Medroxyprogesterone, 944
Melanesian Indians, gout, 960
Melanin concentrating hormone (MCH), 262, 316317
Melanocortin, 321322
leptin, 472473
Melanocortin system, 260261
Melanocyte stimulating hormone (MSH), 303, 543
Menarche, 659
Menopause, 137
weight development, 970
Menstrual abnormalities, 659
Menstrual cycle and thermic eect of food, 622
Mercaptoacetate, 407
Meso-American medicine, 5
Mesolimbic system and dopamine, 334335
Mesopotamian medicine, 4
Metabolic chambers and 24-hour energy expenditure, 713
Metabolic disturbances and visceral adipose tissue (VAT),
852855
Metabolic eciency
energy expenditure, 711712
Metabolic genes, 264267
Metabolic signals, 404408
Metabolic syndrome, 605606, 787805
aromatase, 800801
cortisol, 789791
dened, 787789
elderly, 138
genetics, 800803
hypertension, 796799
hypothalamic-pituitary-adrenal axis, 790792
hypothalamic-pituitary-adrenal (HPA) axis, 802803
leptin, 801
normal LDL cholesterol, 849850
1037
[Metabolic syndrome]
obesity, 799800
physiological elements, 792793
POMC gene, 801
serotonin (5HT), 801803
Metabolism, 12
Metabolites, 498
Metallothionein I, 266
Metallothionein II, 266
Metformin
diabetes, 908
hypertension and obesity, 889
Metroprolol and hypertension in obesity, 889
Mexican-Americans
anthropometry, 69
beta3-adrenergic receptor gene, 885
diabetes, 901
hypertension prevalence, 877
mortality rate, 776
MGL, 516
Mice
hyperglycemia, 224225
insulinopenia, 224225
leptin, 217
leptin receptor (LEPR)
alleles, 222223
Micellar cholesterol transport, 921
Michaelis-Menten kinetics, 739
Micronutrients, 447
Microscopic anatomy, 6
Minnesota Multiphasic Personality Inventory, 1015
Minute ventilation, 937
MKKS gene, 207
Molecular biology, 1415
Molecular genetics, single gene mutations, 201238
Molecular markers, 168177
Monkeys
adiposity measurement, 282283
gastric emptying, 381
Monoglyceride lipase (MGL), 516
Monographs
body composition, 7071
obesity, 22
Mood
assessment, 1015
weight loss, 10121014
Mortality, 813815, 986
elderly, 139
voluntary weight uctuation in elderly, 140141
weight loss, 778779
Mortality rate, 767781
fat-free mass, 774
fat mass, 774
potential moderators, 774779
recent weight loss, 777
Mother Goddess gurines, 3
1038
Moth1 gene, 227
MPO, 305
MSH, 303, 543
Multicomponent measurement of total body fat, 49
Multiple genes, 162, 267268
Multiple sensory cues, 432
Multivariate assessment, 160161
Muscle composition in computed tomography, 51
Muscle sympathetic nerve activity, thermic eect of food, 623
MY09A gene, 207
MYOD1 gene, 208
Na-K-ATPase
insulin, 882883
NASH, 152153, 819
National Health and Nutrition Examinations Surveys
(NHANES), 66
National Institutes of Health, 2223
National Library of Medicine
Visible Man, 38
Nationwide Nutritional Survey, 102103
Native Americans
non-insulin-dependent diabetes mellitus (type 2), 900
Natriuretic peptides, 519520
N-cells, 397
Neck, fat deposits in, 940
NEFA, 515
Negative energy balance experiments
genotype-environment interactions, 180181
Neolithic artifacts, 2
Nerve activity in sympathetic nervous system, 696
Nervous system, 431
Netherlands, 99
Neurochemicals, 303309
abbreviations, 302
Neuromedin U, 329
Neuropeptide systems, 260264
Neuropeptide Y (NPY), 261, 303, 311313, 662663
Agouti gene-related peptide (AGRP), 213214
leptin, 471
Neuroscience, 1516
Neurotensin, 325326, 389, 397
Neurotransmitter release
dopamine, 335336
sympathetic nervous systems, 696697
Neurotransmitters, 263264
Neutron activation analysis in vivo, 41
NHANES, 66
Nhlh2 gene, 208, 267
Nitric oxide, 520
Noise, 429
Nonalcoholic steatohepatitis (NASH), 152153, 819
Nonesteried fatty acids (NEFA), 515
Nonexercise activities
amount performed, 635
energy cost, 633634
Index
[Nonexercise activities]
metabolic cost, 637638
nature and duration quantication, 633
Non-Hispanic blacks, anthropometry, 68
Non-Hispanic whites, anthropometry, 67
Nonhuman primate obesity
diet, food intake, activity, energy expenditure, 282
prevention, 291
Non-insulin-dependent diabetes mellitus (type 2), 100, 899
body fat distribution, 901902
body mass index, 814
children, 117
elderly, 138
global epidemic, 900901
insulin-suppressed fatty acids, 747
physical activity, 994996
Pima Indians, 977
relative risks, 815
skeletal muscle lipid content, 737738
Noninvasive ventilation, 944945
Nonmicellar cholesterol transport, 920
Norepinephrine, 304, 331332
Normal LDL cholesterol
metabolic syndrome, 849850
Novel uncoupling proteins (UCP), 545557
biochemical studies, 546547
genetic studies, 547548
physiological and pathophysiological studies, 548549
transgenic mice, 549550
NPY (see Neuropeptide Y (NPY))
NPY/NYPR gene, 208
Nuclear receptors, 496
Nutrient ux, monitoring of, 437
Nutrient partitioning, 753763
endocrine control, 756761
endocrine inuences, 754
energy expenditure, 754755
exercise, 753754
fuel processing, 755756
glucocorticoids, 762763
growth hormone, 761762
insulin, 761
testosterone, 762
Nutrient receptors, 381
Nutrient stores
long-term energy balance feedback, 438440
Nutritional status and thermic eect of food, 622
Obese individuals, anatomical dissection of, 6
Obese personality, 1009
Obese rhesus monkeys, 283
Obesity
adrenocortical function, 657658
after pregnancy, 967968
asthma, 945946
body image, 10091010
Index
[Obesity]
classication, 9394
cuto points, 8688
denition, 8688
diabetes, 899910
management, 907910
endocrine determinants, 655664
fetal origins, 109114
food and macronutrient intake, 449541
food intake, 412413
gallbladder disease, 919929
gallstones, 923924
gout, 960963
cross-sectional studies, 960961
longitudinal studies, 961
health outcomes, 984
historical development of, 123
hypertension, 874877
epidemiological studies, 874875
ion transport, 882883
management, 888889
mechanism, 877887
vascular structure and function, 881882
infant feeding, 111112
insulin, 656657
international classication, 103
interpersonal consequences, 10081009
late-onset in rodents, 258
metabolic syndrome, 799800
monographs, 22
osteoarthritis, 953960
progression, 959
symptoms and disability, 959
overall quality of life, 10051006
pathological alterations, 463
physical activity, 9831000
recommendations, 9981000
pregnancy complications, 976
prevalence, 93106, 105106
pulmonary function, 935947
quality of life, 10051007
severity and quality of life, 1011
WHO region prevalence, 94103
women
psychosocial outcomes, 118
Obesity and Weight Regulation, 23
Obesity hypoventilation syndrome (OHS), 940942
classication, 941
management, 942945
Obesity Research, 23
Obesity Surgery, 23
Obesity syndromes, 233238
Ob gene, 410411
Ob/ob mouse, genetic defect in, 14
Obstructive sleep apnea (OSA) syndrome, 939940
daytime, 944
1039
[Obstructive sleep apnea (OSA) syndrome]
management, 942945
medications, 944
noninvasive ventilation, 944
obesity, 939940
supplemental oxygen, 945
tracheotomy, 944
OHS, 940942
classication, 941
management, 942945
Old Order Amish population, 175
One-way crossed intestines, 387
rodents, 375, 383384
Opioid peptides, 317318
Opioid reward and eating, 317318
Opioid reward and feeding
inhibition, 318
Opioid subsystems, 317
Orexin, 262, 315316
Orlistat
diabetes, 909
visceral adipose tissue (VAT), 605
OSA [see Obstructive sleep apnea (OSA) syndrome]
Osteoarthritis, 819
body fat distribution, 958959
cholesterol, 958
glucose, 958
hand obesity, 955956
hip obesity, 956957
hypertension, 957
knee obesity, 953955
obesity, 953960
pathogenesis, 957
progression, 959
symptoms and disability, 959
twin studies of obesity, 955
uric acid, 958
weight loss, 959960
Overall quality of life
assessment, 10141015
obesity, 10051006
weight loss, 1012
Overconsumption, sensorily induced, 428429
Overeating, 10161017
high fat content, 412
reinforcement systems, 338340
Overfeeding study, 179180
Overnutrition, 111
Over-the-counter drugs, cardiovascular eects of, 834
Overweight
children, secular trends, 122
cuto points, 8688
development, 124125
international comparisons, 121
Oxidation and alcohol intake, 720
Oxidative enzyme proles of skeletal muscle, 739740
1040
Oxidative phosphorylation
diet composition, 709710
eciency, 713717
energy expenditure, 709710
energy reserve maintenance, 710
futile cycles, 710711
glucose conversion to fat, 710
substrate handling and storage costs, 708709
Oxygen theory, 13
Oxytocin, 303
Pacic Ocean islanders
non-insulin-dependent diabetes mellitus (type 2), 900
Palatability factors, 451453
food intake, 451
Paleolithic artifacts, 2
Paleolithic Venus gurines, 2
Paleomedicine, 2
Pancreatic hormones and food intake, 390392
Pancreatic peptide YY, 398
Pancreatic polypeptide, 261
Parabrachial nucleus (PBN), 305
Parasympathetic nervous systems, 340342
Paraventricular nucleus (PVN), 305
Paris-Lille French Study, 173174
PBN, 305
PC1 gene, 231232
PCOS, 660661, 681, 967
PCSK1 gene, 209, 213
Pediatric obesity, 117129
behavioral environment, 125126
breastfeeding, 125
child feeding practice, 125
denition, 119120
dietary practice, 125
environmental associations, 125128
identication, 119120
physical activity, 125126
physical examination, 125
prevalence, 120123
sedentary behavior, 125126
social environment, 128
weight goals, 120
Pedometers, 633
Peptides
eating, 311321
eating reduction, 321331
Peptide YY (PYY), 389
Perilipin, 264
Peripheral neuroendocrine signals
brain integration, 464465
Peripheral signals
brain pathways, 466
central integration
neuroendocrinology, 463464
Peripheral vascular disease, 833
Index
Peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 489490, 559576, 681
activators, 567569
adipocyte apoptosis, 566
adipocyte dierentiation, 563565
adipocyte-specic genes, 566567
adipogenesis, 561563
genetic studies, 571572
adipose tissue, 569571
atherosclerosis, 572
gene, 559560
2 gene, 209, 213, 232233
glucocorticoid receptor, 565566
insulin, 569571
lipid metabolism, 572
protein, 559560
protein-protein interactions, 572576
RNA, 559560
signal transducers and activators of transcriptions (STAT),
565566
structure, 560561
thrifty response, 561566
transcription factors, 569571
Peroxisome proliferator-activated receptors (PPAR), 266267
primates, 288291
Peroxisome proliferator-activated receptors (PPAR) alpha
receptor and agonists, 288289
Peroxisome proliferator-activated receptors (PPAR) gamma
receptor and agonists, 289290
Personal costs, 150
Personality assessment, 1015
PFC, 305
PGE2, 483
Pharmacology, historical development of, 15
Pharmacotherapy, 2021
Pharynx, distensibility of, 940
Phenothiazines, 17
Phenotypes, 157159
linkage, 177
Phlogiston Theory, 13
Phospholipids, 920
Phospholipid transfer protein (PLTP), 600
Physical activity, 341
all-cause mortality, 989993
amount performed, 635637
body fatness, 644
cancer, 994
cardiovascular disease, 993
characteristics, 640641
clinical practice, 9991000
comorbidities, 994998
coronary heart disease, 993994
energy cost, 637640, 638639
energy expenditure, 631646, 714715
gallbladder disease, 923
health outcomes, 984985
Index
[Physical activity]
increasing, 646
mortality, 986
nutrient partitioning, 755
obesity, 9831000
recommendations, 9981000
obesity etiology, 643646
obesity-related health outcomes, 985998
postpartum weight development, 974
pregnancy
body weight development, 977978
public health, 998999
seasonal variations, 636637
secular trends, 644645
substrate oxidation, 640643, 722
weight gain, 645
Physical inactivity, 770773
metabolic syndrome, 800
Physiology, 1213
Pickwickian syndrome, 17, 940942
classication, 941
management, 942945
Pima Indians
beta3-adrenergic receptor gene, 885
diabetes, 901, 905906
genomewide scans, 171173
non-insulin-dependent diabetes mellitus (type 2), 901, 977
Pioglitazone and hypertension in obesity, 889
Pituitary gland and basophilic adenomas, 17
Pituitary-thyroid axis, 663
PKA, 266, 494
Plasminogen, 499
PLIN gene, 209
PLTP, 600
PMM2 gene, 209
Polycystic ovary syndrome (PCOS), 660661, 681, 967
Polysarcy, 22
POMC (see Proopiomelanocortin (POMC))
Ponderal index, 113
Portal hypothesis
visceral adipose tissue (VAT), 589590
Positive airway pressure, 944
Positive energy balance experiments
genotype-environment interactions, 179180
Postabsorptive satiety signals, 447
Postexercise energy expenditure, 637
Postpartum weight development and physical activity, 974
Postprandial hyperlipidemia
visceral adipose tissue (VAT), 855857
Postreceptor eects, 902903
PPAR, primates, 288291
PPAR alpha, receptor and agonists, 288289
PPAR gamma, receptor and agonists, 289290
PPAR-gamma (see Peroxisome proliferator-activated
receptor gamma (PPAR-gamma))
Prader-Willi syndrome (PWS), 210, 235236
1041
Preadipose cells, 481
Preadolescents and adipose tissue, 485
Precision, 6566
Predictive body composition methods
accuracy and validity, 8386
Pre-eclampsia, 820
Prefrontal cortex (PFC), 305
Pregnancy, 820
age and weight, 968969
body mass index, 85
body weight development
physical activity, 977978
complications of weight gain, 976
energy metabolism, 970
hypertension, 820
obesity after, 967968
physical activity and body weight development, 977978
smoking and weight, 976
weight development, 968975
general clinical consequences, 979
weight development after
characteristics, 973
weight gain
socioeconomic and ethnic aspects, 978
Pregnant adolescents, weight development, 978979
Prehistoric medicine, 2
Prescientic medicine, 3
Primary endocrine disease, 655656
Primate models, common features of, 283
Primates
aging-associated obesity, 281292
candidate genes, 284
energy expenditure, 287288
gene-environment interactions, 284
genetics, 284287
in vivo metabolic and endocrine eects, 283284
peroxisome proliferator-activated receptors (PPAR),
288291
PRIME-MD, 1015
Primitive fat organ, 483
Procolipase, 392
Progesterone, 301
body fat distribution, 675
Prolactin, 320321, 498
Pro-opiomelanocortin (POMC), 214215, 231, 260261,
321322
gene, 209, 213
metabolic syndrome, 801
mutations, 231
posttranslational processing, 214
Prophylactic cholecystectomy and gallstones, 927928
Prostacyclin, 497
Prostaglandin E2 (PGE2), 483
Protein, 441442, 920
satiety, 439
thermic eect, 622
1042
Protein kinase A (PKA), 266, 494
Protein-lipid interactions, 516518
Protein metabolism
endocrine control, 759761
insulin, 759760
nutrient partitioning, 756
Protein-protein interactions
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 572576
Protein tyrosine phosphate 1B (PTRB), 266
Psammomys obesus, 268
Pseudo-Cushing syndrome, 792
Pseudohypoparathyroidism, 233234
Psychosocial outcomes, obesity in women, 118
PTRB, 266
Public health and physical activity, 998999
Pulmonary embolism, 817
Pulmonary function
obesity, 935947
physiological decrements, 935937
Pulmonary function tests, abnormalities in, 936
Pulse recorder, 632
PVN, 305
PWS, 210, 235236
PYY, 389
QTL, 169170, 268
Quality of life, 149, 820821
assessment, 10141017
body image, 1014
hunger, 1014
obesity, 10051007
psychological functioning, 10061008
risk factor models
obesity, 10101011
weight loss, 10111014
Quantitative trait loci (QTL), 169170, 268
Quebec Family Study, 174
Quetelet Index, 22, 39, 85
Quinine, 5
Race
fat distribution, 137
mortality rate, 775
pediatric obesity, 121
visceral adipose tissue (VAT), 593
Radar tracking, 633
Rats
adipose tissue cellularity, 490
daily food intake in diabetes, 391
gastric emptying, 381
leptin receptor (LEPR)
alleles, 222223
two-way crossed-intestines, 386
Recent weight loss
mortality rate, 777
Index
Recumbency, 938
Reduced brain responsiveness
leptin, 469
Reference body composition methods, 8283
Reference values, 6670
Regional adipose tissue in skeletal muscle, 736
Relative weight, 39
Reliability, 66
Renin-angiotensin system
hypertension, 883884
insulin, 883884
visceral adipose tissue (VAT), 600
Repeatability, 66
Reported costs, 150151
Reproducibility, 66
Reproductive health, 820
Resistance training in elderly, 142
Resistin and body fat distribution, 678679
Respiratory compliance, 935936
Respiratory compromise, categories of,
937939
Respiratory control, 936937
Resting energy expenditure
leptin, 621
Resting metabolic rate (RMR), 618621
elderly, 138
genetics, 620
Retinoic acid, 498
Retinoids, 498
Rhesus monkeys
prevention, 291
RMR
elderly, 138
genetics, 620
Rodent models, 253270
visceral adipose tissue (VAT), 592
Rodents
leptin and biological activity, 466467
one-way crossed intestines, 375, 383384
single gene mutations
naturally occurring, 202214
single gene obesities, 228233
Rosiglitazone and hypertension in obesity, 889
RQ/FQ, energy balance, 721
Sagittal trunk thickness, 63
Saline emptying, 381
San Antonio Family Heart Study, 173
Sand Rat (Psammomys obesus), 268
Santorio, Santorio, 12
Satiation, 433434, 441447
Satiety, 428429, 433434
signals, 433
postabsorptive satiety, 447
SBPEBP, 267, 741742
SCID, 1015
Index
Scientic medicine, 617
Screening overweight, 128
Seasonal variations in physical activity, 636637
Second-messenger pathways, 496499
SEE, 83
Segregation studies, 164166
Sensory factors, 451453
Sensory inputs, 338
Serotonin, 304, 332333, 389
Serotonin (5HT), metabolic syndrome, 801803
Serum, 466
Serum lipids and gallbladder disease, 924
Sex anthropometry
Mexican-Americans, 69
non-Hispanic blacks, 68
non-Hispanic whites, 67
Sex hormone-binding globulin (SHBG), 660, 680681,
682, 967
diabetes mellitus in women, 795
Sex hormones
males, 682683
women, 680681
Sex steroids
adipose tissue, 487
secretion obesity, 659
visceral adipose tissue (VAT), 597, 599
SHBG (see Sex hormone-binding globulin (SHBG))
Short-term satiety signals, 377
Sibutramine, 834, 943
visceral adipose tissue (VAT), 605
Signaling proteins, 266
Signals
gastrointestinal tracts, 377378
intestines, 384387
liver, 400404
lower gut, 397400
satiety, 433
stomach, 380384
Signal transducers and activators of transcriptions
(STAT), 266
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 565566
SIM1 gene, 210, 233
Simpson-Golabi-Behmel 1 syndrome, 236
Single gene mutations
molecular genetics, 201238
naturally occurring in rodents, 202214
Single gene obesities in rodents, 228233
Skeletal muscle, 733747
biochemistry, 739742
capillary density, 738739
CT, 734735
distribution, 738
fatty acid metabolism, 742745
fatty oxidation, 740741
hypertension, 882
1043
[Skeletal muscle]
insulin resistance, 881882
lipid content, 736738
lipid metabolism
weight loss, 745
lipid signaling, 741742
microscopic studies, 736739
molecular biology, 739742
MRI, 735
noninvasive studies, 733736
quality, 734736
quantity, 733734
regional adipose tissue distribution adjacent to, 736
size, 738
substrate utilization, 742745
type, 738
Skeletal muscle metabolism
work eciency, 638639
Skinfold, 59
thickness, 84
age-related changes, 136
thickness ratios, 61
Sleep apnea, 819
Small-baby syndrome
metabolic syndrome, 792793
Small intestine, 436437
food delivery, 385
Smell, 377378
Smoking, 768, 769, 779
hypothalamic-pituitary-adrenal axis dysregulation,
792
mortality, 986
pregnancy and weight, 976
Socioeconomic characteristics of pediatric obesity, 121
Socioeconomic factors in obesity prevalence, 105106
Sodium retention
hypertension and obesity, 879880
Software for magnetic resonance imaging, 53
Soluble leptin receptor, 218
Somatostatin, 391392
Southeast Asia, 9798
SOX3 gene, 210
Spermatogenesis, 682
Sphygmomanometer, 874
Spiny Mouse (Acomys caharinus), 268
Spontaneous obesity and dyslipidemia, 283
Spontaneous physical activity
sympathetic nervous system, 699
Stadiometer, 39
STAI, 1015
Standard error of estimate (SEE), 83
STAT, 266
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 565566
STAT5A gene, 210
State-Trait Anxiety Inventory (STAI), 1015
1044
Stature
age-related changes, 136
measurement, 3840
Sterol regulatory element binding proteins (SBPEBP), 267,
741742
Stethoscope, 874
Stomach
aerent receptors, 382
distension, 380
signals, 380384
size, 436437
Stomach emptying, intestines, 381
Stone age, 22
Storage signals, 408410
Stress
cortisol, 799
hypertension, 797798
lipid mobilization, 521
Stress eating, 799800
Stretch receptors, 436437
Stroke, 817, 833
Structural genes, 267
Structured Clinical Inventory for DSM-IV axis I Disorders
(SCID), 1015
Subcutaneous fat
African-Americans, 84
Subcutaneous skinfold ratio
trunk-to-extremity (TER), 163
Substrate oxidation
body composition, 722723
daily patterns, 724
energy expenditure, 713725
factors determining, 713718, 715720
glucose turnover, 716
measurement, 713715
obesity predisposition, 724
physical activity, 640643
regulation, 717720
starvation ketosis, 716717
sympathetic nervous systems, 699
tissue types, 715716
Sucrose, 451
Sudden death, 830831
Sugar intake, 340
Surgery, 21
Sweeteners, 451
Sweetness, 451
Sympathetic nervous systems, 340342, 693701
activity assessment, 696697
dietary stimulation, 700701
energy expenditure, 698700
ethnicity, 885
factors aecting, 697
food, thermic eect of, 623
hypertension, 884885
nerve activity, 696
Index
[Sympathetic nervous systems]
neurotransmitter release, 696697
physiological role, 694696
stimuli response, 699700
structure, 693694
weight gain, 700
weight loss, 700
Sympathomimetics, 834
Symptom Checklist-90, 1015
Syndecan, 261
Syndecan-3, 213
Systolic blood pressure
euglycemic insulin infusion, 884885
mortality, 986
Taiwan, diet and gout, 961
Taste, 377378
Taste reactions and dopamine, 335
TBX3 gene, 211
TEF [see Thermic eect of food (TEF)]
TER and subcutaneous skinfold ratio, 163
Terminology, 22
Testosterone, 659
adipose tissue, 487
elderly, 142
glucose metabolism, 758759
lipid metabolism, 757
nutrient partitioning, 762
protein metabolism, 760
visceral adipose tissue (VAT), 597
TGF-beta, 483, 499
Theophylline, 944
Thermic eect of feeding in elderly, 138
Thermic eect of food (TEF), 340341, 621624, 622, 631632
nutrient partitioning, 755
sympathetic nervous systems, 699
Thermogenesis, 340341
Thermogenic pathways, 265266
Thiazide diuretics and hypertension in obesity, 889
Thiazolidinediones
diabetes, 908
hypertension
obesity, 889
visceral adipose tissue (VAT), 598
Thigh, computed tomography of, 52
THRB gene, 211
Three Factor Eating Questionnaire, 1016
Thrifty gene, 622
Thrifty phenotype hypothesis, 901
Thymidine kinase, 485
Thyroid extract, 15
Thyroid hormones
adipose tissue, 485
body fat distribution, 675676
resting metabolic rate (RMR), 620
Thyrotropin-releasing hormone (TRH), 301
Index
Thyroxine, 301
Tibetan medicine, 45
Time and motion studies, 633
Timeline, 711
TNF alpha [see Tumor necrosis factor-alpha (TNF-alpha)]
TOPS family study, 174
Total body bioelectrical impedance, 84
Total body carbon, 41
Total body fat
versus body mass index, 70
component eld measurement, 5965
multicomponent measurement, 49
Total body potassium, 4041
Total body protein, 42
Total daily energy expenditure
activity thermogenesis, 640
Total energy expenditures, 624626
absolute versus relative values, 624625
Total fat
fat tomography, 168
Transcription factors, 266267, 496
peroxisome proliferator-activated receptor gamma
(PPAR-gamma), 569571
Transforming growth factor-beta (TGF-beta), 483, 499
Transgenic models, 254256, 260267
TRH, 301
Triacylglycerol synthesis
visceral adipose tissue (VAT), 595596
Triglycerides, 35
hydrolysis, 516518
Tri-idodothyronine, 498
Troglitazone and hypertension in obesity, 889
Truncal fat in youth, 110
Trunk-to-extremity (TER)
subcutaneous skinfold ratio, 163
Tubby (tub/tub) mouse, 259
Tubby mutation, 226227
Go-coupled receptors, 227
TUB gene, 211
Tub/tub mouse, 259
TULP1 gene, 211
Tumor necrosis factor-alpha (TNF-alpha), 322, 492, 499, 520
body fat distribution, 677678
insulin resistance, 904905
visceral adipose tissue (VAT), 599
Twin pregnancies, weight gain, 979
Twin studies of osteoarthritis in obesity, 955
Two-way crossed-intestines in rats, 386
Type II steroid receptors, 308309
Type I steroid receptors, 308309
Tyrosine-kinase receptors, 519
UCP, 265, 539551
gene, 213
UCP1 [see Uncoupling protein1 (UCP1)]
UCP2, 550551
1045
UCP3, 550551
Ukraine, diet and gout, 961
Ulnar mammary syndrome (UMS), 236237
human alleles, 237
Ultrasound, 59
UMS, 236237
human alleles, 237
Uncoupling protein1 (UCP1), 539545
energy expenditure, 539540, 620621
feeding behavior, 543544
knockout mice, 542544
regulation, 544545
transgenic mice, 540541, 542544
Uncoupling protein2 (UCP2), 550551
Uncoupling protein3 (UCP3), 550551
Uncoupling proteins (UCP), 265, 539551
gene, 213
Undernutrition, 110111
Underwater weighing, 4546
United Kingdom, 99
University of Pennsylvania Family Study, 174
Upper-airway function
obesity, 940
Upper body fat, 162163
Upper-body obesity, 61
Uric acid and osteoarthritis, 958
Ursodeoxycholic acid (JDCA) and weight loss, 928
Vagotomy and energy balance, 396
Validity of predictive body composition methods, 8386
Valproate, 17
Valvular heart disease, 943
Variability gene, 178
Vascular endothelial growth factor (VEGF), 483
VAT (see Visceral adipose tissue (VAT))
VEGF, 483
Venous thromboembolism, 817
Ventromedial hypothalamus (VMH), 305
Venus gurines, 3, 4
Vertical-banded gastroplasty, OSA, 943944
Very-low-calorie diets (VLCD), OSA, 942
Vesalius, Andreas, 6
Viscera, dened, 37
Visceral adipose tissue (VAT), 589605, 657
anatomical description, 590592
anthropometry versus CT, 860861
atherogenic metabolic prole, 857
composition, 593594
coronary heart disease, 860864
CT, 591, 853
dened, 591592
diabetes, 903904
dyslipidemia, 852857, 860864
cause-eect relationship, 857860
endocrine and secretory functions, 598600
gender, 592593
1046
[Visceral adipose tissue (VAT)]
genetic determinants, 598
gout, 960961
historical perspective, 589
Japanese-Americans, 904
measurement, 590592
metabolic characteristics, 594596
metabolic disturbances, 852855
metabolic syndrome, 605606
MRI, 591
physiological determinants, 596598
portal hypothesis, 589590
postprandial hyperlipidemia, 855857
race, 593
rodent models, 592
therapy, 600604
triacylglycerol synthesis, 595596
in vivo lipolysis, 595
Visceral fat
abdomen, 167168
metabolic syndrome, 788
Visible Man, 38
VLCD, OSA, 942
VLDL, 283, 907
VMH, 305
Voluntary weight uctuation
mortality in elderly, 140141
Von Noordens diet, 19
Waist circumference divided by hip circumference (WHR), 17
Waist girth and atherogenic dyslipidemias, 862864
Waist/hip ratio (WHR), 61
Waist/thigh ratio (WTR), 61
WAT. see White adipose tissue (WAT)
Water in human body, 82
Weight
age-related changes, 135136
high-fat diet, 875
infertility, 977
Weight change and adipose tissue cellularity, 490491
Weight development
menopause, 970
pregnant adolescents, 978979
Weight uctuation and preexisting disease, 768769
Weight gain
blood pressure, 875
physical activity, 645
pregnancy complications, 976
prevention, 646
sympathetic nervous systems, 700
twin pregnancies, 979
Weight goals in pediatric obesity, 120
Weight loss
asthma, 946
atherosclerosis, 833
bile acid supplementation, 928
Index
[Weight loss]
blood pressure, 875876
cardiac structure and function, 828829
coronary heart disease, 833
diabetes, 908
energy expenditure, 625626
exercise and visceral adipose tissue (VAT), 601602
gallbladder disease, 925926
hypertension in obesity, 888889
hypothalamus, lesions in, 374
lipid metabolism
skeletal muscle, 745
mood, 10121014
mortality, 778779, 780
OSA, 942943
osteoarthritis, 959960
overall quality of life, 1012
repeated cycles and gallstones, 926
surgically induced, OSA, 943
sympathetic nervous systems, 700
ursodeoxycholic acid (JDCA), 928
Weight maintenance
energy expenditure, 721722
food intake, 721722
substrate balances, 720725
Weight-reducing medications, 723724
Weight regain, prevention of, 645646
Weight-stature indices, 39
Western Pacic Region, 102103
White adipose tissue (WAT)
apoptosis, 481, 491492
dedierentiation, 491492
development, 481504
gain and loss of function, 504505
genes, 501503
Whole-body glucose uptake
euglycemic clamp studies, 880
WHR, 17, 61
Women
hyperandrogenicity, 794796
obesity
Africa, 94
psychosocial outcomes, 118
sex hormones, 680681
Work eciency
age, 639
exercise training, 639
gender, 639640
genetics, 639
skeletal muscle metabolism, 638639
Work of breathing, 935936
WTR, 61
Yellow Emperor, 5
Yellow Obese mouse, 14
Yellow (Av/a) obese mouse, 259260