Obesity and Metabolism

Frontiers of Hormone Research

Vol. 36

Series Editor

Ashley B. Grossman London

Obesity and Metabolism

Volume Editor

Márta Korbonits London

43 figures, 25 in color, and 11 tables, 2008

Basel · Freiburg · Paris · London · New York ·

Bangalore · Bangkok · Singapore · Tokyo · Sydney
Márta Korbonits
Department of Endocrinology
Barts and the London, Queen Mary’s School of Medicine and Dentistry
University of London
London, UK

Library of Congress Cataloging-in-Publication Data

Obesity and metabolism / volume editor, M. Korbonits.

p. ; cm. – (Frontiers of hormone research, ISSN 0301–3073 ; v. 36)
Includes bibliographical references and indexes.
ISBN 978-3-8055-8429-6 (hard cover : alk. paper)
1. Obesity. 2. Metabolism. I. Korbonits, M. (Márta) II. Series.
[DNLM: 1. Obesity. W1 FR946F v.36 2008 / WD 210 0112182 2008]
RC628.02272 2008
362.196⬘398–dc22
2007047338

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ISSN 0301–3073
ISBN 978–3–8055–8429–6
Contents

VII Foreword
Grossman, A.B. (London)
IX Preface
Korbonits, M. (London)

1 Monogenic Human Obesity

Farooqi, I.S. (Cambridge)
12 Polygenic Contribution to Obesity:
Genome-Wide Strategies Reveal New Targets
Körner, A.; Kiess, W.; Stumvoll, M.; Kovacs, P. (Leipzig)
37 Genetic Obesity Syndromes
Goldstone, A.P.; Beales, P.L. (London)
61 Fetal and Neonatal Pathways to Obesity
Gluckman, P.D. (Auckland); Hanson, M.A. (Southampton);
Beedle, A.S.; Raubenheimer, D. (Auckland)
73 Developmental Origins of Obesity and the Metabolic
Syndrome: The Role of Maternal Obesity
Armitage, J.A. (Clayton/Melbourne); Poston, L.; Taylor, P.D. (London)
85 Childhood Obesity
Sabin, M.A. (Melbourne/Bristol); Shield, J.P.H. (Bristol)
97 Obesity in Old Age
McPhee Chapman, I. (Adelaide)
107 Models of ‘Obesity’ in Large Animals and Birds
Clarke, I.J. (Melbourne)
118 The ␤-Cell in Type 2 Diabetes and in Obesity
Rutter, G.A. (London); Parton, L.E. (Boston, Mass.)
135 Role of the Endocannabinoid System in Energy
Balance Regulation and Obesity
Cota, D. (Cincinnati, Ohio)
146 11␤-Hydroxysteroid Dehydrogenase Type 1 and Obesity
Morton, N.M.; Seckl, J.R. (Edinburgh)
165 Gut and Hormones and Obesity
Wren, A.M. (London)
182 Adipokines in Obesity
Ahima, R.S.; Osei, S.Y. (Philadelphia, Pa.)
198 The Role of AMP-Activated Protein Kinase in Obesity
Kola, B.; Grossman, A.B.; Korbonits, M. (London)
212 Classical Endocrine Diseases Causing Obesity
Weaver, J.U. (Newcastle upon Tyne)
229 Emerging Concepts in the Medical and Surgical Treatment of Obesity
Aylwin, S.; Al-Zaman, Y. (London)
260 The Sociology of Obesity
Rosengren, A.; Lissner, L. (Göteborg)
271 Obesity in Art - A Brief Overview
Woodhouse, R. (London)

287 Author Index

288 Subject Index

VI Contents
Foreword

It has now become a truism that obesity is one of the most serious medical problems of
the developed world, and however unsettling this may be in the presence of famine and
starvation in parts of the developing world, it is nevertheless a situation which must be
faced. It has become difficult for endocrinologists to access all of the recent literature on
the genetics, metabolic phenotype and treatment of obesity, and Dr. Korbonits has been
stunningly successful in putting together an array of chapters from many of the fore-
most authorities and researchers in this field. With recent data indicating that the surgi-
cal therapy of gross obesity is associated with increased longevity, it is now an ideal time
to reveal what we know about the causes, metabolic disturbances and treatment of this
so common condition. I recommend this volume to all who are beginning research in
this area or are responsible for the clinical care of obese patients: this means the volume
will be relevant to almost all practising clinicians in 2008.

Ashley B. Grossman, London

Preface

It was the discovery of leptin in 1994 that completely changed endocrinology’s atti-
tude to obesity. What had until then been a niche subject with little known patho-
physiological pathways, was, by the discovery of a hormone so profoundly affecting
weight, suddenly launched into the fast lane of scientific research.
In the current volume we have attempted to summarise key advances in many facets
of obesity: in the field of genetics, from the spectacular monogenic and syndromal
causes to the less dramatic but more common susceptibility genes, which have only
been recently identified; we have explored the effects of obesity in the pregnant mother,
in foetal life, in childhood and in old age, and have attempted to draw conclusions from
studies of periodic increased weight in animals. We have also mapped out the biochem-
ical and physiological background of the abnormal metabolism in obesity, by scrutiniz-
ing the hormones and enzymes most recently implicated in the development,
maintenance and consequences of obesity. The ‘traditional’ hormonal causes of obesity
are discussed, as they may occasionally cause a differential diagnostic challenge, and we
offer a practical update on clinical approach and treatment of obesity. Finally, we have
attempted to reflect the social aspects of obesity in society, and the view of the obese
body in art throughout the centuries. While a completely comprehensive overview of
the metabolism of obesity is beyond the scope of this book, we have aimed for a timely
and wide-ranging update which we believe will be both interesting and pertinent to all
endocrine clinicians and researchers.
Márta Korbonits, London
Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 1–11

Monogenic Human Obesity

I. Sadaf Farooqi
Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge,
Cambridge, UK

Abstract
We and others have identified several single gene defects that disrupt the molecules in the leptin-
melanocortin pathway causing severe obesity in humans. In this review, we consider these human
monogenic obesity syndromes and discuss how far the characterisation of these patients has informed
our understanding of the physiological role of leptin and the melanocortins in the regulation of human
body weight and neuroendocrine function. Copyright © 2008 S. Karger AG, Basel

The genetic contribution to body weight has been established through family studies,
investigating parent-offspring relationships, the study of twins and adopted children
[1, 2]. These studies consistently report heritability estimates of 40–70% [3]. As is the
case for height, where nutritional changes in the last 50 years have contributed to sub-
stantial increases in mean final height in many populations, environmentally-driven
changes in body weight in the population occur against a background of susceptibil-
ity to weight gain that is determined by genetic factors. Thus, genetic approaches can
be applied to understand both the molecular and physiological mechanisms involved
in human obesity.
We have explored the genetic basis of severe childhood obesity where we consid-
ered that major and more highly penetrant genetic effects were likely to be found. In
1997, we established the Genetics of Obesity Study (GOOS) to recruit patients with
severe obesity (body mass index standard deviation score, BMI SDS, ⬎3) of early
onset (⬍10 years). We were particularly interested in children with a strong family
history of obesity and those from consanguineous families. Our intention was to use
a candidate gene approach to look for mutations in genes thought to play a role in the
regulation of body weight based on evidence primarily from rodent models at the
time. With the help of colleagues throughout the world, we have to date recruited
over 2,500 patients to the GOOS cohort. In the past 9 years, several human disorders
of energy balance that arise from genetic defects have been described by ourselves
and others [4]. All of these are in molecules identical or similar to those known to
cause obesity in genetic and experimental syndromes of obesity in rodents and all
have been identified using a candidate gene approach. These mutations all result in
severe obesity in childhood without developmental pleiotropic features.

Mutations in Genes Encoding Leptin and the Leptin Receptor

In 1997, we reported two severely obese cousins from a highly consanguineous fam-
ily of Pakistani origin [5]. Both children had undetectable levels of serum leptin and
were found to be homozygous for a frameshift mutation in the LEP gene (⌬G133),
which resulted in a truncated protein that was not secreted. We have since identified
5 further affected individuals from four other families [6, 7; unpubl. obs.] who are
also homozygous for the same mutation in the leptin gene. All the families are of
Pakistani origin but not known to be related over five generations. A large Turkish
family in which 3 adults carry a homozygous missense mutation (C→T substitution
at codon 105 resulting in Arg→Trp) in the LEP gene have also been described [8].
The first mutation in the leptin receptor gene was published in 1998 [9]. The muta-
tion was found in homozygous form in 3 severely obese adult siblings from a consan-
guineous family of Algerian origin. This mutation results in abnormal splicing of
leptin receptor transcripts and generates a mutant leptin receptor that lacks both trans-
membrane and intracellular domains. The mutant receptor circulates at high concen-
trations bound to leptin, resulting in very elevated serum leptin concentrations [10].
We recently sequenced the leptin receptor gene in a cohort of patients with severe,
early onset obesity in the absence of developmental delay and identified 8 unrelated
probands with homozygous or compound heterozygous loss of function mutations in
the leptin receptor gene [11]. The prevalence of pathogenic leptin receptor mutations
in this cohort was 3%. Six of the probands were from consanguineous families but 2
probands (including the compound heterozygote) were UK Caucasians whose parents
were unrelated. Although the prevalence of leptin receptor mutations is likely to be
higher amongst ethnic groups where consanguinity is common, leptin receptor defi-
ciency should be considered in all patients with hyperphagic obesity of early onset.

Clinical Phenotypes Associated with Leptin and Leptin Receptor Deficiency

The clinical phenotypes associated with congenital leptin and leptin receptor defi-
ciencies are similar. Leptin and leptin receptor deficient subjects are of normal birth
weight but exhibit rapid weight gain in the first few months of life resulting in severe
obesity [6]. Body composition measurements show that leptin deficiency is charac-
terised by the preferential deposition of fat mass giving a distinct clinical appearance
with excessive amounts of subcutaneous fat over the trunk and limbs [6]. All patients

2 Farooqi
were hyperinsulinaemic, consistent with the severity of obesity and some adults have
developed type 2 diabetes in the 3rd–4th decade [6].
All subjects in these families are characterised by intense hyperphagia with food
seeking behaviour and aggressive behaviour when food is denied [6] and energy
intake at an ad libitum meal is markedly elevated [11].
In leptin deficient humans we found no detectable changes in resting metabolic
rate using indirect calorimetry or total energy expenditure using chamber calorime-
try [12]. However, Ozata et al. [13] reported abnormalities of sympathetic nerve func-
tion in leptin deficient adults consistent with defects in the efferent sympathetic limb
of thermogenesis.
Leptin and leptin receptor deficiency are associated with hypothalamic hypothy-
roidism and hypogonadotropic hypogonadism. Complete leptin deficiency is associ-
ated with a moderate degree of hypothalamic hypothyroidism characterised by low free
thyroxine and high serum thyroid-stimulating hormone (TSH) which is bioinactive. In
leptin deficient children, plasma free thyroxine concentrations are within the normal
range, but 4 children had significantly elevated TSH levels [6] and the pulsatility of
TSH secretion, studied in a single adult with congenital leptin deficiency, was charac-
terised by a markedly disorganised secretory pattern [14]. Two subjects homozygous
for a non-sense mutation in the leptin receptor were diagnosed with hypothyroidism in
childhood and thyroid hormone replacement therapy commenced [9].
Normal pubertal development does not occur in adults with leptin or leptin recep-
tor deficiency, with biochemical evidence of hypogonadotropic hypogonadism [8].
However, there is some evidence for the delayed but spontaneous onset of menses in
leptin and leptin receptor deficient adults [11, 13].
Leptin and leptin receptor deficient children have normal linear growth in child-
hood and normal IGF-1 levels. However, because of the absence of a pubertal growth
spurt the final height of adult subjects is reduced. In the first reported leptin receptor
deficient family, short stature and abnormal serum levels of GH, IGFBP3 were noted
in childhood. However, assessment of the GH/IGF axis is difficult in obese children
and adults as obesity itself is associated with abnormalities in basal and dynamic tests
of the GH/IGF axis. We conclude that while impaired linear growth has been
reported in some cases of LEPR deficiency, this does not appear to be a common
characteristic of this disease [11].
We demonstrated that children with leptin deficiency had profound abnormalities of
T cell number and function [6], consistent with high rates of childhood infection and a
high reported rate of childhood mortality from infection in obese Turkish subjects [13].

Response to Leptin Administration in Leptin Deficiency

We have reported the dramatic and beneficial effects of daily subcutaneous injections
of recombinant human leptin leading to a reduction in body weight and fat mass in

Monogenic Human Obesity 3

a b

Fig. 1. Effects of recombinant human leptin treatment in leptin deficiency. a A 3-year-old boy
weighing 42 kg. b The same boy at 7 years of age weighing 32 kg.

3 congenitally leptin deficient children [6, 12] (fig. 1). All children showed a response to
initial leptin doses that were designed to produce plasma leptin levels at only 10% of
those predicted by height and weight (i.e. approximately 0.01 mg/kg of lean body mass).
Leptin therapy has also been successfully used in the 3 Turkish leptin deficient adults
[15].
The major effect of leptin was on appetite with normalisation of hyperphagia.
Leptin therapy reduced energy intake during an 18MJ ad libitum test meal by up to
84% [6]. Leptin treatment was associated with reduced hunger scores with no change
in satiety in adults with leptin deficiency [15]. We were unable to demonstrate a
major effect of leptin on basal metabolic rate or free-living energy expenditure, but, as
weight loss by other means is associated with a decrease in basal metabolic rate, the
fact that energy expenditure did not fall in our leptin deficient subjects is notable.
The administration of leptin permitted progression of appropriately timed pubertal
development in the single child of appropriate age and did not cause the early onset of
puberty in the younger children [6]. In adults with leptin deficiency, leptin induced the
development of secondary sexual characteristics and pulsatile gonadotrophin secretion.

4 Farooqi
 In the 3 previously reported children there were small, but sustained, increases in
free T4, free T3, and TSH that occurred within 1 month of leptin therapy. These obser-
vations are fully consistent with an effect of leptin at the hypothalamic level. A 4th
patient had substantial elevation of TSH before treatment, such that thyroxine ther-
apy was commenced [7]. However, replacement therapy was stopped when thyroid
function tests normalised after leptin treatment.

Complete POMC Deficiency

In 1998, Krude et al. [16] provided the first description of humans congenitally lack-
ing POMC gene products. One proband was a compound heterozygote for two non-
sense mutations and a 2nd patient was homozygous for a mutation in the
5⬘-untranslated region that introduced an additional out-of-frame start site, thus
interfering with POMC translational initiation. Subsequently, Krude et al. [16] have
reported 3 additional unrelated European children with congenital POMC deficiency
who were either homozygous or compound heterozygous for POMC mutations. We
have recently identified a 6th patient with complete POMC deficiency, being
homozygous for a complete loss of function mutation which results in the loss of all
POMC-derived peptides [17].
These patients all presented in early life with features of hypocortisolaemia sec-
ondary to ACTH deficiency, leading to hypoglycaemia, prolonged jaundice, suscepti-
bility to the effects of infection and in one case, neonatal death. The children
responded well to physiological replacement with glucocorticoids but all subse-
quently developed marked obesity in association with hyperphagia.
Notably, all children thus far reported have pale skin and red hair, features consis-
tent with the known role of POMC-derived peptides in the determination of the
phaeomelanin to eumelanin ratio in melanocytes. Our Turkish proband is the first
reported patient with POMC deficiency who does not have red hair [17]. It is likely
this can be explained by his differing genetic background as the other reported
patients were all white Caucasian subjects of European ancestry. The retention of
dark hair in this child and his similarly affected deceased sibling indicates that the
synthesis of eumelanin in humans is not absolutely dependent on the presence of
melanocortin peptides.

POMC Haploinsufficiency

Krude et al. [18] have previously attempted to assess the impact of loss of one POMC
allele in the parents and heterozygous relatives of their probands. They estimated the
maximum lifetime BMI SDS in adult POMC heterozygotes and suggested that most
had a maximum lifetime BMI SDS of 1, which is at the upper end of the normal range.

Monogenic Human Obesity 5

We had the opportunity to study a large Turkish consanguineous pedigree with
12 heterozygote carriers and 7 wild-type subjects [17]. The significantly higher preva-
lence of obesity/overweight in the carriers provides compelling support for the idea
that loss of one copy of POMC is sufficient to markedly predispose to obesity.
This is particularly relevant as we and others have described a variety of heterozy-
gous point mutations in POMC, including mutations in ␣- and ␤-MSH, which signif-
icantly increase obesity risk but are not invariably associated with obesity.

POMC Mutations Affecting Specific Melanocortin Peptides

In order to determine whether missense/non-sense mutations within the melano-

cortin peptides might predispose to obesity, we screened the coding regions of the
POMC gene for mutations in over 600 UK Caucasian subjects with severe early-onset
obesity. We identified a number of sequence variants in POMC in severely obese chil-
dren. Three of these missense mutations directly affect regions of the POMC gene
that encode melanocortin peptides. R236G was identified in 3 patients but also two
controls. We have previously shown that this mutation disrupts a di-basic cleavage
site between ␤-MSH and ␤-endorphin, resulting in a ␤-MSH/␤-endorphin fusion
protein that binds to MC4R but has reduced ability to activate the receptor [19]. Its
presence in both obese probands and controls reflects previous studies that show that
this is not a highly penetrant cause of inherited obesity but may increase the risk of
obesity in carriers.
We identified 5 unrelated probands who were heterozygous for a rare missense
variant in the region encoding ␤-MSH, Tyr221Cys [20]. This frequency was signifi-
cantly increased (p ⬍ 0.001) compared to the general UK Caucasian population and
the variant co-segregated with obesity/overweight in affected family members. The
overrepresentation of this mutation in obese subjects is supported by independent
studies in a German population [21]. Compared to wild-type ␤-MSH, the variant
peptide was impaired in its ability to bind to and activate signalling from the MC4R
[20]. Obese children carrying the Tyr221Cys variant were hyperphagic and showed
increased linear growth, both of which are features of MC4R deficiency. These stud-
ies support a role for ␤-MSH in the control of human energy homeostasis.

Mutations in Prohormone Convertase 1

Many biologically inactive prohormones and neuropeptides are cleaved by serine

endoproteases to release biologically active peptides. The prohormone convertases
(PC1 and 2) are expressed in neuroendocrine tissues and act upon a range of sub-
strates including proinsulin, proglucagon and pro-opiomelanocortin (POMC) [22].
PC1 is itself synthesised as an inactive precursor, then undergoes two autocatalytic

6 Farooqi
events, firstly within the endoplasmic reticulum and then within the secretory vesi-
cles of the regulated secretory pathway to generate a fully active 66-kDa isoform that
is stored in mature secretory granules.
We have previously reported an adult female with severe early-onset obesity,
hypogonadotropic hypogonadism, postprandial hypoglycaemia, hypocortisolaemia,
and evidence of impaired processing of POMC and proinsulin [23]. She was found to
be a compound heterozygote for PC1 mutations [24]. We have described the second
case of congenital PC1 deficiency, in a patient who was a compound heterozygote for
two loss of function mutations [25]. Intriguingly, this patient suffered from severe
small intestinal absorptive dysfunction as well as the characteristic severe early-onset
obesity, impaired prohormone processing, and hypocortisolaemia. We hypothesised
that the small intestinal dysfunction seen in this patient and, to a lesser extent, in the
1st patient we described may be the result of a failure of maturation of propeptides
within the enteroendocrine cells and nerves that express PC1 throughout the gut. The
finding of elevated levels of progastrin and proglucagon provided in vivo evidence
that prohormone processing in enteroendocrine cells was abnormal [25].

Human MC4R Deficiency

In 1998, two groups reported heterozygous mutations in the MC4 receptor in humans
which were associated with dominantly inherited obesity [26, 27]. Since then, het-
erozygous mutations in MC4R have been reported in obese humans from various
ethnic groups [28–30].
We have studied over 2,000 severely obese probands and found that approximately
5–6% have pathogenic MC4R mutations that are non-conservative in nature, not
found in control subjects from the background population and co-segregate with
obesity in families [31]. The prevalence of MC4R mutations has varied from 0.5% of
obese adults to 6% in patients with severe childhood obesity [31, 32]. Recent studies
provide an important indication of the true population prevalence of this disorder in
UK [33] and European populations [32].
While we found a 100% penetrance of early-onset obesity in heterozygous
probands, others have described obligate carriers who were not obese [29]. Given the
large number of potential influences on body weight, it is perhaps not surprising that
both genetic and environmental modifiers will have important effects in some pedi-
grees. Indeed we have now studied 6 families in whom the probands were homozy-
gotes and in all of these, the homozygotes were more obese than heterozygotes [31].
Interestingly, in these families, some heterozygous carriers were not obese. Taking
account of all of these observations, co-dominance, with modulation of expressivity
and penetrance of the phenotype, is the most appropriate descriptor for the mode of
inheritance. This finding is supported by the pattern of inheritance of obesity seen in
heterozygous and homozygous MC4R knockout mice [34].

Monogenic Human Obesity 7

 70

Mean ad libitum energy intake (kcal/kg lean mass)

60

50

40

30

20

10

0
Leptin Inactive Partial Treated Controls
deficiency MC4R mutations leptin
deficiency

Fig. 2. Genotype-phenotype correlations in human MC4R deficiency. Ad libitum food intake at an 18MJ
test meal for patients with leptin deficiency and complete and partial loss of function MC4R mutations.

We have now studied over 150 MC4R deficient subjects in our Clinical Research
Facility. The clinical features of MC4R deficiency include hyperphagia, which invari-
ably starts in the 1st year of life [31]. Alongside the increase in fat mass, MC4R-defi-
cient subjects also have an increase in lean mass and a marked increase in bone
mineral density, thus they often appear ‘big-boned’. They exhibit accelerated linear
growth in early childhood, which does not appear to be due to dysfunction of the GH
axis and may be a consequence of the disproportionate early hyperinsulinaemia seen
in these patients [31]. The accelerated linear growth and the disproportionate early
hyperinsulinaemia are consistent with observations in the MC4R KO mouse [35].
Although affected subjects are objectively hyperphagic, ad libitum energy intake at
a test meal is not as large as that seen with leptin deficiency [31]. Of particular note is
the finding that the severity of receptor dysfunction seen in in vitro assays can predict
the amount of food ingested at a test meal by the subject harbouring that particular
mutation (fig. 2).
We have studied in detail the signalling properties of many of these mutant receptors
and this information should help to advance the understanding of structure/function
relationships within the receptor [36]. Importantly, we have been unable to demonstrate
evidence for dominant negativity associated with these mutants, which suggests that
MC4R mutations are more likely to result in a phenotype through haplo-insufficiency
[36]. About 70% of missense mutations in MC4R are retained intracellularly [37].

8 Farooqi
 While, at present, there is no specific therapy for MC4R deficiency, it is highly likely
that these subjects would respond well to pharmacotherapy that overcame the reduc-
tion in the hypothalamic melanocortinergic tone that exists in these patients. As most
patients are heterozygotes with one functional allele intact, it is possible that small mol-
ecule MC4R agonists might, in future, be excellent treatments for this disorder [38].

Mutations in the Neurotrophin Receptor Tropomyosin-Related Kinase B

Recently, the concept that hypothalamic neuronal networks involved in energy home-
ostasis are ‘hardwired’ has been challenged. In mice, hypothalamic neurones projecting
from the arcuate nucleus to the paraventricular nucleus develop after birth and their
development is regulated by leptin [39]. In addition, synaptic plasticity in the mature
rodent brain has been identified as a component of the neuronal regulation of energy
homeostasis as leptin has been shown to acutely modulate excitatory and inhibitory
synaptic inputs at the level of first-order arcuate neurones [40]. However, it is difficult to
establish whether synaptic plasticity plays a role in the physiological regulation of energy
homeostasis in humans and whether under pathological conditions, hypothalamic neu-
ronal networks and plasticity may be impaired and contribute to human obesity.
Brain-derived neurotrophic factor (BDNF) regulates the development, survival and
differentiation of neurons through its high-affinity receptor, tropomyosin-related kinase
B (TrkB). Recently, BDNF has been implicated in the regulation of body weight, as its
expression is reduced by fasting [41] and BDNF administration causes weight loss in
wild-type mice through a reduction in food intake. BDNF has also been implicated in
memory and a range of behaviours using a number of conditional knockout models [42].
We previously reported a child with severe obesity, impaired short-term memory
and developmental delay who had a de novo missense mutation impairing the function
of TrkB, the tyrosine kinase receptor that mediates the effects of both BDNF and the
neurotrophin, NT4/5 [43]. We have also identified a patient with severe hyperphagia
and obesity and a complex neurobehavioural phenotype including impaired cognitive
function and memory as well as distinctive hyperactive behaviour. Interestingly, this
patient has a de novo paracentric inversion, 46,XX,inv(11)(p13p15.3), which encom-
passes the BDNF locus and disrupts BDNF expression [44]. Although to date only 2
such patients have been identified, understanding the mechanisms whereby BDNF reg-
ulates hypothalamic neuronal circuits may have potential therapeutic benefits for the
treatment of more common forms of human obesity.

Conclusions

In practical terms the discovery of these genetic disorders has helped de-stigmatise
human obesity and allow it to be seen as a medical condition. The genetic defects

Monogenic Human Obesity 9

found to date all affect the drive to eat resulting in hyperphagia in affected subjects.
Thus human food intake should not be considered as an entirely voluntarily control-
lable phenomenon but one driven by powerful biological signals. It is likely that fur-
ther discovery of causative genetic defects in humans and experimental animals will
continue to highlight other molecular elements of the pathways involved in the regu-
lation of body weight.
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Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 12–36

Polygenic Contribution to Obesity:

Genome-Wide Strategies Reveal
New Targets
Antje Körnera ⭈ Wieland Kiessa ⭈ Michael Stumvollb ⭈
Peter Kovacsc
a
University Hospital for Children and Adolescents, bDepartment of Internal Medicine III,
and cInterdisciplinary Center for Clinical Research, University of Leipzig, Leipzig, Germany

Abstract
Obesity results from the complex interaction of environmental factors that act on a genetic back-
ground that determines the susceptibility to obesity. The identification of such obesity susceptibility
genes can provide important insights into the mechanism underlying this condition. While candidate
gene approaches have not been tremendously successful in identifying relevant genetic contributors
to obesity, except PPAR γ , the advent of genome-wide strategies has recently revealed novel and unex-
pected genetic factors with strong associations with obesity and/or diabetes, i.e. FTO, TCF7L2, INSIG2,
ENPP1, or FASN (reviewed herein), although some of them are not undebated. Considering the function
of the encoded proteins, it will now be of interest to investigate the cellular and molecular mechanisms,
how these genetic variations affect body weight, energy metabolism and/or obesity-associated
morbidity. Copyright © 2008 S. Karger AG, Basel

The ‘Thrifty’ Heritability of Obesity?

Obesity results from an imbalance of energy expenditure and energy intake. There is
a great variety of factors affecting this fragile balance. It is obvious that major envi-
ronmental factors such as the accessibility to food and the degree of physical activity,
but also the psychosocial environment, the perinatal environment and many other
factors affect an individual’s body weight. The pandemic increase in obesity preva-
lence had been attributed to this increasingly urbanized and sedentary lifestyle with
convenient access to food, increased calorie intake and a reduction of energy expen-
diture in the industrialized world.
Nevertheless, over the last two decades, it has become clear that genetic factors
play an important role in the determination of body weight. First evidence for the
heritability of obesity came from early twin studies that observed a heritability for
body weight of 0.78–0.81% in monozygous twins [1–3] and similar values have
been obtained in subsequent studies analyzing the impact of the genetic back-
ground [4–7]. However, this high degree of heritability is rarely attributed to
monogenic forms of obesity [see the chapter by Farooqi, this vol., pp. 1–11], which
usually result in extreme and early-onset obesity and are usually accompanied by
additional phenotypic and endocrine abnormalities. Even though the discovery of
monogenic forms of obesity has allowed important insights into some of these
mechanisms by revealing a highly conserved pathway regulating mammalian body
weight, it is obvious that the pathology of obesity is far more complex.
Considering that the genetic pool has not dramatically changed over the last
decades, the secular trend of increased obesity prevalence is now regarded as the
interaction of the modern lifestyle factors that act on a genetic background that deter-
mines an individuals susceptibility to weight gain and obesity. According to this
‘thrifty gene’ hypothesis [8] individuals with a genetic disposition to accumulate
ample energy stores in times of good food availability were evolutionary more likely
to survive times of nutrient scarcity and to pass these genotypes to successive genera-
tions. For example, if feast and famine cycles characterized early human life, the
‘thrifty genotype’ was more likely to survive periods of food scarcity. This ancient
genetic selection to deposit fat efficiently is maladaptive in our modern obesogenic
environment with excess calorie intake and sedentary life style, and hence the same
genes now contribute to obesity.
It is now well acknowledged that a multitude of genetic polymorphisms and candi-
date regions scattered all over the genome regulate an individual’s susceptibility to
weight gain. Evolutionary concepts together with extensive population genetics to
characterize geographical and haplotypic structures of newly emerging biological as
well positional candidate genes will be inevitable to reveal whether these new genes
could indeed represent the ‘thrifty’ genes. These genetic studies provide valuable
insights as well as promoting new concepts into the mechanisms from the identifica-
tion of previously unsuspected genetic factors.

Overview of Tools for Identifying Genes Relevant to Human Obesity

Genetic Dissection of Complex Diseases

Complex diseases such as diabetes or obesity have genetic components, which due
to their polygenic nature can not easily be identified. Two basic approaches have
been used to identify susceptibility genes for complex diseases: candidate gene
approach and genomic approach (fig. 1). However, only limited success has been seen
so far.

Polygenic Obesity 13
 Human Experimental model

Candidate Genome-wide Linkage QTL

genes strategies

Linkage Association Chromosomal

studies region

Synteny
Chromosomal region

Disease gene

Fig. 1. Identifying genetic factors that underlie complex diseases. QTL ⫽ Quantitative trait locus.

Candidate Gene Approach

Selection of candidate genes for obesity is usually based on their known physiological
role in pathways related to energy expenditure, food intake but also glucose and/or lipid
metabolism and hence requires some a priori knowledge of the pathophysiology of a
disease. In addition, candidate genes are selected on the basis of previous evidence on
association with obesity and/or diabetes in other populations or experimental animal
models. These genes are then analyzed for sequence variation that is associated or
linked with the disease. Even though advances in genotyping technology allied with our
knowledge of the human genome’s structure will lead to novel common gene variants
involved in susceptibility to human obesity, the candidate gene approach may still be
very powerful when it comes to identifying rare variants predisposing to obesity. This is
given by the fact that whereas coverage of common variation in genes by commercially
available single nucleotide polymorphism (SNP) panels (provided by Affymetrix and
Illumina) is generally comparable to the rest of the genome (see association studies
below), other focused classes of functional variants are captured poorly by SNP sets
aimed at common variation [9]. A large number of genes have been associated with the
development of obesity; they have been reviewed recently elsewhere [10, 11].

Genome-Wide Strategies

Alternatively, susceptibility genes can be identified by genome-wide linkage or associa-

tion scans, which are followed by positional cloning (fig. 2). Positional cloning requires
no knowledge and/or judgment of the ‘biologically plausible’ genetic candidates. Instead,
a disease gene is discovered because it resides on a chromosomal region that segregates

14 Körner ⭈ Kiess ⭈ Stumvoll ⭈ Kovacs

 Case Association studies: based on comparisons of the variants’ frequencies between
cases and controls
– analyze if subjects with a particular condition consistently
Control have a particular mutation pattern and if matched controls do
not share this pattern
A T G T C C

p = 0.00000001
Disease allele: strong association with obesity

Lower linkage Linkage equilibrium p = 0.9

disequilibrium
p = 0.01
High linkage
disequilibrium p = 0.001

Genetic marker
(SNP) A C TGA A G C

Affymetrix Genechip (500K) Association plot Potential region/gene of interest

Association with

Linkage studies are

phenotype

being replaced by
genome-wide
association studies.

Genomic distance ( bp)

http://www.affymetrix.com

Fig. 2. Genome-wide association studies.

with a phenotype [12]. In the last two decades, genetic studies have focused on the tech-
nique of genetic linkage. This study design proved to be efficient for identifying rare,
high-risk alleles, i.e. alleles that have a large population attributable fraction (PAF) in rare
single-gene mendelian diseases (cystic fibrosis) [13, 14] but do not appear to have large
PAF in common diseases. Using linkage studies, researchers attempt to find regions of
the genome with a higher than expected number of shared alleles among affected indi-
viduals within a family. Since the design is based on closely related individuals within a
family, and these individuals share larger regions of the genome, genotyping of a rela-
tively small number of polymorphic markers is sufficient to detect region of linkage.
Using positional cloning one may attempt to identify the gene(s), which reside within the
linkage region and segregate with the phenotype. Usually, genetic markers (e.g. SNPs) are
being selected to provide a high-density map (e.g. every 2 kb) within the region of link-
age. The SNPs are then being genotyped in study subjects and analyzed for association
with the disease. SNPs with strongest associations may be the causal disease risk variants
(direct association) or are in a close proximity and thus in high linkage disequilibrium
(non-random correlation between alleles at a pair of SNPs) and possibly indirectly
associated with the disease variants [12].

Polygenic Obesity 15
 In contrast to linkage approaches, association analyses are expected to be more
powerful in identifying alleles that confer modest risk for developing a complex
disease. Common modest risk variants account for a larger PAF than do rare high-
risk alleles and this is often referred to as disease-common variant hypothesis [15].
The advantage of association analyses is based on the fact that for modest-risk alleles
the patterns of sharing between related affected individuals are less striking than pat-
terns of sharing between unrelated affected individuals [16]. This may partially
explain the limited success of linkage studies in identifying genes for common dis-
eases such as obesity. Another advantage of association analyses is that it is much eas-
ier to recruit large cohorts of unrelated individuals than collecting large pedigrees.
However, since the shared region among unrelated individuals is much smaller than
among the family members, association analyses require higher marker densities
than linkage analyses [16]. This seems to be given by recent advances in the field of
high throughput genotyping of SNPs, enabling a high-density coverage of the genome.
Besides the marker coverage, another point that requires consideration in association
analyses based on comparisons of the variants’ frequencies between cases and con-
trols is the power. Most studies are underpowered, especially when considering that
in order to detect associations with an odds ratio of 1.2 one would need 1,000 cases
and 1,000 controls [17]. Therefore, large collaborating networks enabling replications
of initial findings are crucial for successful association analyses. This was impressively
represented by a very recent genome-wide analysis involving research centers from
Europe and including more than 35,000 study subjects, which led to discovering FTO
as the strongest predictor of human polygenic obesity seen so far [18, 19].

Isolated Populations

Along with the polygenic nature and pathophysiologic complexity of diseases such as
obesity or diabetes, another major problem is the genetic heterogeneity of modern
populations. This means that healthy and afflicted subjects are likely to have very dif-
ferent sequences throughout the genome, not only in the area with the disease
gene(s). To reduce genetic heterogeneity, one can use crossing studies with experi-
mental models, which are inbred and so genetically uniform. Furthermore, their
environment can be standardized to overcome gene-environment interaction.
Linkage or quantitative trait analyses using experimental crosses may lead to chro-
mosomal regions associated with a phenotype of interest, which may then point to
syntenic regions in humans and so suggest novel human candidate genes. However,
very often it proves to be extremely difficult to find an experimental model com-
pletely resembling pathophysiological aspects/patterns of human diseases. Therefore,
one may attempt to reduce genetic heterogeneity by studying populations with
limited genetic variability [20]. Isolated populations have already contributed to iden-
tification of mendelian variants of complex diseases, such as Hirschsprung disease in

16 Körner ⭈ Kiess ⭈ Stumvoll ⭈ Kovacs

the Amish or nonsyndromic hearing loss in Beduins [21–23]. There are several rea-
sons to believe that studying genetics in isolated populations will result in genes
involved in susceptibility for complex diseases: (a) genetic homogeneity makes
genetic differences between healthy and afflicted individuals more pronounced; (b)
the number of disease-causing mutations is much smaller because it can be traced
back to very few ancestral carriers (‘founders’); (c) more uniform environment
(reducing the effects of gene-environment interactions); (d) higher prevalence for
some diseases; (e) good genealogical records.
Indeed, current genetic projects on isolated populations are providing a good rea-
son to share this optimism. The project receiving the most attention is the deCODE
project, founded in 1996, which investigates the genetically isolated population of
Iceland. The country of ca. 275,000 Icelanders has an extensive Icelandic genealogical
database that can be traced back over 1,000 years. This unique resource together with
the extensive high throughput genotyping led to the discovery of several genes con-
trolling complex diseases such as prostate cancer [24] or stroke [25]. The Icelandic
cohort was also one of the first populations in which type 2 diabetes (T2D) suscepti-
bility genes have been reported from genome-wide association studies [26]. Another
promising population in the field of metabolic disorders seems to be the population
of the Island of Kosrae in Micronesia, in which a comprehensive epidemiological and
genetic study has been undertaken [27, 28].

Studies in Children

Children represent an interesting population for identifying such primary genetic

determinants involved in the susceptibility to complex polygenic diseases, since
unlike in adults, phenotypes are less influenced by co-morbidities, their treatment,
and environmental factors. In addition, the detailed evaluation of parameters of glu-
cose and insulin metabolism at early stages of metabolic impairment may help to
understand the sequence of events leading to overt pathology and diabetes.

Fatty Acid Synthase and Pima Indians

To identify genetic determinants of human polygenic obesity, researchers at the

National Institutes of Health in Phoenix have focused on the relatively genetically and
environmentally homogeneous Pima Indian population of Southern Arizona. The
Pima Indians of Arizona are one of the most obese populations in the world and also
have the highest reported prevalence of T2D [29]. Their diabetes is characterized
by obesity, insulin resistance, insulin secretory dysfunction and increased rates of
endogenous glucose production [30, 31]. To search for obesity susceptibility genes, a
genome-wide linkage scan in Pima Indians was previously completed [32, 33]. The

Polygenic Obesity 17
strongest evidence for linkage with body mass index (BMI) was on chromosome
11q23–24 (LOD ⫽ 3.6) [32], while the strongest evidence for linkage with percentage
of body fat was on chromosome 17q25 (LOD ⫽ 1.9) in a multipoint sibling-based
variance component analysis [33]. The region on chromosome 17q35 seemed to be
particularly interesting since the human fatty acid synthase (FAS) gene was positioned
at 135 cM, within 7 cM of the peak of linkage to percentage of body fat [33]. The FAS
enzyme is necessary for the de novo synthesis of long-chain fatty acids from acetyl-
CoA, malonyl-CoA and NADPH [34]. Recent physiologic studies have shown that
inhibition of the FAS gene induces a rapid decline in fat stores in mice, suggesting a
role for FAS in energy homeostasis [35, 36]. Based on the chromosomal location and
known physiology of FAS, the FAS was investigated as a candidate gene for determin-
ing body weight and percentage of body fat in Pima Indians. In these studies, a novel
Val1483Ile polymorphism was identified, which was associated with percentage of
body fat and 24-hour substrate oxidation rates measured in a respiratory chamber
[37]. These findings indicate that the Val1483Ile substitution in FAS is protective
against obesity in Pima Indians, an effect possibly explained by the role of this gene in
the regulation of substrate oxidation. The effects of Val1483 on obesity have been
recently also investigated in Caucasian children and adolescents. In a cohort of 738
Caucasian children and adolescents and 205 obese children from Leipzig, Germany, a
significant interaction effect between gender and genotype was observed [38]. The
findings in Caucasian children suggest a gender specific protective effect of the
Val1483Ile polymorphism in FAS for obesity and lipid phenotypes in Caucasian boys.
The story of FAS is an example of how combining different approaches may ultimately
lead to novel genetic targets possibly involved in the pathophysiology of human obe-
sity. FAS is not only an excellent candidate gene based on its known biological func-
tion, but also a positional candidate mapped within a region of linkage to percentage of
body fat. In addition, studies in Pima Indians prove that genetically isolated popula-
tions may definitely help in the search for new obesity risk candidate genes.

Candidate Genes

Peroxisome Proliferator-Activated Receptor Gene

The peroxisome proliferator-activated receptor (PPAR)-␥ is a transcription factor
with a key role in adipocyte differentiation, susceptibility to obesity and insulin sensi-
tivity. The common Pro12Ala polymorphism in PPAR␥ is caused by a missense
mutation in exon B of the adipocyte-specific ␥2 isoform. It was identified in 1997 and
is thought to confer reduced transcriptional activity. The Ala allele is associated with
a reduced risk for T2D. The prevalence of the Ala allele varies from about 4% in Asian
populations [39] to about 28% in Caucasians [40]. Several more genetic variants in
PPAR␥ are known but are much less frequent. For example a very rare gain of func-
tion mutation (Pro115Gln) associated with obesity but not insulin resistance and a

18 Körner ⭈ Kiess ⭈ Stumvoll ⭈ Kovacs

loss of function mutation (Val290Met, Pro467Leu) is reported in 3 individuals with
severe insulin resistance but normal body weight [40].
Subsequently, association with T2D was examined and two meta-analyses strongly
suggested that the Pro variant is a risk-allele [41, 42] and is now considered to be one of
the best replicated genetic risk factors of common T2D. Altshuler et al. [41] evaluated 16
published genetic associations of Pro12Ala and T2D in a family-based design. A modest
(1.25-fold) but significant effect on diabetes risk was reported for the Pro allele. Also the
effect size is similar to other common genetic variants implicated in susceptibility for
T2D (4841T/C in CAPN10/OR 1.2, E23K in KCNJ11/OR 1.2, G972R in IRS1/OR 1.25),
but due to the high prevalence of the Pro allele the resulting population attributable risk
of about 25% is much higher for Pro12Ala [43]. Interestingly, so far none of the genome-
wide scans produced linkage with T2D at the PPAR␥ locus on chromosome 3.
A recent meta-analysis of 57 suitable studies containing data related to the insulin
resistance of cohorts with normal or impaired glucose tolerance revealed no signifi-
cant effect of the Pro12Ala polymorphism on diabetes-related traits across all studies
[44]. However, in the Caucasian subgroup BMI was greater in X/Ala compared with
Pro/Pro (p ⫽ 0.015) and HOMA-IR was significantly higher in Pro/Pro compared
with X/Ala in the obese subjects, indicating greater insulin sensitivity in obese carri-
ers of the Ala allele (standardized effect size 0.148, p ⫽ 0.0025), which was supported
by the meta-analysis of Ala/Ala homozygotes. Masud and Ye [45] found a greater
BMI in Ala carriers in obese subjects, but this study included patients with diabetes in
contrast to the meta-analysis of Tönjes et al. [44]. Furthermore, the Pro12Ala geno-
type of the PPAR␥2 gene predicted the conversion from impaired glucose tolerance to
T2D in the STOP-NIDDM trial [46] and in the Diabetes Prevention Program [47].
Also in NGT subjects, the PPAR␥ Ala allele showed a relatively strong protective
effect on the development of hyperglycemia and hyperinsulinemia during a 6-year
period [48]. One study even suggested that already in childhood the effect of the
Pro12Ala on insulin sensitivity may become detectable [49].
Since PPAR␥2 is exclusively expressed in adipocytes, the mechanism(s) through
which the Pro12Ala influences the risk of developing T2D must originate in adipose tis-
sue [50]. The Ala allele has repeatedly been associated with lower insulin concentra-
tions, a crude indication of greater insulin sensitivity. In a comprehensive study looking
at insulin to C-peptide ratios in a variety of clinical experimental tests, the Pro12Ala
polymorphism in PPAR␥2 was found to be associated with a significantly greater
insulin removal from the circulation and significantly lower FFA concentrations during
hyperinsulinemia [51]. Increased insulin clearance could reflect increased hepatic
insulin removal and sensitivity. Both, hepatic insulin clearance and sensitivity could
well be secondary to decreased FFA delivery which has been shown to strongly interfere
with hepatic insulin removal [52]. It is thus possible that the main regulatory effect of
the Ala allele is the more efficient suppression of lipolysis. Using a stepwise hyperinsu-
linemic clamp in combination with a glycerol tracer lipolysis was directly measured and
found to be more insulin sensitive in carriers of the Ala allele [53]. It is also possible that

Polygenic Obesity 19
PPAR␥-mediated adipocytokine release is involved. Adiponectin levels are higher in
subjects with the Ala/Ala genotype compared to the Pro/Ala and the Pro/Pro genotype
[54]. However, studies are not entirely coherent and an interaction of genetic and envi-
ronmental factors in the regulation of serum adiponectin concentrations is assumed
[40]. Adiponectin renders the liver more sensitive to the suppressive effect of insulin on
glucose production [40]. Since adiponectin release is under transcriptional control of
PPAR␥ [55] it represents a plausible candidate for mediating the effect of the Pro12Ala
polymorphism on hepatic insulin sensitivity and clearance. In support of this scenario,
in Pima Indians insulin suppression of glucose production was 40% more efficient in
carriers of the Ala allele while insulin-stimulated glucose uptake was not different [56].
In macrophages, PPAR␥ regulates production of inflammatory mediators, which mod-
ifies vascular inflammation and endothelial dysfunction [50] providing an alternative
scenario of how the polymorphism exerts its effects.

Genes Identified by Genome-Wide Strategies

With the improved accessibility and availability of genome-wide scan platforms and
gene chips, this technique has increasingly been applied to identify new candidate
genes for obesity and diabetes in a relatively short time period over the last 2 years.

INSIG2 – Obesity or Cholesterolemia?

The identification of INSIG2 as an obesity risk gene in the well-characterized
Framingham cohort by a dense whole-genome scan had gained much attention [57].
Even though the authors investigated several independent cohorts of various ances-
tries – and confirmed their finding in 4 out of 5 cohorts – with the obesity-predispos-
ing genotype present in 10% of obese individuals [57], a number of subsequent and
similarly well-performed studies failed to replicate these initial findings [58–61]. It
was concluded that the effect of INSIG2 polymorphisms on obesity may be restricted
to those individuals already predisposed to at least moderate obesity as a result of
environmental factors and other predisposing genotypes. Nevertheless, in a recent
study aimed to validate the original findings, the rs7566605 was investigated in nine
large cohorts from eight populations across multiple ethnicities in a total of almost
17,000 individuals applying several study designs [62]. The study confirmed a signif-
icant but small risk conferred by this allele that could easily be masked by insufficient
sample size, population stratification, or other confounders. Hence, the original asso-
ciation is less likely to be incidental, but the failure to observe an association in every
data set suggested that the effect of SNP rs7566605 in INSIG2 on BMI may be hetero-
geneous across population samples [62].
Besides the results and associations of INSIG2 with obesity, the gene and its
encoded protein may have a role in cholesterol metabolism. INSIG2 was identified as

20 Körner ⭈ Kiess ⭈ Stumvoll ⭈ Kovacs

a susceptibility gene for cholesterol levels in mice applying quantitative trait loci
analyses [63]. Mice with a germline mutation of INSIG2 and a targeted disruption of
INSIG1 failed to repress cholesterol and fatty acid synthesis in response to cholesterol
feeding and subsequent cholesterol accumulation [64]. The underlying mechanism
may be derived from its function as a protein of the endoplasmic reticulum that
blocks the processing of sterol regulatory element-binding proteins (SREBPs),
thereby preventing the proteolytic processing of SREBPs by Golgi enzymes and con-
sequently blocking cholesterol synthesis [65].
Hence, the role of INSIG2 as an obesity risk gene remains a matter of debate, but
the functional interaction with cholesterol synthesis may still impose a relevance for
this gene in obesity-related disease.

ENPP1/PC-1 – Interaction with the Insulin Receptor?

Significant linkage for T2D had been identified on chromosome 6q16.3-q24.2 that
includes the gene locus of the ENPP1 gene [66]. The encoded protein ENPP1/PC-1
(ectonucleotide pyrophosphate phosphodiesterase/plasma cell glycoprotein-1) binds
to the ␣-subunit of the insulin receptor and can inhibit the insulin-induced conforma-
tional changes and autophosphorylation and the tyrosine kinase activation [67].
Pizzuti et al. [68] identified a nonsynonymous K121Q polymorphism in exon 4 of
ENPP1, which was strongly associated with insulin resistance in healthy nonobese,
nondiabetic Caucasians in Sicily. Subsequently, effects of the K121Q variant on insulin
resistance and T2D have been demonstrated in a number of association studies in
adults [69–74]. Further evidence for ENPP1/PC-1 as a candidate in the development
of T2D was derived from in vitro studies showing that the exonic K121Q amino acid
substitution directly inhibited insulin receptor signaling by inhibiting insulin receptor
autophosphorylation [68, 71]. In vivo, overexpression of PC-1/ENPP1 with the q allele
of PC-1 induces insulin resistance and hyperglycemia in transgenic mice [67].
Considering the direct interaction with the insulin receptor and the association of the
gene variant (K121Q) with T2D in adults, ENPP1 had hence been proposed as a dia-
betes risk gene. In addition, positional cloning studies in French families revealed an
association between a three allele ENPP1 haplotype (K121Q, IVS20delT-11,
A/G⫹1044TGA) and childhood obesity [75]. Already at young age, the risk alleles
were associated with a higher risk of glucose intolerance in obese children as well as
increased serum levels of soluble ENPP1 protein in children [75]. Applying a case con-
trol design of obese children and lean controls, the association with childhood obesity
was confirmed, while in a normal population of Caucasian children evaluating BMI as
a quantitative trait there was no association with the risk allele [76]. Nevertheless, the
[Q-delT-G] haplotype was furthermore associated with increased 2-hour plasma glu-
cose concentrations in obese children [76]. Still, the possibility that the Q121 PC-1
variant and obesity itself have independent but additive effects in causing insulin resis-
tance, as has been shown in adults [70], should also be considered.

Polygenic Obesity 21
 In contrast to the studies confirming the association of ENPP1 variants with T2D
and/or obesity [69–74], metabolic syndrome [77] or T2D and coronary artery disease
[78], there are a number of studies that failed to find these associations [79–83], or
even reported contrary results of the 121Q variant being associated with decreased
BMI or risk for T2D [84, 85] in different populations. However, in meta-analyses that
also included these negative studies, the effect of the 121Q risk allele on T2D was
retained [80, 83]. These divergences may be attributed to ethnic differences as has
been shown in US minority groups [86], although the comparison of ethnic popula-
tions did not reveal such differences [69, 84].
Overall, there is evidence from genome-wide studies, from individual association
studies, from an animal model and from in vitro studies for a role of ENPP1 as a risk
factor for T2D and potentially obesity, but the lack of reproducibility in a consider-
able number of studies raises some caution regarding this hypothesis.

FTO: The Strongest Predictor of Obesity

The FTO gene (fat mass and obesity associated) is currently the strongest and most
promising candidate for the association with obesity in adults and children. Two
international consortia independently discovered this association applying different
approaches [18, 19]. In a setup aimed to verify population stratification by testing
intergenic regions, Dina et al. [18] discovered a strong association of a putatively
intergenic SNP (rs1121980) with obesity in a French case-control cohort. This SNP is
localized in intron 1 of the FTO gene on chromosome 16q12.2. Of 23 (intronic) tag-
ging SNPs, 3 were of potential functional relevance estimated by biomathematical
and computational tools. Two of these SNPs (rs1421085 and rs17817449) with high
association with the initially identified SNP were subsequently genotyped in several
adult and childhood obesity cohorts and revealed a strong association with early-
onset and severe adult obesity with p values of 1.67 ⫻ 10⫺26 and 1.07 ⫻ 10⫺24, and
ORs of 1.47 and 1.46, respectively. The risk haplotype yielded a population attribut-
able risk of 22%, representing disease incidence that would be eliminated if exposure
(risk haplotype) was eliminated. Frayling et al. [19] set out to identify diabetes risk
alleles using a 500K chip and identified a significant association of an intronic SNP
(rs9939609) in the FTO gene with an OR of 1.37 for diabetes. This association was,
however, abolished when they controlled for BMI (OR ⫽ 1.03). The subsequent
analyses for association with obesity in almost 40,000 individuals revealed a strong
association with obesity (p ⫽ 3 ⫻ 10⫺35) and an OR of 1.67 for obesity in homozy-
gous carriers. Similarly, the population attributable risk was estimated as 20.4%.
There was no association with birth weight or adult height and no significant associ-
ation with waist circumference or skinfolds as crude indicators of visceral and subcu-
taneous obesity, respectively. Although there are no replication studies (due to the
immediacy of the finding) to date, the finding was indirectly confirmed by recent
genome-wide association studies aimed to identify diabetes risk genes [87, 88].

22 Körner ⭈ Kiess ⭈ Stumvoll ⭈ Kovacs

 Hence, these studies, empowered by high case numbers and several independent
populations, provide evidence for a strong association of FTO with BMI in Caucasian
populations with the strongest association ever observed so far.
It will now be of interest to investigate potential mechanisms underlying this asso-
ciation. The FTO gene encodes for a putative 58-kDa protein with as yet unknown
function that is translated from a 410-kb mRNA with 9 predicted exons [89] and has
no identified structural domain and no network link to any other protein. The pres-
ence of a bipartite nuclear localization signal at the N-terminus may, however, suggest
a role in the nucleus [89]. The expression pattern is ubiquitous [18, 19, 89], including
white adipose tissue, pancreatic ␤-cells, muscle and, particularly, the brain [18, 19]
with a predominant expression in the cerebral cortex [19]. Of interest is also the high
expression level in fetal tissues in humans [19] and at early embryonic development
in mice [90, 91], again both predominantly in the brain. Further evidence for a poten-
tial role for the transcript in brain development is derived from studies of the fused
toes (Ft) mouse strain that has a deletion of a genomic region on chromosome 8
including the homologous region to the human chromosome 16q [91, 92] and hence
the FTO locus. These mice present with severe defects in brain development [91] and
in the patterning of the neural tube [90] that may be mediated by interaction with
sonic hedgehog, Wnt signaling, bone morphogenic proteins pathway and many other
transcription factors (Hesx1, Six3, Pax6, Fgf8) [90, 91]. In addition, heterozygous Ft
mice show a phenotype with growth retardation, deformation of craniofacial struc-
tures, syn- and polydactyly of the limbs, left-right asymmetry (heart), and apoptosis
of immature thymocytes [92, 93]. From these characteristics, the Ft locus was
hypothesized as a candidate gene for programmed cell death, limb and craniofacial
development or left-right asymmetry. There is, however, no report on obesity or
potential metabolic consequences in these mice and hence the mouse model does not
provide explanation for the obese phenotype seen in humans. It also needs to be con-
sidered that the Ft locus includes 6 genes: 3 of the Iroquois gene family (Irx3, Irx5,
Irx6) and 3 genes with unknown function (Fts, Ftm, Fto) [94].
Of interest are, however, some similarities in the Ft mouse phenotype with some
features of the human Bardet-Biedl syndrome (BBS) [95]. These patients present with
early-onset obesity, retinal defects, polydactyly, developmental delay and kidney
problems. Of the 11 chromosomal regions for BBS, one (BBS2) locates to 16q21 and
variants in the BBS2 gene have been associated with adult-onset obesity [96]. So far,
there has been one patient reported in the literature with a deletion of the 16q and
FTO locus, who suffered from obesity, mental retardation, dysmorphic facies, digital
anomalies and anisomastia [97].
In conclusion, the FTO gene is so far the strongest candidate for a genetic predis-
position for obesity from genome-wide association studies. Since there is as yet no
information on the function of the protein and the animal studies and human mono-
genic forms are not conclusive, the mechanism by which FTO mediates the obese
phenotype warrants further functional studies.

Polygenic Obesity 23
From Obesity to Diabetes: TCF7L2 – The Strongest Predictor of T2D
The TCF7L2 gene encodes for a transcription factor (Tcf-4) that is involved in the
regulation of cellular proliferation and differentiation [98].
Variants in the TCF7L2 gene have recently been associated with an increased risk for
T2D in a genome-wide analysis of the isolate population of Iceland [26]. The relative
risk for diabetes of 1.45 for heterozygous to 2.41 for homozygous carriers of the gene
variants was appreciably greater than for most identified genetic factors so far,
accounting for a population attributable risk of 21% [26]. The strongest associations
with T2D were reported for the rs7903146 variant with a clear gene dose effect [99].
Subsequent independent studies in several distinct ethnic populations, all in adults,
convincingly confirmed the initial findings, which was finally evidenced by a large
global meta-analysis [100]. This knowledge is extended by showing that these risk
alleles actually predict the progression from impaired glucose tolerance to diabetes
prospectively [101] and an increased severity of the disease [102] in adults.
Considering these data that suggest TCF7L2 as a major candidate gene for the pre-
disposition to T2D, one may also hypothesize that carriers of those at-risk variants
have an earlier age of onset than noncarriers. In our obese childhood cohort, three
risk variants (rs7901695, rs7903146, rs1225572) were significantly associated with
higher fasting and 120-min blood glucose levels. Although not statistically signifi-
cant, fasting and peak insulin levels and HOMA-IR appeared with a similar tendency
[103]. These data indicate that TCF7L2 variants confer a higher risk for early impair-
ment of glucose metabolism emerging as soon as in childhood and adolescence,
although we cannot directly predict the progression to overt diabetes from these data.
Studies in nondiabetic subjects may, however, help to understand the mechanisms
involved in this progression. While most studies in adults did not identify an associa-
tion of TCF7L2 variants with measures of insulin resistance [101, 104–106], several
studies did observe a defect in insulin secretion [101, 105, 107–109], possibly by
impaired ␤-cell proinsulin processing [110], or a trend for decreased fasting insuline-
mia [109] in subjects carrying the risk alleles. The insulin secretion in type 1 diabetes
or MODY and neonatal diabetes forms are, however, not affected by TCF7L2 poly-
morphisms [111, 112]. The conclusion from these data was that the polymorphisms
affect the capacity of pancreatic ␤-cells to secrete insulin rather than aggravating
insulin resistance. This was further supported by expression data suggesting a puta-
tive role of TCF7L2 in ␤-cell differentiation [109]. A most recent implication exem-
plifies the potential applicability of genetic variants of TCF7L2 in the prediction of
drug response in the sense of pharmacogenomics. Pearson et al. [113] observed that
carriers of the rs12255372 risk allele were less likely to respond to sulfonylureas.
Considering that TCF7L2 as a transcription factor regulates genes involved in pro-
liferation and differentiation, one may hypothesize that early-onset obesity through
increased or dysregulated adipogenesis may constitute one underlying mechanism
[114, 115]. It has been shown that the TCF7L2 interacts with the Wnt/␤-catenin path-
way and may hence constitute a mediator of inhibition of adipogenesis by TNF␣

24 Körner ⭈ Kiess ⭈ Stumvoll ⭈ Kovacs

[116]. Comparing lean and obese children, the risk alleles of rs11196205 and
rs7895340 were less prevalent in the obese childhood cohort, which would be indica-
tive for a decreased obesity risk [103]. Studies in adults did not find an association of
TCF7L2 variants with obesity [105] or reported a tendency for negative association
with BMI [101, 109]. A direct functional mechanism of the five TCF7L2 risk alleles,
all of which are intronic, has as yet not been shown. Tcf-4, the product of TCF7L2, has
been studied as a transcription factor involved in differentiation of certain tissues and
cell types, particularly intestinal cells. Tcf-4 closely interacts with the Wnt/␤-catenin
pathway [117] and as such has implications for the normal development of endocrine
tissues as well as the development of tumors. A downregulation of Tcf-4 results in the
promotion of more differentiated cell type in colonic epithelial cells [118] and
decreased cell proliferation of prostate cancer cells [119]. Indeed, variants in the
TCF7L2 gene have been correlated with breast cancer risk [120]. Several colorectal
cell lines have mutations in the Tcf-4/TCF7L2 gene resulting in an abrogation of the
␤-catenin binding domain, or more often in a decrease in the proportion of the C-ter-
minal isoform with the consequence of reduced transcriptional activity [121, 122].
This appears to translate to the situation in humans where about 40% of colorectal
tumors with microsatellite instability also show alterations in Tcf-4/TCF7L2 gene
[122]. An animal model of TCF7L2 disruption appears to confirm the role for Tcf-
4/TCF7L2 in the differentiation and proliferation of intestinal epithelial cells, but
does not provide any information as to the putatively functional role with respect to
the development of diabetes [123].
In summary, the role of TCF7L2 as a risk marker for diabetes is strong and stably
replicated in many populations worldwide encompassing thousands of individuals.
Some clinical data point to impaired insulin secretion from ␤-cells as the potential
underlying clinical pathomechanism. The precise molecular mechanism underlying
these defects has not been elucidated, although the function of TCF7L2 as a tran-
scription factor is promising for cellular studies in unraveling the underlying mecha-
nisms and potentially intervention strategies, if successful.

New Genes on Stage for Diabetes Identified by Genome-Wide Scans

The power of genome-wide scans involving not thousands but tens of thousands of
individuals facilitated by a high-throughput chip technology impressively demon-
strates how new genes can be discovered by this approach. In addition, the studies
replicated associations of the genes HHEX, SLC30A8, TCF7L2, FTO, PPARG, and
KCNJ11.
In a large scale study, the gene SLC30A8, encoding for a recently newly identified
zinc transporter exclusively expressed in ␤-cells, and two linkage disequilibrium
blocks encompassing the genes IDE-KIF11-HHEX and EXT2-ALX4, both also
potentially involved in ␤-cell development and function, were associated with T2D
[124].

Polygenic Obesity 25
 Notably, three major and most recent studies were intrigued by a high congruency
in the genes identified with an association with T2D.
CDKAL1 is a gene of yet unknown function that shares homology with a CDK5
regulatory subunit-associated protein, which is supposed to inhibit the activation of
cyclin-dependent kinase 5 (CDK5). An association of CDKAL1 with T2D was previ-
ously unknown but similarly identified by all three of these studies [87, 125, 126].
Another chromosomal region associated with T2D was identified near a cluster
involving CDKN2A (cyclin-dependent kinase inhibitor-2A) [87, 125, 126]. This gene,
also known as p16INK4a, was initially implicated in tumor susceptibility, particularly
for melanoma [127]. However, recently mice lacking p16INK4a were reported to
show enhanced islet proliferation and prolonged survival after ␤-cell ablation [128].
The third new candidate with an association with T2D is IGF2BP2 [87, 125, 126].
IGF2BP2, also known as IMP2, is an IGF-II gene mRNA-binding protein that attaches
to the 5⬘ UTR from the translationally regulated IGF-II leader 3 mRNA and causes a
dose-dependent translational repression of IGF-II leader 3-luciferase mRNA [129].
IMPs are expressed in developing epithelia, muscle, and placenta in both mouse and
human embryos [129]. Hence, this gene is interesting with respect to the fundamen-
tal role of IGF-II in embryonic development. Another large-scale genome-wide asso-
ciation study also confirmed an association of TCF7L2, KCNJ11, and PPARG with
T2D [88].
Of particular note is that many of these genes, i.e. HHEX, SLC30A3, CDKN2A,
potentially TCF7L2, and others recently identified [124] can be implicated in the
physiology of pancreatic ␤-cells through effects on embryonic development, regener-
ation or insulin processing.
Certainly, replication in more cohorts and the elucidation of the underlying mech-
anism remain mandatory. Nevertheless, the discovery of previously unsuspected
genes opens up new directions and potentially important insights into the pathogen-
esis of common diseases.

Perspectives: Interactions

Even though some recent approaches have been successful in identifying important
genetic contributors to obesity, these new genes are obviously not much more than just
a few pieces of the puzzle in the complex framework of pathogenic factors contributing
to obesity and it is obvious that many more genes await discovery. The successful iden-
tification of genetically and clinically significant and relevant genetic factors will
require study setups comprising of a large number of individuals with a defined and
well-characterized phenotype, the appropriate controls, the technological platforms
for high throughput analyses, and finally the statistical tools. For this, increasingly,
consortia that comprise a number of cohorts of distinct origin are being established to
identify genetic factors in genome-wide association studies. In order to separate true

26 Körner · Kiess · Stumvoll · Kovacs

associations from false-positive associations, the credibility of genotype-phenotype
association must be confirmed in subsequent replicative studies [130].
If such genetic markers are then identified, more emphasis should be put on the
investigation of underlying mechanisms, i.e. identifying potential causative SNPs and
identifying the cellular and molecular mechanisms, how genetic variation affects
individual’s body weight, energy metabolism and/or obesity-associated morbidity.
These efforts should not be restricted to SNPs that cause an alteration in the amino
acid sequence (nonsynomynous), but should also include the synonymous SNPs.
These formerly disregarded (‘silent’) modifications may be relevant for protein func-
tion by affecting folding of the protein, ribosome trafficking, or alternative splicing
[131]. Even more relevant may be the effects of SNPs in the 5⬘ prime region of genes
that may affect promoter activity and hence transcription efficacy.
It has also to be considered, that genetic predisposition is not restricted to a limited
number of genes but rather a complex network of a great variety of genes. These genes
may directly or indirectly interact at several levels, such as direct gene-gene interac-
tions (for example transcription factor and its binding site), functional interaction of
genes that are (sequential) components of a common pathway, or functional interac-
tions of genes affecting similar biological, cellular, or developmental processes of
metabolism or signaling.
Hence several genes may operate synergistically or behave as modifiers affecting
the phenotype or the severity of disease. Such a multiple hit model has been proposed
for several other complex diseases as for instance holoprosencephaly [132]. The con-
cept of synergistic heterozygosity similarly hypothesizes concurrent partial defects in
more than one pathway and the compound effects of these defects finally determine
the severity of the phenotype [133].
Besides gene-gene interactions, it is also acknowledged that the genetic back-
ground can interact with environmental factors, such as habitual dietary fat composi-
tion or physical activity and thereby affect the predisposition to obesity through
defining an individuals responsiveness to dietary fat intake. Such gene-nutrient inter-
action has been proposed for the Ala12-polymorphism in the PPARg gene [134]
which is supposed to be protective for the development of obesity. However, this ben-
eficial effect is lost in some individuals with a diet rich in saturated fatty acids [135].
As a potential mechanism, a direct interaction of saturated fatty acids and trans fatty
acids on activating the steatosis pathways resulting in insulin resistance has been sug-
gested [136], even though this notion is not undebated. Finally, other environmental
factors may similarly act on the basis of the genetic predisposition. As such, it has
been suggested that in carriers of the Ala allele the association of dietary fat intake
and insulin resistance was modified by the level of physical activity [137].
Epigenetic modifications may provide a plausible link between the environment
and alterations in gene expression finally affecting the phenotype [138]. Epigenetics is
now generally regarded as a change in gene expression not explained by changes in DNA
sequence. Mechanisms include DNA methylation, microRNAs, or histone modifications.

Polygenic Obesity 27
 Given the polygenic etiology of obesity, it has to be considered that the contribution
of the single genes is small. This challenge necessitates sensitive and powerful tools to
detect the significant but sometimes subtle effects of the genes. For future analyses, an
approach that combines the advantages of genome-wide association studies with the
rationale of candidate gene approaches, and further refined by adding information
from microarray and proteomic techniques may be promising for identifying novel
pathways and molecules as well as selecting the significant and relevant genes [139].
Combining the information from several risk factors can allow the identification
of high-risk groups of individuals and may hence have an important role in the initi-
ation of preventative measures for complex (polygenic) diseases such as obesity.
Similarly to what has recently been stated for diabetes, the genetics of obesity is
still a puzzle but no longer a nightmare [17]. Today we know that even the strongest
genetic predictors of obesity are not likely to exceed an odds ratio of 2.0. But we also
know that these predictors combined between themselves and/or with environment
are likely to explain most genetic factors controlling obesity. Identifying these mecha-
nisms remains to be a very exciting challenge.

Acknowledgments

This work was supported by grants from the Deutsche Forschungsgemeinschaft KFO 152:
‘Atherobesity’, projects KO 3512/1-1 (TP 1) and BE 1264/10-1 (TP5), the European Community
integrated project grant ‘PIONEER’, and by the Interdisciplinary Centre for Clinical Research
Leipzig at the Faculty of Medicine of the University of Leipzig (B27 and N06).

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Note added in proof

In a recent study, the putative role of the Fto protein has been unraveled. By means of bioinformatic
analysis [1, 2] and confirmed [1] by functional in vitro experiments, Fto has been shown to act as
an Fe(II) and 2-oxoglutarate oxygenase. With these enzymatic properties, Fto may be involved in
DNA repair, fatty acid metabolism and posttranslational modifications. Further support that this
enzymatic function may be relevant to the regulation of body weight derives from the observation
that Fto mRNA levels were reduced by fasting and not rescued by leptin supplementation.
1 Gerken T, Girard CA, Tung YC, Webby CJ, Saudek V, 2 Sanchez-Pulido L, Andrade-Navarro MA: The FTO
Hewitson KS, Yeo GS, McDonough MA, Cunliffe S, (fat mass and obesity associated) gene codes for a
McNeill LA, Galvanovskis J, Rorsman P, Robins P, novel member of the non-heme dioxygenase super-
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Sedgwick B, Barroso I, Lindahl T, Ponting CP, Ashcroft
FM, O’Rahilly S, Schofield CJ: The obesity-associated
FTO gene encodes a 2-oxoglutarate dependent nucleic
acid demethylase. Science 2007; Epub ahead of print.

Dr. Antje Körner

Research Laboratory, University Hospital for Children and Adolescents
University of Leipzig, Liebigstrasse 20a
DE–04103 Leipzig (Germany)
Tel. ⫹49 341 97 26854, Fax ⫹49 341 97 26009, E-Mail antje.koerner@medizin.uni-leipzig.de

36 Körner ⭈ Kiess ⭈ Stumvoll ⭈ Kovacs

Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 37–60

Genetic Obesity Syndromes

Anthony P. Goldstonea
Philip L. Bealesb
a
MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London
b
Molecular Medicine Unit, UCL Institute of Child Health, London, UK

Abstract
There are numerous reports of multi-system genetic disorders with obesity. Many have a characteristic pre-
sentation and several, an overlapping phenotype indicating the likelihood of a shared common underlying
mechanism or pathway. By understanding the genetic causes and functional perturbations of such syn-
dromes we stand to gain tremendous insight into obesogenic pathways. In this review we focus particularly
on Bardet-Biedl syndrome, whose molecular genetics and cell biology has been elucidated recently, and
Prader-Willi syndrome, the commonest obesity syndrome due to loss of imprinted genes on 15q11–13. We
also discuss highlights of other genetic obesity syndromes including Alstrom syndrome, Cohen syndrome,
Albright’s hereditary osteodystrophy (pseudohypoparathyroidism), Carpenter syndrome, MOMO syn-
drome, Rubinstein-Taybi syndrome, cases with deletions of 6q16, 1p36, 2q37 and 9q34, maternal uni-
parental disomy of chromosome 14, fragile X syndrome and Börjeson-Forssman-Lehman syndrome.
Copyright © 2008 S. Karger AG, Basel

Monogenic Obesity Syndromes

Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS, OMIM 209900) is a highly heterogeneous disorder

inherited in a mainly recessive manner. Clinical features include retinal degeneration,
cognitive impairment, obesity, renal cystic disease, polydactyly and genital hypopla-
sia/malformation. There are numerous secondary craniofacial, endocrine, neurologi-
cal and behavioural features which can assist in early diagnosis (fig. 1) [1]. Although
most infants with BBS are born with normal birth weight, by 1 year most show signs
of significant weight gain. There may be few other signs of the syndrome during
infancy as up to one third of cases do not have polydactyly and signs of visual impair-
ment do not typically emerge until 6–8 years of age (night blindness). The majority of
adults have a body mass index (BMI) 30 often accompanied by hypertension, dys-
lipidaemia and type 2 diabetes mellitus [1].
a b d

c e

Fig. 1. BBS. a, b Post-axial polydactyly in hands and feet of the same child. c Brachydactyly in hands
of an adult. Note the postaxial scars. d High arched palate is common in BBS. e Dental anomalies
frequently include crowded dentition with hypodontia and short roots.

Twelve genes have now been identified for which there is little evidence of any phe-
notype-genotype correlation. The BBS genes (BBS1–12) have few sequence similarities
to each other or other protein groups. Three, BBS6, BBS10 and BBS12 have strong
homology with the type II group of chaperones and account for around 30% of all muta-
tions [2–4]. Only BBS3/ARL6 (a member of the Ras superfamily of small GTP-binding
proteins) and BBS11/TRIM32 (an E3 ubiquitin ligase) encode known proteins [5–7].
Recent evidence suggests that BBS is probably caused by dysfunction of primary
cilia and the intraflagellar transport (IFT) process. All BBS proteins studied thus far
localise to the cilium/basal body/centrosome complex (fig. 2). In mammalian cul-
tured cells several BBS proteins localise either to the basal body and pericentriolar
region or the ciliary axoneme [7–13].
Studies indicate that many BBS proteins function in microtubular processes such
as IFT as demonstrated in several Bbs mouse mutants, in which each develops severe
retinal degeneration similar to patients [11, 14–17]. In photoreceptors, rhodopsin
relies on IFT for transport to the outer segment – in Bbs mutants rhodopsin accumu-
lates in the cell body triggering apoptosis [11, 17]. Anosmia was recently reported in
Bbs1 and Bbs4 mutants arising from depletion of olfactory proteins in the ciliary layer
of olfactory neurones [15]. Subsequently, anosmia was demonstrated in BBS patients,

38 Goldstone · Beales
 PCM-1
CHE-11
OSM-5 (polaris)
IFT particle
Transition fibres

BBS7 BBS8

BBS4
Cargo
Dynein/dynactin
Kinesin

BBS8
BBS7

BBS4

BBS7
BBS8
BBS4
BBS1 Transition zone (basal body)
BBS6
BBS2

BBS3 BBS5

BBS4

Centriolar
satellites Microtubules
BBS4

Centrosome
Centrioles

Fig. 2. BBS proteins. BBS proteins are found in the basal body, centrosome and occasionally the cil-
iary axoneme. Many are directly involved with IFT, a process dependent on the molecular motors,
dynein and kinesin. BBS4 is thought to behave as an adaptor protein, facilitating loading of cargo
prior to dynein (retrograde) transport.

Genetic Obesity Syndromes 39

a novel feature of the syndrome. Finally, repression of Bbs proteins in zebrafish delays
IFT-dependent movement of melanosomes [18].

Obesity and BBS

Obesity is a cardinal aspect of the BBS phenotype, beginning in early childhood and
progressing with age; it is usually associated with the trunk and proximal limbs. A sur-
vey of UK BBS patients identified 72% of adults as overweight (BMI 25) and 52%
defined as obese (BMI 30) [1]. At present, the physiological and biochemical abnor-
malities underlying obesity in BBS are poorly understood. A case-control study
showed no significant differences between resting metabolic rate between obese BBS
and controls suggesting no underlying defect in metabolism [19]. Bbs-deficient mouse
models (Bbs4 and Bbs6) are initially runty at birth but display progressive weight gain
associated with increased food intake, culminating in obesity at ⬃12 weeks [11, 20].

BBS Association Studies

A study by Croft et al. [21, 22] first suggested that heterozygous carriers were at risk
of obesity. Attempts to show that BBS gene sequence variants may be associated with
general non-syndromic obesity have met with mixed success. Reed et al. [23] investi-
gated 17 genetic markers spanning chromosomal regions implicated in five different
obesity syndromes including BBS and BMI in 44 families segregating for non-syn-
dromic morbid obesity. Sib-pair analyses failed to reveal evidence of linkage between
any of the markers and obesity in these families. Amongst 60 Danish white men with
juvenile-onset obesity who were screened for five variants in MKKS/BBS6, no signif-
icant association was found [24]. Another study did not find any association of the
common M390R mutation in BBS1 with obesity among Newfoundlanders [25]. A
recent large population study however, suggests that variations at BBS genes are asso-
ciated with risk of common obesity. Benzinou et al. [26] genotyped 12 variants from
the coding and conserved regions of BBS1, BBS2, BBS4, and BBS6 in 1,943 French-
Caucasian obese subjects and 1,299 French-Caucasian non-obese, non-diabetic con-
trols. A BBS2 polymorphism (SNP) was associated with common adult obesity
whereas the BBS4 and BBS6 SNPs were associated with common early-onset child-
hood obesity and common adult morbid obesity, respectively.

Alström Syndrome

Alström syndrome (ALS, OMIM 203800) is a rare recessive disorder typically pre-
senting with early-onset obesity, hyperinsulinaemia (often with acanthosis nigricans)
and type 2 diabetes mellitus, dilated cardiomyopathy, short stature and male hypogo-
nadism. Infants usually display nystagmus and photophobia, eventually progressing

40 Goldstone · Beales
to cone and rod photoreceptor degeneration making it a key differential diagnosis
with the BBS [27, 28]. It may be associated with hepatic dysfunction, hepatic steatosis
and hyperlipidaemia. In addition, ALS patients develop variable sensorineural hear-
ing loss owing to cochlear neuronal degeneration [28, 29].
Rapid weight gain occurs during infancy but tends to plateau in adolescence with
a truncal distribution. Despite the improvement in adiposity and BMI with age, the
insulin resistance continues to increase and thus ALS may represent a monogenic
model of the metabolic syndrome [29]. There are numerous associated endocrine
disturbances including growth hormone (GH) deficiency and hyper- or hypogo-
nadotrophic hypogonadism in males [30, 31]. Amongst females with ALS, hirsutism,
precocious puberty, and amenorrhoea have been reported. Like BBS up to 50% will
have renal and/or urological dysfunction.
The underlying gene, ALMS1 was discovered in 2002 on 2p13 [32, 33]. Neither the
predicted gene nor protein sequence has similarity to any other genes, although there
are several conserved sequence motifs of limited functional significance. Of interest
are the presence of a large 8-kb exon containing a tandem-repeat domain and in exon
1, a polyglutamic acid/polyalanine tract, the length of which does not appear to impact
on the AS phenotype. There do not appear to be any phenotype-genotype correlations.
ALMS1 is ubiquitously expressed throughout all organ tissues [32], and is a compo-
nent protein of the centrosome with basal body localisation suggesting involvement in
ciliary function and perhaps explaining the phenotypic overlap with BBS [33].
Common variations in the ALMS1 gene were not associated with type 2 diabetes
mellitus in two studies of a Dutch and UK population [34, 35].

Cohen Syndrome

Cohen syndrome (CS, OMIM 216550) patients characteristically have a history of

developmental delay, severe cognitive impairment, and maladaptive behaviour in addi-
tion to a typical facial appearance. They usually have down-sloping palpebral fissures,
mild maxillary hypoplasia, a prominent nasal root, micrognathia, high arching palate,
thick hair and an open mouth expression where the upper lip barely covers the upper
incisors giving the appearance of incisoral prominence [36–38]. Many have micro-
cephaly at birth [39]. CS babies often have low birth weights and failure to thrive owing
to feeding difficulties [36, 37]. Sometime during mid-childhood, patients gain weight
and develop truncal adiposity, although it is rarely severe. Short stature is common.
Delayed puberty is commonly encountered and cases with GH, testosterone deficiency,
hypogonadotrophic hypogonadism, and insulin resistance were reported [36, 40].
CS patients typically develop a progressive retinopathy with early-onset myopia
[36,41]. There is a wide range of additional ocular defects with pigmentary changes
around the macular (giving rise to the typical ‘bull’s eye’ maculopathy) occurring
as young as 3 years of age [36]. A chorioretinal dystrophy with accompanying

Genetic Obesity Syndromes 41

electroretinographic changes is usually evident by 5 years [42]. Progressive visual
field loss with night blindness is present by 10 years.
Neutropenia has a variable but characteristic association with CS. Despite resting
low neutrophil counts, perhaps related to increased neutrophil adhesion, patients
appear to be able to mount relevant responses to bacterial infection and bone marrow
analysis has shown normal cellularity [43, 44].
Mutations in the responsible gene, VPS13B (originally named COH1) were first
identified in Finnish families in whom CS is most commonly found [45]. VPS13B is a
large gene spanning 864 kb of genome with a transcript of 14 kb and an open-reading
frame of 4,022 codons. Although common founder mutations have been observed in
the Finnish and Amish CS population, the positions of mutations in other cases are
variable and without any phenotype correlation. Most of the 70 plus mutations
described so far are non-sense.
The function of VPS13B remains unknown although homologues such as Vps13p
are involved in intracellular vesicular trafficking [46]. Expression of the Vps13B in the
mouse is widespread amongst neurons of the postnatal brain, but has low level
embryonic expression suggesting a role in neuronal differentiation, but not in prolif-
eration [47]. This may explain the postnatal microcephaly seen in CS patients.

Carpenter Syndrome

Carpenter syndrome (acrocephalopolysyndactyly type II, OMIM 201000), most

often presents with pre-axial polydactyly of the feet, craniosynostosis and progressive
generalised or truncal obesity [48, 49]. Patients often have brachydactyly and syn-
dactyly of the hands. It is autosomal recessively inherited. Only some 40 cases have
been described. Additional clinical signs include prolonged retention of primary
teeth and hypodontia. It is therefore one of the differential diagnoses to consider with
polydactyly, obesity and hypodontia, overlapping with BBS. It is likely that the three
sibs reported as cases of BBS by McLoughlin et al. [50] have Carpenter syndrome.
Recently mutations (truncating and missense) were reported in RAB23, encoding
a RAB/GTPase involved in vesicle transport. RAB23 is a negative regulator of sonic
hedgehog signalling and is purported to act with other intermediaries in the cilium
[51]. Therefore, like BBS and ALS, Carpenter syndrome supports a link between cil-
iary function and obesity.

Albright’s Hereditary Osteodystrophy

In the original report of Albright’s hereditary osteodystrophy (AHO, OMIM 103580),

the authors described a child with a short stocky build, round face, short metacarpals
and metatarsals, and numerous areas of soft tissue ossification [52]. She also had

42 Goldstone · Beales
hypoparathyroidism secondary to end organ resistance to parathyroid hormone, a
component of which they termed ‘pseudo-hypoparathyroidism’ (PHP). Since then
several cases of AHO without end-organ resistance have also be reported and termed
‘pseudo-pseudohypoparathyroidism’ (PPHP). PHP is further subdivided into types Ia,
Ib, Ic and type II. The PHP type Ia and PPHP forms of AHO are caused by inactivating
mutations in the tissue-specifically imprinted gene GNAS1 resulting in reduction of
the encoded Gs protein [53].
Despite normal or even low birth weights, 50–65% of AHO patients develop gen-
eralised obesity. The aetiology of the obesity is far from clear but there are a number
of possible mechanisms. The melanocortin receptor (MC4R), mutations in which are
one of the most common causes of genetic obesity, is transduced by Gs, as are many
of the other G-protein-coupled seven transmembrane receptors that mediate anorex-
igenic signals from hormones and other neurotransmitters. Loss of such anorexigenic
signals such as through MC4R should produce hyperphagia, but this has not been
widely studied in obese AHO individuals [54].
The observations that Gs represses differentiation of fibroblasts (3T3L1 pre-
adipocytes) into adipocytes, and patients with PHP1a may have reduced cAMP
responses to -adrenergic stimulation in fat cell membranes, reduced basal and
adrenergic-stimulated glycerol production and reduced circulating levels of nora-
drenaline suggest that increased adipogenesis and reduced lipolysis and sympathetic
activity may also contribute to obesity in AHO [53].

Rubinstein-Taybi Syndrome

Affected patients have a characteristic appearance which includes microcephaly,

down slanting and widely placed eyes, long eyelashes, mild ptosis, posteriorly rotated
ears and a convex nose with the columella protruding below the alae nasi on lateral
view (OMIM 180849). The thumbs and halluces are typically broad and occasionally
bifid. Many patients develop central obesity for which the cause is unknown. Recently
mutations have been found in the CBP gene [55] which encodes a protein that binds
the phosphorylated form of the CREB transcription factor culminating in increased
expression of genes containing cAMP-responsive elements.

Obesity Syndromes with Chromosomal and Imprinting Anomalies

Prader-Willi Syndrome

Prader-Willi syndrome (PWS, OMIM 176270) is the commonest human genetic

obesity syndrome with a lower estimated birth incidence of 1 in 25,000, and popula-
tion prevalence of 1 in 50,000 [56]. Characteristic phenotypes, including several

Genetic Obesity Syndromes 43

 Fig. 3. PWS: from genes to phenotype. a A 17-year-old female with PWS.
With permission from Goldstone [59]. b PWS chromosomal region on
15q11-q13 (not to scale) showing the genetic map of the 2 Mb PWS
region. Imprinted genes are in blue (paternal allele expressed) and red
(maternal allele expressed). Non-imprinted genes are in green. Orange
arrows indicate the area of regional imprint control through the IC at the
5 end of the bicistronic SNURF-SNRPN locus. Vertical bars indicate
snoRNA transcripts and horizontal bars, the relative positions of identi-
fied exons and other transcripts within the SNURF-SNRPN locus. Also
indicated are the overlapping sense and anti-sense transcripts of the
Angelman syndrome (AS) gene, UBE3A, which is located adjacent to the
PWS locus. The black crosses indicate common breakpoint (BP) regions
for deletions. Adapted with permission from Goldstone [59]. a

PWS AS Non-imprinted

?minimal critical region

snoRNAs

B
A

38
HB 437
HB -436

38
HB II-13

II-4
II-4

GABR
II-

HBII-85 (27 copies) HBII-52 (47 copies)

II

HB
HB

P
ND 2
MA 3

3 5 3
L
1

UBE3A
RN
1
2

GE
FIP

P5
PA
PA

cen
MK
GC
CY
NI
NI

tel
BP1 BP2
exons 1-3 4 -10 13-20 21 52 62 63 142 144 148 ATP10C BP3
SNURF SmN PAR-5 PAR-7 IPW PAR-1 PAR-4
UBE3A-AS
PWCR1

SNURF-SNRPN

PWS imprinting centre

b

suggestive of hypothalamic dysfunction, are reduced foetal movement, increased pre-

maturity, neonatal and infantile hypotonia with poor suck and subsequent improve-
ment with age; genital hypoplasia at birth and cryptorchidism; temporary feeding
problems with poor suck and poor weight gain in infancy often needing gavage or
other special feeding techniques; subsequent childhood development of obesity and
then profound hyperphagia (between ages of 1 and 6 years) leading to progressive
morbid obesity into adulthood (fig. 3a); short stature due to GH deficiency and (pre-
dominantly hypothalamic) hypogonadism with incomplete delayed puberty and
infertility; characteristic facial features of narrow bi-frontal diameter, almond-shaped
palpebral fissures and down-turned mouth; small feet and hands with straight ulnar
border; developmental delay with mild to moderate mental retardation; characteristic

44 Goldstone · Beales
behavioural problem with temper tantrums, obsessive compulsive behaviours, skin
picking, stubbornness, rigidity, stealing and lying; central and obstructive sleep
apnoea; eye abnormalities such as esotropis and myopia; thick viscous saliva and
speech articulation defect; high pain threshold; decreased vomiting; altered tempera-
ture sensitivity; scoliosis or kyphosis [57–60].

PWS Genetics
PWS arises from the lack of expression of genes within the paternally derived chro-
mosome 15q11-q13 which are silenced (imprinted) on the maternally derived chro-
mosome [see 59, 61 for references]. These include NDN, MAGEL2, MKRN3
(previously called ZFP127), the SNURF-SNRPN locus which extends over 460 kb
encoding at least 148 exons and several repeating intronic C/D box small nucleolar
RNAs (snoRNAs) including HBII-52 and HBII-85 (fig. 3b).
The finding of patients with smaller microdeletions and balanced translocations
has permitted narrowing of the critical PWS region from 4.5 MB to less than 4.3 kb,
spanning the promoter and exon 1 of the SNRPN gene and demonstrated the impor-
tance of some snoRNAs in the PWS phenotype [61]. The promotor and first exon of
the SNURF-SNRPN gene locus is an integral part of the imprinting centre (IC) in the
PWS chromosomal region (fig. 3b). The mouse PWS gene homologues are particu-
larly expressed throughout the developing brain, particularly the hypothalamus, and
there is also embryonic and post-natal expression of Ndn and Magel2 outside the
brain [62].
The molecular biology of the genes within the PWS critical region has not been
fully established. The SmN product of the SNRPN locus (exons 4–10) is involved in
RNA alternative splicing, but the role of other transcripts from the SNRPN locus,
including IPW, PAR-1, -4 and -7, are poorly defined [61] (fig. 3b). The locus also
encodes an anti-sense transcript for the paternally-imprinted UBE3A gene involved
in Angelman syndrome.
Necdin has a pivotal role in neuronal differentiation and survival, prevention of
apoptosis and axonal growth, and may interact with several neurotrophic and cell
cycle-regulatory transcription factors and hence proapoptotic genes such as TrkA,
p75, E2F1, Cdc2, p53, hnRNP U, and NEFA [59, 63]. Necdin and Magel2 proteins
can both bind to and prevent proteasomal degradation of Fez1, a fasciculation and
elongation protein implicated in axonal outgrowth and kinesin-mediated transport,
which also binds to the BBS protein BBS4 at or near centrosomes [64]. Ndn-
deficient mice exhibit neonatal lethality with respiratory distress; an abnormal res-
piratory rhythm-generating centre in the medulla; increased skin-scraping activity;
improved spatial learning; hypothalamic structural abnormalities with reduced
oxytocin and LHRH cell number (but preserved fertility); abnormal axonal out-
growth and fasciculation in embryos, including serotoninergic, noradrenergic, sym-
pathetic (e.g. diaphragmatic and superior cervical ganglion), retinal ganglion cell,

Genetic Obesity Syndromes 45

and thalamocortical neurons; defective cytoarchitecture of the cuneate/gracile
nuclei; increased apoptosis in spinal cord sensory neurons; and high tolerance to
thermal pain [64–68].
The HBII-52 snoRNA and its mouse homologue MBII-52 have recently been found
to change methylation editing and alternative splicing of the serotonin 5HT2cR recep-
tor pre-mRNA [69, 70]. The functions of the other snoRNAs are currently unknown.
In 75% of cases, there is a 15q11-q13 paternal deletion, in 22% maternal uni-
parental disomy (UPD), in 1–3% imprinting errors due in around 15% of cases to a
sporadic or inherited microdeletion in the IC and, in 1% there is a paternal chro-
mosomal translocation [61]. Imprinting is achieved partly through parent-of-origin
allele-specific methylation of CpG residues, established during or after fertilisation
and maintained throughout embryogenesis. The IC not only plays a role in erasure of
the grandmaternal imprint during spermatogenesis, but also has a role in the postzy-
gotic maintenance of the maternal imprint.
While there are a number of phenotype-genotype correlations between those PWS
patients with deletions versus UPD, particularly in the severity of several neurologi-
cal, cognitive and behavioural phenotypes (including an increased risk of psychosis
in UPD), hyperphagia and obesity do not seem to differ significantly between geno-
types [59, 71].
Due to loss of expression of the non-imprinted P gene, involved in oculocutaneous
albinism, there is a higher frequency of hypopigmentation of skin, hair, and eyes in
subjects with deletions [61] (fig. 3b). Between the two common proximal breakpoints
(BP1 and 2) are four recently identified genes NIPA1 (mutations in which cause spas-
tic paraplegia), NIPA2, CYFIP1 (whose protein product interacts with the fragile X
protein FMRI) and GCP5 (-tubulin complex compenent-5), whose loss might cause
phenotypic differences in those with the larger type 1 versus shorter type 2 deletions
[72, 73] (fig. 3b).

Obesity and PWS

Birth weight is slightly reduced in PWS [74]. The initial post-natal hypotonia, poor
suck and feeding difficulties (often needing special feeding strategies for weeks to
months to prevent failure-to-thrive) in babies with PWS have usually improved signif-
icantly by 6 months of age. Between the ages of 1 and 6 years, there is initially develop-
ment of mild obesity (from around 1 year of age), and subsequent hyperphagia and
more severe obesity (usually developing between the ages of 2 and 6 years of age).
Without appropriate dietary restriction, environmental control and behavioural input
obesity becomes progressive into adulthood, leading to obesity-related morbidity, such
as cardiopulmonary disease, type 2 diabetes mellitus, thrombophlebitis, chronic leg
oedema, and mortality under the age of 35 (fig. 3a). Deaths from choking and gastric
necrosis after overeating have been reported [75, 76]. Obesity-related sleep apnoea is
common and responds to weight loss. The reason for the later onset development of

46 Goldstone · Beales
hyperphagia and severe obesity in PWS compared to monogenic causes of obesity
such as leptin deficiency or melanocortin-4 receptor mutations is unknown.
Obesity management involves early institution of a low-calorie, well-balanced diet,
with regular exercise, rigorous supervision, restriction of access to food and money with
appreciation of legal and ethical obligations, appropriate psychological and behavioural
counselling of the patient and family [77]. Group homes specifically designed for indi-
viduals with PWS, where available, have been particularly successful in management of
these problems during adulthood. Anecdotally, pharmacological treatment, including
available anorexigenic agents, has not been of benefit in treating hyperphagia, though
there are few published control studies. Restrictive bariatric surgery, such as gastric
banding or bypass, have not been shown to reduce hyperphagia or achieve long-term
weight reduction and are associated with unacceptable morbidity and mortality, but
some of the reports using biliopancreatic diversion which produces intestinal malab-
sorption have reported successful weight loss though with frequent complications [78].
Body composition studies show both increased body fat and reduced muscle in
PWS [79]. Magnetic resonance imaging has found that PWS adults of both sexes have
less visceral adiposity than expected for their overall adiposity [80, 81] (fig. 4a). This
may explain the relative hypoinsulinaemia and lower triglyceride levels with preser-
vation of insulin sensitivity and protective elevation in adiponectin levels in patients
with PWS despite their overall obesity [80, 82, 83] (fig. 4b, c).
Obesity, hypersomnolence and persistent poor muscle strength contribute to
reduced physical activity in PWS. Resting metabolic rate is reduced relative to body
size, as a result of the abnormal body composition, which further contributes to a
reduction in 24-hour energy expenditure [79]. Increased physical activity and exer-
cise programs improve body composition in PWS.
Spontaneous or pharmacologically stimulated GH secretion and IGF-I levels are
reduced in PWS children and adults, and the GH deficiency is independent of obesity
[60]. In PWS children, GH therapy is now licensed and significantly improves height
velocity and final height [60, 84]. GH significantly decreases total body fat, increases
lean body mass, lipolysis and resting energy expenditure, and improves physical
strength and agility in children and infants with PWS, and may also have neurodevel-
opmental benefits [60, 84, 85]. There may also be a potential benefit of lower GH
doses to improve body composition in PWS adults.

PWS and Peripheral Appetite Signals

The abnormal feeding behaviour in PWS includes a morbid obsession about food,
food stealing, money stealing to buy food, hording and foraging, pica behaviour,
reduced satiety and earlier return of hunger after the previous meal [86]. Given free
access to food, PWS subjects will consume approximately three times that of control
subjects. The reduced satiation in PWS occurs despite delayed gastric emptying
which would be expected to produce the opposite effect [87].

Genetic Obesity Syndromes 47

a Control PWS

60 5 1,200
Percent body fat

50 b
4 a, b a, b 1,000

Ghrelin (pM)
b b
HOMA-IR

40 800
3
30 a 600 a, b a, b
2 a
20 400
10 1 200
0 0 0
b NO OB CRHO PWS c NO OB CRHO PWS d NO OB CRHO PWS

Fig. 4. Reduced visceral adiposity, preserved insulin sensitivity and hyperghrelinaemia in PWS.
a A T1-weighted MRI scan at the level of the lower abdomen, showing less visceral adiposity in a PWS
adult female (total adipose tissue, AT, volume 86.9 l, MRI total body fat 54.4%, visceral AT 4.4% of total
AT, visceral AT:subcutaneous AT ratio 0.048) compared to a similarly obese control adult female (total
AT volume 86.4 l, MRI total body fat 50.5%, visceral AT 9.3% of total AT, visceral AT:subcutaneous AT
ratio 0.111). With permission from Goldstone et al. [80]. b–d Mean SEM values for percent body fat
(b), homeostasis model insulin resistance index (HOMA-IR; c) and fasting plasma ghrelin levels (d) in
non-obese (NO, n
15) and obese (OB, n
16) controls, craniopharyngioma subjects with hypo-
thalamic obesity (CRHO, n
9) and subjects with PWS (n
26). a p  0.01 vs. PWS, b p  0.01 vs. NO.
Despite similar degrees of obesity, subjects with PWS have increased fasting plasma ghrelin and pre-
served insulin sensitivity, compared to the other two obese groups. With permission from Goldstone
et al. [82].

Subjects with PWS have marked elevations in the stomach-derived orexigenic hor-
mone ghrelin for their obesity, and increased density of ghrelin immunostaining in
the stomach, though plasma levels do fall appropriately after food [82, 88, 89] (fig. 4d).
This may be explained at least partly by their relative hypoinsulinaemia (fig. 4). A
primary importance for hyperghrelinaemia is questioned by the overlap of ghrelin
levels in PWS with lean subjects despite the former’s near ubiquitous hyperphagia,
and the inability of acute normalisation of ghrelin levels in PWS using somatostatin
to reduce appetite [90]. However somatostatin will also suppress secretion of a wide
variety of anorexigenic gut hormones that might counteract any beneficial effect of
lowering orexigenic ghrelin [90]. Fasting and post-prandial levels of the anorexigenic

48 Goldstone · Beales
hormone pancreatic polypeptide are also reduced in PWS children and adults which
may also contribute to hyperphagia [91, 92]. It seems likely that in addition to these
hormonal abnormalities in PWS, there are overriding brain defects, including hypo-
thalamic, which lead to resistance to peripheral satiety signals [59]. Infusion of PP to
subjects with PWS has only a small anorexigenic effect [93]. The possibility of thera-
peutic avenues for reducing hyperphagia in PWS may depend on the existence of rel-
ative rather than absolute resistance to peripheral satiety signals.

PWS and Hypothalamic Abnormalities

Quantitative neuroanatomical studies of available post-mortem human hypothalamic
tissue from subjects with PWS in the Netherlands Brain Bank have yet to find any
pathological abnormalities of orexigenic neuropeptide Y or agouti-related protein,
anorexigenic POMC neurons or GH-releasing hormone neurons in the infundibular
nucleus, or orexin/hypocretin neurons in the lateral hypothalamus, though interpre-
tation may be complicated by small numbers and effects of pre-mortem illness [59,
94–96]. However, appropriate neuropeptide Y, agouti-related protein and GH-releas-
ing hormone changes in illness, obesity and exogenous GH therapy were found in
PWS subjects, suggesting normal neuronal function in their response to alterations in
peripheral signals. Nevertheless, cerebrospinal fluid orexin concentrations have been
reported to be low in cases of PWS with hypersomnia [97].
There is a reduction in total and oxytocin cell number in the hypothalamic paraven-
tricular nucleus (PVN) of PWS adults, which may play a primary causative role in
hyperphagia [98]. Reduced immunostaining of processed vasopressin, its processing
enzyme, prohormone convertase 2, and its molecular chaperone polypeptide 7B2, have
also been found in the PVN and supraoptic nucleus of hypothalami from subjects with
PWS, though diabetes insipidus is not a recognised clinical problem [99, 100]. Oxytocin
and the PVN have anorexigenic roles in rodents. A 29% reduction in PVN oxytocin
neurons is also seen in ndn knockout mice, though these mice are not obese [65].

PWS and Brain Abnormalities

Detailed MR scanning including techniques such as diffusion tensor imaging are
revealing neuroanatomical abnormalities within extra-hypothalamic brain structures
in PWS, such as ventriculomegaly, hypoplastic or displaced pituitary gland, incom-
plete Sylvian fissure/insula closure, Sylvian fissure polymicrogyria, decreased pari-
etal-occipital grey matter and white matter lesions [101–105]. These may play a role
not only in cognitive, behavioural and neuroendocrine defects in PWS, but also
hyperphagia.
Recent functional neuroimaging techniques such as positron emission tomogra-
phy and functional magnetic resonance imaging in PWS have revealed abnormal
brain activation patterns in corticolimbic structures, such as the amygdala, pre-frontal,

Genetic Obesity Syndromes 49

orbitofrontal and insula cortex in response to food stimuli, after ingestion of oral
glucose or a meal [106–109]. These suggest abnormal reward and motivational
responses to food that may also contribute to the hyperphagia in PWS.

PWS Association Studies

Individual gene mutations or segmental deletions or duplications across the PWS
chr15q region have not yet been reported in patients with PWS-like or specific PWS
phenotypes, including severe early-onset morbid obesity, but negative PWS methyla-
tion testing [61, 101, 110]. No linkage of the PWS chromosomal region with obesity
in sibling studies, nor any association of polymorphisms in NDN or MAGEL2 with
obesity in children or adolescents has been found [23, 111, 112]. A genome-wide scan
found linkage of childhood-onset severe obesity in French Caucasian families to
ch15q12–15q15.1, although finer mapping has yet to be reported [113], while weak
linkage of BMI to ch15q13.3 was found in a genome-wide scan from the National
Heart, Lung, and Blood Institute Family Heart Study [114].

Deletion 6q16

Childhood-onset obesity and hyperphagia has been reported in 5 individuals with

deletions involving chromosome 6q16 [see 115 for references]. These patients have
also been reported as having almond-shaped eyes, strabismus, thin upper lip,
microretrognathia, small hands and feet, hypogonadism, learning disabilities, devel-
opmental delay, behavioural problems, cerebellar signs, hypotonia, neonatal feeding
difficulties, providing overlap with features seen in PWS.
Interestingly, the obesity may result from haploinsufficiency for a transcription
factor involved in neurogenesis, SIM1, since obesity (but not the other syndromal
features) has been seen in a subject with a balanced translocation at chr6q16.2 [116].
The sim1 heterozygote knockout mouse is hyperphagic and obese and has a non-
selective loss of hypothalamic PVN neurons [117, 118]. Sim1 is also expressed in
some non-hypothalamic brain regions involved in appetite, sim1 overexpression pro-
tects against diet-induced obesity and sim1 may mediate some of the anorexigenic
action of the melanocortin pathways [119, 120].

Deletion 1p36

Obesity and/or hyperphagia has also been reported in 23% of 14 evaluated patients
with monosomy 1p36, in whom developmental delay, hypotonia, growth delay, feed-
ing difficulties in infancy, epilepsy, hearing loss, hypermetropia, orofacial clefting
abnormalities, structural heart defects and dilated cardiomyopathy, micro- and

50 Goldstone · Beales
brachycephaly, deep set eyes, flat nasal bridge and nose, pointed chin, thickened ear
helices, asymmetric ears and short fifth finger are also reported [121].

Deletion 2q37

In mid-1990s, several patients with an AHO-like phenotype and a deletion of 2q37

were reported [122, 123]. Characteristically they have a round face with deep set eyes,
a bulbous nasal tip, thin border of the lips, and sparse hair. Many have seizures with
mild cognitive impairment and obesity is occasionally present. Cytogenetic analysis
of further patients has narrowed the deleted interval down to a region including the
G-protein-coupled receptor 35, glypican 1, and serine/threonine protein kinase 25
genes; the importance of each remains to be investigated [124, 125].

Deletion 9q34.3

A de novo terminal deletion of chromosome 9q34.3 has been reported in 2 unrelated

children with early-onset obesity with hyperphagia (between 2 and 3 years old) and
mental retardation, severe developmental delay, neonatal hypotonia, distinctive facial
features (brachycephaly, synophrys, anteverted nostrils, prognathism, thin upper lip),
short neck and extremities, syndactyly of toes, abnormal genitalia with cryp-
torchidism, micropenis, and hypospadias, sleep disturbances with repeated night
awakenings, stereotypic hand movements, short attention span and intolerance to
frustration [126]. However obesity was only seen in 2 of 13 other patients with 9q34.3
deletions, though 3 did die as infants with congenital heart abnormalities [127, 128].
The deleted region encompasses at least 20 genes.

Maternal UPD of Chromosome 14

Maternal UPD 14 (when both of a chromosome 14 pair are inherited exclusively

from mother) is associated with muscular hypotonia, feeding problems, hypercho-
lesterolaemia, characteristic rib anomalies (referred to as the ‘coat-hanger’ sign),
motor delay, small hands and feet, precocious puberty and truncal obesity [129,
130]. Patients with UPD(14)mat show features overlapping with PWS and are prob-
ably underdiagnosed. In a recent study of 33 patients with low birth weight, feeding
difficulties and subsequent obesity in whom PWS had been excluded by methyla-
tion analysis of SNRPN, 12% were found to have UPD(14)mat [131]. Facially,
patients display a prominent forehead, prominent supra-orbital ridges, short
philtrum and down-turned corners of the mouth. The cause of the obesity is
unknown.

Genetic Obesity Syndromes 51

X-Linked Obesity Syndromes

Fragile X Syndrome

Fragile X syndrome (OMIM 300624), a common cause of mental retardation, is

caused by an unstable expansion of a triplet repeat in the FMR1 gene. A sub-pheno-
type, resembling PWS has been reported with extreme obesity, a round face, small,
broad hands/feet, and regional skin hyperpigmentation [132, 133].

Börjeson-Forssman-Lehmann Syndrome

Börjeson-Forssman-Lehmann syndrome (BFLS, OMIM 301900) is a rare X-linked disor-

der characterised by severe cognitive impairment, obesity with gynaecomastia, hypogo-
nadism, a course facial appearance and large fleshy ears [134]. BFLS individuals are
usually born with a normal birth weight but by late childhood have developed signifi-
cant truncal obesity. Although there is considerable variability in the degree of obesity,
those with less generalised adiposity have a tendency to a female-type fat distribution
around the lower abdomen and hips. Almost all BFLS patients develop gynaecomastia
often in childhood but significant enlargement occurs at or after puberty, both from
obesity and breast tissue. Multiple pituitary hormone deficiencies have been reported
including GH, TSH, ACTH and gonadotrophin deficiency, and optic nerve hypoplasia
[135]. These features suggest that the BFL gene product may play an important role in
midline neuro-development including the hypothalamo-pituitary axis. The facial
appearance in post-pubertal patients is striking with deep-set eyes, prominent supra-
orbital ridges, narrow palpebral fissures features which coarsen with age. The majority
also have hyperextensible tapering fingers which like their toes are shortened.
Positional cloning led to the identification of PHF6 as the genetic cause of BFLS
[136]. Its expression is ubiquitous, suggesting an important cellular role. Studies show
that the PHF6 protein is localised in the cell nucleus and in the nucleolus, and it has
been speculated that PHF6 might have a role in cell growth and proliferation, via its
participation in ribosome biogenesis [137].
To date, 19 unrelated cases of BFLS with confirmed PHF6 gene mutations have
been reported [137]. Amongst these, twelve different mutations have been found of
which five are recurrent thus aiding molecular diagnosis for this syndrome. Several
manifesting female carriers have been reported with mild to moderate intellectual
impairment, the characteristic facial phenotype, large ears, obesity and short stature.
Nonetheless, many female carriers have a normal phenotype. Although it is more
likely for a PHF6 mutation carrier female to have skewed X inactivation, there are
also families where the X inactivation is random [138]. There is no obvious correla-
tion between X inactivation skewing and the variability of clinical presentation of the
BFLS phenotype in carrier females.

52 Goldstone · Beales
Obesity Syndromes without Identified Genetic Cause

Macrosomia, Obesity, Macrocephaly, and Ocular Abnormalities

Moretti-Ferreira et al. [139] reported 2 unrelated children with similar clinical fea-
tures comprising truncal obesity, mental retardation and retinal coloboma and nys-
tagmus (MOMO, OMIM 157980). Facially, features were unremarkable with
hypertelorism, downslanting palpebral fissures, a prominent forehead, and a broad
nasal root. A potential third case was reported by Zannolli et al. [140] describing a 5-
year-old girl with mild learning impairment, morbid obesity, macrocephaly, right
optic disc coloboma and left choroidal coloboma, and recurvation of the femur. The
cause is unknown.

Conclusions

Although in many of the aforementioned obesity syndromes the underlying genetic

cause has not yet been identified, in others these are providing potential insights
into biochemical or developmental pathways involved. For example, in BBS, AS and
CS there is considerable phenotypic overlap. In BBS, AS and possibly Carpenter
syndrome, ciliary dysfunction has been implicated and recently the function of pri-
mary cilia has been directly linked with obesity [141]. Study of PWS has identified
mechanisms of genetic imprinting, genes involved in neuronal development and
growth, and hormonal, hypothalamic and cortical circuits that may be important in
appetite and body weight control. By defining the genetic cause of all obesity syn-
dromes we should enrich our understanding of obesogenic pathways in common
obesity.
It is anticipated that the use of array-based comparative genomic hybridisation in
patients with morbid obesity syndromes, often associated with mental retardation,
developmental delay and dysmorphic features, will identify novel chromosomal
regions and genes involved in body weight regulation, for example ch7q22.1–22.3
deletion and ch19q12q13.2 trisomy [142, 143]. However, care will need to be taken
with assigning causality given the frequent presence of gene copy number polymor-
phisms between individuals.

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Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 61–72

Fetal and Neonatal Pathways to

Obesity
Peter D. Gluckmana,c ⭈ Mark A. Hansond ⭈
Alan S. Beedlea ⭈ David Raubenheimera,b
a
Centre for Human Evolution, Adaptation and Disease, Liggins Institute, bSchool of Biological Sciences,
University of Auckland, and cNational Research Centre for Growth and Development, Auckland,
New Zealand; dInstitute of Developmental Sciences, University of Southampton,
Southampton, UK

Abstract
Evolutionary and developmental perspectives add considerably to our understanding of the aetiology of
obesity and its related disorders. One pathway to obesity represents the maladaptive consequences of an
evolutionarily preserved mechanism by which the developing mammal monitors nutritional cues from its
mother and adjusts its developmental trajectory accordingly. Prediction of a nutritionally sparse environ-
ment leads to a phenotype that promotes metabolic parsimony by favouring fat deposition, insulin resis-
tance, sarcopenia and low energy expenditure. But this adaptive mechanism evolved to accommodate
gradual changes in nutritional environment; rapid transition to a situation of high energy density results in
a mismatch between predicted and actual environments and increased susceptibility to metabolic disease.
This pathway may also explain why breast and bottle feeding confer different risks of obesity. We discuss
how early environmental signals act through epigenetic mechanisms to alter metabolic partitioning, glu-
cocorticoid action and neuroendocrine control of appetite. A second pathway involves alterations in fetal
insulin levels, as seen in gestational diabetes, leading to increased prenatal fat mass which is subsequently
amplified by postnatal factors. Both classes of pathway may coexist in an individual. This developmental
approach to obesity suggests that potential interventions will vary according to the target population.
Copyright © 2008 S. Karger AG, Basel

A large body of research has focused on the environmental, physiological and bio-
chemical mechanisms that underlie the susceptibility of humans to obesity [1]. At the
most general level, obesity results from an imbalanced energy budget, where energy
intake chronically exceeds energy expenditure. This may result from poor nutritional
environment (imbalanced diet), weak or deranged satiety signals (overeating), effi-
cient energy storage or reduced energy output (disinclination to exercise or reduced
adaptive thermogenesis [2]).
 Over recent years, there has been a growing trend towards considering obesity and
related medical problems in the context of human evolutionary ecology. In an early
application of this approach – the ‘thrifty genotype hypothesis’ – Neel [3] proposed
that regional differences in the propensity of human populations to store ingested
energy are a consequence of evolutionary adaptation to different ancestral environ-
ments. In this hypothesis, obesity results from a gene-environment interaction, such
that in hypocaloric ancestral environments humans accumulated ‘thrifty’ alleles of
genes associated with energy partitioning and in modern hypercaloric environments
these alleles cause excess energy storage. Although individual variation in obesity
does have a strong genetic component [4], several lines of evidence now suggest that
the thrifty genotype hypothesis cannot account for the temporal and spatial variation
in the incidence of human obesity [5, 6].
Current information thus suggests that there is a substantial developmental compo-
nent to obesity, such that humans are genetically predisposed to develop susceptible phe-
notypes in response to some developmental circumstances but not others. Those with a
developmentally determined susceptible phenotype will develop obesity if exposed to
hypercaloric environments, whereas those with a non-susceptible phenotype will not
become obese in the same environments. Such explanations do not diminish the
explanatory role for evolution, but refine it to consider also those aspects of human
development that favour energy accumulation and disfavour energy expenditure.
Two major developmental pathways can lead to obesity. First is an adaptive path-
way by which signals in early life act through the processes of developmental plastic-
ity to increase the adipogenic potential of exposure of the organism to a high
postnatal nutritional load. We term this the ‘mismatch pathway’, and it may have mul-
tiple forms. Second is a pathway that is likely to be pathogenic in its origin, namely
the effects of fetal hyperinsulinaemia leading to increased fetal fat mass which is then
amplified after birth. This is most typically seen in infants of diabetic mothers. It is
less clear whether maternal adiposity without diabetes induces a similar biology.
These pathways may coexist in individuals and across generations.
In this chapter, we primarily focus on the mismatch pathway and explore the concept
that obesity and metabolic syndrome are the maladaptive consequences of an evolution-
arily preserved mechanism by which environmental influences early in development set
the life course of the organism. We will focus on how such influences can programme
contributors to obesity such as altered energy partitioning and altered neuroendocrine
control of appetite. We will consider environmental signals arising from the fetal envi-
ronment (both undernutrition and overnutrition) and from the neonatal environment.

Patterns of Fat Deposition in Humans

Although humans are the fattest mammals at birth, averaging about 15% fat [7], there
is substantial variability that is related to intrauterine nutrition. Importantly, the

62 Gluckman · Hanson · Beedle · Raubenheimer

variability appears to be in subcutaneous fat, while visceral fat, which represents a
separate metabolic compartment characterised by portal drainage and heightened
susceptibility to lipolysis, is preserved in growth-restricted infants [8]. Fat deposition
continues during the first 6 months of life, with maximum adiposity at about the age
of weaning. Post-weaning growth is characterised by a relative increase in lean body
mass and minimum adiposity is attained in late childhood; fat deposition then
increases (the ‘adiposity rebound’) prior to puberty [7]. Adolescence in both sexes is
associated with a further relative increase in lean mass, but sexual dimorphism in
body composition is accentuated during pubertal development. Infant, childhood
and pre-pubertal fatness are correlated, and adolescent body mass index predicts
that in the adult, but the links between childhood and adult adiposity are much
weaker [9].
Although the thrifty genotype hypothesis postulated that the human ability to
deposit fat as an energy buffer arose as a result of feast and famine cycles during long
periods as hunter-gatherers, recent evidence suggests that the hunter-gatherer nutri-
tional supply was relatively assured [10] and that major selective pressure arising
from such cycles may only have arisen relatively recently during the seasonal fluctua-
tions associated with agriculture [6]. Indeed, the opposing cycles of energy expendi-
ture and energy supply associated with modern subsistence agriculture result in
marked fluctuations of body mass [11].
Explanations for the extreme early adiposity of human infants invoke protection of
the energy supply of the large human brain from nutritional stress caused by post-
weaning infections [7]. Adiposity declines towards mid-childhood, at a time when
the relative demand of brain metabolism has decreased, again arguing that its func-
tion is not to act as a buffer against nutritional uncertainty.

Effects of Adverse Fetal Environment

There is much epidemiological support for the ‘developmental origins of disease’

hypothesis linking an adverse fetal environment, often but not necessarily manifested
as low birth weight, with later risk of metabolic and cardiovascular disease [12].
Within that evidence are specific observations linking impaired fetal nutrition with
obesity [13, 14] and insulin resistance [14, 15] in later life, and with relative central
adiposity at birth [8] and in late adulthood [16]. Hales and Barker [17] proposed that
the link between intrauterine insult and later pathology could be explained by the
fetus adopting a ‘thrifty phenotype’, making immediate adaptations (such as muscle
insulin resistance) that result in more efficient energy utilisation and ensure survival
in utero and the postnatal period but that have deleterious consequences later in life.
However, several observations do not fit easily within this hypothesis. First, there is a
continuous variation of disease risk with birth weight even within the normal range [18],
implying that the processes involved represent some aspect of normative physiology

Fetal and Neonatal Pathways to Obesity 63

rather than survival responses triggered by extremes of intrauterine environment.
Second, alterations in developmental trajectory induced by prenatal cues are not nec-
essarily deleterious: children born after in vitro fertilisation show reduced adiposity
and heightened insulin sensitivity compared with their normally conceived siblings,
implying that developmental responses need not be ‘thrifty’ [19]. Third, growth-
restricted infants fail to demonstrate insulin resistance at birth, with impaired insulin
sensitivity only appearing later in life [20, 21], an observation that is difficult to rec-
oncile with the mechanistic argument.
Numerous animal models have shown that manipulation of fetal nutrition, for
example by maternal global undernutrition or protein restriction, can lead to out-
comes that mirror those observed in epidemiological studies and are typical of those
seen in human obesity [22, 23]. Such outcomes include central and peripheral com-
ponents such as insulin resistance, obesity, sarcopenia, hyperphagia, altered food
preferences and reduced locomotor activity [24–26]. Such manipulations in animals
of uniform genetic background provide little support for a primarily genetic origin of
later metabolic disease.
The ‘thrifty phenotype’ model is adaptive in that it implies survival advantage
for the induced trajectory. We have recently extended this model to overcome the
limitations suggested above by incorporating developmental plasticity, a well-
established concept in comparative biology. Plasticity implies that the developmen-
tal trajectory is sensitive to the environment and that a given genotype can produce
a number of alternative phenotypes in different environments [27]. We note the
numerous examples in animal physiology where developmental choices in
response to environmental cues have advantages for the individual’s survival or
fitness not immediately, as would follow from the ‘thrifty phenotype’ model, but
at some later time [28]. We have termed such processes ‘predictive adaptive
responses’ [29]. Our model suggests that the mammalian fetus is able to ‘predict’ its
future environment from nutritional cues provided by the mother and adjusts its
developmental trajectory accordingly to best match its physiology to that environ-
ment. For example, if it predicts that the environment will be nutritionally sparse,
then the adult phenotype will be adjusted in the direction of metabolic parsimony
by, for example, favouring fat deposition, insulin resistance, sarcopenia and low
energy expenditure [30].
This predictive model can be enhanced in a number of ways. The cues that the
developing mammal receives from the mother may reflect not only nutritional condi-
tions during the pregnancy but also those at conception and during lactation.
Maternal nutritional status at conception integrates her own life history and nutri-
tional status in the years prior to conception, and possibly those of her own mother
[31, 32], whereas responsiveness to cues during lactation will extend the period of
plasticity beyond the uterus [33]. The prediction may affect not only the metabolic
phenotype but can also extend to other life history traits such as reproduction [34].
Moreover, the fidelity of the predictive cue need not necessarily be high as long as the

64 Gluckman · Hanson · Beedle · Raubenheimer

costs of a wrong prediction are relatively low [35]. In an evolutionary environment of
nutritional uncertainty, with a restricted lifespan in which age-related metabolic dis-
ease would have been rare, a ‘fail-safe’ prediction of a sparse environment would not
have been disadvantageous. But in a modern environment of high energy density and
low energy expenditure, with a lifespan extended by improved public health, a mis-
match between predicted and actual nutritional environments will result in metabolic
disease. This effect will be much more apparent in societies undergoing rapid nutri-
tional transition, because the large disparity between the predicted (customary)
nutritional environment and the realised (hypercaloric) environment would impact
on a single generation.
Even in a historically well-nourished society, such disparity may arise from
maternal constraint [36]. Mammalian fetal size is constrained in all pregnancies by
two factors: first, by the operation of parent-offspring conflict [37], through which
the fetus seeks to maximise and the mother to limit maternal investment in any one
pregnancy cycle, and secondly by the need for birth through the pelvic canal. A
large head size and the anatomical constraints placed on the pelvic canal by
bipedality make the latter factor particularly important in humans [38]. Constraint
may act through imprinted genes regulating processes associated with fetal size,
such as growth factors or placental nutrient transporters [39], or more directly by
limitations on uterine size or blood flow; these latter factors are strongest in primi-
parous or adolescent pregnancies and in those of smaller mothers [36]. But the
fetus will interpret reduced nutrient supply arising from limitation of placental
transport or perfusion as a signal of a sparse environment and alter its developmen-
tal trajectory towards metabolic parsimony, again resulting in a mismatch between
the predicted and actual nutritional environments. Other spurious signals can arise
from processes such as maternal smoking that restrict nutrient transfer across the
placenta [40], thus ‘misinforming’ the fetus that it will be born into a nutritionally
lean environment.
The consequences of constraint could be tolerated within the range of environ-
ments experienced through our evolutionary history. But the recent shift in nutri-
tional exposure may be entirely novel in evolutionary terms; that is, we are exposed to
energy load well beyond our evolutionary experience. Neel [3] posited that such evo-
lutionary novelty would generate disease risk because of the repertoire of genes we
have been selected for; maternal constraint implies a limit on the environment that
can be predicted and creates an epigenetic rather than genetic explanation of the con-
sequences of encountering this environmental novelty [30].
Although we are here emphasising the importance of developmental processes in
the aetiology of chronic non-communicable disease, it is clear that the correlation
between environment and phenotype can be modified by genetic factors. For exam-
ple, polymorphisms in the peroxisome proliferator-activated receptor-␥2 gene inter-
act with the prenatal environment, as reflected by birth weight, to influence later risk
of insulin resistance and type 2 diabetes [41].

Fetal and Neonatal Pathways to Obesity 65

Effects of Fetal Overnutrition

Infants of diabetic mothers are born relatively obese as a result of maternal hypergly-
caemia, which causes fetal hyperglycaemia and in turn fetal hyperinsulinaemia which
then promotes fat deposition in the fetus and macrosomia at birth. This overweight
tracks through into childhood and is exacerbated by maternal obesity [42]. The
resulting metabolic derangements persist into adulthood and are transmitted to the
next generation via disturbance of the intrauterine environment. There is experimen-
tal and epidemiological evidence for such transgenerational effects [43–45].
The mismatch pathway may well lead to offspring who, because of the inherent
insulin resistance of pregnancy, are predisposed to develop gestational diabetes, and
in turn their own offspring may have obesity because of the hyperinsulinaemia path-
way [46]. The two pathways can coexist in such circumstances, and this appears to be
frequent in the Indian subcontinent where small maternal size drives maternal con-
straint but with better gestational nutrition and rising rates of gestational diabetes.
The consequence is that maternal diabetes is associated with functional fetal macro-
somia at birth weights considered normal in Caucasian populations [47, 48].

Effect of Infant Nutrition

Epidemiological evidence suggests that both excessive weight gain early in life in
infants of normal birth weight [49–51] and accelerated weight gain (so-called ‘catch-
up’ or ‘compensatory’ growth) in infants of low birth weight [52] may predispose to
later obesity. Such accelerated weight gain represents an increment in central adipos-
ity rather than musculoskeletal growth [53]; the rise in central adiposity continues in
early childhood even after normalisation of weight-for-age in late infancy and is asso-
ciated with the development of insulin resistance [21]. The apparent protective effect
of breastfeeding against obesity in later life [54] may reflect the lower energy density
of human breast milk compared with formulations based on cows’ milk.
These phenomena may represent additional forms of the mismatch pathway – in
which the postnatal environment is inappropriate for the environment determined by
the level of maternal constraint and where the level of nutritional exposure is in
excess of that predicted in utero.

Mechanistic Considerations

Basic Mechanisms
There is considerable evidence that the mechanisms of developmental plasticity are
underpinned by developmental epigenetic processes, as reviewed in depth elsewhere [55,
56]. These are the processes by which access of transcription factors to DNA is altered by

66 Gluckman · Hanson · Beedle · Raubenheimer

chemical modification of DNA or histones in precisely controlled processes such as
methylation of CpG islands. Experimentally, the mismatch pathway has been shown to
be associated with a number of specific epigenetic changes [57, 58]. As the mismatch
pathway is adaptive in origin, although maladaptive in consequences, it involves multiple
systems [30]. In contrast, it seems likely that the hyperinsulinaemia pathway operates
through the pleiotropic effect of insulin to drive adipose tissue development [59].

Metabolic Partitioning
The correlation between an adverse fetal environment and the subsequent develop-
ment of insulin resistance is well established [60], and hyperinsulinaemia subsequent
to insulin resistance will promote fat deposition. In turn, the marked susceptibility of
central adipose tissue to lipolysis will result in release of free fatty acids, which
increases insulin resistance [61]. A parallel study in low birth weight humans and
growth-restricted rats showed reduced muscle expression of specific insulin-sig-
nalling proteins, including protein kinase C-␨ and the glucose transporter GLUT4, in
affected individuals [62], providing a potential mechanism for the insulin resistance
seen in this setting. Dulloo [53] has proposed that preferential deposition of ‘catch-up
fat’ is an evolved mechanism for rebuilding adipose stores after nutritional restriction
and that such redistribution of glucose from skeletal muscle to adipose tissue is medi-
ated by suppression of muscle thermogenesis. Experimentally, prevention of early
catch-up growth reversed the development of glucose intolerance and obesity in a
mouse model of diabetes caused by maternal undernutrition [63].

Glucocorticoids
Resetting of the hypothalamic-pituitary-adrenal axis has been proposed to underlie
many of the phenomena caused by an adverse fetal environment [64], and indeed alter-
ations in basal and stimulated cortisol secretion can be correlated with birth weight in
humans [65]. Although adipose tissue is responsive to glucocorticoids and excessive
glucocorticoid exposure causes central obesity, dyslipidaemia and insulin resistance,
circulating glucocorticoid levels are often not significantly raised in obesity [66].
However, tissue exposure to glucocorticoids is controlled not only by circulating hor-
mone levels but also by tissue levels of the glucocorticoid receptor and tissue activity of
the two enzymes that interconvert active and inactive glucocorticoids, namely 11␤-
hydroxysteroid dehydrogenase (11␤HSD) types 1 and 2, respectively. Visceral adipose
tissue has increased levels of 11␤HSD1, suggesting that local glucocorticoid action may
be amplified in this tissue, and experimental manipulation of levels of 11␤HSD1 affects
propensity to diet-induced obesity [66]. These effects are mimicked by nutritional
restriction during gestation, which increases levels of the glucocorticoid receptor and of
11␤HSD1 and decreases levels of 11␤HSD2 in the offspring [67], enhancing adipose
tissue sensitivity to glucocorticoids in association with greater adiposity.

Fetal and Neonatal Pathways to Obesity 67

Neuroendocrine Control of Appetite
Numerous experimental studies have found that derangement of early nutrition,
either prenatally or postnatally, can have effects on central components of appetite
control, food preference and locomotor activity. In humans, leptin levels are higher in
infants [68] and adults [69] born small, indicating leptin resistance, and there is evi-
dence that infant overnutrition can result in increased leptin levels later in life [70],
suggesting that early nutritional experience can affect leptin synthesis or secretion by
adipocytes. The adipoinsular axis of insulin and leptin secretion links body fat mass
to the function of pancreatic ␤-cells [71], but is disturbed in animals subjected to
maternal undernutrition [72] which develop hyperphagia, leptin resistance and
reduced locomotor activity, especially if subjected to high-fat feeding after weaning
[24, 25]. Exposure in utero to a low-protein diet affects locomotor activity and feed-
ing behaviour in ageing rats [73]. At least in rodents, neural connections involved in
regulation of appetite control are not completed until shortly before weaning, and
both prenatal overnutrition of the maternal-fetal unit, as imposed by gestational dia-
betes [74] or maternal overfeeding [75], and postnatal overfeeding, achieved by
reducing litter number [76], alter the hypothalamic neuronal circuitry and levels of
various appetite-regulating neuropeptides. These effects of the early nutritional envi-
ronment on central aspects of appetite control may underpin some of the associations
reported in humans between early nutrition and later obesity [49, 54].

An Evolutionary Coda

Environmental change, resulting from natural events or migration, was a key driver
of human evolution, and there is paleoclimatic evidence that such change would have
been felt across several generations rather than over a short time-frame [77]. In such
an environment, ‘adaptive versatility’ [77] or ‘forecasting’ [78] using well-established
mechanisms of developmental plasticity would have been valuable in allowing more
rapid adaptation to changing nutritional conditions than possible by genetic means
alone, and integration of the cue across several generations [31] would tend to
increase the fidelity of the prediction. An adaptive mechanism to counter a predicted
sparse environment would be likely to have effects not only on metabolism, for exam-
ple a tendency to deposit fat and reduce energy expenditure, but also on other aspects
of the individual’s life history, such as reproductive strategy and longevity, and such
effects can be observed [30]. But if the prediction is faulty and the individual cannot
adjust, as would occur if there is a major shift in the environment between early child-
hood and adulthood, then the mismatch between phenotype and environment will
lead to disease. Such effects are seen most clearly when individuals move rapidly
between environments [14, 79] or when their society undergoes rapid nutritional
transition [80]. If the later environment does match the prediction, even at a low
plane of adult nutrition [81], then the risk of disease is less. But a continued high

68 Gluckman · Hanson · Beedle · Raubenheimer

plane of energy-dense nutrition coupled with low energy expenditure, a situation
which would have been encountered only rarely if at all during human evolution, will
also have deleterious effects via the cycle of maternal hyperglycaemia and increased
fetal adiposity. In contrast, gestational diabetes is likely to be a novel phenomenon
over evolutionary time; its emergence is dependent on better nutrition and better
medical care, and does not fit an adaptationist model. Thus, both adaptive and non-
adaptive pathways to developmental obesity coexist in modern populations.
In summary, a developmental and evolutionary perspective explains several
aspects of the human obesity epidemic. We propose that adaptive mechanisms that
have evolved to accommodate gradual changes in nutritional environment are unable
to adjust to a rapid transition to a situation of high energy density. This knowledge
provides us with another way of thinking about individual and population health
interventions to prevent obesity, particularly in the developing world where optimisa-
tion of maternal health before and during pregnancy may help to reduce the mis-
match between intrauterine and adult environments. In the developed world,
interventions to reduce energy intake and increase energy expenditure remain para-
mount, and again a focus on maternal nutrition during pregnancy may be of value to
reduce intergenerational transmission of metabolic imbalance. Finally, the demon-
stration of reversibility of intrauterine metabolic programming in an animal model
by neonatal leptin treatment [82] suggests the possibility of pharmacological or nutri-
tional interventions during the plastic phase of early life.

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Front Horm Res. Basel, Karger, 2008, vol 36, pp 73–84

Developmental Origins of Obesity

and the Metabolic Syndrome:
The Role of Maternal Obesity
James Andrew Armitagea,b ⭈ Lucilla Postonc ⭈
Paul David Taylorc
a
Department of Anatomy and Developmental Biology, Monash University, Clayton, and
b
Division of Cardiovascular Neuroscience, Baker Heart Research Institute,
Melbourne, Australia; cMaternal and Fetal Research Unit, Division of Reproductive Health,
Endocrinology and Development, King’s College London, London, UK

Abstract
Obesity and its sequelae may prove to be the greatest threat to human lifestyle and health in the devel-
oped world this century. The so called obesity epidemic has seen the incidence of obesity and over-
weight almost double in Western societies and the trend is mirrored in nations that are transitioning to
first world economies. There is no doubt that much of the rise in obesity can be attributed to lifestyle fac-
tors such as the excess consumption of energy-dense foods and the decline in physical activity.
However, the ‘fetal origins’ hypothesis, first proposed by Barker and colleagues and elaborated by several
groups over the past 15 years to be termed the ‘Developmental Origins of Adult Health and Disease’
(DOHaD), provides an alternative explanation for the rising rates of obesity. The DOHaD hypothesis states
that exposure to an unfavourable environment during development (either in utero or in the early post-
natal period) programmes changes in fetal or neonatal development such that the individual is then at
greater risk of developing adulthood disease. This chapter discusses the effects of maternal obesity on
fetal development and birth outcomes as well as the manner in which DOHaD may contribute to the
obesity epidemic. Copyright © 2008 S. Karger AG, Basel

The Obesity Epidemic

Health care systems around the globe are beginning to recognise the risk that obesity
poses to human health and many programmes are now being put into place in an
effort to reduce the burden of obesity and its related diseases. Current definitions of
obesity are based on the ratio of bodyweight (in kg) and height squared (in m2) and
expressed as body mass index (BMI) with a normal BMI defined as 20–24.9, moder-
ate overweight between 25–29.9 and obesity as ⱖ30. In 2000, the World Health
Organisation released the following statement: ‘Obesity is a chronic disease, prevalent
in both developed and developing countries, and affecting children as well as adults.
Indeed it is now so common that it is replacing the more traditional public health
concerns, including under-nutrition and infectious disease as one of the most signifi-
cant contributors to ill health’ [1]. At the turn of the millennium and the time of pub-
lication of the WHO report, the incidence of obesity in the United States was 30.5%
(compared with 22.9% in 1994) and 64.5% of the population were overweight (com-
pared with 55.9% in 1994) [2]. More recent statistics suggest that the incidence of
obesity and overweight is rising, not falling, in spite of the apparent efforts of govern-
ments and health care agencies. This shift in body mass has occurred over the past
one to two generations and as such it is unlikely that genetic drift is the cause of the
current obesity epidemic. Rather, a change in lifestyle, compounded by epigenetic or
developmental programming of an obese phenotype are the likely causative factors.
Obesity statistics from the United States are most often quoted, perhaps because
they give the greatest impact; however, scientific studies conducted in other nations
emphasise the fact that obesity is a worldwide problem. A study of cause of death in
South Korea illustrates this fact. In 1938, cardiovascular disease accounted for
approximately 1% of deaths in South Korea whilst infectious diseases were the cause
of approximately 23% of deaths. By 1993, this trend had reversed; approximately 30%
of deaths were attributable to cardiovascular disease whereas only 3% of deaths were
caused by infection. Certainly such statistics are affected both by the vast improve-
ments in anti-microbial medication and sanitation in that 60-year period; however,
the fact remains that obesity-related illness is the next public health hurdle.
Obesity may not, in itself, be a great risk to human health. Indeed, there are some
individuals who are overweight or obese but do not show any other signs of disease or
ill health. However, for the vast majority, increased body fat is associated with a range
of other, more serious conditions. These include increased blood pressure, insulin
resistance and diabetes mellitus, atherogenic plasma lipid profiles, and increased lev-
els of vascular inflammatory markers. Collectively, this spectrum of conditions is
termed the ‘metabolic syndrome’ and clinical diagnosis is based on the presence of 3
or more of the above signs. Endothelial dysfunction and leptin resistance are also
likely to contribute to the metabolic syndrome [3].
The rise of obesity is certainly due to the increased availability of food, and the
preponderance of energy dense (high fat and simple carbohydrate) foods that are reg-
ularly consumed in developing and developed societies. Moreover, the industrial era
has produced all manner of labour saving devices that has ultimately seen a reduction
in the physical activity quotient over time [4]. However, despite the obvious impor-
tance of food intake and energy expenditure during adulthood, there is now evidence
that adult lifestyle may not be the only factor at play in determining obesity [5]. The
environment encountered during the in utero and early postnatal periods may also
act to ‘programme’ an individual to have a greater risk of developing obesity and the
metabolic syndrome.

74 Armitage · Poston · Taylor

The Developmental Origins of Adult Health and Disease

The developing fetus and neonate orchestrates its growth and development to best
meet the environmental conditions encountered at any given period. Where environ-
mental challenges or stimuli span a period of organogensis or developmental plastic-
ity, the adaptations made may be permanent.
Epidemiological data from Norway provide the first of many reports that that
environment encountered in early life may affect later health outcomes with regard to
cardiovascular disease [6]. The concept of ‘programming’ was introduced by Lucas
[7] and provides a conceptual framework for the observations made by Barker and
Osmond [8] with regard to an individual’s birth weight and the later risk of disease in
United Kingdom cohort studies. These early Barker studies focused on the relation-
ship between the weight at birth, and subsequently fetal nutrition, with death from
coronary heart disease [9, 10].
The direct relationship between maternal nutrition and later offspring obesity
was revealed in a study of conditions encountered by a discrete population during
the Dutch Hunger Winter of 1944–1945. During the World War II military opera-
tions by Allied forces to liberate The Netherlands, the occupying Nazi forces block-
aded areas of Holland over the winter of 1944–1945 and official rations were cut to
300–500 kcal per day. Later study of adults (at 50 years of age) who were in utero
during this defined period of famine indicate that exposure to famine during the
first half of pregnancy predisposed individuals to the development of obesity [11]
and coronary heart disease [12] and that famine exposure later in gestation resulted
in glucose intolerance and insulin resistance [13]. This direct evidence for the role of
maternal nutrition in the programming of adulthood obesity and disease in the off-
spring was followed by studies from UK cohorts with several studies showing an
inverse association between birth weight and BMI in adulthood [14] as well as
insulin resistance. BMI is used as an indicator of obesity because of the simplicity by
which it can be measured in large trials or retrieved retrospectively from records.
However, use of the BMI parameter as an indicator of obesity has been challenged,
and there are suggestions that it is a measure of heaviness rather than obesity per se.
Consistent with this, studies of monozygotic twin pairs [15] found that lower birth
weight was associated with increased waist–hip ratio, skin fold thickness and
reduced muscle mass, but not necessarily BMI. Nonetheless, body fat measurement
by dual energy X-ray absorptiometry in adult men born of low birth weight shows
these individuals to have a 5% increase in fat mass compared with subjects born of
normal birth weight [16].
These studies formed the basis for various experimental animal models of mater-
nal undernutrition in which to study the Developmental Origins of Adult Health and
Disease (DOHaD) hypothesis and these models support the hypothesis that fetal or
neonatal undernutrition results in aberrant development of the endocrine pancreas,
liver, kidney and cardiovascular systems, such that the offspring born from protein or

The Consequences of Maternal Obesity 75

calorie deprived dams demonstrate many facets of the metabolic syndrome in adult-
hood [reviewed by 3, 17].
In the face of an obesity epidemic, it may be more useful to examine the maternal
factors that result in the developmental programming of obesity [18]. Although
maternal undernutrition is not manifest in many of the societies currently experienc-
ing the increase in obesity rates, one factor that may result in offspring programming
is maternal diabetes. Indeed, insulin resistance and alterations in the structure and
function of the endocrine pancreas is seen in offspring born to calorie or protein-
deprived mothers [reviewed by 3]. This is observed in humans, as evidenced by the
finding of insulin resistance in those that were exposed to the effects of the Dutch
Hunger Winter in the second half of gestation [13], as well as in experiential animal
models. Provision of a low protein diet (50% reduction in protein content but
isocaloric) to rats during pregnancy resulted in a reduction in pancreatic insulin con-
tent, reduced islet size and vascularisation and a reduction in cell proliferation in
term rat fetuses [19]. These animals develop frank insulin resistance later in life [19].
Uteroplacental deficiency, induced by ligation of the uterine artery, produced a simi-
lar phenotype of insulin resistance in adult offspring [20].
Consistent with the developmental programming hypothesis, maternal diabetes
appears to programme a similar offspring phenotype of insulin resistance and type 2 dia-
betes mellitus. This is observed in both human populations and in experimental animal
studies. One of the earliest, but most striking, studies of programming effects of mater-
nal diabetes was carried out in Pima Indian women. After accounting for confounds
such as paternal diabetes, age of diabetes onset in the parents and offspring BMI, Pettitt
et al. [21] observed that in this discrete population 45% of offspring born to diabetic
mothers went on to develop type 2 diabetes mellitus themselves by the age of 24. Only
1.4% of those born to non-diabetic mothers showed signs of type 2 diabetes mellitus
themselves at the same age. The authors conclude that those findings suggested that the
intrauterine milieu was an important determinant in the development of diabetes in the
offspring, and that the effects were additive with any genetic factors [21]. Macrosomia is
often observed in offspring of diabetic mothers, and there is supportive evidence for a
‘U-shaped’ relationship between birth weight and the development of adult obesity [22].
Thus high birth weight may prove to be just as deleterious to later health and well-being
as low birth weight. Data from a Swedish birth cohort suggest that within the past decade
there has been a 25% increase in the incidence of large for gestational age babies and
regression analysis suggests that this increase is attributable to a 25–36% increase in
maternal BMI [23]. The association between maternal obesity and offspring macroso-
mia may be partially influenced by genetic factors; however, a recent study of 150,000
women suggests that weight gain between successive pregnancies is associated with
macrosomia in the second pregnancy [24]. Given the same maternal genetic transmis-
sion, this study suggests that, at least in part, large for gestational age birth weight is
attributable to maternal obesity. Given the link between maternal obesity and maternal
diabetes, a range of animal models of diabetes in pregnancy have been developed.

76 Armitage · Poston · Taylor

 Experimental animal models of diabetes induced by streptozotocin (STZ, which
results in pancreatic ␤-cell death) have been used to dissect the contribution of
intrauterine environment from genetic factors. Aerts et al. [25] studied offspring of
STZ diabetic rats and found increased insulin secretion, plasma insulin concentra-
tion and decreased renal insulin uptake in these rats when compared with controls
[25]. A subsequent study by Holemans et al. [26] utilised euglycaemic hyperinsuli-
naemic clamp in the adult offspring of STZ diabetic rat dams to assess the develop-
mental programming of insulin resistance. This insulin resistance was characterised
by a reduction in insulin sensitivity in peripheral tissue and a reduction in hepatic
insulin sensitivity and responsivity [26]. Offspring of rats made mildly diabetic
by injection of STZ are born macrosomic, and develop insulin resistance and dia-
betes later in life [27]. Moreover when those first-generation females (that are dia-
betic as a result of maternal diabetes) are mated, they produce offspring that are also
diabetic [27].
Thus evidence from human and experimental animal models supports the
hypothesis that fetal undernutrition may result in programming of adulthood obesity
and metabolic syndrome. Fetal undernutrition is, in general, not manifest given the
current dietary status of many women of child-bearing age in westernised societies.
In an era where many women become pregnant whilst obese or overweight, consider-
ation of the effects of maternal obesity on pregnancy outcome and developmental
programming of offspring health are of great relevance and maternal diabetes may
prove to be a condition of great importance when considering the manner in which
the developmental programming of obesity may occur.

Pregnancy Outcomes Associated with Maternal Obesity and

Gestational Diabetes

Given the overall rates of obesity within the general population of many societies, it is
not surprising that rates of maternal obesity are rising. A retrospective analysis of
287,213 pregnancies in the United Kingdom reports that 27.5% of pregnant women
in the cohort were moderately obese (BMI 25–29.5) and a further 10.9% were very
obese (BMI ⱖ30) [28]. This trend is also seen in the US population, where recent
studies estimate that between 18 and 35% of pregnant women are obese [29].
Maternal obesity is associated with a range of adverse effects that directly affect
maternal health and pregnancy outcome. These include, pre-eclampsia, post-partum
haemorrhage, hypertensive disorders and complications of delivery [30]. The finan-
cial cost of obesity is also an important consideration. As health systems have finite,
and often, constrained budgets with which to provide care, any increase in the burden
of cost will further limit the abilities of health care systems to cope with the obesity
epidemic. In the year 2000, a French study estimated that complications arising from
obesity in pregnancy (pre-gravid BMI ⬎30) resulted in a 5.4- to 16.2-fold increase in

The Consequences of Maternal Obesity 77

the financial cost of prenatal care as well as a 4.4-day increase in the postnatal care
period than that required for women with a BMI of 18–25 [30].
In the context of developmental programming of adult disease, gestational diabetes
mellitus (GDM) may prove to be of long-lasting detriment to the fetus. GDM manifests
in approximately 8.8% of pregnancies in the developed world and the risk of GDM is
directly proportional to maternal BMI. This risk of developing GDM is reported to be
2.9-fold (95% CI 2.2–3.9) for women with a BMI ⱖ30 compared with women with a
BMI ⱕ20 [31], but may be as high as 20-fold [30]. In addition to the risk of obese indi-
viduals developing GDM, it is also established that being overweight predisposes the
development of type 2 diabetes, characterised by whole body insulin resistance and
higher plasma insulin concentrations. A study of New Zealand women, by Cundy et al.
[32] observed the rate of fetal or neonatal death in offspring of women with type 2 dia-
betes or GDM to be greater than that seen in non-diabetic controls. This was mainly
due to late fetal death. The authors highlight a strong relationship, observed in their
study as well as others, between the perinatal mortality rate and maternal obesity in
pregnancy women with type 2 diabetes [32]. This relationship between obesity and
complications of labour is also observed in a recent study of Jewish and Beduin popula-
tions in Southern Israel [33]. Major complications in obese women (pre-gravid BMI
ⱖ30, compared with controls pre-gravid BMI ⱕ30) were labour induction (OR 2.3,
95% CI 2.1–2.6), failure to progress to 1st stage of labour (OR 4.0, 95% CI 3.2–4.9),
meconium-stained amniotic fluid (OR 1.9, 95% CI 1.2–1.6) and malpresentation
(breech or shoulder dystocia) of the fetus (OR 1.6, 95% CI 1.3–1.9). The overall odds
ratio for caesarean delivery in that population was 3.2 (95% CI 2.9–3.5) [33].
In addition to the acute complications of delivery, maternal obesity and diabetes mel-
litus (either GDM or existing type 2 diabetes) are associated with long-term risks to fetal
and neonatal health. A Spanish study by Garcia-Patterson et al. [34], of 2,060 infants
born to mothers with GDM assessed the incidence of serious (life-limiting: requiring
surgery, or resulting in significant functional impairment) congenital abnormalities
involving the heart, renal/urinary or skeletal systems. By multiple logistic regression
analysis, these authors observed that pre-gravid obesity and the severity of GDM (also
related to BMI) predicted the increase in congenital malformations observed in the off-
spring [34]. Neural tube defects are also more common in offspring of obese mothers
(OR 1.9, 95% CI 1.1–3.4 for a maternal BMI ⬎29) [35]. Notwithstanding the devastat-
ing impact of such congenital abnormalities, these are present in only 4% of births [34].
The programming of obesity and metabolic syndrome in the offspring of such pregnan-
cies has the potential to exact an even greater burden on future generations.

Programming Vectors – Factors That May Result in DOHaD

The factors present in the maternal or fetoplacental milieu that may instigate alter-
ations in organogenesis or induce morphometric changes in the fetus and thus result

78 Armitage · Poston · Taylor

in developmental programming of obesity or other diseases may be termed ‘program-
ming vectors’. Despite the strong association between maternal obesity, GDM and
subsequent offspring developmental programming of obesity and its related sequel-
lae, there is an incomplete understanding as to which vectors present in the maternal
milieu may be most deleterious to fetal growth and development.
A comprehensive assessment of the maternal milieu in a small cohort of otherwise
healthy obese (n ⫽ 23, median BMI ⫽ 31) and lean (n ⫽ 24, median BMI ⫽ 22.1)
pregnant women in the UK found that maternal obesity was associated with statisti-
cally significant elevation of plasma concentrations of triglycerides, very-low density
lipoprotein cholesterols, insulin, leptin and inflammatory markers (interleukin-6, C-
reactive protein) as well as decreased plasma high-density lipoprotein cholesterols.
Additionally, the obese group demonstrated a statistically significant elevation in sys-
tolic blood pressure and a reduction in endothelium-dependent and -independent
vasodilatation in the microvasculature [36]. This milieu, consistent with that of the
metabolic syndrome, is also observed in experimental animal models of maternal
obesity. Holemans et al. [37] fed rats a highly palatable cafeteria-style diet for 4 weeks
to induce obesity and then mated these obese rats, maintaining the same cafeteria-
style diet regimen. These rats, when pregnant, were insulin resistant (measured by
euglycaemic, hyperinsulinaemic clamp), and demonstrated elevated plasma leptin
concentrations compared with control-fed pregnant rats [37]. Taylor and Poston [38]
fed rats a lard-rich diet for 10 days prior to mating and during pregnancy.
Interestingly, consumption of the lard-rich diet did not change plasma leptin or lipid
concentrations in these animals; however, this may reflect the relatively short period
of time that the rats were obese. Despite the short period of fat feeding, when com-
pared with control-fed rats, fat-fed rats demonstrated significant increases in plasma
insulin and corticosterone concentrations, and blunted endothelium-dependent
vasodilatation in mesenteric but not uterine arteries [38].
Thus, the developing embryo and fetus are exposed to an altered maternal envi-
ronment in the presence of maternal obesity. These alterations are marked, and
despite the capacity that the placenta has to buffer these changes, it is quite likely that
the intra-uterine environment is altered. Interestingly, thus far unidentified culture
conditions used for embryo transfer and cloning also seem to programme the devel-
opment of obesity in the offspring, further highlighting the importance of under-
standing what factors are most important for ideal fetal or embryonic development
[reviewed in 39].
The mechanisms by which these programming vectors may drive changes in fetal
development are not established unequivocally; however, an emerging hypothesis of
alteration of DNA methylation status appears promising. The promoter regions of
many genes contain long repeat sequences of cytosine and guanidine residues and
these regions are prone to methylation. Simplistically stated, high levels of methyla-
tion in the promoter region decrease transcription of a gene [40]. Maternal diet and
the early post-weaning diet have both been shown to alter the methylation status of

The Consequences of Maternal Obesity 79

several genes in the fetus and neonate, including the insulin-like growth factor [41].
Although the hypothesis is in its infancy, and there are no reports of aberrant gene
methylation status in offspring of obese women, this remains an attractive candidate
mechanism.

The Role of Maternal Obesity and Fat Intake in DOHaD

The previous sections of this chapter have focussed on the effect of maternal obesity
and offspring exposure to obesity in the in utero period, and the following chapter
considers in detail the determinants of childhood obesity. Nonetheless, when consid-
ering the developmental origins of obesity, it is important to consider both in utero
and early neonatal environments as the hypothalamic appetite centres ultimately
responsible for the maintenance and determination of body weight set-points mature
in early life [5, 42]. This section will consider the role of maternal obesity and fat
intake in both the in utero and postnatal suckling periods on the developmental pro-
gramming of obesity.
The current dietary intakes in many Western populations are high in saturated
fatty acids, and clearly the intake of energy-dense and potentially pro-inflammatory
fats (those that are prone to becoming oxidised low-density lipoprotein cholesterols)
impacts on adult obesity. However, fat intake and obesity may also be of great impor-
tance in the developmental programming of disease. Despite the obvious reflection
on the food intake in Western societies, there is still a paucity of experimental animal
studies considering the role of maternal overnutrition in the developmental program-
ming of adult disease.
Early studies in baboons showed that overnutrition in the suckling period resulted in
permanent increases in plasma cholesterol concentrations [43] and adipocyte size [44].
Rats exposed to a lard-rich diet during gestation and suckling (via maternal diet),
then weaned onto a control diet, are obese, hypertensive, insulin resistant, dyslipi-
daemic, and demonstrate blunted endothelium-dependent vasodilatation [45–47].
Interestingly, the type of fatty acid predominating in the maternal diet impacts on the
programming of offspring disease. High-fat diets that are also rich in ␻–3 polyunsat-
urated fatty acids have been shown to result in a largely normal offspring phenotype
despite the increased total fat and caloric load of the diet [48, 49]. Moreover, neonatal
rat pups suckled by dams fed fat-rich diets supplemented with ␻–3 and ␻–6 essential
fatty acids show reduced adipose tissue weight and reduced plasma leptin concentra-
tions [50]. Therefore, it appears that exposure to maternal diets that are rich in satu-
rated fatty acids is deleterious to later offspring health, whereas even relatively high
essential ␻–3 and ␻–6 fatty acid intake in the diet results in a normal offspring phe-
notype. There is also emerging evidence in humans that lowering total fat intake
whilst increasing the proportion of ␻–3 and ␻–6 essential fatty acid may have benefi-
cial effects on offspring and maternal health [51].

80 Armitage · Poston · Taylor

 Experiments utilising cross-fostering of pups between control and fat-fed dams sug-
gest that exposure to the maternal fat-rich diet during either the in utero or suckling
periods results in a metabolic syndrome-like phenotype [52]. Combined with other
studies of postnatal overfeeding [53] there is clear evidence that the first 21 days of
rodent life is a developmental critical period. Moreover, overfeeding during this period
can override genetic predisposition; obesity-resistant rats cross-fostered to obese moth-
ers during the suckling period develop diet-induced obesity later in life [54].
As previously discussed, maternal diabetes often accompanies obesity. Pups suck-
led by dams that are obese or diabetic demonstrate permanent alterations in the man-
ner by which hypothalamic appetite circuits respond to the peripheral signals that
normally instigate hunger and satiety. This is a bourgeoning area of research and war-
rants review in its own right [see reviews 5, 55]. However, briefly summarising a com-
plex neural circuitry model, it appears that exposure to the obese or diabetic milieu
during suckling programmes a selective neural leptin resistance at the level of the
hypothalamic arcuate nucleus [56]. The mechanism for such resistance is seen in a
reduction in synaptic integrity of neurons that normally inhibit appetite but not those
that stimulate appetite [56]. The net result of such synaptic plasticity is that normal
satiety signals are not attended and animals develop hyperphagia that persists
through life.
Thus, exposure to a saturated fat, diabetic or energy-rich environment in early life
may programme alterations in the hypothalamic neural circuitry that is ultimately
responsible for the establishment of growth trajectory and energy balance in young
humans and animals. It is most likely that alterations in the plasma concentrations of
peripheral appetite signals such as insulin, leptin and ghrelin are altered in the fetus
or neonate carried or suckled by obese or diabetic mothers. The developing neural
networks in the hypothalamus are then affected and because these changes occur
during a critical period of development, the changes to appetite and energy expendi-
ture circuits become permanent, thereby setting the scene for the subsequent devel-
opment of obesity in the next generation.

Conclusions

There are a myriad of socioeconomic, lifestyle and dietary behavioural factors that
have contributed and continue to add to the worldwide obesity epidemic.
Complications of maternal obesity or type 2 diabetes are summarised in table 1. The
developmental programming of adult disease appears to be one more factor that war-
rants serious consideration and one that should be tackled by public health initiatives.
Because of the alarming rate of obesity in young children across many societies, obe-
sity-related disease will not be eradicated in the near future; however, it is vital that
not only is the population informed of the risks and consequences of obesity to
maternal health, but also of the potential risks to the health of future generations.

The Consequences of Maternal Obesity 81

Table 1. Complications of
Pre-eclampsia
maternal obesity or gestational
diabetes Post-partum haemorrhage
Hypertensive disorders
Complications of delivery
Labour induction
Failure to progress to 1st stage of labour
Meconium-stained amniotic fluid
Malpresentation
Financial cost
Fetal or neonatal death
Congenital malformations
Heart
Renal/urinary system
Skeletal systems
Neural tube defects
Developmental programming of adult health and disease
of the fetus
Obesity
Type 2 diabetes
Hypertension
Atherosclerosis
Altered hypothalamic appetite circuitry

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Front Horm Res. Basel, Karger, 2008, vol 36, pp 85–96

Childhood Obesity
M.A. Sabina,b ⭈ J.P.H. Shieldb
a
Royal Children’s Hospital and Murdoch Childrens Research Institute,
Melbourne, Australia; bUniversity of Bristol, Bristol, UK

Abstract
The prevalence of childhood obesity continues to increase worldwide. Its presence is associated with
significant adverse effects on health including an increased propensity to type II diabetes, cardiovascular,
respiratory, and liver disease. In the vast majority of children, obesity is lifestyle-related, yet there is a
dearth of evidence on how to best develop effective prevention and treatment strategies. This review
outlines the importance of childhood and adolescent growth on long-term health, the definitions used
to define obesity in children (along with up-to-date prevalence data), causes and consequences, and
aspects of prevention and management. Copyright © 2008 S. Karger AG, Basel

Most countries throughout the world, excepting certain areas of Sub-Saharan Africa have
witnessed a continued increase in the prevalence of obesity over the last two decades [1].
This carries major public health implications as there is little doubt that obese children
are at increased risk of developing long-term morbidity and eventual mortality sec-
ondary to increasing adiposity. Despite this, there remain very few effective prevention or
treatment strategies with which to halt this escalating epidemic. Understanding the fac-
tors that regulate adiposity in childhood, and the development of co-morbidities, would
allow us to focus prevention and treatment strategies to those most at risk.

The Importance of Childhood and Adolescent Growth on Long-Term Health

Growth throughout childhood has profound implications for later health. There is now
considerable evidence indicating that size at birth, and growth in the first years of life,
affect the long-term risk of obesity and insulin resistance [2]. The risk associated with
birth weight has been defined as a ‘U-shaped curve’ with infants at both ends of the birth
weight spectrum being at increased risk. Infants born small for gestational age or with
lower ponderal indices [(weight in g/length in cm3) ⫻100], who subsequently show
rapid growth, are at greater risk of type 2 diabetes (T2DM) and cardiovascular disease in
later life, with evidence earlier in life of increased insulin resistance. Children born large
for gestational age are also at risk of subsequent obesity and T2DM, although the degree
to which maternal gestational diabetes accounts for these associations is still poorly char-
acterised. There is evidence that rapid growth in small for gestational age babies is specif-
ically associated with an increased propensity to abdominal obesity.
The transition from childhood to adolescence is fundamentally important in the
development of obesity, as puberty has a profound effect on regional body composi-
tion. During puberty, females accumulate a higher proportion of their total adult fat
mass, than their total adult lean tissue mass. The increased subcutaneous fat that is
seen in women develops during puberty, suggesting that oestrogen may preferentially
promote subcutaneous adipose deposition. During adolescence, boys characteristi-
cally maintain a relatively fixed absolute fat mass, whereas girls display an increase in
fat mass, accruing fat at ⬎1 kg per year [3]. The remodelling of fat mass and distribu-
tion appears to be central to the development of the physiological insulin resistance
that develops during pubertal growth [4].

The Definition of Childhood Obesity

Childhood adiposity can be measured in numerous ways although body mass index
(BMI) remains the most commonly used. Whilst BMI is a relatively simple tool with
which to assess body mass, it is a relatively poor predictor of actual body composition in
both adults and children. Due to its ease of determination however, along with a good cor-
relation with body fat, it has remained the accepted method to define obesity in children
based on current expert opinion [5]. Another important measure is waist circumference
which has been validated as a surrogate marker of visceral adiposity in children [6].
In adults, a BMI ⬎25 and ⬍30 corresponds to ‘overweight’, whereas a BMI ⬎30
identifies those with obesity. These cut-off points correspond to an increased risk of
cardiovascular disease and diabetes in adults. In children, however, BMI changes with
normal longitudinal growth, as shown in figure 1. Therefore, it is inappropriate to sim-
ply express raw BMI in children, without adjusting for age and sex. Instead, BMI stan-
dard deviation scores or z-scores (BMI SDS – representing increases or decreases
around the 50th centile for age and sex) are used to determine which children are rela-
tively ‘overweight’ or ‘obese’. For national statistics, BMI levels of ⬎95th, ⬎97th, or
⬎98th percentile have been used to identify the ‘fattest’ children within different popula-
tions. These limits have high specificity and moderate sensitivity, and allow temporal
changes within countries to be assessed. For across-country comparisons, international
cut-off points must be used and these have been based on the extrapolation of adult
cut-off points back into childhood [7]. The international cut-off points tend to greatly
underestimate obesity prevalence when used for determining prevalence rates within a
specific country [8]. However, BMI SDS may not be the best tool with which to

86 Sabin · Shield
Fig. 1. Boys BMI chart, demonstrating changes in BMI with age. Similar charts for girls are also avail-
able. Reproduced with permission from the Child Growth Foundation. Printed copies and further
information are available from www.healthforallchildren.co.uk.

Childhood Obesity 87
assess longitudinal changes in adiposity in children enrolled into weight management
programs, as the within-child variability over time depends upon the child’s levels of adi-
posity. Under these circumstances, age-adjusted BMI (calculated by subtracting the sex-
and age-specific median BMI) may be a better tool [9]. However, the normative data nec-
essary to make these calculations are currently unavailable so most workers continue to
use BMI SDS when reporting their results.

The Prevalence of Childhood Obesity

There has been a dramatic rise in the number of children who fulfil the criteria neces-
sary for the diagnosis of obesity [10]. Data from the CDC in the USA
(http://www.cdc.gov) demonstrate an increase in the prevalence of children aged 6–19
years old who were considered to be overweight (ⱖ95th percentile) from 4–5% in
1963–1970 to 15% in 1999–2000. Using similar criteria in the majority of cases, the
International Obesity Task Force have inspected the prevalence of obesity in children
aged around 10 years old from data derived from 21 European countries between 1992
and 2001 and found levels to vary between 10 and 36% [11]. Data from the Health
Survey for England in 2002 indicated that 8.5% of all 6-year-olds and 15% of all 15-
year-olds satisfied the criteria for obesity, and similar data from 2003 found that the
prevalence of obesity in children aged 2–10 had increased from 9.9 to 13.7% from 1995
(www.dh.gov.uk). In the non-Westernised world, there is also evidence that obesity in
general is increasing, especially amongst urban populations [12]. For example, China
(a country previously defined as one of the world’s leanest populations) has witnessed
a dramatic recent rise in childhood overweight and obesity prevalence [13].

Causes of Obesity in Childhood

Endocrine and single gene disorders causing obesity in childhood are rare, account-
ing for 1–2% of obese children seen in a tertiary care setting. Nevertheless, an under-
standing of these disorders is required to recognise rare but treatable causes of
childhood obesity. A thorough description of these conditions is beyond the scope of
this review and can be found elsewhere [14].
The majority of cases, however, arise from a simple interaction between host factors
that enhance susceptibility and environmental factors which increase food intake and
decrease energy expenditure [15]. Factors causing the imbalance in energy intake and
energy expenditure are numerous, simply reflecting the components of the obesogenic
environment in which we live. Factors important in excessive energy intake include the
consumption of energy-dense foods, increased portion sizes, between-meal snacking
and regular intake of sugar-sweetened beverages and fruit juices. Decreased energy
expenditure is often due to the coupling of increased sedentary activities, such as TV and
computer games, alongside decreased physical activity. There are also very significant

88 Sabin · Shield
parental [16] and socioeconomic [1, 17] contributions to obesity risk as demonstrated by
a recent study which showed that while 89% of parents of overweight 5- to 6-year-olds
were unaware that their child was overweight, 71% were not concerned, with less edu-
cated parents being less likely to take action [18]. Ethnicity also significantly impacts
upon obesity risk and the development of co-morbidities. For example, data from several
countries show that black children have a higher prevalence of obesity than white chil-
dren [17] while obese children from certain ethnic groups (e.g. South Asia) appear to
exhibit higher rates of complications like T2DM for a given level of obesity [19].
Addressing these complex demographic and lifestyle interactions remains central to the
development of effective prevention and treatment programs for childhood obesity.

Consequences of Childhood Obesity

Childhood obesity tracks into adult life with a high degree of predictability – 68% of
children with a BMI consistently 85th percentile grow up to be obese adults [20].
However, childhood obesity independently has its own short- and long-term adverse
effects on health.

Endocrine Complications
The major endocrine consequence of obesity is impaired glucose tolerance and subse-
quent T2DM – a process that develops in individuals with insulin resistance and relative
(rather than absolute) insulin deficiency. Significant numbers of children and adoles-
cents with obesity seen within specialised clinics have impaired glucose tolerance when
challenged with an oral glucose load. The figures vary across centres but have been put as
high as 25% in the USA, lower in the UK with levels around 10% and possibly even lower
in mainland Europe [21]. Predictions from the USA imply that obesity-associated
T2DM is likely to become the commonest form of newly diagnosed diabetes in adoles-
cent youth with evidence suggesting a global spread in the condition (although actual
incidence data are currently sparse [22]). Various centres in the USA have recorded dra-
matic increases in the number of children diagnosed with T2DM. For example, a 10-fold
increase was recorded from a centre in New York from 1990 to 2000 with 50% of all new
cases of diabetes having T2DM [23]. In Japan, researchers have documented a rise in the
annual incidence of T2DM in children from 1.73/100,000 to 2.76/100,000 over 20 years
[24], whilst evidence is also emerging of an increase in urban South-Asian children. Data
from Europe are scarce: a population based study in Austria established an incidence of
0.25/100,000 children [25], whilst a report from France indicated relatively low but
increasing numbers of children presenting with T2DM [26]. In the UK, Ehtisham et al.
[27] estimated a crude prevalence of T2DM in patients under 16 years of 0.21/100,000,
whilst a recent report reviewing first hospital admissions with a diagnosis of T2DM in
patients under 18 years indicated a significant rise between 1996–7 to 2003–4 [28].

Childhood Obesity 89
 The emergence of T2DM in adolescence has important implications for both the
health of the individual and health service resources. Treatment compliance [29] and
psychological health [30] is often poor in childhood T2DM. Various studies have
implied an accelerated risk of nephropathy [31] and retinopathy [32] compared to
young people with type 1 diabetes, whilst recent data indicate early signs of cardio-
vascular disease in youth with T2DM [33]. The only currently available longitudinal
data make for worrying reading: of 79 children re-contacted up to 15 years after the
diagnosis of T2DM, 9% had died and 6% were on dialysis [34].

Cardiovascular Complications and the Metabolic Syndrome

Obesity is associated with a significant risk for cardiovascular disease independent of
diabetes-related disease. Tounian et al. [35] investigated normotensive, obese, 12-
year-old children comparing them with normal-weight controls. The obese children
had significantly higher arterial wall stiffness and evidence of endothelial dysfunc-
tion. Berenson et al. [36] were able to demonstrate that obesity with attendant abnor-
malities, such as higher LDL cholesterol levels and systolic hypertension, was
associated with greater coronary artery atheromatous plaque formation in childhood.
Furthermore, recent publications indicate that carotid artery intima-media thickness
in adult life, considered predictive of stroke and myocardial infarction, can be directly
related to childhood BMI (independent of adult weight status) [37].
The metabolic syndrome, a clustering of cardiovascular risk factors, is defined in
adults when central obesity (determined by sex and ethnic waist circumference cut-off
points) is present along with 2 of the following: raised triglycerides, reduced HDL cho-
lesterol, hypertension or raised fasting plasma glucose/T2DM (www.idf.org). However,
in children this definition needs adapting and there remains some debate as to the
most appropriate definition and cut-off points that should be used [38]. Cook et al.
[39] estimated the prevalence of the metabolic syndrome in adolescents enrolled in
NHANES 1988–1994, using age-modified standards of the Adult Treatment Panel III
criteria (a combination of three of the following factors: raised fasting plasma glucose,
abdominal obesity, dyslipidaemia with a reduced HDL or elevated triglyceride level,
and hypertension) [40]. They found a prevalence rate for the metabolic syndrome in
overweight (ⱖ95th BMI percentile) adolescents aged 12–19 years of 28.7%, which by
1999–2000 had increased to 32.1% [41]. Others have reported higher prevalence in
cohorts of obese children, with the most severely obese children having levels as high
as 50% [42]. In our cohort of obese children, we identified a prevalence of 25% [43].

Respiratory Complications
Obesity has long been associated with sleep disorders, now termed ‘obstructive sleep
apnoea syndrome’ [44]. This causes decreased overnight oxygen saturation and
repetitive arousal prohibiting qualitative REM sleep, leading to daytime lethargy and

90 Sabin · Shield
somnolence. This not only affects physical activity levels (further compounding obe-
sity), but also school performance and concentration [45].
Interestingly, several studies have also now identified that reduced sleep duration
may be associated with an increased propensity to obesity, probably through changes
in orexegenic hormone levels, suggesting that encouraging longer sleep in childhood
may be a useful public health tool [46].

Gastrointestinal Complications
Obesity causes non-alcoholic fatty liver disease (NAFLD) in childhood [47]. NAFLD
refers to a spectrum of fatty infiltration of the liver, without alcohol consumption,
that encompasses simple fatty deposits seen in the liver, fatty liver with necro-inflam-
mation (termed non-alcoholic steatohepatitis) and ‘cryptogenic’ cirrhosis. Significant
numbers of obese children, particularly those with associated insulin resistance, have
been identified as suffering from this condition. It has a male preponderance and is
intimately linked to insulin resistance. The classical feature is of raised serum amino-
transferases in the absence of significant alcohol ingestion. Weight management
remains the mainstay of therapy for this condition [48], although alternative treat-
ments undergoing investigation in childhood include metformin and vitamin E.

Other Systems
Other complications of childhood obesity include slipped femoral capital epiphysis,
renal abnormalities in a condition now termed ‘obesity-related glomerulopathy’ and
idiopathic intracranial hypertension. The psychological effects of obesity should not
be forgotten with many obese children seen in the clinical setting, lacking self-esteem,
with reduced quality of life scores comparable to those of children diagnosed with
cancer. Interestingly, however, some workers have found that while obese children
may have higher levels of body dissatisfaction than their normal-weight peers, there
is little evidence to suggest that they have significantly reduced self-esteem or higher
levels of depression [49].

Prevention of Obesity in Childhood

Obesity prevention is ‘the only feasible solution for developed and developing countries’
[1], although no prevention strategies have yet been developed which show long-term
efficacy. It is likely that numerous strategies have to be established ranging from popu-
lation-based initiatives to targeted interventions aimed at those most at risk. A recent
report by the British Medical Association stated that ‘prevention strategies will require a
coordinated effort between the medical community, health administrators, teachers,
parents, food producers and processors, retailers and caterers, advertisers and the

Childhood Obesity 91
media, recreation and sport planners, urban architects, city planners, politicians and
legislators’ (www.bma.org.uk/ap.nsf/content/childhoodobesity), highlighting the com-
plexity involved in developing effective prevention programs for childhood obesity.
A comprehensive overview of prevention trials for childhood obesity is outside the
scope of this review and the reader is directed to other sources on the subject [50].
In brief, different prevention programs have included school-based initiatives,
individual and family-based interventions, and antenatal/postnatal/preschool
approaches. None has proven to be particularly effective and it is likely that a combi-
nation of strategies (within a wider context of governmental policy change, changes
in healthcare and service provision to children, and less child-centred advertising) is
required to have a demonstrable effect.
It is clear that the development of well-designed studies to assess which interven-
tions are most effective is now critical if we are to overcome the mismatch between
the prevalence of childhood obesity and the knowledge base from which to inform
preventative activity [51].

Management Considerations

The most recent Cochrane review of obesity therapy in childhood concludes that
‘there is a limited amount of quality data on the components of programs to treat
childhood obesity that favour one program over another’ [52]. In general, it appears
that behaviour modification centred on parent education, by which parents take on
the primary responsibility for change in lifestyle, might be of some benefit [53–55].
This appears to be most likely to work in younger children rather than adolescents, as
shown in figure 2 [56]. Furthermore reducing sedentary behaviour and increasing
exercise might prove useful although the evidence is still very limited [57, 58].
Given the limited resources and ill-defined framework for obesity therapy in child-
hood, it is sensible to consider who is most likely to benefit if weight management is
successful. There is evidence that some racial groups such as Black, African-
Americans and Europeans and South Asians have both an increased prevalence of
obesity and risk for T2DM with some authors suggesting that these groups should be
targeted as a priority [59]. Another priority group should be those with a family his-
tory of T2DM as there is good evidence that obese children from these families are a
greater risk. Given these considerations, it is still important to establish when referral
for obesity management should be undertaken, given that other medical consequences
of profound obesity may not be entirely centred on the above high risk groups.
The most important consideration is the need for the family of the child concerned
to want to address the issue of obesity. Without an acceptance that changes in lifestyle
are required, it is highly unlikely that any progress can be made. It has been demon-
strated that many parents underestimate their child’s weight and the health care risks
associated with obesity. It is therefore important within any consultation in primary

92 Sabin · Shield
 1.0

Change in BMI SDS 0.5

0.0

⫺0.5

⫺1.0

⫺1.5
2 4 6 8 10 12 14 16 18
Age at entry to clinic (years)

Fig. 2. Change in BMI SDS versus age at entry to a hospital-based multidisciplinary paediatric
weight management clinic, demonstrating that younger children achieve better results with this
type of intervention. Reproduced from reference [56].

care or a community setting that the issue of a child’s weight is addressed, but this
should never be at the expense of embarrassing either the child or family. If after con-
sultation, the family accepts that changes need to be made, then an assessment and
plan for action can be developed.
In older children, where simple modification of lifestyle tends to prove more diffi-
cult, there is now some evidence for the use of pharmacological treatments in resis-
tant individuals. Orlistat (a gastrointestinal lipase inhibitor) and sibutramine (a
selective serotonin reuptake inhibitor) are the 2 main anti-obesity medications used
in adults and evidence from the USA suggests that each may be associated with bene-
ficial changes in BMI within the context of appropriate lifestyle modification pro-
grammes. Both orlistat and sibutramine have been tested in randomised controlled
trials in adolescence with some apparent benefit [60, 61]. It is still unclear which ado-
lescents require pharmacological treatment, although it would seem that the best
approach is to stratify treatment by the severity of obesity/co-morbid conditions and
reserve drug therapy for those in whom behavioural therapy has failed [62]. Current
evidence suggests, however, that both medications should only be prescribed from
specialist adolescent weight management centres and as part of an overall lifestyle
modification programme [63]. Rimonabant, an endocannabinoid receptor antago-
nist, is a new anti-obesity medication that has recently been licensed for use in adults.
Although there have been no studies to date that have examined its use in adoles-
cents, data from adult studies do not suggest any significant side effects that would
necessarily preclude its use in this age group in the future [64].

Childhood Obesity 93
 In those in whom lifestyle change and pharmacotherapy have failed, especially
where severe obesity is associated with co-morbid conditions in childhood, then
surgery remains an alternative treatment approach [65]. Surgical procedures have
involved either gastric restrictive or malabsorptive methods, although the laparo-
scopic placement of an adjustable gastric band has become the most widely adopted
procedure. Results of a large randomised controlled trial assessing this surgical
approach versus a modified lifestyle approach in adolescents with severe obesity is
keenly awaited from the Centre for Obesity Research and Education in Australia.

Conclusions

Childhood obesity now affects at least 10% of the world’s children. It is associated
with numerous health consequences that will have a significant impact on healthcare
provision over the next few decades. Despite this, we have very little evidence on the
most appropriate prevention and treatment strategies needed to tackle the problem.
A recent report assessing the cost effectiveness of interventions in childhood obesity
concluded that ‘the greatest health benefit is likely to be achieved by the ‘‘reduction of
TV advertising of high fat and/or high sugar foods and drinks to children’’, ‘‘laparo-
scopic adjustable gastric banding’’ and the ‘‘multi-faceted school-based programme
with an active physical education component’’’ [66].

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Front Horm Res. Basel, Karger, 2008, vol 36, pp 97–106

Obesity in Old Age

Ian McPhee Chapman
Department of Medicine, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia

Abstract
Many older people in developed countries are overweight or obese. The prevalence is increasing as
more people reach old age already overweight. Obesity in old age is associated with increased morbid-
ity and a reduction in quality of life. The relative increase in mortality is less in older than young adults
and the body weight associated with maximal survival increases with advancing age. Although inten-
tional weight loss by overweight older people is probably safe and beneficial, caution should be exer-
cised in recommending weight loss to overweight older people on the basis of body weight alone.
Methods of achieving weight loss in older adults are the same as in younger adults. Weight loss diets
should be combined with an exercise program to preserve muscle mass, as dieting results in loss of mus-
cle as well as fat, and older people have reduced skeletal muscle mass in any case. Weight loss drugs
have not been extensively studied in older people, and there is the potential for drug side effects and
interactions. Weight loss surgery appears to be safe and effective, albeit slightly less so than in younger
adults, but little is known about the outcomes of such surgery in those over 65 years.
Copyright © 2008 S. Karger AG, Basel

Overnutrition and Obesity in Older People

Prevalence

In most developed countries a substantial minority, and in some countries the major-
ity, of older people are overweight according to standard body weight criteria.
According to recent large surveys [1, 2], approximately 71% of Americans 60 years or
older and 60% of those 65 years or older were overweight (body mass index, BMI
ⱖ25 kg/m2), while approximately 32% of those 60 years or older and 20% of those 65
years or older were obese (BMI ⱖ30). Similarly, 29% of 55- to 64-year-olds in
England were obese [3], while 43% of Australians over 65 were overweight and 25%
of Australians aged 65–74 years and 14.4% over 75 years were obese [4].
Not only are many older people overweight or obese, but the rates are increasing
rapidly, in parallel with the dramatic increase over recent years in rates in younger
adults. For example, the prevalence of obesity (BMI ⱖ30) among people in the USA
over 60 years increased from 20 to 32% between 1988–1994 and 1999–2000 [5] and
among those over 70 years from 11.4 to 15.5% between 1991 and 2000 [6]. There have
been similar increases in other countries [4].
An understanding of the causes and consequences of excess weight in older people
is aided by an understanding of the changes in appetite, food intake, energy expendi-
ture and body composition that occur with ageing.

Changes in Appetite and Food Intake with Increasing Age

On average, adults become less hungry and eat less as they get older, even if healthy
[7]. This physiological, age-related reduction in appetite and energy intake has been
termed ‘the anorexia of aging’ [8] and appears to have many causes [9]. Average daily
energy intake decreases by up to 30% between 20 and 80 years [7]. Most of the age-
related decrease in energy is probably a response to the decline in overall energy
expenditure that also occurs as people get older. Changes in body weight and body
composition reflect the balance of these two declines. As indicated below, body
weight tends to increase through early adult life into middle age, suggesting a more
rapid decline in energy expenditure than in food intake during this time. In contrast,
body weight tends to decrease in older people, suggesting a faster decline in food
intake than in energy expenditure in later life.

Changes in Body Weight and Body Composition with Increasing Age

Body Weight

Population studies show that on average people in westernised countries gain weight
until they are about 50–60 years old and after that tend to lose weight [10]. Although
some of the decline in mean body weight after age 50–60 years detected in cross-sec-
tional studies is due to the premature death of obese people, the decline in body
weight among older people has also been demonstrated in longitudinal studies. For
example, in one 2-year prospective study, community-dwelling American men over
65 years lost on average 0.5% of their body weight per year and 13.1% of the group
had weight loss of 4% per annum or more [11]. As a result of this weight loss in older
people, and the premature death of obese people at younger ages, the prevalence of
overweight and obesity, as defined by standard BMI criteria (BMI ⬎25 and ⱖ30,
respectively) peaks around age 50–60 years. It then remains fairly stable until about
age 70–75 years, before decreasing.
A substantial minority of older people have quite marked weight changes over
time. In one study [12], 17% of home-dwelling people in the USA over 65 years lost

98 McPhee Chapman
5% or more of their initial body weight over 3 years, while 13% gained 5% or more.
Other studies provide similar numbers [11]. There is evidence for interactive effects
on health of body weight category and change in body weight, particularly of adverse
effects in already underweight people who lose weight and in already overweight peo-
ple who gain weight [13].

Body Composition

Enlargement and Redistribution of Fat Stores

With normal aging there is a progressive increase in fat and decrease in fat-free mass,
the latter mainly due to loss of skeletal muscle. Consequently, at any given weight,
older people, on average, have substantially more body fat than young adults. In one
study, the mean body fat of 75-year-old men weighing 80 kg was 29%, compared to
15% in 20-year-old men of the same weight [14]. The increase in body fat with aging
is multifactorial in origin, with decreased physical activity as a major cause, and con-
tributions from reduced growth hormone secretion, declining sex hormone action
and reduced resting metabolic rate and thermic effect of food.
Not only do older adults have more body fat than young adults, but it is distrib-
uted differently. A greater proportion of body fat in older than young people is
intrahepatic, intramuscular, and intra-abdominal (versus subcutaneous) [15],
changes that in both young and older adults are associated with increased insulin
resistance [16]. For example, in one study intramuscular fat stores were 50% greater,
intrahepatic stores four times greater and insulin resistance two times greater in
older (65–74 years) than young adults (20–32 years) [16]. In younger adults, such
changes to body fat stores and increases in insulin resistance are associated with
adverse metabolic outcomes, including increased rates of diabetes mellitus and car-
diovascular disease. It might, therefore, be predicted that the age-related changes in
body fat stores would lead to particularly bad metabolic outcomes in older people.
This is not proven, however. Given that the body weight compatible with longest
survival increases with increasing age (see below), and much if not all of the
increase in body weight is due to increased fat stores, it may be that advancing age
blunts in some way the harmful effects of increasing body fat. This possibility war-
rants further study.

Loss of Skeletal Muscle (Sarcopaenia)

Ageing is associated with a decrease in muscle mass and strength, with loss of up to
3 kg of lean body mass per decade after age 50 years. After age 60 years, loss of body
weight is disproportionately of lean body tissue, predominantly skeletal muscle. The
causes of age-related skeletal muscle loss are multiple and not fully understood, but
probably similar to those leading to fat gain, including reduced exercise and anabolic
hormone action. When excessive, this leads to sarcopaenia (from the Greek meaning

Obesity in Old Age 99

‘poverty of flesh’), which can be defined in various ways, such as a skeletal mass
more than 2 standard deviations below the young adult sex-specific mean [17]. The
prevalence of sarcopaenia in older people varies according to the population studied
and diagnostic criteria used, but is in the order of 6–15% in people over 65 years [17].
The reduction of skeletal muscle mass and strength in sarcopaenia is so severe that it
is often associated with marked functional impairment. The presence of sarcopaenia
is an independent predictor of poor gait, balance, falls, and fractures. In the NHANES
III study, for example, older people with marked sarcopaenia (less than 5.75 kg
skeletal muscle/m2) were 3.3 times (women) to 4.7 times (men) more likely to have
physical disability than those with low-risk skeletal muscle mass (more than
6.75 kg/m2) [18].
In young adults, obesity tends to be associated with increased skeletal muscle,
acquired to support the extra weight. In contrast, in older people, excess weight, to
the point of obesity, can co-exist with muscle loss and even sarcopaenia. Hence the
possibly counter-intuitive entity of sarcopaenic obesity or the ‘skinny fat’ elderly. This
combination of an excess of (probably) metabolically bad fat tissue and a deficiency of
beneficial muscle is associated with particularly adverse effects [19, 20]. In one
prospective study of elderly people followed for up to 8 years, those with sarcopaenic
obesity (skeletal muscle mass more than 2 standard deviations below young adult
mean and percentage body fat above the 60th percentile) at baseline were two to three
times more likely to develop disabilities in activities of daily living than were lean sar-
copaenic, non-sarcopaenic obese or normal body composition subjects [21]. The age-
related loss of skeletal muscle and its adverse effects help explain the consistently
demonstrated benefits of exercise programs in elderly people, particularly those that
increase muscle mass and function.

Causes of Overweight and Obesity in Older People

As indicated above, people do not usually gain weight in old age. From this, it follows
that the high and increasing proportion of overweight and obesity in older people is
mainly due to the high and increasing proportion of adults who reach old age already
overweight. The causes of obesity in the elderly are therefore largely those of obesity
in younger adults. These have been addressed elsewhere in this book.
Older people are often not weight stable and a substantial minority of older people
have quite marked weight changes over time [11]. There are therefore some people
who only become overweight or whose weight increases dramatically in later life.
This can be due to medical illnesses, which restrict mobility and hence alter the food
intake-energy expenditure balance in favour of the former. Most common among
these is musculoskeletal disease, such as osteoarthritis of the lower limbs or back,
while cardiac failure and depression are also important causes, as is increased food
intake due to corticosteroid use.

100 McPhee Chapman

Table 1. Obesity-related
Reduced mobility
co-morbidities in older people
Reduced quality of life
Type 2 diabetes mellitus
Hypertension
Cardiovascular disease
Sleep apnoea
Increased rate of malignancies
Breast
Colon
Prostate
Uterus
Fatty liver
Thromboembolic disease

Consequences of Obesity in Older People

As in younger adults, obesity in older adults is associated with absolute and rela-
tive increases in both mortality and morbidity. Obesity-related co-morbidities are
summarised in table 1. Most of these conditions become more common and severe
with increasing age even in those who are not overweight. These effects of age are
exacerbated by excess weight.

Mortality

The relative increase in the risk of death associated with being obese compared to being
of normal weight is not as great in older as in young adults. An assessment of thirteen
observational, prospective studies in which non-hospitalised people over 65 years were
followed for at least 3 years [22] found an association between mortality and increased
BMI in only a few, and then only above a BMI of 27–28.5, with little or no increase in
mortality at any BMI for people over 75 years. Where an optimum BMI could be identi-
fied, it was usually in the range 27–30. Consistent with this, a combined analysis of the
American NHANES I–III (1974–2000) study results found no significant increase in
mortality with any degree of overweight in people over 70 years, and an increased death
rate only in the ‘morbidly’ obese (BMI ⱖ35) among those 60–69 years [23]. Nevertheless,
the relative risk of mortality is still increased at high BMIs until about the age of 75 years,
and because of the greater background death rate in older people the absolute increase in
death rate attributable to obesity is substantial; 25% of the excess deaths attributed to
obesity in that NHANES analysis occurred in people over 70 years of age [5].
The causes of increased mortality are essentially the same as those in younger adults:
diabetes, hypertension, sleep apnoea, cardiovascular disease and an increased risk with
obesity of developing certain cancers, including breast, uterus, colon and prostate.

Obesity in Old Age 101

Morbidity

Obesity in older people is associated with increased rates of cataracts, mechanical uri-
nary and bladder problems, sleep apnoea and other respiratory problems [reviewed in
10]. After the age of 65 years, over 60% of people have symptomatic osteoarthritis [24]
commonly affecting the hip and knee, and this is a major cause of disability. Excess
weight hastens the development of knee osteoarthritis [25], exacerbates the symptoms
of lower limb osteoarthritis, and makes surgical treatment more hazardous.
Functional capacity and mobility are significantly reduced in obese compared to
lean older adults [26]. Obesity at any age is associated with a reduced quality of life
[27], but this is particularly so in older adults, in whom it is associated with reduced
muscle mass and strength and hence with physical frailty [20]. Compared to their
non-obese counterparts, obese older people are less likely to be pain free, have greater
limitations of physical function and are more likely to be homebound. Obesity is pre-
dictive of a greater rate of future disability, declines in functional status [10], particu-
larly when associated with loss of skeletal mass [21], and an increased admission rate
to nursing homes. Among women age 65 years or more in the Nurses Health Study, a
weight gain of 20 lb (⬇9 kg) or more over 4 years was associated with a reduction in
reported physical functioning [13]. Increased fat mass appears to be the factor specif-
ically responsible for obesity-related disability [26].
A beneficial effect of obesity in older people is that it is associated with increased
bone density in both weight bearing and non-weight bearing bones. This combines with
cushioning of falls provided by the extra fat stores, particularly around the hips
(‘endogenous’ hip protectors) to reduce fracture rates in older people [28]. Most studies
show that when overweight adults, young or older, intentionally lose weight they also
lose bone [reviewed in 10, 29]. Substantial unintentional weight loss in older people is
associated with an increased risk of hip fracture [30]. This is probably due to a combina-
tion of reduced bone mass and the effects of whatever illness caused the weight loss, for
example by increasing the likelihood of falls. Although it is reasonable to assume that
there is at least some increase in fracture risk due to the weight loss-associated bone loss,
in overweight older people who intentionally lose weight this has not been established.

Management of Obesity in Older People

Should Overweight Older People Be Advised to Lose Weight?

This is a controversial question. Obesity in older people is associated with increased

morbidity and reduced life expectancy at very high BMIs up to at least 70 years. There
is evidence that weight loss by overweight older people is associated with improved
quality of life; in the Nurses Health Study weight loss in initially overweight women
was associated with improved physical function and vitality as well as decreased

102 McPhee Chapman

bodily pain [13]. This must be balanced against the detrimental effects of weight loss
on muscle mass and bone density and the association repeatedly detected in large
population studies between all-cause weight loss and increased mortality in older
people, even those who are initially overweight.
Studies demonstrating an association between weight loss and increased mortality
in older people have largely examined all-cause weight loss, whether intentional or
unintentional. There is little doubt that unintentional weight loss is not good for the
elderly. Although some study results have been interpreted to show increased mortal-
ity after even intentional weight loss in older people [12], it is difficult to determine
what proportion of weight loss labelled intentional was instead unintentional. On bal-
ance, it appears that intentional weight loss by initially overweight older people has
either no significant effect [31, 32] or even beneficial effects on mortality. In the US
National Health Interview Survey, for example, which followed 20,847 adults with
mean age 54 years for 9 years, all-cause weight loss was associated with a significant
increase in mortality, as in other studies [33]. Reported attempted weight loss, how-
ever, even if unsuccessful, was associated with a 24% reduction in mortality [RR 0.76
(0.64–0.9)], as was successful intentional weight loss [RR 0.76 (0.6–0.97)]. There was
no interaction between weight loss intention and age in the effect on mortality, con-
sistent with a prolongation of life by intended weight loss in older as well as young
adults.
Studies involving predominantly younger adults have found that intentional
weight loss can reduce mortality in those with obesity-related health problems, such
as type 2 diabetes, ischaemic heart disease and hypertension [34]. Although such
studies have not been done in older people, available evidence provides no evidence
of harm and suggests that it is safe to recommend weight loss to overweight older
people with obesity-related morbidities, particularly reduced mobility and function.
This is the group that appears to have the most to gain. There are few if any indica-
tions for recommending weight loss to older people based on their weight alone.

Weight Loss Measures in Overweight Older People

Treatment options available to achieve weight loss in older people are the same as
those in younger adults; changes in diet and exercise, medications and surgery [10].
There is limited information about the effectiveness and safety of weight loss treat-
ments, particularly medications and surgery, in older people.

Lifestyle Measures

Lifestyle interventions, combining a reduced energy diet (reduction of about

500–750 kcal/day) and exercise are at least as effective in producing weight loss in

Obesity in Old Age 103

people over 60 years as in younger adults [10], and possibly more so [35]. The incorpo-
ration of an exercise component, particularly weight-bearing aerobic and resistance
exercise, is very important, as low muscle mass (even sarcopaenia) is often present
even before deliberate weight loss, and is usually exacerbated by it. In the absence of
an exercise program, up to 20–30% of diet-induced weight loss is accounted for by
loss of skeletal muscle [36]. A meta-analysis of the results of twenty-eight studies, not
specifically performed in older adults, found that the addition of an exercise program
to diet reduces the diet-induced loss of muscle significantly, from 29 to 17% of weight
lost in men and from 22 to 17% in women [37]. Similar benefits are likely to occur
with older people, in whom exercise also inhibits the regional loss of bone density
that accompanies weight loss, improves physical function by increasing muscle mass
and fitness [38, 39] and reduces the risk of falls [40]. Older people should be assessed
prior to starting an exercise program, to determine whether there is a need for formal
stress testing to exclude significant underlying coronary artery disease [41] and the
exercise intensity should be gradually increased. Multivitamin supplements together
with calcium (1,000–1,500 mg/day) and vitamin D (800–1,000 IU/day) for bone pro-
tection should also be taken.

Medications and Surgery

There is little reported experience with weight loss drugs such as sibutramine, which
reduces appetite and food intake, and orlistat, which inhibits lipase activity and thus
fat absorption, in older people. Such drugs should be used with caution in older peo-
ple, because of limited efficacy data, the possibility of interactions with other (multi-
ple) medications, and potentially worse side effects. Orlistat appears to be as effective
in older as in young adults [10], with a weight loss over 1 year approximately 3 kg
more than with placebo, but can cause diarrhoea and other gastrointestinal side
effects such as faecal incontinence. Side effects of sibutramine can include insomnia,
constipation and increased blood pressure.
Only a few studies so far have examined the outcomes of weight loss surgery in
overweight people over 60 years. The results are encouraging. In three studies com-
paring the effects of gastric bypass surgery in 115 people over 60 years to those in
3,470 people less than 60 years [42–44], there was one peri-operative death in the
older group (0.86%) and a possible but not definite slight increase in operative com-
plication rate compared to the younger patients. The surgery resulted in a marked
mean weight loss of 39–43 kg at 1 year in the older subjects and a significant reduc-
tion in the number of obesity-related morbidities and number of medications
needed to treat these. Both reductions were slightly, but significantly less in older
than young adults. The mean age of the ‘older’ subjects in these studies was quite
young, however, at 63–65 years, and the results of such surgery in even older people and
also of other forms of obesity surgery in these age groups remain to be determined.

104 McPhee Chapman

Bariatric surgery is thus an effective weight loss option in older people, particularly
for selected older people substantially disabled by complications of obesity, but
greater caution should be exercised in undertaking these procedures in older than
young adults.

Conclusions

Many older people are overweight or obese and this is associated with increased mor-
bidity and mortality. Weight loss is achievable and is beneficial in these people, par-
ticularly when the excess weight is associated with functional impairments. Weight
loss should probably not be recommended to older people on the basis of their body
weight alone, rather than co-existent morbidity, as the relative disadvantages of excess
weight per se are less in older than young adults.

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Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 107–117

Models of ‘Obesity’ in
Large Animals and Birds
Iain J. Clarke
Department of Physiology, Monash University, Melbourne, Australia

Abstract
Most laboratory-based research on obesity is carried out in rodents, but there are a number of other
interesting models in the animal kingdom that are instructive. This includes domesticated animal species
such as pigs and sheep, as well as wild, migrating and hibernating species. Larger animals allow particu-
lar experimental manipulations that are not possible in smaller animals and especially useful models
have been developed to address issues such as manipulation of fetal development. Although some of
the most well-studied models are ruminants, with metabolic control that differs from monogastrics, the
general principles of metabolic regulation still pertain. It is possible to obtain much more accurate
endocrine profiles in larger animals and this has provided important data in relation to leptin and ghrelin
physiology. Genetic models have been created in domesticated animals through selection and these
complement those of the laboratory rodent. This short review highlights particular areas of research in
domesticated and wild species that expand our knowledge of systems that are important for our under-
standing of obesity and metabolism. Copyright © 2008 S. Karger AG, Basel

Obesity is clearly a major issue for humans and there is a very substantial research
effort directed towards a better understanding of the causes and consequences of the
problem. Basic and clinical researchers seek ways to prevent or treat obesity, and most
laboratory-based research is carried out in rodents such as rats and mice, since these
species have obvious advantages. Nevertheless, a range of other species offer special
attributes that allow lines of investigation different to those achievable with small lab-
oratory rodents. In particular, domesticated animal species allow some experimental
procedures that are not possible in smaller animals. A good example of this is the
methodology for the sampling of hypothalamic secretions into the hypophysial portal
blood in a sentient state; this was established as a technique 25 years ago and is clearly
the method of choice if one wishes to measure the output of hypothalamic hormones.
Advantages in using livestock and poultry for studies of metabolic function and
body composition are as follows:
– Farmers have been selecting for various traits related to millennia which has
segregated genes in relation to breed. Genomic analysis is well advanced for a
number of breeds and gene chips are available for species such as cattle, pigs and
poultry.
– Most farm animals are relatively easy to keep and are low cost, without the require-
ment for special housing. Their ‘natural’ habitat and social structure is also some-
what different to that of laboratory rodents in cages.
– Larger animals allow serial sampling of blood, other body fluids and tissues. Serial
sampling of cerebrospinal fluid can provide an index of neuronal activity. Multiple
sampling of fat and muscle tissues allows longitudinal analysis of metabolism and
different compartments of fat can be studied by serial sampling.
– Domesticated animals are not nocturnal, as are rodents, so that important diur-
nal patterns of behaviour and physiology of the former are more similar to
humans. Environmental effects on food intake, energy expenditure and meta-
bolic function may be studied and the role of factors such as photoperiod, are
well described.
Disadvantages in using livestock and poultry are that the technology for genetic
manipulation is not as well developed as in small laboratory species such as mice.
Nevertheless, cloning is clearly possible in sheep (e.g. Dolly) and is now a relatively
straightforward procedure in cattle. The creation of transgenic animals is also some-
what more difficult, although this has been achieved; it is only a matter of time before
this becomes more straightforward. Mice are obviously the species of choice for gene
knock-out and knock-in studies. Genetic selection studies can be done in domesti-
cated animals, but the longer generation times, compared to those of smaller labora-
tory species, make this somewhat arduous. Nevertheless, important models of obesity
can be generated and should provide important insights into the genetics of obesity
and related physiology.
This chapter will discuss how non-rodent models of metabolic function, appetite
and energy expenditure contribute to our understanding of the mechanisms involved
in the development of obesity. Predisposing genetic and epigenetic factors will be
examined and endocrine factors will be discussed. Natural models of appetite drive
and energy expenditure will be explored, including those that are found in migrating
species and those in animals adapted to extreme environments.

Metabolic Regulation in Large Animals and Birds

In the broadest sense, the model of metabolic control that pertains to laboratory rats
and mice as well as humans also relates to larger animals and birds. There are, how-
ever, some differences that are mentioned below. In animals subjected to ‘natural’
environment, especially in non-domesticated species, seasonal patterns of energy
intake and expenditure are evident and can be quite profound. Some widely

108 Clarke
studied species, such as sheep and cattle, are ruminants and this has significant
implications in regard to metabolic control. Ruminants have 4 stomachs, which are
specialised for the digestion of cellulose, and the predominant source of energy from
nutrient is absorbed as volatile fatty acids. Accordingly, the livers of ruminants have
exceptional capacity for gluconeogenesis and low hexokinase activity, favouring glu-
cose rather than glucose-6-phosphate which is a substrate for complex carbohy-
drates [1]. This means that the animal is able to ‘buffer’ blood glucose levels very
effectively with minimal changes over extreme body conditions. Thus, in sheep, pro-
found alteration of body weight and adiposity alters insulin levels but does not
change plasma glucose levels and a 72-hour fast has minimal effect on plasma glu-
cose levels [2]. On the other hand, short-term fasting elevates plasma non-esterified
fatty acid levels, indicating mobilisation of fat reserves to provide substrate for
gluconeogenesis. The study of ruminants is valuable because it allows us to compare
and contrast control of energy balance in animals that have different metabolic
substrates.
In terms of appetite control by central mechanisms, there is also widespread con-
formity across the species, although some species differences are apparent.
Accordingly, the most important appetite regulators such as neuropeptide Y (NPY)
and agouti-related peptide (AgRP) are found in all species, including avians. In sheep,
as in small laboratory rodents, leptin reduces food intake when administered intrac-
erebroventricularly or peripherally [3, 4], even though these animals are ruminants
and do not experience short-term emptying of their gastrointestinal tract. The acute
response to leptin treatment in the ruminant, in terms of food intake, is similar to that
observed in rats [5] such that, in both, the anorectic effect is not sustained with con-
tinued treatment. In rats given continuous treatment, body weight is reduced and
remains low, even though food intake returns to normal with continued leptin treat-
ment; this seems most likely due to an effect of leptin on energy expenditure.
Intracerebroventricular infusion of leptin into sheep for 3 months did not cause pro-
found loss of body weight [6], even though other effects (such as on bone morphol-
ogy and function) were manifest. In birds (quail), leptin treatment caused a transient
reduction in food intake and body weight, but this lasted for only 2 days [7]. Thus,
sustained loss of body weight occurs in rats treated with leptin, but this does not
occur in sheep or birds. Extensive studies in cattle and in pigs have led investigators in
these fields to conclude that the predominant role of leptin is to act as a ‘barometer’ of
energy reserve, such that low levels of circulating leptin indicate energy deficiency. In
states of negative energy balance, the neuroendocrine system of the brain responds in
a predicable manner.
Another ‘appetite regulator’ that has received widespread attention is ghrelin,
produced by the stomach. In laboratory species and in humans, this hormone stim-
ulates food intake [reviewed in 8], but knockout mice show minimal phenotype [9],
raising the question as to the extent that ghrelin is involved in normal metabolic
regulation. Given the precedent that NPY knockout mice also have only minor

Animal Models of ‘Obesity’ 109

perturbation in relation to metabolic function, the genetic models may not be as
important as the observations which show that ghrelin administration has effect.
Certainly, it is clear in sheep [10] that ghrelin levels rise pre-prandially and fall
post-prandially, suggesting an important regulatory role in metabolic process.
Interestingly, exhaustive attempts to demonstrate a central role for ghrelin in the
regulation of food intake of sheep consistently showed no effect [11], but recent
studies have shown that peripherally infused ghrelin did stimulate food intake [12]
in this species. Other peripheral effects of ghrelin have been shown in sheep, such as
enhancement of glucose-induced insulin secretion. The expression of the ghrelin
receptor gene is altered with changing adiposity in sheep [13], increasing in lean
condition, suggesting that correction in the ghrelin signalling to the CNS corrects
with altered metabolic state. Growth hormone (GH) secretion is elevated in lean
sheep, so an increase in ghrelin signalling may be permissive of this since ghrelin is
a GH secretagogue.
In contrast to the situation in mammals, centrally delivered or peripherally admin-
istered ghrelin reduces food intake in the chicken [14]. On the other hand, the lack of
an effect on heat production is similar to the effect in mammals.
Extensive studies of appetite regulators have been made in various domestic
species, with few surprises, compared to the effects observed in laboratory rodents.
NPY is a potent orexigen in laboratory species and the same is true for large animals,
such as sheep [15] as well as birds [16]. In particular, production in the arcuate
nucleus of the hypothalamus is upregulated in lean sheep [17], which may be an
adaptive mechanism to stimulate food intake. In this species, the orexigenic effect is
mediated through the Y1 subtype receptors [18]. Y2 subtype-specific agonists had no
effect on food intake in sheep when delivered intracerebroventricularly, in spite of an
effect on the reproductive axis. Thus, whereas PYY3–36 may act via the Y2 receptor
to inhibit food intake in rats and humans [19], this mechanism does not appear to be
operative in sheep. Leptin reduces NPY expression in the arcuate nucleus of normally
fed sheep, as in other species, but this effect is not seen in animals of lean condition.
Presumably, the upregulated NPY expression and the appetite drive is such that it
does not respond to satiety signals.
The role of the melanocortin system in control of homeostasis is well documented
for smaller laboratory animals; this is not the case for domestic animals.
Melanocortins, produced by the pro-opiomelanocortin (POMC)-expressing cells of
the arcuate nucleus, are anorexigenic in rodents [reviewed in 20], although there are
no published data to show an effect in species such as sheep, pigs or birds.
Unpublished work by Henry and Clarke showed a negative effect of melanocortin
agonist on food intake in sheep. Studies in rodents show that reduction in body
weight reduces POMC expression in the arcuate nucleus, but this does not appear to
be true for the sheep [21]. Even so, the melanocortin system appears to be important
in appetite regulation in this species, since AgRP (an endogenous melanocortin
receptor antagonist) stimulates food intake [22].

110 Clarke
 70
Body
35
weight (kg)
0
40
Percent
20
body fat
0
GUR 16
(µmol/kg/min)
8
at 2 mU/kg/min
insulin 0

GUR 30
(µmol/kg/min)
15
at 6 mU/kg/min
insulin 0
Thin Normal Fat

Fig. 1. Insulin resistance develops with increasing adiposity in sheep. Hyper-insulinaemic-eugly-

caemic clamps were performed in ovariectomised female ewes of 3 different levels of body weight
and adiposity as indicated in the upper two panels. Reduction in body weight was achieved by
dietary restriction and elevated body weight was obtained by high-energy supplementation.
Glucose utilisation rates (GURs) were calculated for infusion (i.v.) of insulin at the rate of 2 or
6 mU/kg/min. Significance level ⬍0.01 [Clarke and Clarke, unpubl. data].

Insulin Dynamics in Ruminants Are Similar to Those in Other Species

In sheep [10] and in cattle [1], insulin levels rise after a meal and glucose levels fall, in
spite of the fact that these animals absorb most of their energy from substrates other
than sugar. The rise in insulin levels leads to a fall in plasma glucose levels.
It is well known that the obese state leads to a state of insulin resistance in humans
and in laboratory animals. Even though plasma glucose levels remain relatively stable
over a wide range of body weight in sheep (vide supra), insulin resistance develops
with increasing adiposity. This is exemplified in figure 1. In spite of this, obese rumi-
nants do not progress to fully developed type 1 diabetes, but the reason for this is not
known.

Endocrine and Reproductive Effects of Leptin (Leptin as a Barometer)

The notion that leptin informs the brain of metabolic status has been expounded by
various writers in the field and this is well demonstrated in a recent human study

Animal Models of ‘Obesity’ 111

[23], showing reproductive function is compromised by a 3-day fast, but can be fully
restored by leptin replacement. The central system (gonadotropin-releasing hor-
mone, GnRH, neurons) controlling reproductive function is a sensitive barometer of
energy status, even thought the GnRH neurons do not express leptin receptors. At the
other end of the spectrum, obesity compromises reproductive function in humans.
This may relate to so-called ‘leptin resistance’ but does not appear to occur in large
animal species, which do not show reproductive compromise.

Genetic Models of Obesity

There is a wide variety of genetic models of obesity in rodents, due to the ease with
which transgenics can be created. In domesticated animals, genetic models have
relied on selection or identification of naturally occurring mutations. A flock of sheep
in New Zealand was screened for backfat thickness and then the extreme phenotypes
were backcrossed through a number of generations [24]. The selection process cre-
ated flocks of fat, lean and normal (unselected) groups. Interestingly, the three groups
have similar body weights and food intake, but differ profoundly in the level of adi-
posity. Predictable differences are seen in circulating GH concentrations, with lean
animals having high levels and fat animals having low levels. No single mutation has
been identified in these animals and the genetic selection was probably polygenic.
This is consistent with observations made in humans, lending support to the notion
that body conformation has a high heritability. Studies are in progress to ascertain the
levels of gene expression for appetite-regulating peptides in the hypothalami of these
animals, but analysis of a range of body tissues may be required in order to under-
stand the genetic and/or phenotypic character of these animals.
Polymorphisms have been identified in the leptin gene of the pig and more exten-
sively in dairy cattle [reviewed in 25]. Various polymorphisms in the bovine gene
appear to be important for production (such as milk yield) and fertility. In some
cases, polymorphisms have been linked to food intake and relative adiposity, but
further studies are probably required before this can be regarded as conclusive.
Perhaps the most interesting allelic variant is the C to T transition in exon 2 of the
leptin gene, which causes an Arg25Cys transition in the mature protein [26]. The T
allele is associated with fatter carcasses. It has been speculated that the extra Cys in
the leptin sequence destabilises the molecule, which normally has a single Cys-Cys
disulphide bridge. Another explanation offered by these researchers is that the tran-
sition affects the A helix of the leptin molecule which affects binding to the leptin
receptor.

112 Clarke
 90

Body weight (kg)

80
70
60
50
40
3/11/2000
3/01/2001
3/03/2001
3/05/2001
3/07/2001
3/09/2001
3/11/2001
3/01/2002
3/03/2002
3/05/2002
3/07/2002
3/09/2002
3/11/2002
3/01/2003
3/03/2003
3/05/2003
3/07/2003
3/09/2003
3/11/2003
3/01/2004
3/03/2004
3/05/2004
3/07/2004
3/09/2004
3/11/2004
Date

Fig. 2. Natural variation in the propensity to gain weight with high-energy diet. Mature ovariec-
tomised ewes were run on pasture with supplementation of pasture hay. Over the period indicated
by the bars, the animals were given a dietary supplement of 500 g lupin grain per week as a high-
energy source. The animals were managed so that there was no competition for the supplement and
were weighed at regular intervals. As can be seen from the heavy lines representing two animals of
similar starting weight, particular animals have a propensity to gain much more weight than others
in a repeatable manner [Clarke, unpubl. data].

Predisposition to Obesity

The rodent model of diet-induced obesity that is unmasked by feeding a high fat diet
is one which has particular pertinence to the human condition of obesity and has
been extensively studied by Levin and colleagues. This model is predicated on the
propensity of a subset of animals in a population becoming obese (diet-induced
obese) when fed a high-fat diet as opposed to another subset that do not develop obesity
(diet-resistant) on the same diet. The model unmasks genetic variants in the popula-
tion. Such a model can also be applied to sheep even though these animals are rumi-
nants and do not eat high-fat foodstuffs. Figure 2 shows data from a group of animals
that were given a high-energy dietary supplement (lupin grain) for various periods
over a 5-year period. Although the animals were of similar body weight at the start of
the study, it is clear that some animals gained more weight on the high-energy sup-
plement than others. The data from this relatively small sample of animals suggest
that the relative propensity to become obese with high-energy intake is genetically
determined in sheep as in other species.

Natural Models of Changes in Adiposity

Non-domesticated, semi-domesticated and feral animals provide especially useful

models since they respond to environmental cues to control of appetite, energy

Animal Models of ‘Obesity’ 113

expenditure and metabolic function. An extreme example of such a model is found in
reindeer, which adapt to an especially harsh environment. In the wild state, these ani-
mals live in snow-covered territory for up to 200 days/year, when the only food avail-
able is lichen, for which they must dig in the snow. It is understandable that they
possess inbuilt adaptive mechanisms that promote food intake to increase body
reserves in the summer months. An example of the seasonal change in voluntary food
intake of these beasts is provided by Mesteig et al. [27], who studied an animal that ate
33.8 g dry matter/kg body weight/day in mid-summer and 14.5 g dry matter/kg body
weight/day in mid-winter. The study of appetite-driving mechanisms of these ani-
mals and seasonality of different adipose stores could prove extremely informative.
Given that reindeer are probably somewhat difficult to procure for scientific study,
alternatives for the examination of seasonality and metabolic function are sheep and
other smaller species. The Soay breed is derived from animals that became feral on the
Island of St Kilda in the Atlantic Ocean, when people departed. Some of this breed are
now found on the British mainland and represent a valuable research resource. Soay
sheep display marked seasonal cycles of food intake and energy expenditure due to
photoperiodic regulation. Thus, under laboratory conditions, food intake is high in
long-day photoperiod and low in short-day photoperiod. This photoperiodically con-
trolled cycle is driven by alterations in the expression of NPY, AgRP and POMC genes
in the arcuate nucleus of the hypothalamus and melanin-concentrating hormone in
the lateral hypothalamus [28, 29]. Interestingly, the pattern of response to short-day
photoperiod is different in gonad-intact and gonadectomised animals (fig. 2), indicat-
ing an intimate interaction between the seasonal reproductive cycle and the appetite
cycle. Another recent paper [3] showed that there is marked seasonality in the extent
to which leptin is transferred from blood to the cerebrospinal fluid in Soay sheep, but
this transfer was greater under long-day photoperiod, when food intake is maximal.
Migrating birds provide another very interesting example of programmed storage
of energy in fat. In such species that migrate south for the winter, a number of
stopovers are made to restore energy reserves. One remarkable case is that of the
semipalmated sandpiper, which migrates from the arctic, stopping at the Bay of
Fundy in Canada to restore body reserves before a non-stop flight to South America.
During this 2-week stopover, the birds double in body weight. Interestingly, the birds
feed on a particular mud shrimp, which has unusually high levels of n-3 polyunsatu-
rated fatty acids and it has been hypothesised that this singular diet contains ‘perfor-
mance-enhancing’ substances [30]. Most fat is deposited in adipose depots and to a
lesser extent in muscle and the fat composition of the birds is modified during re-
fuelling, with an increase in the level of unsaturated fats, so as to maximise efficiency
of conversion. This massive intake of particular fatty acids modifies the muscle mem-
branes of the birds and increases efficiency for flight. Whereas this study showed that
there was very little deposition of fat in the liver, another recent study of migratory
dunlins showed that the liver synthesises leptin [31]; as to whether the latter repre-
sents an important signalling system in the bird, remains to be determined.

114 Clarke
Understanding the particular dietary preferences and the factors that drive appetite
and appetite preference during migration would be most instructive.
The study of hibernating animals could also prove most instructive with respect to
the mechanisms controlling food intake and energy expenditure. Whereas much is
known about the phenomenon and the switch from carbohydrate to fatty acid metab-
olism, very little is known about the central control mechanisms [32]. Understanding
the profound circannual cycles of appetite drive, fat deposition and altered metabo-
lism during torpor could provide key indicators of points at which fat accumulation
and/or utilisation could be manipulated.

Early-Life Events and Epigenetics

Large animals with relatively long gestation periods are ideal for the study of fetal
development because the fetus can be accessed surgically for the purpose of sampling
or manipulation. Studies on effects of maternal overfeeding, underfeeding, disease,
environmental stress (such as heat) and toxins have been carried out in ruminants,
pigs and horses. Intra-uterine growth retardation of the fetus in the sheep has been
widely used as a model of low birth weight. This can be achieved by surgical removal
of some of the placental caruncles, restriction of the uterine arterial flow, prenatal
testosterone treatment (female fetuses only) or altered nutrition (over-nutrient or
under-nutrition) of the mother. The result is reduced birth weight, followed by catch-
up growth with significant sequelae in adult life, such as disturbed metabolic ‘set point’,
insulin resistance, hypertension and relative obesity amongst other things [reviewed in
33] and with focus on large animals [34]. In general, intra-uterine growth retardation
results in reduced muscle fibre and increased adipose mass in the offspring.
Some work on possible epigenetic effects of environmental factors has been car-
ried out in sheep. For example, treatment of ewes with bisphenol between days 30–90
of gestation led to reduced birth weights and minor reproductive disruptions, but
metabolic effects were not reported [35]. It would be of considerable interest to ascer-
tain whether domesticated and/or wild animals show metabolic perturbations and/or
develop obesity following endocrine disruption, since exposure to environmental dis-
ruptors such as pesticides is likely in particular habitats.

Conclusion

This brief review has sought to highlight how work on species other than laboratory
rodents has contributed to our understanding of mechanisms that control adiposity.
The examples that have been discussed exemplify the utility of work in these species,
in an attempt to promulgate the notion that examination of a range of animal models
will enhance our knowledge of the fundamental mechanisms of homeostasis.

Animal Models of ‘Obesity’ 115

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Front Horm Res. Basel, Karger, 2008, vol 36, pp 118–134

The ␤-Cell in Type 2 Diabetes

and in Obesity
Guy A. Ruttera
Laura E. Partonb
a
Department of Cell Biology, Division of Medicine, Imperial College London, London, UK; bBeth Israel Deaconess
Medical Center, Harvard Medical School, Boston, Mass., USA

Abstract
The current worldwide epidemic of obesity and metabolic diseases has energised the search for new
approaches to treat these conditions. Type 2 diabetes appears to involve an interplay between suscepti-
ble genetic backgrounds and environmental factors including highly calorific westernised diets. The lat-
ter may generate ‘glucolipotoxic’ conditions which affect both the pancreatic β -cell and insulin-sensitive
tissues. Here we focus on efforts to better understand the basic signalling mechanisms through which
the β -cell senses changes in glucose concentration and how this process may become defective in type
2 diabetes. The recent demonstrations, through whole genome association studies, of important roles
for genes involved in the control of cell cycle, as well as intracellular ion homeostasis, further highlight
the central role of the β -cell in both the pathogenesis of the disease and as a therapeutic target.
Copyright © 2008 S. Karger AG, Basel

Diabetes mellitus is emerging as an ‘epidemic’ of the 21st century, currently afflicting 150
million individuals and projected to affect 200 million by 2025 [1]. Likewise, obesity is a
growing health care problem with ⬃20% of UK. (http://www.statistics.gov.uk/StatBase/)
and 30% of the U.S. (http://www.cdc.gov/nccdphp/dnpa/obesity/) adult population now
clinically obese. In this review we will discuss potential mechanisms whereby -cell
function and/or mass are altered both in each condition.

Stimulus-Secretion Coupling in the Healthy ␤-Cell

Insulin secretion is usually tightly regulated and ensures near-constant blood glucose
levels in the face of changes in supply and utilisation.
At the level of the individual -cell, glucose is generally believed to prompt the first
phase of insulin secretion via metabolic coupling mechanisms [2–6]. Uptake of
glucose involves a facilitative glucose transporter (Glut2 in rodents; Glut2 or Glut1 in
man) [7], followed by glucokinase-mediated glucose phosphorylation [8–10] and the
glycolytic generation of pyruvate. Oxidation of pyruvate by mitochondria is strongly
favoured over its conversion to lactate by remarkably low levels of lactate dehydroge-
nase [11–14] and plasma membrane lactate/monocarboxylate (MCT) transport activ-
ity [15, 16] in -cells: disposal of glycolytic NADH is facilitated by correspondingly
elevated levels of mitochondrial glycerolphosphate dehydrogenase activity [11, 17] and
ensures that at least 85% of glucose carbon is fully oxidised to CO2 and H2O [11, 13].
Enhanced mitochondrial oxidative metabolism [18] then leads to increases in intracel-
lular ATP/(ADPAMP) ratio [19, 20] and the closure of ATP-sensitive K (KATP)
channels [21–23] followed by cell depolarisation. The consequent opening of L-type
voltage-gated Ca2 channels and Ca2 influx [24] prompt the exocytosis of preformed
large dense core insulin-containing vesicles at the plasma membrane [25] via still
incompletely defined vesicle-associated Ca2 sensors such as synaptotagmin V [26],
Ca2-dependent activator protein for secretion [27] or cysteine string protein [28, 29].
Increases in intracellular citrate, malonyl-CoA [30] or glutamate [31] have each
been proposed to play a role in amplification, although both the ‘malonyl-CoA’ [32]
and ‘glutamate’ [33] hypotheses have been challenged.
A further important player in the control of insulin secretion are nutrient-sensitive
protein kinases including AMP-activated protein kinase (AMPK) [34–38] and per-
arnt-sim kinase [39]. Whereas the former seems likely to be regulated through
changes in the concentrations of adenine nucleotides [34] and to affect recruitment of
dense core vesicles to the cell surface [40], the means by which per-arnt-sim kinase is
regulated remain obscure. These mechanisms are illustrated in figure 1.

The ␤-Cell in Diabetes and Obesity

The ability of the -cell to respond to changes in secretory demand is illustrated by

the fact that while most type 2 diabetics are insulin resistant, the majority of insulin
resistant obese patients are not diabetic. At present, however, the cues through which
insulin resistance leads to compensatory increases in -cell function and mass
remain for the most part obscure.
Whereas the autoimmuno-mediated destruction of -cells underlies the pathology
of type 1 diabetes [41], the role of any loss of -cell mass in type 2 diabetes (T2D),
although observed to be as great as 60% [42], is hotly debated [21]. Importantly, large
changes in -cell number were only observed in cases of the very advanced disease
associated with islet amyloidosis, and it is unclear whether these are either the ‘primary’
cause of the secretory inadequacy or even sufficient to lead to frank diabetes. By con-
trast, there seems little doubt that deterioration of glucose-stimulated insulin secretion
(GSIS) from the extant -cell complement in humans [43] as well as in other species
[44–47] is an early and critical component in the pathophysiology of this disease [48].

The -Cell in Type 2 Diabetes and in Obesity 119

 ATP-sensitive K Ca2 channel opens
channel closes


ATP
Lactate
X Ca2
Glut2 Pyruvate AMPK
Glucose
GK
Glucose G-6-P

PKC
IP3 Docking Priming Kiss and run
PLC DAG Ca 2
Ca2

Insulin release

Fig. 1. Molecular mechanisms of GSIS in the healthy -cell. Uptake and phosphorylation (via glu-
cokinase, GK) of glucose ultimately leads to increases in intracellular ATP concentrations, closure of
KATP, plasma membrane depolarisation and Ca2 influx. Fusion of docked vesicles at the plasma
membrane via a transient ‘kiss and run’ or ‘cavity recapture’ mechanisms leads to release of cargo
insulin. Increases in ATP/AMP ratio also cause inhibition of AMPK, leading to the mobilisation of vesi-
cles from a reserve to a readily releasable pool and the ‘second phase’ of insulin release. Note that
non-nutrient secretagogues such as acetyl-choline may potentiate secretion by activating phospho-
lipase C, generating Ca2 increase and the activation of protein kinase C (PKC) as well as other pro-
teins. See Rutter [6] for other details and the text for discussion of changes in the T2D -cell.

Molecular Basis of Defective Insulin Secretion in T2D

It seems likely that a combination of susceptibility genes and of a ‘pro-diabetic’ envi-

ronment underlie the development of T2D. We consider these contributions below.

Genetic Contribution

As discussed above, both insulin resistance [49] and changes in -cell function [50,
51] appear to underlie the progression of T2D (fig. 2). Strongly suggestive of an inher-
ited component, concordance rates for T2D in monozygotic twins have been reported
to be as high as 90% [52], and the dynamics of insulin release (i.e. the size of the first
and second phases) are remarkably similar between monozygotic twins [53]. Clear
linkage has been demonstrated to individual genes in monogenic forms of diabetes
(‘maturity-onset diabetes of the young’, MODY) [54], and has been shown to involve

120 Rutter · Parton

 NGT Glucotoxicity
Lipotoxicity
Oxidative stress/ROS
Alterations in AMPK activity
Elevated SREBP1c/PPAR
Apoptosis

Loss of -cell mass Loss of glucosesensing

Rising insulin resistance

IGT
-Cell failure

Type 2 diabetes

Fig. 2. Contribution of -cell failure to the development of T2D. Increases in blood glucose concen-
tration during the development of diabetes are indicated by the pyramid on the left, showing the
change from normal (NGT) to impaired (IGT) glucose tolerance, before the onset of frank diabetes.

mutations in the transcription factors hepatocyte nuclear factor (HNF) 4 and HNF1
(MODY 1 and MODY3), as well as PDX1/IPF (MODY4) glucokinase (MODY2), all
of which affect -cell development or function. Recent studies have also revealed
mutations in subunits of the ATP-sensitive potassium channel, kir6.2 (encoded by
KCNJ11) [55] and SUR1 (ABCC8) [56] as contributing to certain cases of permanent
neonatal diabetes.
On the other hand, genetic associations with more common forms of T2D have
been more elusive [57]. Genome scanning in several different ethnic groups has iden-
tified chromosome regions harbouring susceptibility to more common forms of T2D
such as calpain 10 (CAPN10) [58], E23K in KCNJ11 [59] and P12A in PPARG [60],
where the ‘odds ratio’ (i.e. the increased likelihood of affected individuals having the
disease) is small (⬃1.2). Most recently, and dramatically, a highly significant associa-
tion with T2D has been demonstrated for polymorphisms in an intronic region of the
transcription factor TCF7L2 (formerly known as TCF-4) gene [61–75] involved in
wnt/-catenin signalling. The odds ratio for inheritance of the at-risk allele (i.e. the
increased risk of diabetes compared to the common allele) is ~1.5. These findings have
been confirmed in recent ‘whole genome scans’ [76–78], and it has been estimated
that as much as 20% of disease cases may be attributable to variants in this gene [74].
The functional significance of the effects of these intronic changes remains unclear,

The -Cell in Type 2 Diabetes and in Obesity 121

though it is interesting that increases in TCF7L2 are observed in a rodent model of
T2D [47]. Likewise, changes in the activity of the zinc transporter ZnT8 appear also
to be important, raising the possibility of therapeutics which target zinc accumulation
across the plasma membrane as well as into dense core vesicles [79].

Environmental Factors

Glucolipotoxicity and b-Cell Dysfunction

Both glucose and free fatty acids (FFAs) are essential -cell fuels in the normal state
and act to stimulate and potentiate insulin secretion, respectively. However, chronic
hyperglycaemia is known to induce multiple -cell defects including early reductions
in GSIS [80, 81] and irreversible changes in insulin gene transcription [81–84] and -
cell mass [85]. Similarly, chronic exposure to FFAs ( 24 h) is known to inhibit
insulin gene expression [86–88] and secretion [89–93].
-Cell ‘damage’, and loss of the first phase of insulin secretion, occur in the devel-
opment of T2D even before fasting blood glucose levels are more than 7 mM, consid-
erably below those considered to be ‘glucotoxic’. Thus, in vivo, other ‘potentiating’
factors, which may include elevated triglyceride or FFA levels [94], as well as pro-
inflammatory cytokines such as IL-1 which may be released directly from -cells
[95] [but see 96 for an alternative view] are required to observe deleterious effects on
-cell function and/or survival.
The toxic effects of chronic glucose may thus result, at least in part, from the
effects of glucose on lipid partitioning and the resulting inhibition of FFA oxidation
and potentiation of de novo FFA synthesis [97–99]. This observation, along with
reports that elevated glucose concentrations are required for the deleterious effects of
FFAs [87, 100], have lead to the perhaps more appropriate term ‘glucolipotoxicity’.

FA-Induced b-Cell Apoptosis: Evidence from Animal Models

Chronic exposure of pancreatic islets to FFA has been shown to induce -cell death
by apoptosis [101, 102] and reductions in -cell proliferation [101, 102] in vitro.
Further evidence for a role of FFA in the induction of -cell apoptosis comes from
obese animal models of T2D. In rodents, mutations in the ob gene [103], or in genes
that encode the leptin receptor (Ob-R), cause leptin deficiency and leptin unrespon-
siveness, respectively. The ob/ob mouse is an example of absence of functional leptin
[103], whereas the db/db mouse [104] and the fa/fa rat [105, 106] lack functional Ob-
R. These animals are hyperphagic due to lack of leptin action on the appetite centres
of the hypothalamus [107, 108], which rapidly leads to obesity. This imbalance
between calorific intake and energy expenditure is associated not only with an
increase in adipose tissue mass, but also with a progressive increase in lipid deposi-
tion in non-adipose tissues, including the pancreatic islets [109].

122 Rutter · Parton

 In the Zucker diabetic fatty (ZDF) rat, onset of obesity occurs at about 4 weeks of
age. Initially, as islet lipid content rises to about ten times that of normal levels, there
is increased -cell proliferation and -cell mass, along with associated increases in
insulin secretion [110, 111]. Initially this ensures sufficient insulin production to
compensate for rising insulin resistance. However, as this pre-diabetic stage of obesity
progresses, islet lipid content continues to rise and severe mitochondrial abnormali-
ties develop together with marked increases in -cell apoptosis [112]. At this stage,
the rate of apoptosis exceeds the rate of -cell replication and a net loss of -cells
occurs. Insulin secretion no longer compensates for the increased insulin resistance
and so overt diabetes develops.

Role of SREBP1c in b-Cell Failure

Sterol regulatory element binding proteins are a family of transcription factors
involved in the regulation of genes associated with cholesterol and FFA metabolism.
SREBP1c is expressed in pancreatic islet -cells [113] where its expression [114, 115]
and activity [116] are induced by elevated [glucose]. Increased expression of
SREBP1c has been described in the islets of several animal models of T2D and
mounting evidence supports a role for SREBP1c in the development of -cell dys-
function. Increased SREBP1c expression has been described in the islets of ZDF and
diet-induced obese rats, where it is correlated with increased lipogenic gene expres-
sion and triglyceride content [47, 117]. Furthermore, suppression of SREBP1c expres-
sion by treatment with the anti-lipogenic drug, troglitazone, reduces islet triglyceride
levels and partially prevents the development of diabetes in ZDF rats [117]. Hence,
SREBP1c may play a key role in inducing triglyceride accumulation and as a conse-
quence -cell dysfunction. This induction of lipogenic gene expression by SREBP1c
in the -cell was supported by initial studies in -cell lines that demonstrated
increased lipogenic gene expression and lipid accumulation in response to overex-
pression of the active N-terminal portion of SREBP1c [114, 118, 119]. Similar results
have since been described in rodent islets, where overexpression of SREBP1c results
in increased lipid content which is associated with reduced GSIS [120]. Islets from
transgenic mice that overexpress SREBP1c specifically in -cells have increased FAS
mRNA expression and elevated lipid content. Importantly, these mice display
impaired glucose tolerance as a result of defective insulin secretion [121]. The delete-
rious effects of SREBP1c on islet function are thought to involve an impairment in
glucose-induced ATP production, mediated by an increase in the mitochondrial
uncoupling protein, UCP2 [119]. Overexpression of SREBP-1 may also lead to an
endoplasmic reticulum stress response, leading ultimately to cell death [120].
We [47] recently showed that inhibition of endogenous SREBP1c activity in
ZDF rat islets, whilst restoring elevated basal insulin secretion, had little effect on
GSIS, suggesting that SREBP1c alone is not sufficient to induce defective insulin
secretion.

The -Cell in Type 2 Diabetes and in Obesity 123

PPARg and Defective Insulin Secretion
The thiazolidinedione (TZD) class of antidiabetic drugs act as high-affinity peroxi-
some proliferator-activated receptors (PPAR) agonists [122]. Mice that lack PPAR
specifically in -cells ( knockout mice) have increased islet size, largely due to -
cell hyperplasia [123]. When fed a high-fat diet to induce insulin resistance and obe-
sity,  knockout islets are protected from obesity-induced hyperplasia, suggesting
that PPAR is required for the normal expansion of islet mass observed in obese
rodents. The effects of TZD treatment appear to be specific for PPAR in the islet in
vitro, as rosiglitazone treatment increased basal and GSIS in normal islets but had no
effect on  knockout islets. In contrast however, no differences in serum insulin lev-
els in wild-type or  knockout mice were detected in response to rosiglitazone treat-
ment in vivo, suggesting that TZD action within -cells does not significantly
contribute to the effect of these drugs. Whether deletion of PPAR in islet -cells
affects the efficacy of TZDs in the context of other models of T2D remains to be
established.

Other Molecular Players in Defective Insulin Secretion in T2D

As discussed above, the precise molecular basis of the changes in glucose sensing in
the T2D -cell remains as yet unclear. There is nonetheless good evidence for
decreased glucose-induced ATP rises, and oxygen consumption appears to be
decreased in diseased islets from T2D subjects [124] and in rodents, e.g. GK rat [44].
Changes in the expression of multiple genes were identified in islets from ZDF rats
[46], including in the pre-diabetic stage, where glucose-induced insulin secretion is
abnormal [47]. Of note, the latter study revealed decreases in the expression of the
glucose transporter, Glut2. Very recent studies have shown that Glut2 is subject to
post-translational modification (N-glycosylation), a process which may become
defective in T2D models [125].
A recent microarray-based study of human T2D islets [126] revealed changes in
the expression of a wide range of mRNAs, including the glycolytic genes glucose 6-
phosphate isomerise and phosphofructokinase (note that GK and Glut2 mRNAs dis-
played a non-significant tendency towards lower levels in T2D islets), and most
strikingly in the expression of a PAS domain containing transcription factor termed
ARNT/HIF1 (hydrocarbon nuclear receptor translocator/hypoxia-inducible factor
1, decreased 90%). Moreover, knock-out of ARNT selectively in the -cells of
mice or silencing in MIN6 cells led to defective glucose-induced insulin secretion.
Both in rodent and human studies, decreases in the expression of glycolytic genes
were observed, and seem likely to underlie the defective glucose-induced increases in
metabolic signalling. Interestingly, increases in the levels of lactate dehydrogenase,
which are vanishingly low in -cells [11] (see above and fig. 1) are also observed at
least in some models of -cell dysfunction including partial resection [127] and in

124 Rutter · Parton

the ZDF rat [47] and suggest that a loss of pyruvate ‘funnelling’ towards mitochondr-
ial oxidation may contribute to defective stimulation of insulin release. Likewise,
mutations shown to lead to increases in the level of the plasma membrane
lactate/pyruvate (monocarboxylate) transporter, MCT-1, normally absent from
mature -cells, have recently been reported [128] in patients suffering from exercise-
induced hyperinsulinism [129]. Whether such individuals display abnormal glucose-
induced insulin secretion, or a greater risk of T2D in later life, is presently unclear.
If defective glucose-induced increases in electrical activity and calcium influx are
strongly implicated in the pathology of defective insulin secretion in T2D islets, there
seems little doubt that ‘downstream’ processes, including the fusion of secretory vesi-
cles at the plasma membrane, may also be affected. Thus, Ostensen et al. [130] found
decreases in the expression (at the protein and mRNA levels) of several proteins
implicated in exocytosis including SNAP-25, nSec1/Munc18, synpatophysin and
synaptotagmin V in human islets obtained post-mortem from 4 T2D subjects versus
normoglycaemic controls. Likewise, Abderrahmani et al. [131] reported decreases in
the levels of the key exocytotic proteins, including granuphilin/slp4, Noc2, Rab3a and
Rab27a, which are proposed to result from an up-regulation of the CREB family
member, CREM or ICER (inducible cAMP early repressor) as a result of hypergly-
caemia-induced increases in intracellular cAMP levels. By contrast, other studies in
animal models [132] have proposed that increases in granuphilin levels are associated
with defective insulin secretion in the islets of mice overexpressing the lipogenic tran-
scription factor, SREBP-1c. Finally, inactivation of the Rab protein Rab27, implicated
in the regulation of vesicle trafficking to the plasma membrane [131], led to defective
GSIS in ashen mice [133]. Whether the expression of downstream effectors of Rab27,
including myosin Va [134] might also be altered in T2D is unclear, though we have
reported that knockdown of this molecule leads to defective secretion and vesicle
motility in MIN6 -cells [135].

Role of Changes in Mitochondrial Oxidative Metabolism in T2D

Conditions such as hyperglycaemia and hyperlipidaemia are known to increase

superoxide production in pancreatic islets through increased mitochondrial oxida-
tion of glucose and FFAs [136]. In turn, accelerated superoxide production results in
increased exposure of the -cell to reactive oxygen species (ROS) which are known to
have deleterious effects on islet cell function and survival [137, 138].
A potentially interesting insight into a mechanism of defective GSIS which seems
unlikely to involve changes in triglyceride accumulation are substrains of C57BL6 mice,
which carry a mutation in the nicotinamide nucleotide transhydrogenase gene [139].
This may lead to a lowering in intramitochondrial levels of reduced glutathione and
enhanced damage by ROS. The latter are of particular interest, being implicated in the
-cell damage elicited by ‘oxidative stress’ ensuing from chronic elevation of glucose

The -Cell in Type 2 Diabetes and in Obesity 125

concentrations (see above) [140]. In this context, the role of AMPK, whose activation
appears to block GSIS [36, 141] (fig. 1), is interesting since activation of the latter
enzyme, e.g. with the antidiabetic agent metformin [37, 142], has been suggested to
inhibit insulin release from ‘healthy’ -cells and islets, consistent with findings in which
activated forms of AMPK are expressed [36, 40, 141] whereas metformin appeared to
improve secretion from diabetic islets. One possible explanation for this dichotomy is
that the activation of AMPK leads to decreases in islet triglyceride (thanks to the inhibi-
tion of acetyl-CoA carboxylase and the consequent lowering of malonyl-CoA and
release of inhibition of fatty acid oxidation on carnitine transferase) in islets from
(obese) type 2 diabetics. Alternatively, the metformin-elicited inhibition of the respira-
tory chain at complex I [143], whilst decreasing ATP levels in the healthy -cell and
thus compromising glucose-induced ATP increases and stimulated insulin secretion,
may chiefly lead to decreased ROS production in the diabetic -cell, thus removing or
reducing damage to the cell by these compounds.
Whether in vivo exposure to metformin (and, indeed rosiglitazone, which also
activates AMPK) at physiologically relevant doses (⬃15
M in the case of metformin)
also leads to improved -cell function in diabetes remains to be determined, but is an
important question with respect to the development of future therapies based on
AMPK as a target. Whether, for example, it may be possible selectively to activate
AMPK in extrapancreatic tissues (liver, muscle and adipose tissue), thus exerting pos-
itive effects on blood glucose and lipid levels, whilst leaving the -cell enzyme unaf-
fected, is presently unclear. It should be emphasised that this is likely to require drugs,
possibly derived from modifications of 5-amino-imidazole-4-carboxamide riboside,
which act directly on AMPK complexes of bearing different combinations of the sub-
units, rather than on agents such as metformin and the TZDs which act via the mito-
chondrial respiratory chain [143]. Alternatively, agents which act on leptin signalling
pathways may also be promising given the fact that leptin stimulates AMPK activity
in muscle, whilst exerting no apparent effect on AMPK in -cells [37].
These questions are all the more pressing, given the reported pro-apoptotic effects
of AMPK activation in the -cell [142].

Changes in the Mode of Dense Core Vesicle Exocytosis in T2D

In an attempt to explore the impact of the above changes in gene expression on

insulin-containing vesicle behaviour in living -cells, we have used vesicle targeted
probes, a method previously deployed in healthy -cells [144, 145] to monitor dense
core vesicle dynamics in rat -cells exposed to elevated glucose concentrations [146].
This treatment, which aimed to mimic the hyperglycaemia observed in vivo in dia-
betes, led to a shift in the type of exocytosis observed. Thus, studied using total inter-
nal refection of fluorescence microscopy, a significant (fivefold) but reversible
decrease in the proportion of secretory events which led to the complete release of

126 Rutter · Parton

labelled insulin from individual vesicles from ⬃25 to just 5% was found (fig. 1).
Whilst it was not possible to observe release events from -cells obtained from 6- to
8-week-old ZDF rats [47], we noted fewer vesicles at the cell surface. On the other
hand, treatment of MIN6 -cells with an adenovirus overexpressing SREBP-1c, a
manoeuvre previously shown to decrease insulin release at the population level [114]
reduced the number and type of event. The latter studies, which involved the use of
animals or of model systems in which the -cell triglyceride content was massively
increased, may or may not adequately mimic the situation in the ‘typical’ T2D -cell;
future studies are required to compare the alterations in vesicle behaviour and the
nature of the fusion event in -cells from lean and T2D -cells. Likewise, it will be
important to dissect the nature of the changes in gene expression in each scenario.

MicroRNAs

Another exciting area is that of microRNAs. Recent studies by Poy et al. [147] and by
Plaisance et al. [148] have revealed the important role played by this new class of
short RNA species, termed microRNAs [147], in regulating -cell function. Thus,
miR-375 regulates late events in vesicle movement and fusion [147] whereas miR-9
appears to be involved in the control of multiple genes including granuphilin/slp4
[148] which in turn regulate the secretory process. Similarly, our own data [149] indi-
cate that miR-124, an miR whose expression is massively induced during pancreatic
development, controls the expression of both key proteins involved in determining -
cell excitability and Ca2 influx (including KATP channel subunits) but also regulating
the sensitivity of the secretory machinery to these Ca2 changes.

Acknowledgements

G.A.R. is supported by grants from the Wellcome Trust and the Medical Research Council UK.
L.E.P. thanks the American Heart Association for a Fellowship.

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Prof. Guy A. Rutter
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Sir Alexander Fleming Building, Exhibition Road
London SW7 2AZ (UK)
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Front Horm Res. Basel, Karger, 2008, vol 36, pp 135–145

Role of the Endocannabinoid

System in Energy Balance
Regulation and Obesity
Daniela Cota
Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA

Abstract
The endogenous cannabinoid system (ECS) is a neuromodulatory system recently recognized to have a
role in the regulation of various aspects of eating behavior and energy balance through central and
peripheral mechanisms. In the central nervous system, cannabinoid type 1 receptors and their endoge-
nous ligands, the endocannabinoids, are involved in modulating food intake and motivation to consume
palatable food. Moreover, the ECS is present in peripheral organs, such as liver, white adipose tissue, mus-
cle, and pancreas, where it seems to be involved in the regulation of lipid and glucose homeostasis.
Dysregulation of the ECS has been associated with the development of obesity and its sequelae, such as
dyslipidemia and diabetes. Conversely, recent clinical trials have shown that cannabinoid type 1 receptor
blockade may ameliorate these metabolic abnormalities. Although further investigation is needed to
better define the actual mechanisms of action, pharmacologic approaches targeting the ECS may pro-
vide a novel, effective option for the management of obesity, type 2 diabetes and cardiovascular disease.
Copyright © 2008 S. Karger AG, Basel

The appetite-stimulating and antiemetic properties of Cannabis sativa have been known
for centuries. However, although synthetic and plant-derived cannabinoids (CBs) such
as ⌬9-tetrahydrocannabinol (⌬9-THC) have long been recognized to influence food
intake, only recently CB receptors, endogenous CBs (endocannabinoids), and their
biosynthetic and degradative pathways have been identified. Collectively, these discover-
ies have led to the characterization of an endogenous signaling system now known as the
endocannabinoid system (ECS). In mammals, the ECS has been recently recognized to
have a role in the modulation of several physiological processes, including neuroprotec-
tion, regulation of hormone secretion, locomotion, and energy homeostasis, among oth-
ers. The purpose of this chapter is to outline the recent advances in our understanding of
the role of the ECS in energy balance regulation and to discuss the clinical relevance of
this work with respect to obesity and associated metabolic risk factors.
 Cannabinoid agonists
Ca2⫹

Extracellular

CB1

G
Intracellular K⫹

AC
MAPK

Fig. 1. Cellular effects of CB1 receptor activation in the brain. Activation of CB1 through the action
of CB receptor agonists, such as ECs, induces stimulation of Gi/o heterotrimetic proteins (G). CB1 stim-
ulation of Gi/o proteins is directly coupled to stimulation of inwardly rectifying K⫹ channels and inhi-
bition of voltage-activated Ca2⫹ channels, effects that in neurons lead to inhibition of
neurotransmitter release. Activation of CB1 leads also to inhibition of adenylate cyclase (AC) or to
stimulation of mitogen-activated protein kinase (MAPK). Modulation of these intracellular pathways
may affect gene expression. See also references [1–3, 7].

Components of the ECS

CB Receptors
The first CB receptor was characterized using reverse pharmacology approach in
1988. This receptor was named CB1 after the second CB receptor, named CB2, was
cloned in 1993. CB1 is found in the central nervous system as well as in peripheral
organs [1]. CB2 is mainly localized in the immune system, and shares a 48% homol-
ogy with CB1 [2, 3]. Both are 7-transmembrane-spanning Gi/o receptors that inhibit
adenylyl cyclase and activate mitogen-activated protein kinase [1, 2]. In addition,
the CB1 receptor is reported to affect both potassium and calcium channels (fig. 1).
CB1 receptors are among the most abundant G-protein-coupled receptors in the
brain, having similar densities as receptors for ␥-aminobutyric acid (GABA) and
glutamate-gated ion channels [2]. In the central nervous system, the distribution of
CB1 receptors is heterogeneous, with higher densities in the basal ganglia, hip-
pocampus and cerebellum [2]. CB1 expression in the hypothalamus, a key integra-
tive area in the regulation of energy homeostasis, is relatively low; however,
activation of hypothalamic CB1 is highly efficient [2]. Activation of CB1 receptors,

136 Cota
usually located presynaptically, modulates the release of several neurotransmitters,
such as GABA, dopamine (DA), noradrenaline, glutamate and serotonin. CB1
receptors are expressed by astrocytes as well as by neurons [4]. Interestingly, activa-
tion of CB1 on astrocytes increases available energy to local neuronal circuits, and
the administration of CB agonists increases overall energy metabolism in the brain
[4]. CB1 are also located on nerve terminals innervating the gastrointestinal tract as
well as found in other organs involved in energy balance regulation, such as white
adipose tissue, liver, pancreas and skeletal muscle [reviewed in 5]. Although CB2 are
located mainly in tissues of the immune system, they have recently also been identi-
fied in neurons in several regions of the brain [6]. For an in-depth description of the
characteristics and functions of CB receptors, the reader should refer to recent
reviews [1–3, 7].

Endocannabinoids
All endocannabinoids (ECs) identified so far are amides, esters or ethers of arachi-
donic acid, a long-chain polyunsaturated fatty acid that is a constituent of cell mem-
branes [1]. Anandamide (the ethanolamide of arachidonic acid) was the first
described EC, and 2-AG was later identified. These two ECs are the best character-
ized and their properties have been largely studied in recent years. Their biosynthetic
and degradative pathways have been recently reviewed [1, 2]. Other putative ECs
have been discovered [1]; however, neither the mechanisms of synthesis and deacti-
vation, nor the specific functions have been defined for these other compounds. The
concentrations of anandamide and 2-AG within the brain vary considerably by area.
In most brain areas, 2-AG is around two orders of magnitude more abundant than
anandamide, with the highest levels of both occurring in the brainstem, hippocampus
and striatum [1, 2, 7]. Both anandamide and 2-AG are produced in several peripheral
tissues, including skin, gut, liver, adipose tissue and testis [1, 2, 7]. Moreover,
although its physiological function is unknown, anandamide is present in the blood-
stream where it is bound to albumin [reviewed in 5]. Anandamide and 2-AG each
bind to both CB1 and CB2 receptors. However, 2-AG is a full agonist at CB1, whereas
anandamide is a partial CB1 agonist [1]. Unlike the case for classical neurotransmit-
ters which are synthesized and stored in vesicles until needed, ECs are made de novo
during neuronal hyperactivity and immediately released into the extracellular space
of synapses [7]. As they bind to CB1, a sequence of intracellular events is induced,
and the ECs are then rapidly eliminated via reuptake and degradation by neurons and
possibly glia cells [1, 2]. This ‘on demand’ process is mainly utilized by neurons dur-
ing periods of high-frequency membrane stimulation [7]. For instance, many CNS
CB1 receptors are localized presynaptically on GABAergic interneurons. ECs released
from postsynaptic membranes therefore must diffuse or be transported retrogradely
in order to interact with CB1 and thereby decrease the release of presynaptic neuro-
transmitter. The generally accepted model is that when electrical activity in the form

Cannabinoids and Obesity 137

of repeated action potentials in the presynaptic neuron (i.e. a GABAergic neuron)
becomes particularly high, the continuous neurotransmitter-induced modulation of
the postsynaptic membrane results in the accumulation of intracellular Ca2⫹ in the
postsynaptic neuron. One important consequence is that elevated Ca2⫹ activates
enzymes that synthesize ECs in the postsynaptic neuron’s cell membrane, thus gener-
ating anandamide and/or 2-AG. The ECs then retrogradely diffuse back across the
synapse, where they bind to presynaptic CB1 receptors [1–3, 7]. Therefore, activation
of CB1 results in reduced neurotransmitter (i.e. GABA) release from the presynaptic
neuron in response to further action potentials. In fact CB1 are located on many
GABAergic neurons, where they are involved with what has been called depolariza-
tion-induced suppression of inhibition; however, they are also found on neurons
which have excitatory influences on postsynaptic cells [1, 2]. For instance, some glu-
tamatergic neurons also express CB1 which are therefore involved with depolariza-
tion-induced suppression of excitation. Recent evidence has demonstrated that there
might be constitutive release of ECs, in the absence of external stimulation, in both
the hippocampus [8] and the arcuate nucleus (ARC) in the hypothalamus [9].

Synthetic CB Receptor Agonists and Antagonists

Among the synthetic CB receptor agonists, CP 55,940, WIN 55,212-2 and HU 210 are
worth mentioning since they are largely used to investigate the physiological func-
tions of the ECS and, specifically, its role in energy balance. Among the synthetic
antagonists, SR 141716, AM 251 and AM 281 are specific for CB1 receptors. Several
inhibitors of anandamide cellular reuptake or transport and of anandamide hydroly-
sis have also been identified, presenting multiple pharmacologic opportunities to
modulate the ECS [1].

Role of the ECS in the Regulation of Energy Balance

The ECS influences energy balance at many sites in the brain and throughout the
body, with the net and highly coordinated effect being anabolic, i.e. increased EC
activity enhances food intake and supports fat deposition. Within the brain, CB1 and
ECs are present in both hypothalamic and extrahypothalamic circuits. Both networks
contribute to excessive eating when ECS activity is high. Within peripheral organs
including adipose tissue, liver and skeletal muscle, locally produced ECs are also ana-
bolic, contributing to lipogenesis and fat storage and reduced energy expenditure. In
the gastrointestinal system, ECs are thought to increase fuel absorption and decrease
satiety. Thus, the ECS biases behavioral and metabolic processes to promote obesity.
Consistent with this, genetic polymorphisms of components of the ECS have been
associated with overweight and obesity in humans [10].

138 Cota
The ECS and the Hypothalamus
The hypothalamus is an important integrative center for the control of energy
homeostasis. Neurons in the ARC are sensitive to the circulating hormones leptin
and insulin, and the ARC in turn projects to many other sites in the hypothalamus
and elsewhere in the brain [11]. Two categories of ARC neurons are known to
participate in energy balance regulation. ARC pro-opiomelanocortin (POMC)
neurons synthesize the neurotransmitter ␣-melanocyte-stimulating hormone (␣MSH),
which acts at melanocortin receptors to induce reduction in food intake and body
weight [11]. Increased plasma levels of leptin and/or insulin, both signals of
increased body fat, stimulate POMC neurons, initiating the catabolic response.
POMC cells in the ARC release ECs [9], and leptin reduces hypothalamic endo-
cannabinoid levels, inhibits ECs’ action in several hypothalamic areas, thus facili-
tating its anorexigenic effect [12]. Other ARC neurons synthesize the anabolic
neurotransmitters neuropeptide Y (NPY) and agouti-related protein [11]. NPY
acts on Y receptors throughout the hypothalamus to stimulate food intake,
whereas agouti-related protein antagonizes ␣MSH, thus inhibiting the catabolic
action of POMC cells [11]. Recent findings have demonstrated that CB agonists
increase the secretion of NPY in the hypothalamus, consistent with ECs increasing
food intake. Moreover, hypothalamic 2-AG levels increase during fasting, decline
as animals are re-fed and return to normal values when animals eat to satiation
[13]. CB1 mRNA has been colocalized with many hypothalamic neuropeptides
involved in energy balance regulation, including corticotropin-releasing hormone,
cocaine-amphetamine-regulated transcript, pre-pro-orexin and melanin-concen-
trating hormone [14]. Moreover, as discussed above, CB1 are also expressed by
GABAergic neurons entering the ARC [9]. Intrahypothalamic administration of
⌬9-THC increases food intake in laboratory rats. Anandamide not only increases
food intake when administered systemically, but does so also when injected into
the hypothalamus; and pretreatment with the selective CB1 antagonist SR 141716
(rimonabant) attenuates anandamide-induced hyperphagia [reviewed in 5].
Interestingly, animals lacking CB1 (CB1⫺/⫺ mice) have reduced food intake,
decreased body weight and a lean phenotype [14]. CB1⫺/⫺ mice have increased lev-
els of hypothalamic anorexigenic neuropeptides [14], and they do not increase
their food intake when treated with orexigenic compounds, such as NPY.
Moreover, the hyperphagia elicited by ghrelin and by orexin A can be attenuated by
administration of SR 141716; and CB1 are coexpressed with orexin 1 receptors
[reviewed in 5]. Thus, the actions of several orexigenic peptides within the hypo-
thalamus, including NPY, orexin and ghrelin, seem to be facilitated by ECs.
Furthermore, administration of SR 141716 attenuates the orexigenic effect of
melanocortin antagonists, but the administration of melanocortin agonists does
not interfere with the action of CB agonists, suggesting that endocannabinoids may
act downstream of melanocortins [reviewed in 5].

Cannabinoids and Obesity 139

The ECS and the Brain Reward System
The system controlling the rewarding aspects of food is comprised of a series of synap-
tically interconnected circuits linking the prefrontal cortex, the amygdala, the ventral
tegmental area, the nucleus accumbens and the ventral pallidum. This integrated net-
work connects forebrain, hindbrain and midbrain areas with hypothalamic areas and
is thus able to modulate food intake [15]. In the 1970s, anecdotal observations of
humans smoking marijuana pointed out that they have increased appetite and often
have cravings for palatable foods [reviewed in 16]. Studies carried out in rats following
administration of ⌬9-THC found increased preference for palatable foods, such as
sucrose. Thus, ECs might help mediate palatability or other positive aspects of food
[reviewed in 17]. Accordingly, systemic SR 141716 not only decreases intake of bland
food, but specifically reduces intake of alcohol, sucrose and other sweet foods in ani-
mals [reviewed in 16]. While only 2-AG is increased in the hypothalamus, both anan-
damide and 2-AG levels are increased in limbic areas of rats that have been fasted, thus
indicating that brain ECs are responsive to fasting and that there are differences in the
response between the brain areas controlling energy homeostasis and reward, respec-
tively [13]. Interestingly, rats maintained on a palatable diet for 10 weeks, not only
become obese, but have less CB1 mRNA in several limbic areas. Furthermore, when 2-
AG is administered directly into the shell of the nucleus accumbens (a limbic area with
high levels of CB1 that is strongly associated with reward processes) a rapid and pro-
found hyperphagia is reported [13]. The neurotransmitter DA is recognized to be an
important mediator of the rewarding effects of food and drugs of abuse. The ECS has
been recently reported to directly and indirectly affect DA release [16]. Moreover,
serotonin, another neurotransmitter involved with both reward and food intake, also
interacts with the ECS. Finally, there is considerable anatomical overlap between CB1,
opioid receptors and their respective endogenous ligands in brain areas involved with
food intake and reward mechanisms [reviewed in 16]. Interactions between the ECS
and opioid system have been hypothesized to be a critical component for the reward-
ing aspects of food intake and are thought to possibly provide a molecular basis for
drug or food dependence [reviewed in 16].

The ECS and Peripheral Metabolism

In agreement with the hypothesis that peripheral metabolic mechanisms might be
directly modulated by the ECS independent of and in addition to modulation by cen-
tral nervous pathways, CB1 and ECs are present in several peripheral tissues related to
energy homeostasis. White adipocytes express CB1 receptors [14, 18, 19], and in vitro
experiments demonstrate that the CB1 agonist WIN-55,212 stimulates adipocyte dif-
ferentiation and increases the activity of lipoprotein lipase; both actions are blocked by
pretreatment with SR 141716 [14]. These findings imply that EC activity in white fat
might facilitate growth of new fat cells as well as enhance the ability to remove fat from
the bloodstream and deposit it into fat cells. Furthermore, mature adipocytes express a

140 Cota
greater number of CB1, and CB1 expression is higher in adipocytes of obese as com-
pared to lean animals [18]. Studies in humans also indicate that mature adipocytes
have increased CB1 expression as compared to preadypocytes [19]. ECs are also pro-
duced in the liver [20] where they help regulate hepatic blood flow. Interestingly, acti-
vation of CB1 in hepatic tissue induces lipogenic enzymes, thus stimulating de novo
fatty acid synthesis [20]. Diet-induced obese mice have increased activity of this
hepatic lipogenic pathway as well as elevated expression of CB1 and increased anan-
damide levels in the liver [20]. Interestingly, recent evidence has shown that the activ-
ity of AMPK (an enzyme that may mediate the action of antidiabetic drugs, such as
metformin) is inhibited by CB agonists in both liver and adipose tissue [21]. Most
meal-generated satiety signals from the gastrointestinal tract reach the hindbrain via
vagal afferent nerves, and the signals are then conveyed to the hypothalamus and else-
where in brain areas controlling food intake. CB1 have been localized in vagal afferent
nerves, in neurons in the dorsal vagal complex and in vagal efferent nerves. The obser-
vation that cholecystokinin (CCK) inhibits the expression of CB1 on vagal afferents
[22] is consistent with CCK’s role as a satiety signal that reduces food intake. Moreover,
anandamide levels are greatly increased in the small intestine during fasting, and
decreased during refeeding, suggesting a role of ECs in influencing food intake via
modulation of gastrointestinal signals [reviewed in 5]. In fact, ECs modulate many
aspects of gastrointestinal function including gastric emptying and intestinal peristal-
sis. Although its function is less defined, the ECS is also present in the muscle (with
increased levels of CB1 expression during exposure to high fat diet) and in the pan-
creas. Furthermore, few studies suggest that ECs might affect energy expenditure. The
administration of the CB1 antagonist SR 141716 reportedly increases glucose uptake
and basal oxygen consumption of skeletal muscle from genetically obese mice, and
chronic administration of SR 141716 elicits increased expression of genes for thermo-
genesis in brown adipose tissue [reviewed in 5].

Role of the ECS in Obesity

There is mounting evidence that the ECS, normally transiently activated, might become
tonically overactivated in both animal models of genetic and diet-induced obesity and
in human obesity. For instance, the levels of hypothalamic ECs are increased in geneti-
cally obese rodents with defective leptin signaling, and treatment of these genetically
obese mice with a CB1 antagonist attenuates their hyperphagia and reduces their weight
gain, implying that overactivation of the hypothalamic ECS system may be a contribut-
ing factor in the development of obesity [12]. Interestingly, CB1⫺/⫺ mice do not become
obese on a high-fat diet and have increased sensitivity to the catabolic action of leptin
[reviewed in 5]. In animal models of diet-induced obesity, there is evidence of increased
CB1 receptor expression and ECs levels in both adipose tissue and liver. In obese
women, plasma anandamide and 2-AG levels are significantly elevated compared with

Cannabinoids and Obesity 141

lean women [19]. However, differently from the data reported in animals, obese
humans have decreased CB1 mRNA levels in the adipose tissue. Moreover, they also
show decreased levels of FAAH mRNA, the primary enzyme responsible for the degra-
dation of anandamide [19]. Dysregulation of the ECS is also associated with eating dis-
orders. Patients diagnosed with restricting anorexia nervosa or binge eating disorder
have elevated plasma levels of anandamide. Moreover, specific gene polymorphisms
affecting the regulation of the ECS activity seem to contribute to the development of
obesity. For instance, a specific gene missense polymorphism, FAAH 385 A/A, has been
found to occur at a higher frequency among individuals with a higher body mass index
(BMI) [10]. A number of environmental factors may contribute to dysregulation of the
ECS, including stress and diet. Stress may impact the ECS as suggested by evidence
linking glucocorticoids and the ECS in the hypothalamus. Preliminary findings also
indicate that diets high in long-chain polyunsaturated fatty acids, known biological pre-
cursors of N-acylethanolamines (anandamide and 2-AG), are associated with increased
levels of N-acylethanolamines in the brain. Finally, alteration in the function or in the
circulating levels of hormones involved in the regulation of energy balance (i.e. leptin,
CCK, ghrelin) might be linked to dysregulation of the ECS [7].

Use of CB1 Antagonists to Treat Obesity

When rodents are fed a high-fat diet, they overeat and become obese. In one series of
experiments, mice maintained on high-fat diet and chronically administered the CB1
antagonist SR 141716 ate less food [reviewed in 5]. Significantly, the anorectic action
of the antagonists lessened and then disappeared altogether over a week or two in
spite of continued dosing, indicating the development of tolerance. Nevertheless,
there was a sustained reduction of body weight and body fat mass over the next sev-
eral weeks, suggesting that possibly other actions of the CB1 antagonists were contin-
uing to exert metabolic effects. At the end of the experiments, mice receiving the CB1
antagonists chronically had reduced body weight, body fat, plasma leptin and plasma
insulin, and an improved lipid profile, perhaps due to the ability of the drug to
increase adiponectin expression and secretion from adipose tissue [reviewed in 5].
Adiponectin, differently from other adipokines, improves insulin sensitivity and
induces fatty acid oxidation in muscle and liver. Somehow related to these findings,
experiments using CB1⫺/⫺ mice revealed that the lean phenotype is predominantly
caused by decreased caloric intake when the mice are young, whereas peripheral
metabolic factors are the major cause of maintaining the lean phenotype in the adults
[14]. As discussed above, CB1⫺/⫺ mice are resistant to diet-induced obesity. They
maintain their lean phenotype and they do not develop hyperglycemia or insulin
resistance. Accordingly, chronic treatment with the CB1 antagonist in mice exposed
to high-fat diet altered gene expression profiles in both white and brown adipose tis-
sue to support fat oxidation and increased thermogenesis [reviewed in 5]. Therefore,

142 Cota
chronic treatment with a selective CB1 antagonist reduces body fat as well as
improves many alterations commonly associated with the metabolic syndrome.
Hence, it seems that the early transient reduction of food intake when animals are
started upon the antagonist cannot account for the sustained improvement in meta-
bolic parameters. Recent data from clinical studies seem also to support this hypoth-
esis. Clinical trials conducted on overweight and obese patients with BMI ⱖ27 who
were on a hypocaloric diet, have shown that oral CB1 receptor antagonist (rimona-
bant 20 mg/day) administration for 1 year resulted in weight loss of up to 8.6 kg com-
pared with 2.3 kg in placebo-treated individuals [23, 24]. The reduction in body
weight occurred during the first 36–40 weeks of the study period. Long-term treat-
ment (2 years) with CB1 receptor antagonist was able to stabilize body weight and
prevent weight regain [25]. CB1 receptor antagonist (rimonabant 20 mg/day) treat-
ment in overweight and obese individuals also improved lipid profiles by increasing
high-density lipoprotein cholesterol (HDL) and decreasing triglycerides [23, 24].
Levels of HDL increased continuously throughout 2-year treatment with the CB1
receptor antagonist, whereas body weight stabilized [25]. Significantly, only a portion
(approximately 50%) of the effect associated with CB1 receptor antagonist treatment
on HDL and triglycerides was attributed to weight loss. Hence, the additional
improvement in lipid profile appears to involve a CB1 receptor-mediated effect that is
independent of weight loss [25]. Moreover, fasting glucose and fasting insulin in
overweight and obese individuals are decreased following CB1 receptor antagonist
therapy [24]. The amelioration of metabolic indices related to insulin sensitivity after
treatment with CB1 receptor antagonists are, at least in part, a consequence of the
decrease in body weight, and specifically in adipose tissue. However, a direct effect of
CB1 receptor antagonists on peripheral metabolism, specifically glucose homeostasis,
cannot be currently excluded. A possible explanation that has been given for the
improved glucose metabolism resides in the increased mRNA and plasma levels of
adiponectin observed after treatment with CB1 receptor antagonists.

Conclusions

To summarize, the ECS is a varied intercellular communication system whose activity

leads to a net anabolic tone. This is manifest in the brain as an increased tendency to
consume more food, and especially palatable, rewarding food. In several peripheral
organs including adipose tissue, liver, skeletal muscle and gut, increased levels of ECs
facilitate the intake of food and the formation and storage of fat, while possibly simulta-
neously decreasing energy expenditure (table 1). The administration of CB1 antagonists
to normal and especially obese animals reverses many of these actions, thus implying
that CB1 antagonists may be useful for treating obesity and related metabolic complica-
tions. Data from clinical trials recently disclosed support the efficacy of CB1 blockade
in reducing body weight and in ameliorating peripheral metabolic parameters.

Cannabinoids and Obesity 143

Table 1. Effects of the ECS on energy balance and peripheral metabolism

Site of action Effects

Hypothalamus increased food intake; interaction with neuropeptides/hormones

Brain reward areas
(nucleus accumbens)
White adipose tissue
Liver
Gastrointestinal tract
Muscle
Pancreas
regulating food intake; stimulation of AMPK activity
increased consumption of palatable food; interaction with
DA, serotonin and opioid pathways
increased lipogenesis; decreased adiponectin; inhibition of
AMPK activity
induction of de novo fatty acid synthesis; inhibition of AMPK activity
modulation of peristalsis and gastric emptying; interaction
with satiety hormones
role in glucose uptake?
effect on insulin secretion?

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11␤-Hydroxysteroid Dehydrogenase
Type 1 and Obesity
Nicholas M. Morton ⭈ Jonathan R. Seckl
Endocrinology Unit, Centre for Cardiovascular Sciences, Queens Medical Research Institute,
Edinburgh University, Edinburgh, UK

Abstract
The metabolic syndrome consists of a constellation of co-associated metabolic abnormalities such as
insulin resistance, type 2 diabetes, dyslipidaemia, hypertension and visceral obesity. For many years
endocrinologists have noted the striking resemblance between this disease state and that associated
with Cushing’s syndrome. However, in the metabolic syndrome plasma cortisol levels tend to be normal
or lower than in normal individuals. Nevertheless there is strong evidence that glucocorticoid action
underlies metabolic disease, largely from rodent obesity models where removing glucocorticoids
reverses obesity and its metabolic abnormalities. The apparent paradox of similar metabolic defects –
despite the opposing plasma glucocorticoid profiles of Cushing’s and idiopathic metabolic syndrome –
remained intriguing until the discovery that intracellular glucocorticoid reactivation was elevated in adi-
pose tissue of obese rodents and humans. The enzyme that mediates this activation, conversion of corti-
sone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone in rodents), locally within tissues is
11 β -hydroxysteroid dehydrogenase type 1 (11 β -HSD1). In order to determine whether elevated tissue
11 β -HSD1 contributed to obesity and metabolic disease, transgenic mice overexpressing 11 β -HSD1 in
adipose tissue or liver were made. Adipose-selective 11 β -HSD1 transgenic mice exhibited elevated
intra-adipose and portal, but not systemic corticosterone levels, abdominal obesity, hyperglycaemia,
insulin resistance, dyslipidaemia and hypertension. In contrast, transgenic overexpression of 11 β -HSD1
in liver yielded an attenuated metabolic syndrome with mild insulin resistance, dyslipidaemia, hyperten-
sion and fatty liver, but not obesity or glucose intolerance. Together with early data using non-selective
11 β -HSD1 inhibitors to insulin sensitise humans, this corroborated the notion that the enzyme may be a
good therapeutic target in the treatment of the metabolic syndrome. Further, a transgenic model of
therapeutic 11 β -HSD1 inhibition, 11 β -HSD1 gene knock-out (11 β -HSD1⫺/⫺) mice, exhibited improved
glucose tolerance, a ‘cardioprotective’ lipid profile, reduced weight gain and visceral fat accumulation
with chronic high-fat feeding. Recent evidence further suggests that high fat-mediated downregulation
of adipose 11 β -HSD1 may be an endogenous pathway that underpins adaptive disease resistance in
genetically predisposed mouse strains. This mechanism could feasibly make up a genetic component of
innate obesity resistance in humans. The efficacy of 11 β -HSD1 inhibitors has recently been extended to
include increased energy expenditure and reduction of arteriosclerosis, and therefore may be of signifi-
cant therapeutic value in the metabolic syndrome, with complementary effects upon liver adipose tis-
sue, muscle, pancreas and plaque-prone vessels. Copyright © 2008 S. Karger AG, Basel
The incidence of obesity and its associated metabolic syndrome has grown to ‘epidemic’
proportions globally. At least 300 million are estimated to be clinically obese (World
Health Organisation 2003) and more than three times this number are overweight.
Within the next 5 years a quarter of adults in the UK are expected to be clinically obese
and obesity of childhood, a predictor of morbidity and mortality in adulthood, is accel-
erating [1]. Whilst obesity associates with a substantially increased risk of serious
adverse effects ranging from type 2 diabetes, hypertension and cardiovascular disease to
cancers and arthritis, and thus to increased mortality, not every obese subject will get
these complications. The distribution of fat is important in determining the risks of
such disorders; excess upper body, centripetal or visceral adipose excess has a dire rep-
utation, whereas peripheral lower body or peripheral fat has little adverse effect.
There are strong morphological and metabolic resemblances between rare
Cushing’s syndrome of glucocorticoid excess and the extremely common insulin resis-
tance or metabolic syndrome [2]. Excess cortisol production and release in Cushing’s
syndrome causes predominantly visceral (abdominal) fat deposition, while peripheral
fat is reduced. This may result from opposing effects of glucocorticoids on these dis-
tinct adipose depots and their differential sensitivity both to catecholamine-mediated
fat mobilisation and insulin-mediated lipogenic effects. Whilst the association between
visceral adiposity and metabolic and cardiovascular disease risk is clear [3], the molec-
ular mechanisms linking the two are unknown. Current theories include evidence that
visceral fat is relatively more sensitive to lipolytic stimuli from the adrenergic receptor
system, though subcutaneous adipocytes are bigger and make a larger overall contribu-
tion to whole body lipolysis [4]. On the other hand other factors such as adipokines
and cortisol may be released from the visceral fat and have a pronounced and more
immediate detrimental impact on hepatic function because these fat depots drain
directly into the liver. This is the ‘portal hypothesis’ of insulin resistance [5]. In terms of
glucocorticoid action, glucocorticoid receptors are more highly expressed in visceral
fat [6, 7] and therefore glucocorticoids are expected to have a greater impact on both
metabolic responses and adipokine expression and release into the portal blood (fig. 1).
Thus, glucocorticoids may increase lipolysis and downregulate lipoprotein lipase, liber-
ating free fatty acids from peripheral fat, but also stimulate pre-adipocyte differentia-
tion and lipoprotein lipase expression, enhance glyceroneogenesis and triglyceride
synthesis in visceral adipose tissue [6–9]. However, despite the phenotypic similarities
with Cushing’s syndrome, in the metabolic syndrome plasma cortisol levels are mod-
estly if at all elevated and are usually reduced in ‘simple’ obesity [2, 9–10].

The Hypothalamic-Pituitary-Adrenal Axis and Obesity

Plasma glucocorticoid levels are determined by the activity of the hypothalamic-

pituitary-adrenal axis (HPA) (fig. 1). Forward HPA ‘drive’ at the diurnal maximum (morn-
ing in humans, evening in rodents) or during stress is rapidly and negatively controlled

11␤-Hydroxysteroid Dehydrogenase Type 1 and Obesity 147

 11␤-HSD2
Cortisone
11-DHC
HPA
Cortisol
corticosterone
Negative
KEY 11␤-HSD1 feedback

Subcutaneous fat ACTH

Skeletal muscle
All
Pancreas tissues

Ffa
adipokines Insulin Adrenal
glucagon Cortisol
Visceral fat Liver ?
Kidney

Ffa Excretion
adipokines clearance
cortisol
All Portal blood
Cortisone
tissues

Fig. 1. 11␤-HSD1 is a local tissue amplifier of glucocorticoid action. Glucocorticoid action is modulated
by 11␤-HSD1 (re-activation of inert cortisone in humans, 11-dehydrocorticosterone in rodents) and is
represented by the rightward-pointing green arrow boxes. The number of boxes represents an approxi-
mation of the relative expression levels of the enzyme within the tissues. Substrate for 11␤-HSD1 is cre-
ated principally by the inactivation of adrenal gland-derived circulating cortisol (corticosterone in
rodents) by the enzyme 11␤-HSD2 (leftward-pointing red arrow boxes) in the kidney. Circulating cortisol
(corticosterone) is generated largely by the adrenal gland through the action of the HPA axis of the brain
by release of ACTH from the anterior pituitary and by clearance through the kidney and liver. Tissue-spe-
cific changes in the expression level of 11␤-HSD1 may contribute to altered glucocorticoid action in
obesity and metabolic syndrome with increased adipose 11␤-HSD1 and reduced hepatic 11␤-HSD1.

by ‘feedback’ of glucocorticoids upon (1) adrenocorticotrophin (ACTH)-producing

pituitary corticotrophs, (2) corticotrophin-releasing hormone producing hypothala-
mic paraventricular nucleus neurons and (3) a number of suprahypothalamic sites
[11]. Although plasma cortisol levels appear normal in the metabolic syndrome or
obesity, the response of cortisol to stressors or food intake is enhanced [12, 13].
Moreover, obesity, particularly abdominal obesity, associates with increased urinary
free cortisol excretion [12, 14] and increased total cortisol production rates [15, 16].
Thus, there are exaggerated cortisol responses in obesity, suggesting that there is
either increased forward drive upon the HPA axis [10] or reduced sensitivity to feed-
back inhibition [9, 17, 18]. Whilst obesity has been associated with reduced sensitiv-
ity to glucocorticoid feedback [9, 18], this appears somewhat counter-intuitively
given their more favourable fat distribution, more profound in women than in men
[19]. Similarly, whilst several case-control and cross-sectional studies of metabolic

148 Morton · Seckl

syndrome patients have suggested associations with elevated cortisol concentrations
[e.g. 20, 21], these are independent of obesity. Obesity per se appears associated with
lower plasma cortisol. Overall, such studies do not strongly support a causative role
for enhanced cortisol secretion in the metabolic syndrome in humans in contrast
with certain rodent obesity models [22].
Increased total cortisol secretion in the presence of lower plasma cortisol levels dur-
ing peak secretion in obesity may also reflect increased peripheral cortisol clearance
(fig. 1). Increased glucocorticoid clearance could both reduce plasma levels and invoke
a compensatory HPA axis activation. Metabolic clearance rates for cortisol are elevated
in obesity [15, 23, 24], a phenomenon which is probably explained by increased hepatic
inactivation of cortisol by ‘A-ring reductases’ such as 5␣-reductase type 1 and 5␤-reduc-
tase [15, 25]. Whether the increased (largely hepatic) clearance of glucocorticoids via
this route is a primary driver of the altered HPA response in obesity is unknown.
On the other hand, peripheral metabolism of cortisol by the 11␤-hydroxysteroid
dehydrogenase (11␤-HSD) enzymes is strongly implicated in determining local corti-
costeroid receptor activation, and perhaps HPA regulation.

Tissue Metabolism of Glucocorticoids

11␤-HSD, discovered over 50 years ago, catalyses the interconversion of active gluco-
corticoids (cortisol, corticosterone) and their inert 11-keto forms (cortisone, 11-dehy-
drocorticosterone) that have very low affinity for nuclear receptors. 11␤-HSD activity
was subsequently described in a broad range of cells and tissues [26]. In the 1980s
Monder and White [27] purified an 11␤-HSD activity from rat liver. Homogenates,
microsomal preparations and purified enzyme catalysed both 11␤-dehydrogenation of
cortisol to inert cortisone and the 11␤-reduction of cortisone to active cortisol. As
with A-ring reductases, 11␤-HSD was originally thought to represent one of several
routes for clearing glucocorticoids. Subsequently, two 11␤-HSD isozymes, the prod-
ucts of distinct genes, were characterised and their cDNAs cloned [28, 29].
11␤-HSD type 2 is a high affinity, NAD-dependent 11␤-dehydrogenase which
catalyses the rapid conversion of active cortisol to inert cortisone [28, 30]. In adults
11␤-HSD2 is expressed principally in tissues where aldosterone induces its effects on
sodium excretion, including distal nephron, sweat glands, salivary glands and colonic
mucosa as well as the endothelium [30]. The 11␤-HSD2 enzyme excludes active glu-
cocorticoids from intrinsically non-selective MR in vivo [31]. Kidney 11␤-HSD2
serves also as a high throughput clearance route for circulating cortisol and indeed as
the principal generator of substrate for the 11␤-HSD1 enzyme and therefore regula-
tion of its activity may have profound effects on circulating and tissue glucocorticoid
levels where 11␤-HSD1 is expressed [32].
11␤-HSD1 has a much lower affinity for cortisol and corticosterone and is an
NADP(H)-dependent enzyme. 11␤-HSD1 is widely expressed in many tissues [33],

11␤-Hydroxysteroid Dehydrogenase Type 1 and Obesity 149

most highly in lung and liver [34, 35] and at lower levels in adipose tissue [36, 67],
skeletal muscle, cardiac and vascular smooth muscle [38, 39], anterior pituitary
gland, hippocampus [40], hypothalamic feeding centres [41] and adrenal cortex [42].
These are organs with high glucocorticoid receptor expression [43], with the excep-
tion of hippocampus and heart where MR act as high-affinity sites for glucocorticoids
rather than aldosterone in vivo.
In intact cells, when there is adequate provision of co-factor by the co-localised
enzyme hexose-6-phosphate dehydrogenase [44, 45], 11␤-HSD1 acts as an 11-ketore-
ductase, reactivating inert cortisone into cortisol [2]. Intriguingly, 11␤-HSD1 also
metabolises 7-ketocholesterol, a pro-atherogenic cholesterol metabolite that is pre-
sent in high concentrations in atherosclerotic plaques and in cholesterol-rich food
[46]. These data suggest that glucocorticoid and cholesterol metabolism may be
closely linked in a number of tissues, particularly the liver, adipose and plaque
macrophages.
Oral administration of cortisone (the first pharmacological glucocorticoid used in
man) is rapidly activated to cortisol in humans, and very little oral cortisone reaches
the systemic circulation [47] and hepatic vein cortisol/cortisone ratios are high [48].
Recent studies have employed hepatic vein sampling in humans using radioactive
tracers that reflect the fate of substrate metabolism and the rate of product appear-
ance (deuterated cortisol method [49]) to determine the magnitude of splanchnic
cortisol production by 11␤-HSD1 [50, 51]. These studies indicate that splanchnic
(liver and visceral tissue blood supply) cortisol production is comparable to rates of
adrenal cortisol secretion. In one study [51], oral cortisone was administered to dis-
tinguish the contribution of hepatic generation of cortisol from generation in visceral
adipose tissue; the resulting model estimated that visceral adipose contributes some-
what more cortisol production than does the liver, in part because portal vein con-
centrations of cortisone are predicted to be lower than arterial concentrations.
However, this view was challenged by similar studies in dogs infused with tracer cor-
tisol that suggest, at least in this species, that most if not all splanchnic cortisol pro-
duction occurs in the liver [52].

Substrate Levels for 11␤-HSD1

In vivo, the main source of 11-ketosteroid is 11␤-HSD2 dehydrogenation of cortisol

and corticosterone, occurring predominantly in the kidney [53, 54]. In humans, cor-
tisone circulates at 50–100 nM [48], similar to cortisol levels at night, the diurnal
nadir. Whilst this level is lower than morning peak cortisol ⬃400–600 nM, around
95% of cortisol is sequestered by binding to plasma proteins such as CBG (cortisol-
binding globulin) [55]. Estimates of ‘free’ cortisol levels are rather imprecise, but
approximate 0.5–1 nM at the diurnal nadir. Cortisone in contrast shows no pro-
nounced diurnal rhythm and is unbound to CBG and so is available for conversion to

150 Morton · Seckl

active glucocorticoid [48]. In the rat, plasma concentrations of 11-dehydrocorticos-
terone are also approximately 50 nM, and around 3–5 nM in mice [56]. Thus, for at
least the quiescent part of the diurnal cycle, circulating cortisone levels equal or
exceed free cortisol levels and similar ratios pertain in rodents. However, recent find-
ings in mice homozygous for disruptive mutations of the gene encoding CBG suggest
a role for CBG in active delivery of steroid to target tissues, so perhaps such calculations
are erroneous [57]. Nevertheless, studies in 11␤-HSD1 null mice suggest that the
enzyme contributes significantly to intracellular glucocorticoid load in vivo.

Functional Studies of 11␤-HSD1

Liver
Studies using relatively non-selective liquorice-based inhibitors [58, 59] and, more
recently with selective 11␤-HSD1 inhibitors [60, 61] show that reduced activity of
11␤-HSD1 in liver is associated with features of reduced glucocorticoid action,
reduced glucocorticoid levels and increased insulin sensitivity in hepatocytes. 11␤-
HSD1⫺/⫺ mice develop normally and are viable, fertile and grossly normotensive
[56]. This model demonstrated that 11␤-HSD1 is the sole major 11␤-reductase, at
least in mice, since adrenalectomised 11␤-HSD1 knockout mice cannot convert
exogenous 11-dehydrocorticosterone to corticosterone. Plasma corticosterone levels
are modestly elevated at the diurnal nadir, presumably due to somewhat deficient
feedback upon the HPA axis (11␤-HSD1 is expressed in hippocampus, paraventricu-
lar nucleus and anterior pituitary) [62]. This is in contrast to the H6PDH null mice,
which have low circulating corticosterone because the 11␤-HSD1 lacks co-factor to
drive reduction of 11-dehydrocorticosterone and thus acts as a dehydrogenase [45].
Despite slightly elevated basal plasma corticosterone levels, 11␤-HSD1⫺/⫺ mice have
a phenotype compatible with impaired intracellular glucocorticoid regeneration and
increased insulin sensitivity. They show impaired induction of the key glucocorti-
coid-inducible hepatic enzymes PEPCK and glucose-6-phosphatase with fasting and
attenuated hyperglycaemic responses to novel environment stress or chronic high-fat
feeding [56, 63]. Importantly, the mice have more than adequate stress-induced HPA
axis responses [62] and do not exhibit hypoglycaemia with prolonged fasting [56].
11␤-HSD1⫺/⫺ mice also have lower plasma triglyceride and elevated ‘cardioprotec-
tive’ HDL cholesterol levels [63], including higher circulating levels of the HDL
apolipoprotein AI, whereas serum apolipoprotein CIII, which interferes with efficient
transfer of triglycerides into the liver, is reduced. There is evidence for increased
hepatic insulin sensitivity when the mice are re-fed after fasting, and hepatic expres-
sion of the co-ordinate transcription factor that drives fatty acid ␤-oxidation, PPAR␣,
is elevated in 11␤-HSD1⫺/⫺ mice. Additionally, preliminary data suggest favourable
effects upon haemostasis as in liver the glucocorticoid-inducible A␣-fibrinogen tran-
script levels are reduced [63].

11␤-Hydroxysteroid Dehydrogenase Type 1 and Obesity 151

Adipose Tissue
Glucocorticoids play a key role both in the regulation of adipose tissue metabolism and
in the differentiation of pre-adipocytes into adipocytes [64]. 11␤-HSD1, but not 11␤-
HSD2, mRNA is expressed in rat [37] and in human white adipose tissue [36, 65–75].
11␤-HSD1 is also expressed in differentiated murine fibroblast-adipocyte 3T3-F442A
and 3T3-L1 cell lines and the reaction direction is 11-ketoreduction [37]. By contrast,
intact human adipose stromal cells have varying developmental expression of hexose-6-
phosphate dehydrogenase and appear to inactivate the substrate [76]. Intriguingly,
whilst polymorphisms in the gene encoding 11␤-HSD1 (HSD11B1) correlate rather
poorly if at all [77, 78] with adipose distribution in humans, it may be changes in the
hexose-6-phosphate dehydrogenase gene that are key. Thus, in 3 rare patients with cor-
tisone reductase deficiency [79] more subtle mutations in both HSD11B1 and in
H6PDH have been found although their significance is debatable since such digenic tri-
allelic polymorphisms have also been found commonly in normal subjects [80, 81].

Regulation of 11b-HSD1 in Fat and Liver in Obesity

A host of hormones including insulin pro- and anti-inflammatory cytokines, adren-
ergic agonists corticotrophin-releasing hormone and ACTH reduce 11␤-HSD1, and
metabolic factors have been proposed to regulate 11␤-HSD1 [reviewed in 82]. These
controls are tissue-specific. Although glucocorticoids reduce adipose 11␤-HSD1
expression in some systems, in others they stimulate its activity with effects reflecting
the assay conditions and perhaps species. Whilst PPAR␥ ligands such as the anti-dia-
betic thiazolidinediones downregulate 11␤-HSD1 in 3T3 cells in vitro and in epididy-
mal fat in mice in vivo [83], the same was not observed in lean or obese Zucker rats
[25]. LXR agonists also partially downregulate 11␤-HSD1 in vitro and in vivo [84].
In terms of more direct effects, the transcription factor C/EBP␣, which is a master
regulator of metabolic pathways in many tissues, binds to several sites on the 11␤-HSD1
promoter. C/EBP␣ increases 11␤-HSD1 promoter activity in transfected hepatoma cells
[85]. In contrast, C/EBP␤ acts as a dominant negative repressor of (11␤-HSD1) tran-
scription when added to C/EBP␣, though alone it is a weak inducer. These data suggest
the possibility that 11␤-HSD1 regulation in the adipocyte by insulin and glucocorticoids
is indirectly mediated through changes in C/EBP-related proteins. Since under many cir-
cumstances the regulation of 11␤-HSD1 in liver and adipose tissue is discordant, indeed
often reciprocal [25, 86] as for other well-characterised C/EBP-regulated genes such as
PEPCK [87], the fine details of control are expected to be tissue-specific and modulated
by tissue-specific changes in insulin (and other hormones) sensitivity.

11b-HSD1 in Obesity
Studies in leptin-resistant obese Zucker rats and leptin deficient ob/ob mice revealed
that obesity was associated with decreased 11␤-HSD1 expression and activity in liver,

152 Morton · Seckl

but increased 11␤-HSD1 in omental adipose tissue [7, 25, 88]. However, this is not a
universal finding and is likely strain-dependent in rodents [86, 89]. For example,
db/db mice with monogenic obesity resulting from leptin receptor deficiency have
higher hepatic 11␤-HSD1 activity [89] and mice with obesity of polygenic origin have
low adipose but elevated liver 11␤-HSD1 [86] again reflecting a tissue reciprocity
in regulation of the enzyme that hints at a conserved tissue-specific regulatory
mechanism.
In humans, conversion of cortisone after oral administration to cortisol in periph-
eral plasma, reflecting first pass metabolism by hepatic 11␤-HSD1, is reduced in obe-
sity [16, 66–67]. In contrast, in subcutaneous abdominal adipose tissue 11␤-HSD1
activity is increased both in vivo and in vitro [66–69, 71–73, 75]. Further studies have
confirmed that the increased 11␤-HSD1 activity in adipose biopsies is accompanied
by increased 11␤-HSD1 mRNA, and microdialysis in subcutaneous adipose tissue
directly demonstrated an increased 11␤-HSD1 activity in obesity [90]. Recent studies
suggest that, in contrast to earlier reports [73, 74], 11␤-HSD1 mRNA levels are also
increased in intact omental adipose tissue of obese women and are a strong predictor
of fat cell size in this visceral depot [75]. Further studies on visceral adipose tissue are
needed to clarify this important potential aspect of 11␤-HSD1 dysregulation given
the unproven ‘Cushing’s disease of the omentum’ hypothesis [36] and the impact that
elevated visceral fat glucocorticoid action and production would have on the portal
hypothesis of insulin resistance described below.
The mechanisms underlying increased adipose 11␤-HSD1 in simple obesity are
uncertain. Attempts to link the 11␤-HSD1 genotype with obesity have not been suc-
cessful [77, 91], though specific polymorphisms of 11␤-HSD1 gene do associate with
hypertension [78] insulin sensitivity/diabetes [92] and with apolipoprotein levels
[93]. Studies in identical twins also support environmental causes for the association
between increased adipose 11␤-HSD1 expression and obesity [94].

Adipose 11␤-HSD1 Overexpressing Mice: A Model of the Metabolic Syndrome

The key question is whether increased adipose 11␤-HSD1 is a cause or a conse-

quence of obesity and the associated metabolic syndrome. To dissect this, mice over-
expressing 11␤-HSD1 selectively in adipose tissue have been generated exploiting
the adipocyte fatty acid-binding protein (aP2) promoter [7]. These aP2-11␤-HSD1
mice express 2- to 3-fold more 11␤-HSD1 in all adipose depots, but not in other tis-
sues. The transgene causes approximately doubled corticosterone levels within adi-
pose tissue and increased release of corticosterone into the portal circulation, but
systemic glucocorticoid levels are unaltered. As a consequence of local intra-adipose
glucocorticoid excess, aP2-11␤-HSD1 mice are modestly obese, presenting with pre-
dominantly intra-abdominal obesity. The visceral adipose expansion in these animals
may relate to the higher levels of glucocorticoid receptor in visceral than peripheral

11␤-Hydroxysteroid Dehydrogenase Type 1 and Obesity 153

fat depots in the mice [7]. In association with this aP2-11␤-HSD1 mice develop all
major features of the metabolic syndrome. The animals are markedly glucose intol-
erant and insulin resistant, features exacerbated by high-fat feeding. They do not
show obvious fasting hyperglycaemia, but this becomes markedly manifest after a
glucose load suggesting the deficit is in peripheral glucose uptake, rather than
hepatic glucose production. They show elevated free fatty acid and triglyceride levels
[7]. Glucocorticoids stimulate leptin secretion from adipose tissue and serum leptin
levels are elevated in the transgenic animals disproportionately to the obesity, sug-
gesting leptin resistance. Within adipocytes, aP2-11␤-HSD1 mice show changes
concordant with decreased sensitivity to insulin and/or increased corticosterone lev-
els with decreased expression of the insulin sensitising adipokine adiponectin [95]
and increased expression of TNF␣ which causes insulin resistance [96]. Serum
TNF␣ levels are also elevated. Curiously, adipose mRNA encoding resistin, which
promotes insulin resistance in mice [97], is reduced in aP2-HSD1 transgenic adipose
tissue, perhaps also as a consequence of the glucocorticoid excess [98]. Intriguingly,
angiotensinogen mRNA, which is normally expressed at low levels in adipose tissue,
is strikingly elevated in aP2-11␤-HSD1 transgenic mouse fat. This glucocorticoid-
regulated transcript may underpin the marked hypertension seen in these animals
[99]. Finally the animals exhibit hyperphagia, which may be partly related to their
leptin resistance or other novel mechanisms of adipose-satiety centre cross-talk.
Thus the aP2-11␤-HSD1 transgenic mouse faithfully models the major features of
the metabolic syndrome. The effects of adipose 11␤-HSD1 overexpression and defi-
ciency on food intake deserve special note. Whilst adipose-specific 11␤-HSD1 over-
expression causes hyperphagia [7] and adipose expression of the glucocorticoid
inactivating enzyme 11␤-HSD2 (see below) causes hypophagia [100], global 11␤-
HSD1 deficiency leads to transient hyperphagia [41, 101]. It is likely that this diver-
gence in otherwise complementary phenotypes is due to the effects of 11␤-HSD1
deficiency within the hypothalamic feeding centres and indeed recent data suggest
that 11␤-HSD1 can constrain high-fat diet-induced hyperphagia perhaps by modu-
lating opiate reward centres linked to the hypothalamic agouti-related peptide
expressing cells within the arcuate nucleus of the hypothalamus [68]. These data
have implications for therapeutic inhibitor strategies where hyperphagia would be
an undesirable side effect. However, recent studies on the effects of specific 11␤-
HSD1 inhibitors on food intake in mice show in fact that they reduce food intake
and increase energy expenditure [102], perhaps because of predominant peripheral
actions of the drugs involved.

Liver Glucocorticoid Excess: ApoE-11␤-HSD1 Transgenic Mice

Blood from visceral adipose tissue drains via the hepatic portal vein to the liver.
Unsurprisingly therefore, aP2-11␤-HSD1 transgenic mice have elevated levels of

154 Morton · Seckl

corticosterone and free fatty acids in the portal plasma, implying that the liver is
exposed to excess glucocorticoids. The ‘portal theory’ contends that release of fac-
tors such as glucocorticoids, free fatty acids and adipocytokines directly leads to
pronounced hepatic insulin resistance [5]. To address this and to examine whether
excess 11␤-HSD1 in the liver per se, as can be found in certain rodent models of dia-
betes and obesity [86, 89], can cause the metabolic syndrome, transgenic mice over-
expressing 11␤-HSD1 in the liver have been generated under the ApoE promoter
[103]. These mice are also viable and appear normal. As adults, the mice show mod-
est insulin resistance and hypertriglyceridaemia along with slightly elevated fat
accumulation in the liver. ApoE-11␤-HSD1 transgenic mice have normal weight
and adipose depot mass and show normal glucose tolerance. However, the animals
are hypertensive, with activation of the renin-angiotensin-aldosterone system, in
part due to overexpression of angiotensinogen in the liver. Thus liver overexpression
of 11␤-HSD1 produces an attenuated metabolic syndrome phenotype without vis-
ceral obesity. This might be of pathogenic relevance in patients with the insulin-
resistance of myotonic dystrophy [104] and in some metabolic syndrome models
[86, 89] in which liver 11␤-HSD1 activity is raised. One notable recent finding is
that liver 11␤-HSD1 overexpression can correct the basal hypercorticosteronaemia
found in the 11␤-HSD1⫺/⫺ mice when the two models are inter-crossed [105]. This
suggests that hepatic cortisol regeneration by 11␤-HSD1 may have an important
regulatory influence on the HPA axis and, by inference, the downregulation of
hepatic 11␤-HSD1 found in human obesity may contribute to the altered HPA
responsiveness described above, with implications for therapeutic 11␤-HSD1 inhi-
bition in the context of chronic stress.

Deficiency of 11␤-HSD1

Adiposity in 11␤-HSD1 knock-out animals has been examined on both intrinsically

obesity-resistant and obesity-prone genetic backgrounds. Intra-adipose corticos-
terone levels are substantially lowered in the 11␤-HSD1⫺/⫺ animals in the face of
modestly elevated plasma corticosterone concentrations [106]. On the obesity-prone
C57Bl/6J genetic background, high-fat diet fed 11␤-HSD1⫺/⫺ mice gain significantly
less weight than controls despite a relative hyperphagia. This appears due to an
enhanced metabolic rate as inferred by increased core body temperature [106]. With
high-fat diet on either genetic background, 11␤-HSD1 knock-out mice preferentially
gain adipose tissue in the ‘metabolically safer’ peripheral depots rather than in the
‘metabolically disadvantageous’ visceral sites. Whilst the explanation of this redistrib-
ution of fat in 11␤-HSD1⫺/⫺ animals is uncertain, these mice show higher expression
of the thiazolidinedione target adipogenic transcription factor PPAR␥ receptor in all adi-
pose tissue beds. Further, 11␤-HSD1⫺/⫺ mice show a greater increase in adipose PPAR␥
receptors with high-fat feeding than wild type. PPAR␥ ligands cause fat redistribution

11␤-Hydroxysteroid Dehydrogenase Type 1 and Obesity 155

to the periphery and this may underpin the favourable morphology [107, 108] seen if
increased circulating free fatty acids are acting as endogenous ligands [109] for the
PPAR␥ receptors. Additionally, the 11␤-HSD1 null animals also show greater induc-
tion of uncoupling protein-2 in mesenteric adipose tissue than wild type [106] which
may allow local calorie wastage rather than storage as fat. Uncoupling protein-2 is
downregulated by glucocorticoids [110] and upregulated by PPAR␥ activation [111],
so its induction in the 11␤-HSD1 null mouse adipose tissue is not unexpected.
In terms of adipose endocrine changes, adipose leptin mRNA and plasma leptin
levels are reduced in 11␤-HSD⫺/⫺ mice, particularly in peripheral adipose [106]. On
the obesity-prone C57Bl/6J genetic background, the 11␤-HSD1 null animals are
clearly insulin-sensitised and resist hyperglycaemia that occurs with high-fat feeding
in wild-type mice. This occurs at least partly at the level of the adipocyte since iso-
lated primary adipocytes show increased basal and insulin-stimulated glucose uptake
[106]. Adipocyte resistin and TNF␣ mRNAs are reduced whereas adiponectin is
increased, again compatible with an adipose-mediated insulin-sensitised phenotype.
Thus, overall the mouse shows improved glucose tolerance, increased insulin sensi-
tivity and reduced intra-tissue glucocorticoid levels in the face of modest hypercorti-
costeronaemia. These beneficial effects of deletion in 11␤-HSD1 in adipose tissue are
accompanied by changes in hepatic gene expression consistent with increased ␤-oxi-
dation of lipids in the liver, as described above [63]. A further recent development
within the obesity field is the growing recognition that not only are the pro-inflam-
matory cytokines described above increased in obesity, in fact there is an adipose-
specific infiltration of macrophages that correlates with obesity in rodents and
humans [112]. 11␤-HSD1 is induced upon macrophage activation [113] and modu-
lates macrophage phagocytosis and potentially resolution of inflammatory processes
[114]. This suggests that regulation of 11␤-HSD1 within these cells and their interac-
tion with adipocytes, where 11␤-HSD1⫺/⫺ adipocytes have lower levels of proinflam-
matory cytokines, will be a key determinant of metabolic disease progression.
Intriguing new data also demonstrate that 11␤-HSD1 deficiency, through reducing
the angiostatic effects of glucocorticoids, increases angiogenesis in vitro and in 11␤-
HSD1⫺/⫺ mice after myocardial infarction in vivo [115]. Therefore, 11␤-HSD1 inhi-
bition potentially promotes improved healing in ischaemia in myocardial infarction
and tissue injury.

Adipose 11␤-HSD2 Overexpressing Mice: A Model of Adipose-Specific

Glucocorticoid Deficiency

To confirm the key importance of reduced adipose tissue glucocorticoid levels in the
beneficial phenotype of 11␤-HSD1 null mice, a new strain ectopically expressing the
glucocorticoid inactivating isozyme, 11␤-HSD2, selectively in adipose tissue were
generated, again exploiting the aP2 promoter [100]. Expression levels were chosen to

156 Morton · Seckl

mimic levels seen in kidney, where the isozyme completely excludes corticosterone
from intrinsically high-affinity MR. In aP2-11␤-HSD2 mice, as expected, plasma cor-
ticosterone and markers of systemic glucocorticoid exposure, such as thymic and
adrenal weight and bone mineral density, are unaltered. However, the mice resist
weight gain on high-fat diet due to reduced fat mass accumulation. The improved
energy balance appears due to decreased food intake, increased energy expenditure
and improved glucose tolerance and insulin sensitivity. Again, as anticipated by the
phenotype of 11␤-HSD1⫺/⫺ mice, aP2-11␤-HSD2 transgenic mice show decreased
expression of leptin and resistin and increased expression of adiponectin, PPAR␥ and
uncoupling protein 2 in fat tissues. This model reinforces the concept that reducing
levels of active corticosterone exclusively in adipose tissue engenders a favourable,
metabolic disease-resistant phenotype. Intriguingly, aP2-11␤-HSD2 mice show high-
est transgene expression in subcutaneous adipose tissue. Whilst the independent risk
associated with visceral adiposity and cardiometabolic disease has long been clear [3,
116], these data also demonstrate that the peripheral fat stores and glucocorticoid
metabolism within them – 11␤-HSD1 is expressed at highest levels in this depot in
mice [88] – have a large impact on metabolism and systemic insulin sensitivity. Thus,
the human observations of correlations between 11␤-HSD1 in subcutaneous rather
than visceral adipose tissue [74] and adverse metabolic outcomes may also pertain in
mice. The precise roles of glucocorticoids, other hormones (such as insulin) and tran-
scription factors (such as PPAR␥) and their downstream adipokines in each adipose
depot require further dissection.

Downregulation of Endogenous Adipose 11b-HSD1 as an

Adaptation to Chronic High-Fat Feeding
Intriguing recent data have shown that wild-type mice markedly downregulate 11␤-
HSD1 mRNA and activity in fat in response to a high-fat diet [88]. Similar findings
have been reported in rats [117]. Whether this downregulation results in lower intra-
adipose glucocorticoid levels is still under investigation since one study showed that
adipose 11␤-HSD1 levels were indeed higher in obese and diabetic KKY mice but
that intra-adipose corticosterone levels were not affected by high-fat diet [118].
Differences in experimental design and methodology require careful consideration in
future studies. Strikingly, the metabolic disease-resistant A/J mouse strain has lower
basal levels of 11␤-HSD1 mRNA and activity in visceral and peripheral fat depots,
and downregulates adipose 11␤-HSD1 more markedly upon high-fat feeding than
metabolic disease-prone C57Bl/6 mice. The AJ strain almost completely shuts off adi-
pose 11␤-HSD1 upon high-fat diet becoming, in effect, null in this tissue [88]. This
suggests that downregulation of adipose 11␤-HSD1 represents an adaptive mecha-
nism, more pronounced in metabolic disease-resistance, that tends to counteract the
adverse metabolic consequences of chronic high-fat diet [88]. In rats, high-fat diet
downregulation of adipose 11␤-HSD1 is transient and reverses after several months

11␤-Hydroxysteroid Dehydrogenase Type 1 and Obesity 157

as weight is gained and insulin resistance develops, suggesting that this metabolic
adaptation is not sustained with worsening obesity in rats [117].

11␤-HSD1 as a Drug Target for Therapy in Obesity and the Metabolic Syndrome

11␤-HSD1 inhibition is an attractive target for treatment of the metabolic syndrome.

Carbenoxolone has been a ‘prototype’, though non-selective 11␤-HSD1 inhibitor.
Carbenoxolone enhances insulin sensitivity in the euglycaemic hyperinsulinaemic
clamp technique in humans [58]. Indeed, in lean patients with type 2 diabetes carbenox-
olone inhibits hepatic glucose production [59]. However, by contrast with enhanced
adipose insulin sensitivity and glucose disposal in 11␤-HSD1⫺/⫺ and aP2-11␤-HSD2
mice, carbenoxolone has no effect on glucose disposal, perhaps because carbenoxolone
inhibits adipose 11␤-HSD1 poorly [119]. Moreover, liver 11␤-HSD1 appears to be
downregulated in human and several rodent models of obesity so that the incremental
effect of inhibition may be smaller in the obese [25, 66, 67]. Whether inhibition in liver
alone is sufficient to confer clinically useful metabolic benefits thus remains uncertain.
Future studies using tissue-specific knock down with transgenic cre-lox technology will
be important to answer the roles of respective tissue-specific inhibition.
With a view to therapeutic development, several new classes of selective 11␤-
HSD1 inhibitors have been described, including the arylsulfonamidothiazoles [120],
and more recently perhydroquinolylbenzamides [121]. These compounds inhibit
11␤-HSD1 and enhance insulin action in liver, lowering blood glucose concentra-
tions in diabetic and obese mouse models [60, 61]. However, euglycaemic hyperin-
sulinaemic clamps in mice suggest that arylsulfonamidothiazoles do not increase
peripheral glucose uptake [61]. Despite this, selective 11␤-HSD1 inhibitors improve
metabolic syndrome, dyslipidaemia and, in a key recent observation, prevent the
development of atherosclerosis in mice that are prone to developing plaque lesions
[102]. Overall, the efficacy of 11␤-HSD1 inhibition in attenuating obesity and, partic-
ularly, in disconnecting obesity from its metabolic consequences remains to be estab-
lished in the crucial setting of human therapy. The rodent data highlight that care
should be taken when extrapolating to potential clinical outcomes, and emphasise the
crucial influence of species, strain background and environmental influences such as
dietary fat, stress and inflammatory status on glucocorticoid-mediated processes
within adipose, other key metabolic tissues and on the HPA axis.

Acknowledgments

Work described from the authors’ laboratory was generously funded by a Wellcome Trust
Programme Grant (J.R.S.) and a Wellcome Trust Intermediate Research Fellowship (N.M.M.).
N.M.M. is a Wellcome Trust Career Development Fellow.

158 Morton · Seckl

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Prof. Jonathan R. Seckl
Endocrinology Unit, Centre for Cardiovascular Sciences
Queens Medical Research Institute, Edinburgh University
Edinburgh EH16 4TJ (UK)
Tel. ⫹44 131 242 6077, Fax ⫹44 131 242 6079, E-Mail J.Seckl@ed.ac.uk
164
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Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 165–181

Gut and Hormones and Obesity

Alison M. Wren
Department of Endocrinology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK

Abstract
Following the discovery of secretin in 1902, a host of further peptide hormones that are synthesised
and released from the gastrointestinal tract have been identified. While their roles in the regulation
of gastrointestinal function have been known for some time, it is now evident that many of these
hormones also physiologically regulate energy balance. Our understanding of how gut hormones
signal to the brain has advanced significantly in recent years. Several hormones, including peptide
YY, pancreatic polypeptide, oxyntomodulin, glucagon-like peptide 1 and cholecystokinin function as
satiety signals. In contrast, only ghrelin, produced by the stomach, has emerged as a putative hunger
signal, appearing to act both as a meal initiator and a long-term body weight regulator. Recent
research suggests that gut hormones can be manipulated to regulate energy balance in man
and that obese subjects retain sensitivity to the actions of gut hormones. The worldwide obesity
pandemic continues unabated, despite public health initiatives and current best therapy. Future
gut hormone-based therapies may provide an effective and well-tolerated treatment for obesity.
Copyright © 2008 S. Karger AG, Basel

Energy Homeostasis and Obesity

The concept of the gut as an endocrine organ is hardly a new. The gut peptide secretin
was the first substance to be termed a hormone whilst the appetite inhibitory actions
of cholecystokinin (CCK) were first reported over 30 years ago [1, 2]. However, in
recent years, further scientific endeavour in this field has been motivated by the need
to develop new strategies to tackle the global pandemic of obesity.
The prevalence of obesity in adults has increased by over 75% worldwide since
1980. Given that obesity is causally associated with cardiovascular disease, type 2 dia-
betes, hypertension, stroke, obstructive sleep apnoea and certain cancers, this has
translated into healthcare costs of over half a billion pounds every year in the UK
alone. Obesity is not only a problem in the developed world, but is set to overtake
infectious diseases as the most significant contributor to ill-health worldwide and has
been classified as an epidemic by the World Health Organization [3].
 Public health initiatives have failed to reverse the rising incidence of obesity.
Medical and behavioural interventions, with the exception of bariatric surgery, have
limited success, as discussed in the treatment section of this volume. This chapter will
focus on the peptide hormone signals from the gut that communicate the status of
body energy stores to the brain and the brain centres on which they act. These regu-
latory systems are not only of academic interest, but are likely to underpin any future
strategy to tackle obesity, by providing drug targets for the holy grail of safe sustain-
able weight loss.

Long-Term and Short-Term Energy Balance Signals

Peripheral signals that regulate energy balance are often categorised as long and short
acting. Long-acting signals, typified by the adipocyte hormone leptin, characteristi-
cally reflect the levels of energy stores and regulate body weight and the amount of
energy stored as fat [see the chapter by Ahima and Osei, this vol., pp. 182–197].
Short-acting gastrointestinal signals are typified by gut hormones such as CCK and
mechanical factors, such as gastric distension, which characteristically relay a sense of
‘fullness’ resulting in post-prandial satiation and meal termination. Other gut hor-
mones, including peptide YY (PYY) and ghrelin appear to blur the boundaries
between long- and short-term signals, having features of both. Current evidence sug-
gests that they not only regulate appetite on a meal-by-meal basis but also participate
in longer term energy balance.

Central Integration of Peripheral Signals

Neuro-hormonal signals from the gut and adipose tissue converge on the hypothala-
mus where they are integrated and in turn regulate energy intake and energy expen-
diture. The hypothalamic neurocircuits regulating energy balance have been
reviewed extensively [4, 5]. In brief, the hypothalamic arcuate nucleus (Arc), a cir-
cumventricular organ which is accessible to circulating factors via a relatively defi-
cient blood brain barrier, may be viewed as a conduit for peripheral signals. Two key
neuronal populations have been identified within the Arc with opposing effects on
energy balance. A group of neurones in the medial Arc co-express neuropeptide Y
(NPY) and agouti-related peptide (AgRP) and act to stimulate food intake and weight
gain. In contrast pro-opiomelanocortin (POMC) and cocaine- and amphetamine-
regulated transcript co-expressing neurones in the lateral Arc inhibit feeding and
promote weight loss. The balance of activity between these two groups of neurones is
critical to body weight regulation. The Arc neurones have multiple connections with
other central nervous system (CNS) sites of appetite regulation, including the brain-
stem and other hypothalamic nuclei.

166 Wren
 Adiponectin
Resistin
Visfatin
Leptin

Adipose
tissue

Insulin
PP

Pancreas
Vagal
afferents

OXM

PYY 3-36

CCK + GLP-1

Ghrelin Stretch
Intestine Nutrients

Stomach

Fig. 1. Overview of peripheral factors regulating energy balance and their routes of signalling to the
brain; from Wren and Bloom [29].

The nucleus of the solitary tract (NTS) and the area postrema (AP), components
of the dorsal vagal complex are also key central integrators of peripheral signals. They
receive inputs from vagal afferents and circulating factors and are reciprocally con-
nected with hypothalamic nuclei controlling energy balance. These brainstem centres
can also respond independently to peripheral signals when communication with
higher brain centres are surgically interrupted [6]. In addition, inputs from the cortex
(emotional, social and behaviour cues) and the mesolimbic dopaminergic reward cir-
cuits influence energy balance and communicate with the hypothalamus.
Peripheral feedback to the hypothalamus is complex, as illustrated in figure 1. Many
circulating signals, including gut hormones, have access to the Arc and leptin, for exam-
ple, is thought to act primarily via a direct action here [5]. In contrast, other peripheral

Gut and Hormones and Obesity 167

signals influence the hypothalamus indirectly via afferent neuronal pathways and
brainstem circuits. The most extensively characterised of these is CCK, which binds to
receptors on the vagus nerve, thus activating the NTS, which in turn relays information
to the hypothalamus. In the cases of ghrelin and PYY, there is evidence for both a direct
action on the Arc and an action via the vagus nerve and brainstem.

Ghrelin, the Hunger Hormone

Ghrelin is the only known circulating orexigen. In contrast, all the other peripheral
factors that regulate energy balance act to restrain eating and weight gain. Ghrelin
was discovered as an endogenous ligand for the growth hormone (GH) secretagogue
receptor (GHS-R1a) [7]. However, early work on this peptide demonstrated a GH-
independent action to powerfully increase food intake and body weight. The pre-
dominant focus of subsequent research has shifted onto the role of ghrelin in energy
balance [8–11].
Ghrelin is a 28-amino acid peptide, cleaved from a precursor, preproghrelin [7]. It
is principally synthesised in endocrine cells of the stomach, termed X/A-like or ghre-
lin cells, and particularly found in the gastric fundus. About two thirds to three quar-
ters of circulating ghrelin is of gastric origin. Lesser concentrations of ghrelin are
found throughout the small intestine, with the duodenum producing approximately
ten times less than the stomach and progressively lower concentrations found more
distally [12]. Ghrelin undergoes post-translational modification with attachment of a
medium-chain fatty acid, typically octanoic acid, to the serine-3 residue. This acyla-
tion is entirely unique among biologically active peptides and is required for ghrelin
to bind to and activate its classical receptor, the GHS-R1a [7]. The GHS-R1a is widely
expressed. In the CNS, it is found in areas involved in regulation of appetite and
energy balance including hypothalamic nuclei, the dorsal vagal complex and the
mesolimbic dopaminergic system. Peripherally, it is expressed in the pituitary, and
pharmacologically ghrelin acts at both pituitary and hypothalamic levels to power-
fully stimulate GH secretion [7, 9, 12, 13]. The physiological relevance of ghrelin in
GH regulation is debated. Ghrelin is not essential for GH secretion as ghrelin and
GHS-R1a null mice are not growth restricted, but it may play a role in augmentation
of GHRH-stimulated GH pulses. GHS-R1a receptor expression has also been
described in diverse peripheral sites including the myocardium, stomach, small intes-
tine, pancreas, colon, adipose tissue, liver, kidney, placenta, and T cells. An equally
diverse series of biological actions of exogenous ghrelin have been documented,
including effects on glucose homeostasis, gut motility, pancreatic exocrine secretion,
cardiovascular function, immunity and inflammation. The physiological relevance of
these actions remains unclear. There is also evidence for a number of pharmacologi-
cal actions of des-acyl (or unacylated) ghrelin, which must be mediated via receptors
other than the GHS-R1a. The physiological significance of these actions is contentious,

168 Wren
as reviewed elsewhere. However, experiments in GHS-R1a knockout mice have
definitively established that this receptor is required for the orexigenic and GH-stim-
ulating effects of acylated ghrelin [14–16].
When administered into the CNS, ghrelin stimulates food intake as potently as NPY,
previously the most powerful known orexigen, and more powerfully than any other
substance examined [8–10]. Ghrelin also stimulates appetite and food intake when
administered systemically in rodents [8, 11] and humans [17]. This property is unique
to ghrelin and not shared by any known neuropeptide or circulating hormone. The
duration of feeding stimulation in response to central or peripheral ghrelin administra-
tion is short, similar to that observed for central NPY. Indeed several lines of evidence
suggest that ghrelin acts via arcuate NPY/AgRP neurones, almost all of which express
the GHS-R1a. Ghrelin stimulates feeding most potently when injected directly into the
Arc and also stimulates release of NPY from hypothalamic explants in vitro [11, 13].
Arcuate NPY/AgRP neurones are activated by ghrelin, as demonstrated by enhanced c-
fos, NPY and AgRP expression following ghrelin administration and by electrophysio-
logical studies. Further, the orexigenic actions of ghrelin are abolished in NPY/AgRP
dual knockout mice and in mice with post-embryonic ablation of NPY/AgRP neurones.
Whilst this neuronal population is the most well-characterised ghrelin target, there is
also evidence for an indirect action on these neurons via the vagus nerve. Some authors
have found that surgical vagotomy or vagal deafferentation using capsaicin abolished
the feeding and Arc c-fos response to peripheral ghrelin. However, more recently it has
been reported that the orexigenic response to peripheral ghrelin is intact in rats follow-
ing subdiaphragmatic vagal deafferentation, suggesting that the acute orexigenic
actions of ghrelin do not require vagal afferent signalling. Other ghrelin targets include
several other hypothalamic nuclei, the dorsal vagal complex of the brainstem and com-
ponents of the mesolimbic dopaminergic system [14–16].

Does Ghrelin Contribute to Pre-Prandial Hunger?

Circumstantially, the distribution of ghrelin, predominantly in the stomach and

upper small intestine, is ideal to monitor meal to meal nutrient intake. In keeping
with a role as a putative meal initiator, systemic administration of ghrelin stimulates
food intake, at doses which result in plasma concentrations similar to those found in
the fasted (hungry) state [11]. The onset of action is rapid, duration is short and ghre-
lin appears to delay latency to feed and promote food seeking behaviour in rodents.
Ghrelin stimulates food intake across a broad range of species, including humans
[17]. In further support of ghrelin’s role as an endogenous appetite stimulator, block-
ing CNS ghrelin action, by infusion of anti-ghrelin antibodies into the rat brain,
inhibits fasting-induced feeding [10].
Plasma ghrelin levels were first noted to increase on fasting and fall on re-feeding
in rodents, as would befit a hunger signal [8, 11]. Subsequently more detailed studies

Gut and Hormones and Obesity 169

have demonstrated pre-prandial plasma ghrelin elevation in humans and animals fed
at scheduled times. More importantly, plasma ghrelin also peaks pre-prandially in
human subjects, who have been deprived of time cues, initiating meals voluntarily.
These plasma ghrelin peaks correlated well with hunger scores. Post-prandially,
plasma ghrelin is suppressed in proportion to calories ingested, when macronutrient
content and volume are kept constant. Interestingly, fat appears to suppress ghrelin
less potently per calorie than carbohydrate or protein. This may in part explain the
reduced satiety and enhanced weight gain associated with high fat diets. Thus, most
data suggest that ghrelin is a physiological meal initiator. By extension, inhibition of
ghrelin may be able to reduce meal size or frequency [15].

Ghrelin and Long-Term Energy Homeostasis

In addition ghrelin appears to promote long-term weight gain. Chronic administra-

tion of ghrelin in rodents results in prolonged hyperphagia and weight gain [8, 9].
The weight gain observed is greater than that expected for the degree of hyperphagia.
This may reflect several reported actions of ghrelin which could combine to promote
weight gain. These include stimulation of adipogenesis, inhibition of adipocyte apop-
tosis, transfer from fatty acid oxidation to glycolysis for energy expenditure and inhi-
bition of sympathetic nervous system activity. Thus, prolonged elevation of plasma
ghrelin promotes weight, in contrast to the classical short-term appetite regulator
CCK, where prolonged administration does not reduce body weight. However, this
does not prove that endogenous ghrelin physiologically regulates body weight [15].
In humans, ghrelin levels are inversely correlated with adiposity, being low in the
obese, higher in lean subjects and markedly elevated in subjects who are cachectic
due to a diverse range of conditions including anorexia nervosa, cancer and chronic
cardiac failure [15, 18]. These findings are the converse of those for plasma leptin and
similarly, this has been interpreted as an adaptive response to restrain further overeat-
ing in the obese or to stimulate it in the underweight, to maintain a stable body
weight. This hypothesis is supported by longitudinal studies. Ghrelin is increased in
response to weight loss achieved either by diet alone or diet and exercise and is sup-
pressed by overfeeding or successful treatment of anorexia nervosa. However, longer
total fasting in healthy volunteers, (several days or longer) results in low circulating
ghrelin levels. An exception to the inverse correlation of ghrelin with body weight is
observed in subjects with Prader-Willi syndrome (PWS), who have very high fasting
and post-prandial ghrelin levels, which may contribute to their obesity [12, 15] [as
discussed in the chapter by Goldstone and Beales, this vol., pp. 37–60].
If ghrelin is critical for body weight maintenance, reduction in ghrelin should
promote weight loss and restoration of ghrelin should promote weight re-gain. This
has been demonstrated in mice undergoing total gastrectomy that have an 80%
reduction in circulating ghrelin associated with weight loss. Replacement of ghrelin

170 Wren
to physiological levels results in weight regain. However, mice with global deletions of
ghrelin or the GHS-R1a were initially reported to have minimal disruption of body
weight homeostasis. As always with such mouse models, one must consider con-
founding by developmental adaptation, and indeed the phenotype of conditional
knockout models is more robust. Further studies on mice lacking ghrelin or the GHS-
R1a have demonstrated resistance to diet-induced obesity in mature mice. The phe-
notype of ghrelin null mice might be further complicated by the observation that the
gene that codes for ghrelin has been found to code for another peptide, named
obestatin. Obestatin was originally reported to reduce food intake when administered
peripherally or ICV, and to reduce body weight gain when administered peripherally,
via the orphan G protein-coupled receptor, GPR39. However, subsequent reports
have not supported the initial findings and suggest that obestatin may not signal via
GPR39 or play a role in the regulation of food intake. Mice devoid of ghrelin sig-
nalling certainly lack the extreme phenotypes associated with mice lacking leptin sig-
nalling. However, taken together, data from knockout models are compatible with a
role for ghrelin in long-term energy homeostasis [15].

Ghrelin as a Drug Target

Given that circulating ghrelin is already low in obese subjects, one might question
how much therapeutic benefit could be obtained from further ghrelin suppression.
However, it has been shown that obese subjects may be more sensitive to appetite
stimulation by exogenous ghrelin [19]. Thus inhibition of ghrelin may have therapeu-
tic potential, particularly in enhancing further weight loss and preventing weight
regain following diet-induced weight loss, when ghrelin levels become elevated.
Several major pharmaceutical companies have pursued programmes investigating
ghrelin inhibition. Interestingly, the GHS-R1a exhibits constitutive activity, suggest-
ing that an inverse agonist may be more therapeutically useful than an antagonist.
Another strategy is to design compounds which bind to ghrelin itself and prevent
interaction with its receptor. A novel group of molecules called RNA spiegelmers,
oligonucleotides containing L-ribose, have been designed which block interaction of
ghrelin with the GHS-R1a, inhibit ghrelin-induced GH secretion and reduce food
intake and adiposity in mice fed a high-fat diet. As expected, these molecules have no
effect in ghrelin knockout mice, attesting to the specificity of their actions. To date, no
ghrelin-blocking products have progressed as far as phase I trials [14–16].
Theoretically, there may be safety concerns about ghrelin blocking agents in view
of the possible role of ghrelin in regulation of the growth axis, as well as reported ben-
eficial cardiovascular and anti-inflammatory effects of ghrelin. Regulation of
octanoylation of ghrelin may provide an alternative drug target which is, as yet, rela-
tively unexplored. A more direct therapeutic application of ghrelin is in the treatment
of anorexia and cachexia. To this end, proof of principle studies have demonstrated

Gut and Hormones and Obesity 171

that ghrelin stimulates appetite in patients with anorexia and weight loss due to can-
cer and chronic kidney disease, and may also improve meal enjoyment, without any
adverse effects [20, 21]. Ghrelin administration by intravenous infusion over 3 weeks
results in weight gain in patients with cardiac cachexia and chronic obstructive pul-
monary disease [22, 23]. However, weight gain due to improved cardiac function and
to placebo effect are significant possible confounders in these latter open-label stud-
ies. Whilst intravenous infusion is not a practical route for chronic administration in
most therapeutic settings, ghrelin is also effective when given by subcutaneous injec-
tion in healthy lean individuals and in malnourished patients on peritoneal dialysis
[21, 24]. Further placebo-controlled trials of long-term subcutaneous ghrelin admin-
istration in anorectic/cachectic patients are required to establish whether this may be
a useful therapy. In addition, a wide variety of orally active agonists for the GHS-R1a
were developed throughout the 1980s and 1990s which may have therapeutic poten-
tial in this context [25].

Satiety Signals

After a meal, nutrients pass into the stomach and intestine, and a number of gastroin-
testinal signals are released. These peptides and other signals act to optimise the diges-
tive process. Some also function as short-term satiety signals and possibly long-term
regulators of body weight. CCK is the prototypical satiety hormone. It is now over 30
years since CCK was first shown to inhibit food intake and it remains one of the most
intensively studied of the gut hormones. CCK will not be discussed in depth and the
reader is directed to an excellent recent review [26]. However, the use of CCK as a
potential novel obesity therapy is in some doubt as, in animals, repeated pre-prandial
administration of CCK reduces food intake but also increases meal frequency, with no
net effect on body weight. Furthermore, continuous CCK administration is ineffective
after the first 24 h.

PYY and Pancreatic Polypeptide

PYY, pancreatic polypeptide (PP) and NPY are members of the PP-fold peptide family,
i.e. they share a common tertiary structure, called the PP-fold structural motif. In addi-
tion there is significant homology between peptide sequences within the family. They all
have 36 amino acids, contain several tyrosine residues and require C-terminal amidation
for biological activity. PYY and PP are putative satiety signals. The PP-fold family exert
their effects via the Y family of G protein-coupled receptors. Four receptor subtypes have
been identified, Y1, Y2, Y4 and Y5, all of which are expressed in the hypothalamus. Y1 and
Y5 have both been put forward as the putative receptors via which NPY exerts its orexi-
genic action. The Y2 receptor is thought to function as an autoinhibitory pre-synaptic

172 Wren
receptor, expressed on NPY neurones, and to mediate the anorectic actions of PYY,
whilst the Y4 receptor appears to mediate the anorectic actions of PP [27–29]

Peptide YY

PYY occurs in two forms, PYY1–36 and PYY3–36. PYY3–36, the major circulating form, is
a truncated 34-amino acid form created by cleavage of the N terminal Tyr-Pro residues
by dipeptidyl peptidase IV (DPPIV). Whilst full length PYY binds with similar affinity
to all Y receptors, PYY3–36 shows selectivity for the Y2 receptor, for which it has high
affinity. PYY is secreted from entero-endocrine L-cells. These PYY immunoreactive
cells are found throughout the entire gastrointestinal tract, but particularly in the dis-
tal portion. PYY immunoreactivity is almost absent in the stomach, sparse in the duo-
denum and jejunum, common in the ileum and colon, and at very high levels in the
rectum (the opposite distribution pattern to that observed for ghrelin). The pattern of
secretion is also a mirror image of ghrelin, i.e. PYY is released into the circulation fol-
lowing meals and suppressed by fasting [27–29]. PYY has long been known to exert
numerous effects on the gastrointestinal tract. Administration of PYY increases the
absorption of fluids and electrolytes from the ileum after a meal and inhibits pancre-
atic and gastric secretions, gallbladder contraction and gastric emptying. Peripheral
administration of PYY, like ghrelin, also exerts effects on numerous other body sys-
tems. For example, it reduces cardiac output, causes vasoconstriction and reduction in
glomerular filtration rate, plasma renin and aldosterone activity. The physiological sig-
nificance of these numerous actions has not been established [27–29].

Does PYY Contribute to Post-Prandial Satiety?

PYY levels rise to a plateau at 1–2 h post-prandially, with these peak levels influenced
by both the number of calories and the composition of the food consumed. The onset
of PYY release occurs before nutrients have reached the predominant sites of PYY
production in the distal gastrointestinal tract. This implies that peptide release may
occur via a neural reflex, possibly through the vagus nerve. Systemic administration
of PYY3–36 inhibits food intake in rodents and man. Initially these findings were con-
tentious, with several authors unable to reproduce feeding inhibition in rodents. A
probable explanation is that the effects of anorectic agents in rodents are easily
masked by stress, causing a reduction of food intake in the control group. Thus sig-
nificant inhibition of feeding by PYY3–36 cannot be detected in rodents that are not
fully acclimatised to experimental procedures or following transfer to a novel envi-
ronment [27–29]. In man intravenous infusion of PYY3–36 reduces appetite and food
intake at a subsequent meal by about one third. Whilst initial reports detected inhibi-
tion of food intake at plasma PYY concentrations in the physiological range, others

Gut and Hormones and Obesity 173

have only detected an effect at pharmacological doses. Thus whilst there remains
some debate over whether PYY3–36 is a physiological meal terminator in man, appetite
inhibition in response to exogenous PYY, in both lean and obese individuals is a
robust and reproducible finding [27–29].

PYY and Long-Term Energy Homeostasis

Chronic systemic administration of PYY3–36 results in weight loss in some but not all
rodent models. Data from knockout mice also provide evidence for a long-term role
for PYY in regulation of energy balance. Three separate knockout models have been
generated, two of which develop obesity. One model did not become obese. This
model also had disruption of expression of the PP gene. One would not predict that
loss of a second putative anorectic signal would attenuate obesity. However, subtle
differences in technique and background strain have frequently been reported to
result in differing phenotypes in other knockout mouse models. In one of the obese
PYY null models administration of PYY corrected the phenotype, suggesting that
obesity was being driven by PYY deficiency [28, 29]. In contrast to leptin, circulating
levels of PYY are not elevated in obese individuals who also retain full sensitivity to
the anorectic actions of PYY3–36. It has been reported that obese subjects have lower
fasting and post-prandial circulating PYY than lean subjects. In order to produce an
equivalent stimulation of PYY and equivalent satiety, obese individuals needed to
consume a much greater caloric load than their lean counterparts. However, not all
studies have detected a difference in fasting PYY concentrations between lean and
obese groups. Current data suggest that impaired post-prandial PYY release may, at
least, impair satiety and help to maintain obesity, if not act as a primary driver of ini-
tial development of obesity. Whether or not reduced PYY signalling is a primary
cause of obesity, it is certainly true that retained PYY sensitivity in the obese make it
an attractive therapeutic target [27–29].

Mechanism of Action of PYY

The exact mechanism whereby PYY3–36 inhibits appetite and food intake is unclear.
Interestingly, in contrast to peripheral administration, intracerebroventricular admin-
istration of PYY stimulates food intake. This is thought to be via an action on Y1 and
Y5 receptors in the paraventricular nucleus (PVN), the second order neurones tar-
geted by orexigenic Arc NPY neurones. Several lines of investigation suggest a direct
anorectic action of circulating PYY3–36 on the Arc. C-fos is observed in the Arc in
response to peripheral administration of PYY3–36 and direct micro-injection into the
Arc inhibits feeding. This action is thought to be via auto-inhibitory Y2 receptors on
the orexigenic NPY neurones. In support of this hypothesis, a highly specific Y2

174 Wren
agonist inhibits feeding following intra-arcuate injection, whilst the anorectic actions
of PYY3–36 are absent in the Y2 knockout mouse and blocked by a Y2 receptor antago-
nist. Furthermore, PYY3–36 reduces expression of NPY in the Arc and release of NPY
from hypothalamic explants. Electrophysiological studies suggest that PYY3–36 directly
inhibits activity of arcuate NPY neurones, secondarily disinhibiting anorectic POMC
neurones. However, POMC does not appear to be essential for the anorectic action as
PYY3–36 is effective in mice with lacking melanocortin signalling. However, the picture
appears to be more complex than a simple action on the Arc. There is also evidence
that PYY3–36 acts at the level of the vagus and the dorsal vagal complex. The relative
contribution of these various putative sites of action to physiological appetite regula-
tion remains unclear. The ascending vagal-brainstem-hypothalamic pathways have,
however, been implicated in mediating sensations of nausea. In keeping with this
PYY3–36 has, at high doses, been reported to cause conditioned taste avoidance in
rodents and nausea in humans. However, lower doses inhibit appetite and food intake
in rodents and humans without aversive effects or nausea. Coupled with the observa-
tion that PYY null mice become obese, this suggests a role for PYY in appetite regula-
tion independent of aversive effects [27–29]. Drug companies developing analogues of
PYY for treatment of obesity will need to be mindful of the potentially narrow thera-
peutic window in order to design successful agents.

Pancreatic Polypeptide

PP is produced largely in the endocrine pancreas, but also in the exocrine pancreas,
colon, and rectum. Like PYY, PP is released in response to a meal and inhibits
appetite. PP binds with greatest affinity to Y4 receptors (with greater affinity than
PYY) and Y5 receptors. The role of PP in appetite regulation has been investigated
for over 30 years. It was initially noted that ob/ob mice lacked pancreatic PP cells,
and peripheral administration of PP reduced their food intake and body weight.
Peripheral administration of PP resulting in physiological plasma levels has
been shown to reduce food intake in normal mice, with associated reduction in
gastric emptying and gastric ghrelin expression and increased vagal tone. PP also
increased oxygen consumption and stimulated sympathetic activity, leading to the
suggestion that PP may also increase energy expenditure. In normal-weight human
volunteers infusion of PP reduces food intake without altering gastric emptying.
Subjects with PWS are reported to have suppressed basal and post-prandial PP lev-
els, whilst PP administration to PWS subjects reduces food intake. It is, therefore,
possible that PP deficiency contributes to the hyperphagia in this obesity syndrome
[28, 29].
Apart from its acute effects on appetite and food intake, PP may also modulate
long-term energy balance. Transgenic mice that overexpress PP have a lean pheno-
type with reduced food intake [30]. Repeated administration of PP to ob/ob mice

Gut and Hormones and Obesity 175

decreases body weight gain and ameliorates insulin resistance and dyslipidaemia.
However, rodents with diet-induced obesity are less sensitive to the anorectic actions
of PP. Plasma PP is increased in individuals with anorexia nervosa, and there have
been reports of suppressed plasma PP in obese subjects. However, the effects of obe-
sity on circulating concentrations of PP are conflicting; others have found no differ-
ence between lean and obese subjects or between obese subjects before and after
weight loss. The effects of PP on appetite and body weight in obese humans are
unknown. Further investigation in obese subjects may indicate whether PP has the
potential to be a novel treatment for obesity.
PP, like PYY, has opposing effects on appetite, depending on the route of adminis-
tration. Injection of PP into the third ventricle stimulates daytime food intake in sati-
ated rats. Similarly, central injection of PP has the opposite effect to peripheral
administration on gastric motility, stimulating rather than inhibiting gastric empty-
ing. These contrasting effects of central and peripheral administration of PP probably
reflect differing sites of receptor activation. PP is unable to cross the blood brain bar-
rier. Circulating PP acts on circumventricular CNS sites, such as the AP. The anorec-
tic effect of peripheral PP probably occurs via the Y4, which is highly expressed in
this region [28, 29].

Oxyntomodulin and Glucagon-Like Peptide-1

Oxyntomodulin and glucagon-like peptide-1 (GLP-1) are products of the pre-

proglucagon gene. Preproglucagon is expressed in the pancreas, L-cells of the intes-
tine and in the NTS of the brainstem and undergoes differential processing by
prohormone convertase 1 and 2 depending on the site of synthesis [31, 32] as illus-
trated in figure 2. In the pancreas, classical preproglucagon processing yields
glucagon and the apparently inactive N-terminal fragment glicentin-related PP
(GRPP) whilst the GLP sequences remain within a larger peptide, major proglucagon
fragment (MPGF). The post-translational processing in the gut and brain are very
similar. In these tissues, the glucagon sequence remains in a larger peptide, glicentin,
which is thought to be inactive. Glicentin is further cleaved to yield oxyntomodulin
and GRPP. Oxyntomodulin is a 37-amino acid peptide comprising the 29 amino acids
of pancreatic glucagon with an eight amino acid c-terminal extension, sometimes
called spacer peptide 1. The other major products of preproglucagon processing in
gut and brain are the two GLPs, GLP-1 and GLP-2.
GLP-1 and oxyntomodulin, along with PYY, are released from intestinal L-cells in
response to food intake and appear to act in part as satiety signals as well as possibly
participating in long-term body weight regulation. GLP-1 is the most powerful
known incretin in humans and manipulation of the GLP-1 system forms the basis of
several major new treatments for type 2 diabetes. These include a subcutaneously
administered DPPIV-resistant GLP-1R agonist, exendin-4, a peptide component of

176 Wren
 Oxyntomodulin

SP1
GRPP Glucagon
Gut
Brain

SP1
GRPP Glucagon
GLP-1 GLP-2
Glicentin

Preproglucagon
Signal

SP1

SP2
peptide
GRPP Glucagon GLP-1 GLP-2

Pancreas
MPGF
GRPP Glucagon GLP-1 SP2 GLP-2

Fig. 2. Overview of differential preproglucagon processing in pancreas versus brain and gut.
SP ⫽ Spacer peptide.

Gila monster saliva marketed as exenatide (Byetta), as well as orally active DPPIV
inhibitors. Central administration of GLP-1, both intracerebroventricularly and into
the PVN, reduces food intake in rodents, whilst the GLP-1 receptor antagonist
exendin 9–39 increases food intake. Chronic administration of GLP-1 into the CNS
attenuates weight gain and peripheral GLP-1 injection inhibits food intake in rodents
and man. Evidence suggests GLP-1 secretion is reduced in obese subjects, and weight
loss normalises the levels. Reduced GLP-1 secretion could, therefore, contribute to
obesity, and replacement may restore satiety. Obese subjects receiving subcutaneous
GLP-1 for 5 days, just before each meal, reduced their calorie intake by 15% and lost
0.5 kg in weight. However, in view of the powerful incretin action of GLP-1 there is a
risk of hypoglycaemia in non-diabetic subjects [28, 29].

Oxyntomodulin

Oxyntomodulin inhibits caloric intake in rodents when given either centrally or

peripherally and results in decreased weight gain when administered peripherally.
Oxyntomodulin is also effective in humans. An infusion of oxyntomodulin to nor-
mal-weight volunteers reduced immediate caloric intake by 19.3% and suppressed

Gut and Hormones and Obesity 177

plasma ghrelin. It is possible that postprandial oxyntomodulin release may contribute
to the normal physiological inhibition of plasma ghrelin after meals. In contrast to
GLP-1, oxyntomodulin is a much less potent incretin but may have more potent
effects on weight loss. Oxyntomodulin only causes a small increase in plasma insulin
without affecting plasma glucose. When administered three times daily in overweight
volunteers for 4 weeks, subcutaneous oxyntomodulin resulted in 2.3 kg weight loss
compared with 0.5 kg in the control group. Enhanced weight loss in response to oxyn-
tomodulin may be due to increased energy expenditure. Acute administration of
oxyntomodulin has been shown to increase voluntary activity in human subjects and
to increase heart rate in rodents. The circulating levels of oxyntomodulin in obesity
remain to be established [28, 29].
Both GLP-1 and oxyntomodulin are thought to exert their effects via the GLP-1
receptor (GLP-1R). Antagonists of the GLP-1R, such as exendin (9–39), antagonise
the effect of both GLP-1 and oxyntomodulin, and both peptides are ineffective in the
GLP-1 receptor knockout mouse. However, the affinity of oxyntomodulin for GLP-
1R is approximately 2 orders of magnitude less than that of GLP-1, yet both peptides
appear to be similarly effective at reducing food intake. The mechanisms of action of
GLP-1 and oxyntomodulin appear to be similar but not identical. Peripheral and cen-
tral GLP-1 administration have been reported to activate neurones in the hypothala-
mic Arc, PVN, NTS and AP. In addition ablation of vagal-brainstem-hypothalamic
projections attenuates feeding inhibition by GLP-1 [33]. Whilst systemic oxyntomod-
ulin administration results in a similar pattern of neuronal activation to GLP-1,
intra-arcuate administration of exendin 9–39 blocks the anorectic effects on oxynto-
modulin but not GLP-1, suggesting a direct action of oxyntomodulin on the Arc
[28, 29].
The duration of inhibition of food intake in response to peripheral oxyntomodulin
administration is short, necessitating three times daily subcutaneous injection in
weight loss studies in humans. This may be due to rapid cleavage of the two N-termi-
nal amino acid residues by DPPIV, as observed for GLP-1 and PYY. DDPIV-resistant
analogues of oxyntomodulin may, thus, have greater therapeutic potential than the
native peptide [28, 29].

Dietary Manipulation of Gut Hormones

It has been suggested that a cause of the current obesity epidemic may be that mod-
ern processed foods bypass our natural satiety mechanisms. Low fat diets are the
most well-established means of dietary weight loss. It has been reported that weight
loss in response to a low-fat diet does not produce the expected elevation in plasma
ghrelin. This may be due to an increase in the proportion of calories consumed as
carbohydrate that more potently suppresses ghrelin per calorie consumed than
does fat. High-protein diets have also become popular in recent years as a means to

178 Wren
promote satiety and weight loss. Diets high in protein have recently been reported
to elevate circulating PYY and enhance satiety more effectively that other macronu-
trients; however, previous data suggested that, at a single meal, higher plasma con-
centrations of PYY were stimulated by high fat isocaloric meals, compared with
protein or carbohydrate. It is an intriguing possibility that designer diets may help
promote the most favourable gut hormone profile to allow sustained weight loss
[15, 28, 29].

An Obesity Poly-Pill?

The only treatment to date associated with dramatic and sustained weight loss in the
morbidly obese is gastric bypass surgery. However, its cost and associated morbidity
and mortality make it an impractical treatment for the majority of obese patients
and it is generally reserved for the morbidly obese. Gastric bypass results in signifi-
cant increases in plasma PYY, GLP-1 and oxyntomodulin whilst ghrelin either falls
or fails to rise, despite significant weight loss [15, 28, 29]. Interestingly, bypass
patients report dramatically reduced hunger long before substantial weight loss
occurs. Furthermore, in rodent models many of the beneficial effects of bypass can
be mimicked by gut hormone administration [34]. It is notable that the changes in
the four gut hormones above all favour weight loss following gastric bypass. This co-
ordinated action, mimicking natural satiety, may be a key to effective anti-obesity
therapy. As noted above, individual gut hormones administered at high concentra-
tions, have been associated with aversive behaviours in rodents and nausea in
humans. We have reported that low doses of PYY3–36 and GLP-1 inhibit food intake
additively [35]. Analogous to current treatment for hypertension where several
agents are commonly used, a smart cocktail of gut hormone-based drugs may prove
a more effective anti-obesity treatment than targeting a single hormone. This
approach could potentially provide the sustained weight loss offered by gastric
bypass surgery, without the associated morbidity and mortality. The major thera-
peutic disadvantage of gut hormones is their short duration of action and the
requirement for subcutaneous or intravenous administration. In the GLP-1 system,
degradation-resistant analogues and drugs that inhibit enzymes that degrade the
endogenous hormone have already been brought to market for the treatment of type
2 diabetes. Similar approaches may be successful for oxyntomodulin, PYY and PP,
whilst intra-nasal delivery systems or development of orally active small molecule
mimetics could avoid the need for administration by injection.
The obesity epidemic is advancing relentlessly and current treatments, bar
bariatric surgery, are insufficiently effective. Recent data suggest that gut hormones
regulate when and how much we eat for every meal and offer a logical drug target.
Mimicking natural satiety mechanisms by delivering combinations of gut hormones
may replace bariatric surgery as the only truly effective anti-obesity treatment.

Gut and Hormones and Obesity 179

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Dr. Alison M. Wren

Department of Endocrinology
Chelsea and Westminster Hospital NHS Foundation Trust
Fulham Road
London SW10 9NH (UK)
Tel. ⫹44 20 8237 2730, Fax ⫹44 20 8237 2732, E-Mail a.wren@imperial.ac.uk

Gut and Hormones and Obesity 181

Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 182–197

Adipokines in Obesity
Rexford S. Ahima ⭈ Suzette Y. Osei
Division of Endocrinology, Diabetes and Metabolism,
Department of Medicine, University of Pennsylvania School of Medicine,
Philadelphia, Pa., USA

Abstract
Adipose tissue is the source of soluble mediators (adipokines), secreted mainly by adipocytes. Leptin acts
on the brain and peripheral organs to regulate energy homeostasis and the neuroendocrine axis.
Adiponectin regulates glucose and lipid metabolism by targeting the liver and skeletal muscle. Adipose-
derived proinflammatory cytokines, vasoactive peptides, coagulation and complement factors, visfatin,
vaspin and retinol-binding protein signal through paracrine and hormonal mechanisms. Understanding
the biology of adipose tissue and the rapidly growing list of adipokines provides new insights into nor-
mal physiological regulation, as well as the pathogenesis and treatment of obesity, diabetes and disor-
ders of lipid metabolism and cardiovascular system. Copyright © 2008 S. Karger AG, Basel

The obesity epidemic has focused attention on the biology of adipose tissue.
Adipocytes provide a large energy storage capacity mainly in the form of triglyceride
[1]. The levels of insulin, glucose and nutrients increase during feeding and stimulate
energy storage in the liver and adipocytes [1]. Conversely, fasting activates the sym-
pathetic nervous system and increases the levels of glucagon, epinephrine and gluco-
corticoids, leading to enhancement of glycogenolysis and gluconeogenesis, and
maintenance of glucose supply to the brain and vital organs [1]. Prolonged fasting
also stimulates lipolysis, generating fatty acids to be used by muscle, liver and periph-
eral organs, in addition to providing ketones for the brain [1].
Interactions between adipose tissue and the vascular and immune systems are now
increasingly recognized [2, 3]. As the number and size of adipocytes expand in obe-
sity, the vascular supply increases under stimulation of angiogenic factors secreted by
adipocytes [2]. Conversely, antiangiogenic treatment reduces adipose vascularity and
prevents obesity in rodents [4, 5]. Obesity is associated with histological and bio-
chemical changes characteristic of inflammation [3]. Adipose tissue from obese indi-
viduals accumulates a large number of activated macrophages which form giant cells
and secrete cytokines, e.g. tumor necrosis factor-␣ (TNF-␣) and interleukin-6 (IL-6)
[3] (table 1). C-reactive protein is also increased in obesity, and the levels of intracel-
lular cell-adhesion molecule-1 and platelet/endothelial cell adhesion molecule-1
increase in adipose endothelial cells, inducing the migration and adhesion of mono-
cytes [3]. Monocyte chemoattractant protein-1 and various chemokines recruit
monocytes to adipose tissue [6, 7]. Collectively, these changes induce insulin resis-
tance in adipose and liver, and interact with adipose-derived coagulation factors and
vasoactive peptides, leading to cardiovascular disease in obesity [3].
This chapter will discuss the current understanding of leptin as a prototypic
adipokine related to energy balance and neuroendocrine regulation. Next, the role of
adiponectin in glucose and lipid metabolism and vascular biology will be reviewed.
Finally, putative roles of retinol-binding protein 4 (RBP4), resistin and visfatin and
various adipokines will be reviewed (table 1).

Leptin

The discovery of leptin more than a decade ago was a major turning point in our under-
standing of adipokines [8]. Mice and humans homozygous for the leptin gene mutation
develop hyperphagia, severe early-onset obesity, insulin resistance preceding obesity,
excess lipid accumulation outside adipose tissue (steatosis), and neuroendocrine abnor-
malities, notably, hypothalamic hypogonadism and tertiary hypothyroidism [9–11].
Moreover, there is evidence for immunosuppression in congenital leptin deficiency [10,
11]. Leptin is expressed and secreted mainly by adipocytes, but low levels are present in
the gastric fundus, mammary gland, placenta, pituitary and skeletal muscle [9].
Leptin has a relative molecular mass of 16 kDa and circulates in free or bound
forms. The latter represents leptin bound mainly to its soluble receptor and is thought
to be inactive. The concentration of leptin is higher in obese than lean individuals [9].
Leptin falls rapidly during fasting and increases gradually during feeding. Studies in
rodents and human indicate a link between these changes in leptin and insulin [9].
Higher leptin level in women is explained partly by increased production in subcuta-
neous adipose tissue and stimulation by estrogens. On the other hand, leptin is sup-
pressed by androgens in males [9]. Chronic glucocorticoid exposure, TNF-␣ and IL-6
increase leptin, while adrenergic stimulation decreases leptin [9]. Leptin exhibits a
diurnal rhythm, peaking at night in humans and in the morning in rodents [12, 13].
A pulsatile leptin rhythm has also been recognized in humans, although the underly-
ing mechanisms and functional significance are unknown [12, 14].
Five leptin receptor isoforms, LRa–LRe, are derived from alternate splicing of lepr
mRNA [15, 16]. LRa is the predominant ‘short leptin receptor’ which lacks the key
cytoplasmic domain required for signaling through the JAK/STAT (signal transduc-
tion and activators of transcription) pathway. LRa is abundantly present in brain cap-
illary endothelium and peripheral tissues, and is thought to mediate leptin transport.

Adipocyte Hormones 183

Table 1. Actions of adipokines

Adipokine: source Energy, lipid and Immune system Other

and signaling glucose metabolism actions

Leptin – produced by Inhibits feeding Proinflammatory Trophic action on

adipocytes; subcutaneous Increases energy Induces TNF-␣, IL-6, hypothalamic
expression is higher expenditure (in IL-12, neutrophil feeding circuits
than visceral adipose; rodents) activation and Stimulates
low levels expressed Reduces body fat chemotaxis, reactive reproductive and
by muscle, gastric Lowers glucose, oxygen species thyroid hormones
fundus, intestine and insulin and lipids Stimulates Promotes brain
placenta; plasma levels Stimulates lymphopoeisis, growth in leptin-
increase in obesity; fatty acid oxidation T-cell proliferation deficient animals
circulates as free or and TH1 response, Inhibits bone
LRe bound leptin; and reduces TH2 formation in
signals via LRb and response rodents
JAK2-STAT3
Adiponectin – produced Chronic peripheral Anti-inflammatory
by adipocytes;level or central treatment and anti-atherogenic
in visceral adipose is reduces body Reduces endothelial
higher than weight and fat in adhesion, NF-␬B, TNF-␣,
subcutaneous; low rodents IL-6, IL-10, IFN␥
expression has been Stimulates Reduces B- and T-cell
reported in liver and thermogenesis responses
skeletal muscle; plasma (in rodents)
levels decrease in Increases
obesity; LMW and HMW insulin sensitivity;
complexes in plasma; suppresses glucose
trimer and LMW in production
cerebrospinal fluid; TZD Stimulates fatty
treatment increases acid oxidation
total and HMW
adiponectin; signals
via AdipoR1 and
AdipoR2 and AMPK
Resistin – produced by Inhibits adipogenesis Proinflammatory
adipocytes in rodents in rodents Increases endothelial
and monocytes/ Stimulates adhesion, TNF-␣, IL-1␤,
macrophages in humans; thermogenesis in IL-6, IL-12, NF-␬B
plasma levels increase in rodents
obese rodents; trimer and Induces
hexamer form in mouse insulin resistance
serum; receptor is and gluconeogenesis
unknown; inhibits AMPK in rodents
phosphorylation and
induces SOCS3

184 Ahima · Osei

Table 1. (continued)
Adipokine: source
and signaling
TNF-␣ – produced by
adipocytes and
stromal cells; precursor
17-kDa active protein;
26-kDa transmembrane
protein is cleaved into
expression in subcutaneous
adipose is greater than
visceral adipose; signals via
type I and II TNF receptors
IL-6 – produced
by adipocytes and
stromovascular cells;
expression in visceral
adipose is greater than
subcutaneous adipose;
circulates in multiple
glycosylated forms;
IL-6 receptor exists in
membrane bound and
secreted forms
Plasminogen activator
inhibitor (PAI)-1–
produced by adipocytes
and stromal cells; levels
are higher in visceral
adipose; plasma levels
increase in obesity; TZD
treatment suppresses PAI-1
Adipsin (complement
factor D/ASP) – produced
by adipocytes; adipsin is
reduced in obese rodents
but increased in humans;
ASP is increased in obesity
RBP4 – produced by
adipocytes; plasma levels
increase in obesity;
reduced by TZD
treatment
Adipocyte Hormones
Energy, lipid and Immune system Other
glucose metabolism actions
Inhibits feeding Proinflammatory
Induces cachexia
Induces insulin
resistance,
hyperglycemia and
dyslipidemia in
rodents, but role in
glucose and lipid
metabolism in humans
is controversial
Inhibits feeding Proinflammatory
Increases energy
expenditure
Decreases weight
Induces insulin
resistance,
hyperglycemia
and dyslipidemia
Increases adiposity Stimulated by TNF-␣ Promotes
in rodents thrombosis and
Induces insulin atherogenesis
resistance in rodents
ASP promotes fatty acid
uptake, decreases fatty
acid release from
adipocytes, increases
glucose uptake by
adipocytes, and
enhances insulin
secretion in rodents
Increases insulin
sensitivity in rodents
Reduces glucose and
lipids in rodents
185
Table 1. (continued)

Adipokine: source Energy, lipid and Immune system Other

and signaling glucose metabolism actions

Renin-angiotensin Angiotensin II ? influences

system – peptides, promotes vascular
enzymes and receptors adipogenesis reactivity
of RAS are expressed in and lipogenesis,
adipocytes and stromal reduces insulin
cells; adipose levels of sensitivity, and enhances
angiotensin II increase gluconeogenesis and
in obesity glycogenolysis
Visfatin – Visfatin acts as
produced by adipocytes insulin-mimetic in
and mostly by the liver cells and mice
and B cells; levels Role in glucose and
reportedly lipid metabolism in
increased in obese humans is uncertain
rodents but uncertain
in humans

LRe is shed into the circulation as a ‘soluble receptor’ and binds leptin. The ‘long lep-
tin receptor’ LRb mediates effects of leptin in the brain [15, 16]. Leptin crosses the
blood-brain-barrier via a saturable transport system, and acts directly on neurons in
the arcuate nucleus that express neuropeptide Y (NPY), agouti-related peptide
(AGRP), pro-opiomelanocortin (POMC) and cocaine-and amphetamine-regulated
transcript [9]. Binding of leptin to LRb leads to association with JAK2, autophospho-
rylation of JAK2, phosphorylation of Tyr985 and Tyr1138 on LRb and phosphoryla-
tion and activation of signal transducer of transcription-3 (STAT3), which acts as a
transcription factor to regulate neuropeptides and various leptin target genes [16].
LRb-phosphorylated Tyr985 recruits the tyrosine phosphatase SHP-2 (Src-homology
protein tyrosine phosphatase-2), and terminates leptin signaling via induction of sup-
pressor of cytokine signaling-3 (SOCS3) [16]. Rising leptin level suppresses NPY and
AGRP and increases ␣-melanocyte-stimulating hormone (␣-MSH), derived from
POMC. ␣-MSH inhibits feeding and induces thermogenesis through melanocortin 4
receptors in the paraventricular nucleus and other areas of the hypothalamus [14].
Normally, AGRP serves as an antagonist of ␣-MSH and stimulates feeding in concert
with NPY. Thus, by suppressing expression of AGRP and NPY, leptin has a net effect
to reduce appetite and decrease weight [9].
As predicted, deletion of LRb or STAT3 in the hypothalamus, or specifically in POMC
neurons, resulted in obesity [17–20]. In contrast, SOCS3 deficiency prevented obesity by
improving sensitivity to leptin [21–23]. Studies have also revealed a cross-talk between

186 Ahima · Osei

leptin and insulin signaling in the hypothalamus mediated through JAK2, phosphoinosi-
tide 3-kinase and insulin receptor substrate 1 and 2 [9, 16].
Leptin plays a dual role in energy homeostasis. The fall in leptin during fasting
signals to the brain, leading to hyperphagia, reduced energy expenditure, and sup-
pression of thyroid, reproduction and growth hormones, and immune system [10,
13]. These changes are similar, albeit less profound, to congenital deficiency of leptin
[10, 11, 24, 25]. Furthermore, fasting-induced hypoleptinemia and congenital leptin
deficiency both increase NPY and AGRP and reduce POMC in the hypothalamus
[9]. We have proposed that the dominant action of leptin is that of a ‘starvation sig-
nal’ [9, 13]. In agreement, leptin deficiency in lipodystrophic rodents and humans
induces hyperphagia and changes in neuroendocrine and immune function akin to
fasting [26–31].
In contrast with the robust responses to low leptin level, increasing leptin from the
fasted to fed levels elicits a minimal response [9]. Obesity is typically associated with
elevated leptin levels and reduced sensitivity to leptin treatment, indicative of ‘leptin
resistance’ [32]. Studies have demonstrated a reduction in brain leptin transport in
obese rodents, but whether this occurs in humans is uncertain [33]. Leptin resistance
has been attributed to induction of SOCS3 and protein tyrosine phosphatase 1B
which normally inhibit leptin signal transduction [21, 22, 34, 35]. Fatty acids and
amino acids have also been implicated in the disruption of leptin signaling in the
hypothalamus [36, 37].
Leptin receptors are present in extrahypothalamic sites including the nucleus soli-
tarius, lateral parabrachial nucleus and ventral tegmental area [9]. Leptin treatment
activates neurons in these areas via STAT3 phosphorylation [38]. Recent studies have
shown a crucial role of leptin in the feeding-reward circuitry, through induction of
STAT3 phosphorylation in dopamine and ␥-amino butyric acid neurons of the ven-
tral tegmental area and mesoaccumbens [39, 40].
AMP-activated protein kinase (AMPK) is another leptin target of interest [41].
AMPK is phosphorylated and activated in response to energy deficits during cellular
stress or fasting, leading to increased fatty acid oxidation and inhibition of anabolic
pathways. In the hypothalamus, AMPK is colocalized with STAT3, NPY and other
peptides implicated in energy balance. Leptin inhibits the phosphorylation and acti-
vation of AMPK in the hypothalamus, leading to appetite suppression [42]. Studies in
rodents suggest that melanocortin 4 receptor is a critical mediator of the leptin-
AMPK interaction in the hypothalamus [42].
Leptin exerts rapid effects on neurotransmission that cannot be explained by JAK-
STAT signaling. For example, leptin depolarizes hypothalamic POMC neurons and
decreases the inhibitory tone of ␥-amino butyric acid on POMC neurons [43].
Conversely, leptin hyperpolarizes and inactivates NPY neurons in the arcuate nucleus
[43]. The fall in leptin during fasting increases the action potential frequency in
NPY/AGRP neurons in the arcuate nucleus, and the latter correlates with hyperpha-
gia [44]. Leptin hyperpolarizes glucose-responsive neurons in the hypothalamus by

Adipocyte Hormones 187

opening KATP channels, an effect that has been linked to appetite suppression and
weight loss [45].
Short- and long-term effects of leptin on neuronal plasticity have been described
[46, 47]. Leptin normalizes synaptic density in NPY and POMC neurons in the hypo-
thalamus within 6 h after systemic treatment, and this change has been linked to inhi-
bition of food intake [46]. Congenital leptin deficiency results in reduced brain size
due to impaired myelination and neuronal loss [47, 48]. Leptin treatment restores
brain structure in leptin-deficient rodents and humans [47, 48]. Furthermore, leptin
enhances the maturation of neuronal projections from the arcuate nucleus to the par-
aventricular nucleus, and this trophic action may provide insights into neuronal
defects underlying eating disorders and obesity [49].
Leptin has profound effects on the neuroendocrine axis [9]. Leptin stimulates
gonadotropin-releasing hormone secretion, and is positively related to gonadotropin-
releasing hormone and estradiol pulsatility [12, 30]. Leptin-deficient mice and
humans fail to undergo normal pubertal maturation and are sterile [24, 25]. Leptin
treatment, but not weight loss per se, restores fertility in congenital leptin deficiency
[50]. Furthermore, leptin has a permissive effect to restore menstrual cycles in
patients with functional or exercise-induced amenorrhea [30, 31]. These effects may
involve all levels of the reproductive axis, i.e. hypophysiotropic neurons in the par-
aventricular hypothalamus, anterior pituitary and gonads [9].
Leptin prevents the fasting-induced suppression of prothyrotropin-releasing hor-
mone mRNA in paraventricular nucleus neurons, reverses the inhibitory effect of
fasting on pulsatile thyrotropin secretion and blunts the decline in thyroid hormone
levels during fasting [29, 51]. Leptin inhibits somatostatin and prevents the suppres-
sion of IGF-I during fasting [29]. Interestingly, leptin-deficient rodents exhibit
reduced linear growth, consistent with lack of permissive effect on growth hormone
[9]. The ability of insulin-induced hypoglycemia to stimulate growth hormone is
blunted in patients with leptin receptor mutation [52]. These patients have low IGF-I
and IGF-binding protein-3 levels and delayed growth [52].
LRb is also expressed in peripheral tissues and involved in metabolism. Deletion of
LRb from pancreatic ␤-cells results in increased islet mass, hyperinsulinemia,
impaired glucose-stimulated insulin release and glucose intolerance [53]. However,
unlike the complete loss of LRb, attenuation of leptin signaling in islets does not alter
food intake [53].
LRb is expressed by CD34⫹ hematopoietic bone marrow precursors, monocytes
and macrophages and T and B cells. Leptin promotes innate immunity through acti-
vation of monocytes/macrophages, neutrophils and natural killer cells [10, 11].
Leptin also influences adaptive immunity by increasing the expression of adhesion
molecules by CD4⫹ T cells, proliferation and secretion of IL-2 by naive CD4⫹ T
cells, and promoting T helper 1 cell responses on memory CD4⫹ T cells. Leptin defi-
ciency is associated with reduced numbers of circulating CD4⫹ T cells, impaired T
cell proliferation and cytokine release and thymic atrophy, all reversible by leptin

188 Ahima · Osei

treatment [10, 11]. A leptin surge has been linked to the development of pathogenic T
cell responses and autoimmune encephalomyelitis in mice, while leptin antagonism
prevents this condition [54, 55].

Adiponectin

Adiponectin was discovered independently by several laboratories, hence its various

names: Acrp30 (adipocyte complement-related protein of 30 kDa), apM1 (adipose
most abundant gene transcript 1), adipoQ and GBP28 (gelatin-binding protein of
28 kDa) [56]. Adiponectin is composed of an N terminal sequence, hypervariable
domain, 15 collagenous repeats and a C terminal domain [56]. A trimeric form of
adiponectin is secreted by adipocytes and gives rise to higher order complexes, i.e.
dimers of trimers (hexamers, low molecular weight, LMW) and six trimers (18-mers,
high molecular weight, HMW) through noncovalent bonding. HMW adiponectin is
thought to be the bioactive form in plasma [56]. In contrast, trimeric and hexameric
adiponectin is predominant in the cerebrospinal fluid [57]. Adiponectin also under-
goes posttranslational modifications including glycosylation [56]. Although there is
structural similarity between the globular (head) of adiponectin and TNF-␣, these
adipokines do not appear to be functionally related [58].
In contrast to other polypeptide hormones, adiponectin circulates at very high
concentrations (␮g/ml), raising the possibility that a smaller cleaved product medi-
ates its action on various tissues [56]. Total and HMW adiponectin are more abun-
dant in females, partly due to suppression of adiponectin by androgens in males [56].
Adiponectin is inversely related to adiposity, in contrast to leptin and most
adipokines. Thus, adiponectin is markedly reduced in obesity and rises with pro-
longed fasting and severe weight reduction. Adiponectin, particularly HMW, is
increased by thiazolidinediones (TZDs) and mediates the insulin sensitizing effect of
this class of antidiabetic drugs [59, 60]. A role for adiponectin in glucose homeostasis
is further exemplified by hepatic insulin resistance in rodents and humans lacking
adiponectin [59–61]. In contrast, adiponectin treatment enhances insulin sensitivity,
primarily by suppressing glucose production [59, 60, 62]. Adiponectin produced in
bacteria has been shown to decrease glucose, stimulate fatty acid oxidation and
reduce body weight and fat; however, these are likely to be pharmacological effects
since bacterially derived adiponectin is incapable of forming high order complexes
[63–66]. Administration of full length or globular adiponectin via systemic or intrac-
erebroventricular injection induces thermogenesis, fatty acid oxidation and weight
loss in mice [67]. These actions are abrogated in agouti mice (Ay/a), indicating a cru-
cial role for melanocortin signaling in the central action of adiponectin [67].
Hypoadiponectinemia is related to insulin resistance, inflammation, dyslipidemia
and cardiovascular risk among various populations [56]. Lack of adiponectin promotes
atherosclerosis in rodents [56]. Adiponectin reverses this by inhibiting monocyte

Adipocyte Hormones 189

adhesion, macrophage transformation, proliferation and migration of smooth muscle
cells in blood vessels. Studies have implicated activation of AMPK and inhibition of
nuclear factor ␬B (NF-␬B) and vascular adhesion molecules as putative mechanisms
underlying the effects of adiponectin on the vascular system [56]. Adiponectin also
exerts a protective action in myocardial remodeling in response to acute ischemia-
reperfusion [68]. Adiponectin-deficient mice had increased myocardial apoptosis
and infarct size than wild-type [68]. Importantly, adiponectin treatment diminished
infarct size, apoptosis and TNF-␣ production in both knockout and wild-type mice.
These actions appear to be mediated through activation of AMPK, induction of
cyclooxygenase-2-dependent synthesis of prostaglandin E2 [68].
Adiponectin receptors (AdipoR1 and AdipoR2) contain seven transmembrane
domains, but are structurally and functionally distinct from G-protein-coupled recep-
tors [69]. AdipoR1 is abundant in muscle and binds with high affinity to globular
adiponectin and low affinity to the full-length protein, whereas AdipoR2 is enriched in
liver and has intermediate affinity for globular and full-length adiponectin. Both
receptors mediate the phosphorylation and activation of AMPK [69]. Although stud-
ies have failed to demonstrate a blood-brain transport of adiponectin, both AdipoR1
and AdipoR2 are distributed widely in the brain [70–72]. Injection of adiponectin into
the 4th ventricle depolarized AdipoR1 and AdipoR2-positive neurons in the area
postrema, suggesting a potential mechanism for its central adiponectin action [72].
In a recent study, adenovirus-mediated expression of AdipoR1 and AdipoR2 acti-
vated AMPK and peroxisome proliferator-activated receptor (PPAR)-␣ in the liver of
lepr null mice, reduced gluconeogenesis and increased fatty acid oxidation [73].
Targeted disruption of AdipoR1 prevented adiponectin-induced AMPK activation,
whereas disruption of AdipoR2 decreased PPAR-␣ activity [73]. Disruption of both
AdipoR1 and AdipoR2 abolished adiponectin binding and induced steatosis, inflam-
mation, oxidative stress, insulin resistance and glucose intolerance [73]. Together, these
results support a role of AdipoR1 and AdipoR2 as major mediators of adiponectin
action on glucose and lipid metabolism.

Resistin

Resistin has a relative mass of 12 kDa and belongs to a family of cysteine-rich C-termi-
nal domain proteins called resistin-like molecules [74, 75]. Initial studies demonstrated
that resistin was suppressed by TZDs and induced insulin resistance when administered
in rodents [74]. Multimeric complexes of resistin have been identified [76]. Each
resistin protomer consists of a C-terminal disulphide-rich ␤-sandwich head and an N-
terminal ␣-helical tail. The latter associates with itself forming three-stranded coils.
Interchain disulphide linkages form tail-to-tail hexamers. Thus, resistin exists as hexa-
mers and trimers in mouse serum [76]. As predicted, the lack of resistin decreased glu-
cose and enhanced insulin sensitivity in mice [77]. Conversely, transgenic overexpression

190 Ahima · Osei

of resistin or infusion of recombinant resistin, particularly a mutant resistin protein
lacking the intertrimer disulphide bonds, induced insulin resistance [78, 79]. The
resistin receptor is not known; however, studies in rodents suggest that resistin inhibits
the phosphorylation and activation of AMPK, and induces SOCS3 [77–79].
Unlike rodents where resistin is produced exclusively by adipocytes, human
resistin is secreted by mononuclear cells and activated macrophages [80]. So far, the
role of resistin in glucose homeostasis in humans remains controversial [81]. Resistin
has been associated with insulin resistance and obesity in some studies, but others
have failed to establish such a relationship [82–86]. A connection between resistin
and inflammation and atherogenesis has been reported, but whether this is clinically
relevant is unknown [87–89].

Additional Adipokines

Adipose tissue produces TNF␣, IL-6, plasminogen activator inhibitor-1 as well as

complement factors B, C3 and adipsin (factor D). These latter factors interact, leading
to cleavage of acylation-stimulating protein (ASP) from C3. ASP mediates effects of
adipsin on glucose and lipids.
Visfatin was discovered as a secretory protein highly enriched in rodent and
human visceral adipocytes; however, this adipokine is also expressed by liver, muscle,
bone marrow and lymphocytes, where it was first identified as pre-B-cell colony-
stimulating factor [90]. Initial studies described an increase in adipose and circulat-
ing visfatin in obesity, and this was related to preservation of insulin sensitivity [90].
Visfatin appeared to exert an insulin-mimetic effect in adipocytes, hepatocytes and
myotubes, and following systemic administration in mice [90]. However, the link
between visfatin and adiposity and glucose in humans is uncertain [91]. Studies have
not consistently found an association between visfatin and adiposity, insulin sensitiv-
ity and glucose, and the functional relevance in humans remains to be ascertained
[92, 93].
RBP4 is important in the metabolism of vitamin A. RBP4 was discovered in mice
lacking glucose transport-4 and shown to be elevated in insulin-resistant mice and
obese and diabetic patients [94, 95]. Conversely, antidiabetic treatment and exercise
reduced RBP4 in parallel with improvement in insulin sensitivity [94, 95]. Transgenic
overexpression of human RBP4 or injection of recombinant RBP4 induced insulin
resistance in mice, whereas deletion of Rbp4 enhanced insulin sensitivity [94]. Some
studies have confirmed that serum RBP4 levels are increased in insulin-resistant
human subjects even before overt diabetes develops [96, 97]. RBP4 is related to adi-
posity, lipids and cardiovascular risk [96, 97]. On the other hand, other studies have
not consistently observed a relation between RBP4 and glucose and lipid metabolism
[98, 99]. This discrepancy may be attributed to the current RBP4 assays [100]. The
Kahn laboratory, which first described the link between RBP4 and glucose, has

Adipocyte Hormones 191

shown that a quantitative Western blotting standardized to full-length RBP4 protein
is more sensitive and reliable than commercial immunoassays [100]. Recent reports
have provided compelling data regarding the molecular identity of an RBP receptor
[101, 102]. Kawaguchi et al. [101] showed that STRA6, a high-affinity cell-surface
receptor for RBP, is highly expressed in the basolateral membrane of retinal pigment
cells, blood vessels of the retina, hippocampus and spleen. Pasutto et al. [102] showed
that homozygous mutations in the human STRA6 gene causes multisystem malfor-
mation and lethality in the perinatal period. The malformations are commonly asso-
ciated with maternal retinoid deficiency and disruption of transcription factors
involved in retinol metabolism, RAR and RXR. Whether STRA6 binds to RBP4 and
affects adiposity, lipids or glucose remains to be determined.
Vaspin (visceral adipose tissue-derived serpin) is a member of serine protease
inhibitor family isolated from visceral white adipose tissue of Otsuka Long-Evans
Tokushima fatty rat, a model of abdominal obesity and type 2 diabetes [103]. The tis-
sue expression of vaspin and its serum levels decreased in diabetes and increased in
response to insulin or TZD treatment [103]. Administration of vaspin to diet-
induced obese mice improved glucose tolerance and insulin sensitivity [103].

Conclusions

This review highlights the switch from the notion of adipose tissue as a dormant tissue
to one where adipose tissue actively regulates energy homeostasis and diverse systems
via adipokines. Key areas under investigation include the depot-specific functions of
adipose tissue, and how these relate to normal physiology and disease. Apart from
their classic roles as hormones, leptin and various adipokines have paracrine and
autocrine actions which may serve to modulate adipogenesis, nutrient fluxes and
metabolic changes locally and in adjacent organs. Knowledge of specific signaling
pathways will benefit the treatment of obesity and associated metabolic diseases. There
is no doubt that genetic technology in rodents has contributed immensely to the cur-
rent understanding of adipokines and their targets in the brain and peripheral organs.
In some cases, e.g. leptin and adiponectin, the biology of adipokines is similar between
mice and humans (table 1). However, there are numerous examples where putative
adipokines in rodents are derived from different sources and act differently in humans
(table 1). Thus, future research on adipokines demands a combination of cellular and
molecular approaches, rodent physiology and importantly human studies.

Acknowledgements

This work was supported by grant RO1-DK62348 and PO1-DK49210 from the National Institutes
of Health.

192 Ahima · Osei

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Section Title
Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 198–211

The Role of AMP-Activated

Protein Kinase in Obesity
Blerina Kola ⭈ Ashley B. Grossman ⭈ Márta Korbonits
Department of Endocrinology, Barts and the London, Queen Mary’s School of Medicine and Dentistry,
University of London, London, UK

Abstract
AMP-activated protein kinase (AMPK) is a major regulator of energy metabolism at both the cell and at
the whole body level. Numerous genetic and obesity models as well as human studies have suggested a
role for AMPK in the physiological regulation of fatty acid and glucose metabolism, and in the regulation
of appetite. Changes in AMPK activity have been reported in obesity, type 2 diabetes, the metabolic syn-
drome and cardiovascular disease, which jointly represent a major health and economical problem
worldwide. Whether AMPK changes are one of the causes or the consequence of these pathological
conditions remains a matter of debate, but AMPK clearly represents a major potential pharmacological
target in the treatment of these conditions. Copyright © 2008 S. Karger AG, Basel

Obesity is a major health and economic problem in both Western and developing
societies. Its continuing rise in prevalence, 20% in England and 30% in USA [1, 2]
seems to be unstoppable despite multiple efforts to attempt to halt this trend. Obesity
is characterised by multiple metabolic changes such as insulin resistance, dyslipi-
daemia and hypertension. The diseases arising as a consequence of obesity such as
type 2 diabetes (T2D), cardiovascular disease and certain cancers, are increasingly
important causes of morbidity and mortality. In the last decades, a huge amount of
research has been dedicated to the study of the complex pathophysiology of obesity
and to the research for new medical therapies.
AMP-activated protein kinase (AMPK) has emerged in the last years as a major regu-
lator of cell and whole body metabolism. Numerous papers have reported evidence for
its role in the regulation of appetite, of body weight and of metabolism [3–5]. Therefore,
it is natural to consider AMPK as a major player in the development of obesity. The
AMPK complex is an evolutionally conserved serine/threonine heterotrimer kinase
complex consisting of ␣-, ␤- and ␥-subunits [for detailed reviews see 5, 6]. AMPK is
activated by cellular stress, which depletes cellular ATP leading to a concomitant rise in
AMP. AMP activates AMPK by three distinct mechanisms: (a) allosteric activation, (b)
stimulation of phosphorylation of the ␣-subunit on Thr172 by upstream kinase(s)
[LKB1 and calmodulin kinase kinase-␣ or -␤ and recently a new possible AMPK kinase
candidate, the transforming growth factor-␤-activated kinase (TAK1), which phospho-
rylates AMPK on Thr-172 in HeLa cells [7], has been reported], and (c) inhibition of
dephosphorylation by protein phosphatases [5, 8–10]. Cellular stresses that cause a rise
in the AMP/ATP ratio include metabolic poisons (arsenite, oligomycin), oxidative
stresses, hypoxia, low glucose, muscle contraction and nutrient deprivation. Osmotic
stress also activates AMPK even without a change in the AMP/ATP ratio. Once acti-
vated, AMPK switches off anabolic pathways such as gluconeogenesis, glycogen, fatty
acid, triglyceride, cholesterol and protein synthesis (mTOR-p70SK-E2 pathway), and
switches on catabolic pathways such as glycolysis, glucose uptake, and fatty acid oxida-
tion. It also leads to mitochondrial biogenesis, which improves the ATP synthesis capac-
ity of the cell [11]. Metabolic changes induced by AMPK are both acute changes due to
phosphorylation of key enzymes and longer-term effects on the expression of genes
involved in metabolic regulation. AMPK, through several mediators, plays a role in vari-
ous physiological and pathological processes in different tissues (fig. 1). Therefore, it was
logical to hypothesise that abnormal AMPK activity would be present in conditions of
deregulated energy balance, such as obesity and T2D.

Role of AMPK in Normal Physiology

Role of AMPK in Skeletal Muscle Metabolism

Skeletal muscle is the major site of glucose uptake [12], a process that is mainly stim-
ulated by insulin but also by other alternative pathways. Exercise stimulates glucose
uptake in the skeletal muscle independently of the insulin pathway and AMPK
appears to be the mediator of this effect, primarily in the glycolytic white muscle.
These conclusions derived from studies in which in vivo AMP-mimetic 5-aminoimi-
dazole-4-carboxamide ribonucleoside (AICAR) treatment stimulated glucose uptake
[13]. The effect was not inhibited by the inhibition of the insulin-dependent PI3K
pathway and was additive to insulin-stimulated glucose uptake [14]. AICAR also
stimulates glucose transporter GLUT4 expression [15, 16] and its translocation to the
cell membrane in rat skeletal muscles [17]. Chronic AMPK activation also increases
the expression of hexokinase II, the first enzyme of the glycolysis pathway [18] and
inactivates glycogen synthase [19]. The effect of AMPK is fibre dependent and is dif-
ferent in resistance (weight lifting) or endurance (distance running) exercise. AMPK
stimulates glucose uptake and GLUT4 expression/transport in fast-twitch (glycolytic,
white) muscle but not in slow-twitch (oxidative, red) muscle [20]. AMPK in muscle is
activated during exercise, probably as a result of the exercise-induced IL-6 release, a
cytokine which activates AMPK in isolated rat muscles [21]. Moreover, it seems that

AMPK and Obesity 199

 GLUT4 (MEF-2, GEF, AS160)
hexokinaseII, glycogen synthase

ACC

Skeletal muscle
PEPCK, G6Pase, GPAT, L-PK,
ChREBP, TORC2, HNF␣,

ACC, FAS, SREBP-1c,

Liver HMGR, Spot 14

GLUT4

HSL, PEPCK, FAS, SREBP-1c, ACC

Adipose tissue

Fig. 1. Metabolic targets of AMPK in muscle, liver and adipose tissues. AMPK regulates the expres-
sion and phosphorylation of enzymes and genes involved in glucose and lipid metabolism.
GLUT4 ⫽ Glucose transporter 4; MEF-2 ⫽ myocyte enhancer factor-2; GEF ⫽ GLUT4 enhancer factor;
AS-160 ⫽ Akt-substrate-of-160 kDa; ACC ⫽ acetyl-coenzyme A carboxylase; PEPCK ⫽ phospho-
enolpyruvate carboxykinase; G6Pase ⫽ glucose-6-phosphatase; GPAT ⫽ glycerol-3-phosphate acyl-
transferase; L-PK ⫽ L-pyruvate kinase; ChREBP ⫽ carbohydrate response element-binding protein;
TORC2 ⫽ transducer of regulated CREB activity 2; HNF␣ ⫽ hepatic nuclear factor ␣; FAS ⫽ fatty
acid synthase; SREBP-1c ⫽ sterol regulatory element binding protein-1; HMGR ⫽ 3-hydroxy-3-
methylglutaryl-coenzyme A reductase; HSL ⫽ hormone-sensitive lipase.

only endurance exercise and not resistance exercise can induce AMPK activation
[20, 22]. AMPK activation in endurance exercise could also explain the lack of mus-
cle hypertrophy in distance running in contrast to weight lifting. This is possibly
due to the effect of AMPK on the mTOR pathway [20]. The mTOR pathway stimu-
lates protein synthesis and hence cell growth and hypertrophy in response to growth
factors and amino acids. Therefore, AMPK inhibition of this pathway would result in
inhibition of protein synthesis and lack of muscle hypertrophy. AMPK also stimulates
fatty acid oxidation in muscle. This results in lower lipid deposition and increases the
ability of the muscle to meet energy needs by increasing glucose uptake and fatty acid
oxidation as well. Studies with transgenic animals (AMPK ␣1 and ␣2 knockout mice,
muscle-specific over-expression of dominant negative AMPK ␣2, AMPK ␥3 knock-
out, muscle-specific over-expression of AMPK ␥3 and muscle-specific over-expression
of AMPK ␥3 R225Q overactive mutant and skeletal muscle-specific LKB1 knockout
[for detailed descriptions, see 20, 23]), have provided further evidence for AMPK
being the main mediator, although not the only one, of the adaptations (i.e. increased

200 Kola · Grossman · Korbonits

glucose uptake, fatty acid oxidation, inhibition of glycogen synthesis) of skeletal mus-
cle in response to exercise.

Role of AMPK in Liver Metabolism

The liver is the major site for storage and release of carbohydrates and for fatty acid
synthesis. It responds to fasting with increased glucose output and increased fatty
acid oxidation, while in post-prandial conditions liver glucose uptake increases with
consequent glycogen and triglyceride synthesis [24]. AMPK regulates liver lipid and
glucose homeostasis via phosphorylation of multiple enzymes (e.g. ACC1 – ↓ lipid
synthesis, ACC2 – ↑ lipid oxidation, 3-hydroxy-3-methylglutaryl-coenzyme A reduc-
tase – ↓ cholesterol synthesis, glycerol-3-phosphate acyltransferase – ↓ glycerolipid
synthesis), and influences the expression of genes involved in gluconeogenic, gly-
colytic and lipogenic processes and their upstream regulators [for a comprehensive
review on the topic, see 25]. Therefore, overall AMPK activation in the liver results in
inhibition of gluconeogenesis, fatty acid, triglyceride and cholesterol synthesis, and
stimulation of fatty acid oxidation. Changes in hepatic metabolism are certainly pre-
sent in obesity and T2D. Elevated glucose production by the liver is the major cause
of fasting hyperglycaemia, and it is possible that AMPK activation by decreasing glu-
coneogenesis and cholesterol synthesis could be beneficial in these patients. Nevertheless,
one needs to be cautious as AMPK activation, by increasing fatty acid oxidation and
ketogenesis, might lead to ketoacidosis, and by inhibiting protein synthesis might
lead to a negative nitrogen balance together with enhanced urea synthesis [25].

Role of AMPK in Adipose Tissue Metabolism

Adipose tissue has been considered for decades simply as an energy storage organ, while
in the last years it has emerged as an active endocrine organ, which by secreting several
proteins, known as adipokines, contributes to the regulation of appetite and metabolism.
AMPK ␣1 subunit is the prevalent AMPK subunit expressed in the adipose tissue [26
and our own unpublished data]. AMPK regulates lipogenesis and lipolysis in adipose tis-
sue. Activation of AMPK in rodent adipocytes leads to a decreased fatty acid uptake,
decreased triglyceride synthesis and increased fatty acid oxidation via inhibition of ACC1
and ACC2 and, as in the liver, inhibition of the expression of lipogenic genes [27, 28].
During fasting, lipolysis is activated in adipose tissue in order to provide fatty acids
and glycerol as fuels for peripheral tissues, but reports on the effect of AMPK activation
on lipolysis are contradictory. There is evidence that AMPK activation, either by AICAR
or by over-expression of a constitutively active AMPK isoform or by biguanide treat-
ment, has an inhibitory effect on lipolysis [26, 29]. In conditions where lipolysis is acti-
vated, such as fasting and exercise, AMPK is also activated but as a feedback mechanism
this activation leads to inhibition of lipolysis, which is an energy-consuming process for
the adipocytes [27]. Furthermore, in the AMPK ␣1 knockout mice, the size of the

AMPK and Obesity 201

adipocytes is reduced and basal and isoprotenerol-induced lipolysis is higher than that
of control adipocytes [26]. On the contrary, the study of Yin et al. [30] suggested a lipoly-
tic action for AMPK and the study by Koh et al. [31] suggested that the adrenaline-
induced lipolysis is due to AMPK activation. There are also contradictory findings
related to the effect of AMPK on glucose transport in adipose tissue [32–34].
In conclusion, AMPK activation in adipose tissue, under conditions such as exer-
cise, fasting or after stimulation with leptin, adiponectin or biguanides, decreases
lipogenesis, triglyceride synthesis and lipolysis and increases fatty acid oxidation,
contributing therefore to improved insulin sensitivity.

Role of AMPK in Endocrine Pancreas

The effects of AMPK activation in ␤-cells are complex: further data for the role of AMPK
in endocrine pancreas are available in the chapter by Rutter and Parton [this vol., pp.
118–134]. AMPK might be involved in the expression of insulin receptor family mem-
bers, such as the IGF-I receptor, insulin receptor and insulin receptor-related receptor,
which are mandatory for several steps in insulin secretion [35], while AICAR increases
the phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser789 leading to
increased IRS-1 activity [35]. On the other hand, AICAR and metformin inhibit rapid
insulin release [35] and the activation of AMPK also enhances ␤-cell apoptosis; it remains
to be determined if this is the cause or the consequence of the altered glucose metabolism
[36–38]. AMPK appears to be a key regulator of hepatocyte nuclear factor-4␣, which is
linked to type 1 maturity-onset diabetes of the young [for further details, see 36]. The
overall effect of AMPK on glucose homeostasis [6, 36] is determined by the joint effect on
insulin secretion in addition to the prominent effects of AMPK activation on glucose
transport, gluconeogenesis and glycogenolysis, in muscle and liver.

Role of AMPK in Hypothalamus

The role of AMPK in the regulation of body weight and energy homeostasis is not lim-
ited to its actions in the peripheral tissues. AMPK is a central regulator of food intake.
AMPK mediates the effects of multiple orexigenic and anorexigenic signals in the hypo-
thalamus [35]. Fasting increases and refeeding decreases the AMPK activity in the
hypothalamus [39]. The downstream pathways of AMPK in the hypothalamus could
involve the ACC-malonyl-CoA-CPT1 pathway [3] and the mTOR pathway [40, 41] (fig.
2). Leptin and changes in glucose concentration affect the activity of glucose-inhibited
cells (40% of which are NPY-expressing neurons) in the hypothalamus via AMPK [42].
Actually, AMPK activity in the hypothalamus is probably responsible for some of the
peripheral effects of leptin, of hypoglycaemia and of the FAS inhibitor C75 [3, 35],
emphasising the complexity of the regulation of whole body metabolism and the role of
AMPK, being not only a peripheral or a central mediator but also a key enzyme in coor-
dinating the interaction between peripheral and central energy regulation.

202 Kola · Grossman · Korbonits

 Appetite stimulation Appetite inhibition
Ghrelin Leptin
Cannabinoids Insulin
AgRP ␣-MSH
2-deoxyglucose C75 (fatty acid synthase inhibitor)
(hypoglycemic-like state) ␣-lipoicacid
Fasting High glucose
AMPK
Refeeding
Leucine
PI 3-kinase/PDK1

PKB1 ACC

TSC1/TSC2 Acetyl CoA Malonyl CoA

mTOR CPT1

p70S6K 4E-BP1 Long-chain Acyl CoA β-oxidation

Fig. 2. Regulation of hypothalamic AMPK and possible downstream pathways. Black lines show path-
ways established in the hypothalamus, grey lines show pathways that have been described in rat mus-
cle, rat liver, myotubes, hepatocytes, fibroblasts and lung carcinoma cells [97, 98] but not directly in the
hypothalamus.

AMPK as a Mediator of Action of Metabolically Active Hormones

AMPK mediates the effects of many hormones/peptides/substances/drugs in numer-

ous physiological and pathological processes. Insulin, leptin, adiponectin, cannabi-
noids and ghrelin influence peripheral metabolism at least partially via activation or
inhibition of AMPK activity in the skeletal muscle, liver, adipose tissue and the hypo-
thalamus (table 1) [35]. AMPK has been found to be the mediator of many hormones
and its role in the interplay between these compounds and their metabolic effects is
being actively investigated [for a detailed review on the topic, see 35].

AMPK in Animal Models of Obesity

Animal models of obesity and diabetes have provided evidence for implication of
AMPK in the pathogenesis of these conditions and also provided evidence for a pos-
sible role of AMPK modulators in their treatment (table 2).

AMPK and Obesity 203

Table 1. Effect of hormones and drugs on AMPK activity in different tissues [modified and updated
from 35]

Hormone/ Hypothalamus Skeletal Liver Adipose Pancreas: Cardiac

substance Muscle tissue ␤-cells muscle

High glucose ⇓[39, 60, 61] ⇓[36] ⇓[62] ⇓[36, 63, 64]
Insulin ⇓[39] ⇒[36] ⇒[50] ⇒[36] ⇓[30] ⇒[36] ⇓[65]
Leptin ⇓[39, 42, 66] ⇑[67, 68] ⇑[46, 50, 69, 70] ⇑[71] ⇒[63] ⇒[72, 73]
Ghrelin ⇑[66, 74] ⇒[74] ⇓[74, 75] ⇓[74] ⇑[74]
Adiponectin ⇑[76–78] ⇑[50, 76, 77] ⇑[33] ⇑[79] ⇑[80, 81]
Resistin ⇓[82] ⇓[83, 84]
Glucagon ⇑[85]
Cannabinoids ⇑[74] ⇒[74] ⇓[74] ⇓[74] ⇑[74]
Metformin ⇓[60] ⇑[86] ⇑[62, 86] ⇑[87] ⇑[37, 63] ⇑[88]
Rosiglitazone ⇑[54, 89, 90]

References are listed in brackets. ⇑ ⫽ Stimulation; ⇓ ⫽ inhibition; ⇒ ⫽ no change.

Martin et al. [43] showed that diet-induced obesity (DIO) in mice alters the effect
of leptin on AMPK activity both in skeletal muscle and in the hypothalamus. Leptin
increases AMPK activity in the skeletal muscle of chow-fed mice and decreases it in
the hypothalamus of the same animals but does not have an effect in the DIO mice.
While, most interestingly, a ciliary neurotrophic factor analogue (CNTFAx15) given
intracerebroventricularly not only reduces food intake in high-fat diet (HFD) mice
but also suppresses hypothalamic AMPK activity, bypassing therefore diet-induced
leptin resistance [44]. Rats on an HFD for 5 months exhibited decreased AMPK
phosphorylation and expression in skeletal muscle associated with decreased levels
of ACC and GLUT4 as well. Metformin treatment restored insulin sensitivity and
increased AMPK activity [45].
In Zucker rats who do not respond to leptin treatment because of defects in the
leptin receptor, administration of the AMPK activator AICAR results in leptino-
mimetic effects, leading to the prevention of ectopic lipid deposition and diabetes
[46]. Transgenic mice over-expressing leptin in liver are lean on a chow diet but
despite the high pre-existing leptin levels become obese and insulin resistant on an
HFD [47]. HFD for 15 weeks abolishes the increase in muscle AMPK activity
observed in the same animals on a chow diet.
Short hepatic over-expression of a constitutively active form of AMPK decreased
blood glucose levels in normal mouse, abolished hyperglycaemia in streptozotocin-
induced and in ob/ob mice and also reduced gluconeogenic enzyme expression. The
resulting low glucose levels led to a switch from glucose utilisation to fatty acid utili-
sation, associated with a decrease in white adipose tissue mass and development of
fatty liver [48].

204 Kola · Grossman · Korbonits

Table 2. AMPK changes in animal models of obesity

Animal model AMPK-related changes Reference

Obese Zucker fa/fa rat AICAR increased muscle glucose transport and suppresses [91, 92]
endogenous glucose production and lipolysis
Reduced AMPK and ACC phosphorylation LKB1 activity [90]
and PGC-1 content
Rosiglitazone restores AMPK ␣2 activity in skeletal [46, 93]
muscle
Chronic AICAR/exercise training prevented
hyperglycaemia and increased whole-body
insulin sensitivity
ob/ob and db/db mice AICAR and short hepatic over-expression of a constitutively [48, 94]
active form of AMPK decreased blood glucose levels

HFD in rats Reduction of AMPK activity, ACC and GLUT4 levels in [45]
skeletal muscle. Metformin increases AMPK activity
Rosiglitazone enhanced AICAR-stimulated glucose [95]
uptake in muscle and adipose tissue. Total AMPK and
AMPK ␣2 activity increased in muscle

DIO mouse AICAR administration blocked weight gain, reduced total [96]
content epididymal fat and lipid accumulation in
adipocytes, restored adiponectin levels, improved glucose
tolerance and insulin sensitivity
DIO mice compared to chow-fed mice ate less, had lower [43]
respiratory exchange rate and lower ACC activity in
muscle. Leptin did not improve either of these
parameters or the AMPK ␣2 activity in muscle and
hypothalamus of the DIO
Ciliary neurotrophic factor analogue reduced food intake [44]
and AMPK hypothalamic activity, bypassing therefore
diet-induced leptin resistance

Adiponectin inhibits glucose production in wild-type mouse and also in T2D

mouse (ob/ob, non-obese diabetic or streptozotocin-treated mice) [49] and the
effect of adiponectin is completely dependent on the presence of hepatic AMPK ␣2
subunit [50].
Studies on ob/ob and adiponectin double knockout mice or knockout only for
adiponectin showed an impaired ability to improve glucose tolerance with rosiglita-
zone treatment and this was, at least partly, due to reduced activation of AMPK [51].
These results not only showed the role of adiponectin as a TZD mediator but also
confirm the importance of AMPK activation in the mechanism of action of TZD type
anti-diabetic drugs.

AMPK and Obesity 205

AMPK in Human Obesity

The majority of the research studies published have been performed on animals,
and it is important to establish that their conclusions can be extrapolated to human
physiology and pathology as the number of studies about AMPK activity in human
diseases is much more limited. Skeletal muscle AMPK activity has been analysed in
a limited number of obese vs. lean subjects, in obese diabetic versus obese non-
diabetic patients and in healthy subjects before and after exercise. Obesity in
humans is associated with leptin and insulin resistance and lipid accumulation.
Adiponectin or AICAR activate muscle AMPK in obese rodents, which stimulates
fatty acid oxidation, and it is reasonable therefore to hypothesise that pharmacologi-
cal activation of AMPK might be of therapeutic benefit in human obesity. However,
AMPK is not down-regulated in human skeletal muscle of obese females [52] and
AMPK activity and specific isoform expression are similar in muscle of obese sub-
jects with and without T2D [53]. These data suggest that impaired insulin action on
glycogen synthesis and lipid oxidation in skeletal muscle of these patients is
unlikely to involve changes in AMPK expression and activity. However, AICAR
treatment of muscle biopsies stimulated AMPK ␣2 activity and fatty acid oxidation,
suggesting that AMPK activation above basal levels may still be a valid therapeutic
approach [52]. In contrast to the previous studies, Bandyopadhyay et al. [54] showed
that there is a decrease in AMPK activity and an increase in ACC activity in insulin-
resistant muscle from obese and from T2D patients that results in elevated intracel-
lular levels of malonyl-CoA. Because, for the most part, the defects appear to be
expressed equally in the obese subjects and in T2D subjects (who were also obese),
the authors conclude that these differences from lean control subjects are caused by
insulin resistance/obesity rather than hyperglycaemia/diabetes. Finally, when the
T2D subjects were treated for 3 months with rosiglitazone, the various defects in
fatty acid and mitochondrial metabolism reverted towards normal. The beneficial
effect of AMPK activation in muscle was demonstrated in a study which showed
that acute intensive exercise (3 h) increased AMPK and ACC phosphorylation
altogether with an increase in expression of adiponectin receptor in the skeletal
muscle of 5 healthy females [55]. Interestingly, Roepstorff et al. [56] showed that
AMPK activation in muscle is sex-dependent: 90 min of exercise activated AMPK
in skeletal muscle of healthy male volunteers but in contrast to the former study,
not in females. Further data are needed to study the role of oestradiol on skeletal
muscle AMPK activity. The effect of exercise on AMPK is probably due, at least in
part, to IL-6, which is synthesised and released from skeletal muscle in large
amounts during exercise [57], and in rodents, the resultant increase in IL-6 concen-
tration correlates with increases in AMPK activity in multiple tissues. There are
no direct data of the effect of IL-6 on AMPK activity in humans but IL-6 treatment
was recently shown to enhance insulin-stimulated glucose disposal in humans
in vivo [58].

206 Kola · Grossman · Korbonits

Role of AMPK in Cardiovascular Disease
Cardiovascular disease is a common consequence of obesity and obese patients are
often treated for hypertension, atherosclerosis, and heart failure. AMPK is a key reg-
ulator of energy metabolism in the heart, too [for an extensive review on the topic, see
59]. The obvious beneficial effects of AMPK activation in ischaemia could be coun-
terbalanced by the excessive fatty acid oxidation and reduced glucose oxidation lead-
ing to accumulation of pyruvate and protons [59]. In view of this and in view of the
fact that AMPK is proposed as a possible target for obesity and diabetes treatments, it
is important to know the role of AMPK in cardiac physiology and pathology in order
to avoid possible side effects of future AMPK activators/inhibitors.

AMPK as an Overall Metabolic Regulator

In conclusion, AMPK has emerged as a key regulatory enzyme of cell and whole body
metabolism. It influences cell metabolism in a way that favours insulin sensitivity and
maintains a favourable body energy homeostasis. It is the mediator of the metabolic
effects of many of the known hormones, nutrients and drugs. Thus, not only are
changes in AMPK implicated in the pathogenesis of insulin-resistant states, but
AMPK might also constitute a target for new treatments of these conditions.
However, a note of caution is required as generalised AMP activation might result in
unwanted effects (i.e. an appetite-stimulating effect and ␤-cell inhibition), and thus
there is a need for tissue-specific modulators.

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Section Title
Korbonits M (ed): Obesity and Metabolism.
Front Horm Res. Basel, Karger, 2008, vol 36, pp 212–228

Classical Endocrine Diseases

Causing Obesity
Jolanta U. Weaver
School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne, UK

Abstract
Obesity is associated with several endocrine diseases, including common ones such as hypothyroidism
and polycystic ovarian syndrome to rare ones such as Cushing’s syndrome, central hypothyroidism and
hypothalamic disorders. The mechanisms for the development of obesity vary in according to the
endocrine condition. Hypothyroidism is associated with accumulation of hyaluronic acid within various
tissues, additional fluid retention due to reduced cardiac output and reduced thermogenesis. The patho-
physiology of obesity associated with polycystic ovarian syndrome remains complex as obesity itself
may simultaneously be the cause and the effect of the syndrome. Net excess of androgen appears to be
pivotal in the development of central obesity. In Cushing’s syndrome, an interaction with thyroid and
growth hormones plays an important role in addition to an increased adipocyte differentiation and adi-
pogenesis. This review also describes remaining rare cases: hypothalamic obesity due to central hypothy-
roidism and combined hormone deficiencies. Copyright © 2008 S. Karger AG, Basel

The heterogeneity of physical appearance in obesity and the association with various
endocrine disorders lead some clinicians and almost every patient with obesity to
believe that there is an underlying hormonal imbalance to account for their problem.
This is the reason that endocrinologists are frequently consulted to advise on the pos-
sible underlying diagnosis for secondary obesity. The term ‘secondary’ means that
obesity accompanies another illness that is considered to be the primary disease state.
Secondary morbid obesity (body mass index, BMI, ⱖ40) due to endocrine causes
is quite rare and is usually associated with hypothalamic disorders. However, lesser
degrees of a weight problem (BMI 26–39) are associated with thyroid disorders, poly-
cystic ovarian syndrome (PCOS) or Cushing’s syndrome.
An appropriate evaluation is the first step in developing a treatment plan for
overweight patients. A medical history should evaluate the natural history of the
development of obesity and aetiological factors involved. The physical examination
and laboratory testing should extend this evaluation to exclude likely endocrine
causes. The result of those then provide a guide to selecting an appropriate treatment plan.
 The conditions associated with overweight to morbid obesity are discussed below,
in order of prevalence.

Hypothyroidism

Primary hypothyroidism is the commonest cause of hypothyroidism (99% of cases)

and occurs in 2% of women and up to 0.2% of adult men: 54% of patients with overt
hypothyroidism report weight gain as opposed to13.8% in controls [1]. Undiagnosed
hypothyroidism may go unnoticed for sometime due to insidious onset of symptoms
including weight gain. There is a slow progression of thyroid underactivity and devel-
opment of clinical symptoms. Most patients with hypothyroidism gain a moderate
amount of weight. As early symptoms are variable and non-specific, there should be a
low threshold for screening patients for primary hypothyroidism with a serum thy-
rotropin-stimulating hormone (TSH) determination.

Symptoms of Overt Hypothyroidism

Hypothyroidism often remains undetected because of the difficulty of ascribing symp-

toms to the disease. The pathophysiological changes generally require months or years
to manifest as clinical signs and symptoms. Furthermore, the onset of hypothyroidism
is so insidious that even classic symptomatology may go unnoticed or undiagnosed
[2]. Although most hypothyroid patients do have some signs and symptoms indicative
of disease [3], it may be difficult to identify a ‘classic’ clinical picture because symp-
toms may be non-specific and thus confused with other health problems [4].
The relation between symptoms and physiologic disease is so complex that clini-
cians turn to biochemical measures of thyroid dysfunction for diagnosis. However, it
is unclear who should be tested. Many investigators and several organisations, such as
the American Thyroid Association and the American Association of Clinical
Endocrinologists, recommend testing persons who have a greater likelihood of being
hypothyroid [5]. The U.S. Preventive Services Task Force does not recommend for or
against screening in high-risk patients, such as older women. However, it does alert
clinicians to maintain a low threshold for diagnostic evaluation of thyroid function
when subtle or non-specific symptoms of thyroid dysfunction occur in such patients
[6]. In the UK, the Working Group of the Royal College of Physicians and Society for
Endocrinology, in a consensus statement for good practice in thyroid diseases, did
not focus on presenting symptoms or signs since they were detailed in the report by
the American Thyroid Association [7]. Evidence is lacking as to which symptom or
symptoms increase the likelihood of confirming biochemical hypothyroidism.
However, patients who report more symptoms, and more recently developed symptoms,
are more likely to have hypothyroidism. Therefore patients who report more symptoms,

Endocrine Causes of Obesity 213

Table 1. Laboratory investigations of patients suspecting hypothyroidism

TSH Free T4 index Thyroid peroxidase Diagnosis

antibodies

⬍0.4 mU/l low/low-normal ⫺/⫹ post-hyperthyroid hypothyroidism

0.4–4.0mU/l low 2 central hypothyroidism
⬎4 and ⬍10 mU/l normal/low ⫺/⫹ subclinical hypothyroidism; early
primary autoimmune hypothyroidism;
central hypothyroidism
⬎10 mU/l low ⫹ Primary hypothyroidism due to
autoimmune thyroid disease
⬎10 mU/l low/low-normal ⫺ inter-current illness, drug-induced
external radiation, iodine deficiency
⬎10 nM normal/elevated ⫺/⫹ thyroid hormone resistance, drugs;
assay artefact

particularly recent symptoms, should be tested with serum thyroid function tests [8].
The same group showed that change in symptoms is more powerful in predicting the
disease than current symptoms and the higher number of symptoms reported (cur-
rent as well as changed), the greater the likelihood of predicting hypothyroidism.
It is interesting that weight problem has not been even listed among the common
symptoms by Canaris et al. [8] but featured highly among symptoms and signs
analysed by Zulewski et al. [1].
Thus, overt hypothyroidism is a common condition that may be difficult to diag-
nose on clinical grounds alone and requires a high degree of clinical suspicion as well
as confirmation with biochemical testing for serum TSH and thyroid hormone levels.
Reliance on blood testing to diagnose an easily treatable condition has led to a
spectrum of results listed below (table 1).
Untreated hypothyroidism is well known to lead to hypercholesterolaemia, which
may improve or completely normalise on statin treatment. In cardiovascular patients
who do not reduce their cholesterol levels adequately on statin treatment, testing for
hypothyroidism is essential. Cardiovascular disease in hypothyroidism may have the
potential to be fatal, although this has never been tested in a controlled fashion.

The Mechanism of Thyroid Hormones Action

Thyroid hormones are essential for the regulation of a number of important processes
in the body including growth and development, neuromuscular activity, thermogenesis,
energy consumption and many metabolic reactions [9]. The thyroxine (T4) pro-hormone

214 Weaver
is synthesised in the thyroid gland together with a small amount of the active hor-
mone 3,5,3⬘-L-triiodothyronine (T3). However, the majority of circulating T3 is gen-
erated by pre-receptor ligand metabolism resulting from activity of the iodothyronine
deiodinase enzymes D1 and D2 which convert T4 to T3 by 5⬘ monodeiodination.
In contrast, the D3 enzyme inactivates T4 and T3 by inner ring or 5-deiodination.
The intracellular level of T3 is dependent on the relative activities of these three deio-
dinases [10].

The Classical Genomic and Non-Genomic Actions of T3

T3 regulates nuclear gene expression by binding the thyroid hormone receptors TR␣
and TR␤ (genomic action). Thyroid hormone receptors recognise specific thyroid
response elements in the promoters of T3-target genes and activate or repress tran-
scription in response to hormone. The effect of genomic action of T3 can vary as from
hours to days [9]. Some of the T3 effects occur rapidly and are unaffected by inhibitors
of transcription and protein synthesis. Those actions are defined as non-genomic [11].

The Pathophysiology of Weight Gain in Hypothyroidism

The weight gain in hypothyroidism is related to several factors:

1 Hypothyroidism causes accumulation of hyaluronic acid within the dermis and
other tissues. As this material is hygroscopic, it produces mucinous oedema
responsible for thickened structures and puffy appearance [12].
2 Due to reduced bowel peristalsis and deposition of glycoproteins in the bowel wall,
patients invariably complain of constipation which may lead to faecal impaction,
myxoedema, megacolon and myxoedema ileus.
3 The effects of thyroid hormone have also been reported in the myocardium and
vasculature. T3 enhances cardiac output and reduced systemic vascular resistance
in normal adult males within 3 min [13], and cell culture studies suggest that thy-
roid hormones rapidly, and non-genomically, regulate the Ca2⫹ATPase enzyme,
the Na⫹ channel via PKC, the K⫹ channel via PI3-kinase, the Na⫹/H⫹ anti-porter
via PKC and MAPK and the inward rectifying potassium channel [14]. T3 also
increases sarcoplasmic reticulum Ca2⫹, cell shortening, contractility and calcium-
mediated arrhythmic activity, suggesting that T3 has a non-genomic, positive
ionotropic and arrhythmogenic effect [15]. Thus, lack of thyroid hormones leads to
a reduced inotropic and chronotropic effect on the cardiac output. In severe
hypothyroidism, patients may develop pericardial and pleural effusion but rarely
ascites. The exudates are rich in protein and glycosaminoglycans. Renal blood flow,
glomerular filtration rate, tubular reabsorption and secretion are also reduced. This
leads to reduced water clearance due to reduced urine flow. There is an overall

Endocrine Causes of Obesity 215

 increase in total body water content due to retention of water by the hydrophylic
deposits in the tissues. There is an increase in the extravascular space also due to
increased permeability of the capillaries to proteins.

Interaction with Other Hormones

Growth Hormone
Lack of thyroid hormones leads to reduced growth hormone secretion and thus gen-
eration of IGF-I [16].

Leptin
Leptin and thyroid hormones possess the ability to increase energy expenditure.
Hypothyroidism has been shown to be associated with raised leptin levels [17].
Furthermore, thyroxine treatment reduced leptin secretion independently of adiposity
and noradrenaline levels. It appears that thyroxine and leptin are closely regulated by a
negative feedback mechanism. Leptin has been shown to stimulate the hypothalamo-
pituitary-thyroid axis and also to modulate 5⬘-deiodinases in different tissues, depending
on the energy status of animals. Leptin promoted a rise in serum TSH, suggesting that
leptin acts at the hypothalamus in order to stimulate the thyrotropin-releasing hormone
(TRH)-TSH axis. Leptin may alter thus hypothalamic, pituitary and brown adipose tis-
sue functions by regulation of 5⬘-deiodinases and directing the local T3 production [18].
In animals, hypothyroidism is characterised by decreased insulin responsiveness,
partly mediated by an exaggerated glucose-fatty acid cycle that is partly alleviated by
intracerebroventricular leptin administration [19].

Catecholamines
The hypothyroid state is characterised by decreased adrenergic activity due to
reduced responsiveness of cAMP to adrenaline. This may be related to the effect of
thyroid hormones on cAMP generation [20]. In vivo, thyroxine regulates thermogen-
esis and the lipolytic activities of catecholamines within 30 min [21]. However, there
is also evidence for a direct effect of thyroid hormone on mitochondrial gene expres-
sion and oxidative phosphorylation [22]. Thyroid hormones accumulate in mito-
chondria [23] and are major regulators of mitochondrial biogenesis playing a role in
proliferation, differentiation and maturation [24]. The synergistic actions of cate-
cholamines and thyroid hormone together result in a threefold increase in mitochon-
drial UCP1 levels in brown adipose tissue [25]. Catecholamines also rapidly increase
D2 expression in brown adipose tissue, leading to tissue-specific hyperthyroidism
and a twofold increase in plasma T3. Uniquely in brown adipose tissue, D2 induction
is potentiated by T3, whereas in other tissues T3 suppresses D2 [10]. In addition,

216 Weaver
thyroid hormones have been shown to increase expression of the non-BAT UCP2,
UCP3 and the ADP/ATP carrier suggesting a regulatory role in mitochondria from
other tissues [26]. Thyroid hormones also regulate mitochondrial gene expression by
increasing steady state mitochondrial mRNA levels, respiration, enzyme activity and
protein synthesis [27], and by increasing mitochondrial metabolic activity [28, 29].

Direct Actions of Thyroid Hormone on the Mitochondria

In isolated rat liver mitochondria, T3 can increase oxidative phosphorylation within

minutes [30] but it has been suggested that these very rapid effects are in fact medi-
ated by 3,3⬘-diiodothyronine (T2) [31]. In vitro, T3 also rapidly stimulates the mito-
chondrial adenine nuclear translocase [32] and a 28-kDa truncated isoform of TR␣
(p28) co-localises with the adenine nucleotide translocase and the mitochondrial
uncoupling proteins on the inner mitochondrial membrane, therefore possibly medi-
ating a rapid thermogenic response to T3 [22, 33]. Thus, both T3 and T2 facilitate
very rapid mitochondrial responses. Thyroid hormone has been shown to directly
increase transcription of genes coded either by the nucleus or the mitochondrial
genome (mitochondrial transcription factor A [34], ATPase subunit six [35], NADH
dehydrogenase subunit three [36] and subunits of cytocrome-c-oxidase [37]). It has
recently been shown that T3 stimulates the tub gene, which when mutated in tubby
mice causes obesity and insulin resistance [38]. Hypothyroidism in rats has been
shown to be associated with altered tub mRNA and protein in discrete brain areas and
T3/T4 treatment restored normal tub expression.

Polycystic Ovarian Syndrome

PCOS is a very common endocrine problem occurring in up to 10% of premenopausal

women [39]. This is by far the most complex endocrine disorder associated with obe-
sity. The diagnosis of PCOS is made by excluding non-classical adrenal hyperplasia,
androgen-secreting tumours, Cushing’s syndrome and hyperprolactinaemia. PCOS is
viewed as a heterogeneous disorder of multifactorial aetiology. In 1990, the National
Institutes of Health criteria for PCOS were published and agreed the following diagnos-
tic features of the syndrome which should be present: hyperandrogenism and ovarian
dysfunction, while the presence of PCO morphology was not required [40]. In contrast,
13 years later at the 2003 Rotterdam consensus it was agreed that PCOS should be con-
sidered a syndrome of ovarian dysfunction, with features of hyperandrogenism and
PCO morphology [41]. Taking the heterogeneity of the syndrome into consideration,
none of the criteria was considered absolutely required for the diagnosis. The new crite-
ria truly reflect the meaning of syndrome. It broadens rather than replaces the previous
National Institutes of Health criteria for PCOS diagnosis. Under the new criteria, the

Endocrine Causes of Obesity 217

prevalence of PCOS among the general female population could well rise. According to
the Rotterdam consensus criteria, additional PCOS phenotypes would include PCO
and hyperandrogenism in women with normal menstrual cycles and especially women
presenting with PCO and anovulation without androgen excess. The most prominent
feature of PCOS is the history of ovulatory dysfunction: amenorrhoea or oligomenor-
rhoea of pubertal onset. The weight gain in later life may also lead to acquired insulin
resistance and clinical picture of PCOS: 50% of women with PCOS are obese [42] or
even higher (between 38 to 88%) as shown by others [43, 44]. Increased body weight
has been one of the features for the diagnosis of PCOS in the classical description by
Stein and Leventhal. The adiposity appears to play a crucial role in maintaining and pre-
sumably precipitating PCOS. Obesity per se probably also contributes to features of
hyperandrogenism even in women with normal ovaries [45]. The support for a pivotal
role of obesity in PCOS comes from often dramatic improvement in menstrual regular-
ity in response to weight reduction in women with PCOS [46]. There is no doubt, there-
fore, that adiposity plays a crucial role in the development and maintenance of PCOS
and strongly influences the severity of both its clinical and endocrine features in many
women with the condition. However, the cause of obesity in PCOS is not fully clarified.
Evidence from family-based and association studies suggest that PCOS has a significant
genetic basis, although the genes predisposing to PCOS have yet to be clearly defined.
Likely candidate genes for PCOS include those involved in the regulation of ovarian
steroidogenesis but also those genes that influence BMI and adiposity. A likely explana-
tion for the mechanisms underlying the development of obesity in women with PCOS
is the combined effect of a genetic predisposition to obesity in the context of a Western
environment (high caloric diet and reduced exercise). The development of obesity in
women with PCOS in turn amplifies and may even unmask the biochemical and clini-
cal abnormalities characteristic of this condition. However, most women with PCOS
have insulin resistance to a significantly greater extent than in age- and BMI-matched
control women, this disparity being more marked for higher BMIs [47].

Body Fat Distribution in PCOS

The majority of currently presenting cases of PCOS are characterised by obesity (BMI
⬎27) with a central fat distribution. As this type of overweight is particularly associ-
ated with increased risk of cardiovascular disease and type 2 diabetes, obesity is often
defined as a waist circumference of more than 80 cm for women in classifications that
serve the diagnosis of the metabolic syndrome. In a large case series studies from
Pittsburg, the waist/hip ratio was associated with PCOS independently of BMI [48].
The insulin resistance seen in PCOS is partly determined by the presence of central
obesity, as when PCOS women are compared with control women matched for
abdominal adiposity, the difference in insulin resistance between the two groups is
much less marked than if the two groups are matched for BMI [49].

218 Weaver
 The possible causal relation for central fat deposition may exist between excessive
testosterone concentrations in early development. This relation exists in women
during adulthood as seen in non-obese female to male transsexuals [50] and obese
postmenopausal women [51]. In addition, hyperinsulinaemia, through its direct
effect on the adipocyte, has also been suggested to be a possible determinant of
android fat deposition in women with PCOS [52]. In women with PCOS, it is possi-
ble that android fat deposition per se contributes to hyperandrogenaemia through its
adverse effects on insulin sensitivity and consequent gonadotrophic effects of hyperin-
sulinaemia on the ovaries. Thus, in women with PCOS, android fat may be both a
cause and an effect of hyperandrogenaemia [53]. The vicious circle in which android
fat begets android fat, and further exacerbates the predisposition towards weight gain
in women with PCOS has been suggested. The cycle can be interrupted by dietary
intervention and/or use of insulin-sensitising drugs.
Simple obesity and obesity associated with PCOS is associated with increasing
androgenicity due to generation of: (1) testosterone from androstendione mediated
by 17␤-hydroxysteroid dehydrogenase [54]; (2) dihydrotestosterone from testos-
terone mediated by 5␣ reductase [55]; (3) reduced generation of oestradiol from
testosterone, oestrone from androstenedione and oestriol from 16␣-hydroxylated
dehydroepiandrosterone due to reduced aromatase activity [56].

Role of Glucocorticoid Steroids in PCOS

Both simple obesity and PCOS-associated obesity are characterised by the mecha-
nisms of limiting exposure to cortisol by reducing cortisol generation from cortisone.
Two key enzymes involved in the metabolism of cortisol include 11␤-hydroxysteroid
dehydrogenase type 1 (11␤-HSD1), involved in the conversion of cortisone to corti-
sol, and 5␣-reductase, involved in the catabolism of cortisol in addition to the con-
version of testosterone to dihydrotestosterone. It has been demonstrated that in
normal men and women or hypopituitary patients on fixed hydrocortisone replace-
ment therapy, obesity is associated with impairment of 11␤-HSD1 reductase and
enhanced 5␣-reductase activities [57, 58]. It has also been shown that 11␤-HSD1
activity is strongly related to fat distribution [57, 58]. The changes in 11␤-HSD and
5␣-reductase activity are even more accentuated when studied in PCOS as compared
to BMI-matched controls [59].

Hormones Involved in Appetite Regulation in PCOS

Leptin plays an important role in the regulation of appetite, body weight and metab-
olism and reproductive capacity in women, buts its role in PCOS is controversial. It
has been proposed that abnormally high serum concentrations of serum leptin may

Endocrine Causes of Obesity 219

provide a link between PCOS and ovarian dysfunction (leading to anovulation and
infertility) in some women with this condition [60]. Hyperleptinaemia has been
shown to contribute towards the lowered sensitivity of dominant ovarian follicles to
IGF-1, resulting in anovulation and impaired regulation of human ovarian follicle
development [61]. Serum leptin concentrations correlated with percentage body fat
in both normal controls and PCOS [62]. Serum leptin concentrations do not correlate
with PCOS but rather with adiposity [63]. However, there are no significant differ-
ences in serum leptin concentrations between ovulatory and anovulatory women
with PCOS, suggesting that serum leptin probably does not play an important role in
regulating ovulation in these women [63].
Ghrelin is known to enhance appetite, reduce fat utilisation and cause adiposity
following central or peripheral administration to both rodents and humans [64].
Circulating ghrelin typically increases on fasting and decreases following food intake.
In PCOS, ghrelin is negatively correlated to insulin resistance [65]. The concentra-
tions of ghrelin are particularly low in insulin-resistant PCOS similar to gastrec-
tomised subjects [66], unlike women with PCOS and normal insulin sensitivity in
whom levels are similar to controls [65, 66]. A further study suggests that the primary
association is primarily between ghrelin and androgens rather than ghrelin and
insulin [67]. More importantly, dysregulation of hunger, food consumption and sub-
sequent weight gain in PCOS may be related to lack of reduction of ghrelin postpran-
dially [68]. Achievement of weight loss and its maintenance in PCOS proves to be
continuing clinical challenge for both patients and their clinicians.

Cushing’s Syndrome

Obese patients may present an opportunity for an early diagnosis of Cushing’s syn-
drome. This requires a high level of clinical suspicion as patient may not display all the
typical symptoms or signs. Harvey Cushing first described in 1932 a constellation of
symptoms of obesity, hirsutism and amenorrhoea attributed to primary pituitary
abnormality associated with adrenal hyperplasia. Adrenal tumours causing the same
syndrome were later described, but Cushing’s syndrome due to ectopic adrenocorti-
cotrophin hormone (ACTH) was only recognised in 1962 [69]. The term Cushing’s
syndrome describes all causes of cortisol excess, whereas Cushing’s disease one type due
to pituitary-dependent disease. In Cushing’s syndrome, patients usually present with
insidious onset of weight gain with central fat deposition. In addition, patients develop
a ‘buffalo hump’ due to fat accumulation over the thoracocervical spine. Typical ‘moon
shape facies’ are produced by fat depots over cheeks and temporal regions.
The most discriminating symptoms and signs of Cushing’s syndrome are bruising,
muscle weakness, skin thinning, plethora and truncal obesity. The associated condi-
tions include diabetes mellitus, hypertension, hirsutism, osteoporosis and impaired
glucose tolerance test [70].

220 Weaver
Table 2. Causes of Cushing’s syndrome

ACTH dependent
Cushing’s disease (pituitary dependent)
Ectopic ACTH syndrome
Ectopic CRH syndrome
Macronodular adrenal hyperplasia
Iatrogenic treatment with ACTH 1-24
ACTH independent
Adrenal adenoma and carcinoma
Primary pigmented adrenal nodular hyperplasia and Carney’s syndrome
McCune-Albright syndrome
Aberrant receptor expression (gastric inhibitory polypeptide, interleukin-1␤)
Iatrogenic Cushing (pharmacological doses of steroids)
Pseudo-Cushing’s syndrome
Alcoholism
Depression

Symptoms and signs of Cushing’s syndrome arise as a result of prolonged exposure

to excessive free cortisol levels, either endogenous cortisol or exogenous (iatrogenic
Cushing’s syndrome) due to prednisolone, dexamethasone or various forms of topical
and inhaled steroids.
The causes of Cushing’s syndrome are listed in table 2.
Cushing’s disease is quite rare; its incidence is 5–10 cases per million population per
year, whereas iatrogenic Cushing’s is very common due to the widespread use of exoge-
nous steroids. Ectopic ACTH secretion is associated with 0.5% of bronchogenic carcino-
mas being the most common cause of ectopic Cushing’s followed by carcinoid tumours
(pancreas, lung) and other carcinomas. Patients with iatrogenic Cushing’s syndrome
develop varying symptoms and signs depending on the individual sensitivity, dose and
length of exposure to glucocorticoids. They are less likely to have symptoms or signs
associated with androgen excess such as oligomenorrhoea, amenorrhoea or hirsutism.

Pseudo-Cushing’s Syndrome

This is a condition characterised by some if not all clinical features of Cushing’s syn-
drome. There may be evidence of an intermittent rise of cortisol. Chronic alcoholism
is the commonest cause of pseudo-Cushing’s syndrome; however, the aetiology is not
very clear. Studies showed that in chronic liver disease there is an impairment of cor-
tisol metabolism. Furthermore, alcohol and/or vasopressin raised in patients with
alcohol excess were found to be a stimulant for cortisol secretion [71].
Many patients with Cushing’s syndrome are depressed [72]. On the other hand,
depression may display some of the features of Cushing’s syndrome which resolve on

Endocrine Causes of Obesity 221

the treatment of depression. How do we then differentiate those two conditions?
Patients with depression have greater suppressibility after dexamethasone and a lesser
ACTH response to the corticotrophin-releasing hormone (CRH) test. In order to dis-
tinguish true from pseudo-Cushing’s it has been recommended to perform a CRH
test after low-dose dexamethasone suppression test or use loperamide which lowers
cortisol in pseudo-Cushing’s [73, 74].
Simple obesity is occasionally listed as pseudo-Cushing’s syndrome. But simple
obesity is not associated with cortisol excess, and morning cortisol values can actually
be lower than in normal-weight controls. If urinary free cortisol is raised in excep-
tional circumstances, this reflects the reduced specificity of this investigation. Obesity
is characterised by reduced cortisone to cortisol conversion due to suppressed 11␤-
HSD1 activity by increasing fatness and insulin resistance. It appears that increasing
energy intake may downregulate cortisol production in vivo [58]. Another form of
the syndrome difficult to diagnose is cyclical Cushing’s syndrome.
It is characterised by intermittent periods of normal cortisol activity. It is rela-
tively rare but can cause serious problems during diagnosis. Sometimes it occurs in
patients previously operated on for Cushing’s disease [75], but it can occur with all
aetiologies.

The Diagnosis of Cushing’s Syndrome

The diagnosis of glucocorticoid excess and differential diagnosis is complex and

requires a number of investigations, as listed in table 3. As very few investigations of
Cushing’s syndrome have 100% sensitivity and specificity, endocrine expertise com-
bined with clinical experience is essential in the diagnosis of Cushing’s syndrome.
The specificity of the investigations will increase with adjustment of the threshold
levels of measured hormones. The ambulatory investigation may need to be repeated
as in-patient if there is uncertainty about the investigations.

The Mechanism of Obesity in Cushing’s Syndrome

Cortisol acts via intracellular receptor glucocorticoid and mineralocorticoid recep-

tors, members of thyroid/steroid hormone receptor superfamily of transcription
factors. Exposure to glucocorticoids stimulates adipocyte differentiation and adipo-
genesis by transcriptional activation of key differentiation genes including lipopro-
tein lipase, glycerol-3-phosphate dehydrogenase and leptin [76]. The chronic effect of
glucocorticoids on adipose tissue leads to the characteristic increased deposition of
central fat ‘lemon-on-stick’ appearance. This may be related to greater expression
of 11␤-HSD1 in visceral as opposed to subcutaneous tissues, responsible for the con-
version of cortisone to cortisol [77].

222 Weaver
Table 3. Diagnostic tests used in investigations of Cushing’s syndrome

Application Sensitivity/specificity %

Screening for glucocorticoid excess

Spot urine cortisol/creatinine ratio ambulatory 85–92/95
24-hours urinary free cortisol (2–3⫻) ambulatory 85–92/95
Overnight 1 mg dex suppression test (F ⬍ 50 nM) ambulatory 100/82
Low-dose dex suppression test ambulatory 95/99
Midnight cortisol ⬎200 nM/l in-patient 90/100
Differential diagnosis
9 am plasma ACTH (Cushing’s disease) ambulatory 50/70
ACTH ⬎5 PM at midnight (ACTH dependent) in-patient 100/99
Plasma potassium, bicarbonate (ectopic ACTH) ambulatory 95/90
High-dose dex suppression test (Cushing’s disease) ambulatory 90/1001
High-dose dex suppression test (ectopic ACTH) ambulatory 50/95
CRH test (Cushing’s disease) ambulatory 90/90
CRH test (exclude ectopic ACTH) ambulatory 100/1002
Imaging pituitary and adrenal (MRI) ambulatory 80/78
Imaging pituitary and adrenal (CT) ambulatory 20–60/78
Inferior petrosal sinus sampling in-patient 97/100

Sensitivity and specificity values calculated from data provided in Stewart [87]. F ⫽ Cortisol;
CT ⫽ computed tomography; MRI ⫽ magnetic resonance imagining; dex ⫽ dexamethasone.
1
Ninety percent suppression of urinary basal cortisol.
2
Hundred percent rise in ACTH and 50% rise in cortisol excludes ectopic ACTH.

Indirect Mechanisms
Effect on Thyroid Status. Glucocorticoids suppress thyroid axis through suppression
of TSH secretion and additionally inhibiting 5⬘deiodination mediating the conver-
sion of thyroxine to triiodothyronine.
Effect on Growth Hormone Status. Chronic hypercortisolism leads to a blunting
response of GH secretion to all stimuli [78].
Successful treatment of Cushing’s syndrome and a reduction of glucocorticoid
levels lead to remarkable weight loss, although often not back to the pre-morbid state.

Hypothalamic Obesity

Acquired obesity not present from infancy, coupled with headache, a growth disorder
and other growth dysfunction, requires investigations for hypothalamic/pituitary disease.
Selective pituitary failure can arise from the deficiency of one or more hypothala-
mic hormones, including TRH and growth hormone-releasing hormone. The reason
for obesity associated with TRH deficiency has been discussed above under the sec-
tion ‘Hypothyroidism’.

Endocrine Causes of Obesity 223

 One of the most severe types of endocrine obesity results from hypothalamic dam-
age. Commonly, this is due to craniopharyngiomas and/or their surgical solutions
damaging the hypothalamus. Craniopharyngiomas are benign suprasellar tumours
that arise from epithelial remnants of the Rathke’s pouch. Morbid obesity develops in
52% of patients [79]. Historically, the mechanism had been thought to be largely due
to hypothalamic dysregulation of feeding, leading to hyperphagia, obesity and insulin
resistance [80]. The medial hypothalamus (‘satiety centre’) synthesises anorectic hor-
mones such POMC and CART in the arcuate nucleus and CRH and TRH in the par-
aventricular nucleus and damage to these neurons in animal models leads to obesity.
Harz et al. [81] suggested that craniopharyngioma patients develop hypothalamic
obesity because their hypothalamic structures are insensitive to endogenous leptin.
The elevated serum leptin concentrations found only in patients with a suprasellar
tumour may be explained by a disturbed feedback mechanism from the hypothala-
mic leptin receptors to the adipose tissue and reduced physical activity, and abnormal
thermoregulation in addition to the effect of reduced pituitary hormones is a combi-
nation which presents a powerful drive towards obesity.
Patients with growth hormone deficiency have increased fat mass and reduced fat-
free mass compared to BMI-matched healthy subjects of around 6–8 kg [82]. The fat
mass in males is related to GH deficiency as judged from the insulin-like growth fac-
tor-1 levels [82]. The increased adiposity in growth hormone deficiency is centrally
distributed [83] and is reversed by GH replacement therapy [84]. As the treatment of
childhood brain tumours has improved, long-term survival has become more com-
mon. Cognitive, physical and psychological complications of the tumour and its
treatment have been recognised more frequently in long-term survivors. Endocrine
complications are uncommon when the tumour has been treated with surgery alone.
The risk of developing endocrine dysfunction is increased by radiotherapy, and some
studies suggest that chemotherapy has an additional deleterious effect. Primary
hypothyroidism may be caused by scattered irradiation from spinal and cranial radio-
therapy. Direct involvement of the hypothalamus by the tumour, and hypothalamic
damage secondary to surgery or radiotherapy, may cause obesity [85]. An attempt to
understand the factors that contribute to the long-term morbidity of childhood brain
tumours can lead to changes in treatment that improve the quality of life in survivors.
Prevention, early recognition and treatment of these complications are attainable
goals.
Central hypothyroidism is a rare cause of hypothyroidism, generally due to either
pituitary or hypothalamic defects. On the basis of its aetiology, it is possible to distin-
guish acquired and hereditary forms. Hereditary central hypothyroidism can be iso-
lated or associated with combined pituitary hormone deficiency. In the former case,
alterations of only two genes, TSH-␤ and the TRH receptor, have so far been
described as responsible for the disorder. In hereditary central hypothyroidism asso-
ciated with combined pituitary hormone deficiency, inactivating mutations of differ-
ent pituitary transcription factors (HESX1, PROP-1, PIT1) have been found to be

224 Weaver
involved in the pathogenesis of the disease. Finally, an association between central
hypothyroidism and severe obesity has been described in patients with leptin recep-
tor mutations. The clinical consequences of central hypothyroidism in adult life vary
greatly depending on the aetiology, the severity of the thyroid impairment, the extent
of the associated hormone deficiencies, and the age of the patient at the time of the
onset of the disease. In general, acquired central hypothyroidism is less severe than
the congenital form because of the constitutive activity of the wild-type TSH receptor.
Symptoms and signs of thyroid insufficiency are usually milder than those of primary
hypothyroidism, and goitre is always absent [86].
One can conclude that obesity due to endocrine causes is not as common as per-
ceived by patients and some physicians. However, since the effective treatment of less
common underlying endocrine causes is available, the clinical management of
patients with obesity should include appropriate screening for endocrine conditions
which may be amenable to treatment.

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Dr. Jolanta U. Weaver, PhD, FRCP
Department of Diabetes, School of Clinical Medical Sciences
University of Newcastle, Framlington Place
Newcastle upon Tyne NE2 4HH (UK)
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Front Horm Res. Basel, Karger, 2008, vol 36, pp 229–259

Emerging Concepts in the Medical

and Surgical Treatment of Obesity
Simon Aylwin ⭈ Yayha Al-Zaman
Department of Endocrinology, King’s College Hospital NHS Foundation Trust, London, UK

Abstract
The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of
obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese
co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be
evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their
remission or improvement. In combination with lifestyle measures, currently available pharmacological
therapies – rimonabant, orlistat and sibutramine – achieve 5–10% weight loss, although a return to base-
line is the norm after cessation of medication. All these agents demonstrate approximately 0.5% reduc-
tion in HbA1c in diabetic subjects; orlistat also reduces the new incidence of type 2 diabetes. Modest
improvement in lipid profiles and reduced calculated cardiovascular risk is observed, but data on
improvement of other co-morbidities are sparse. In contrast, surgical procedures that restrict food inges-
tion and/or curtail the absorptive surface area of the gut consistently achieve substantial weight loss,
typically 20–35%, effect resolution of co-morbid conditions and improve quality of life. Although mortal-
ity is low, complications and hospitalisation are not uncommon after bariatric surgery. Intriguingly, surgi-
cal patients experience a reduction in appetite and report changes in food preference. Accentuation of
the normal gastrointestinal hormonal response to food intake and possible changes in vagal afferent sig-
nalling are proposed to induce satiety. Increased understanding of body weight homeostasis and
appetite regulation has provided an impressive list of potential targets for drug development, with the
promise that single or combination therapy may ultimately challenge the supremacy of bariatric surgery.
Copyright © 2008 S. Karger AG, Basel

The rising prevalence of obesity has attracted the attention of the medical and scientific
communities, editors of highbrow and popular lay press, broadcasters, intergovern-
mental agencies and political bodies. Whilst headlines, opinions and initiatives abound,
solutions at a population level remain elusive. Far from reversing the trend, the number
of WHO-defined obese subjects with a body mass index (BMI) ⬎ 30 grows at an ever-
increasing rate. In 2001 20.9% of the US population were obese (BMI ⬎ 30) and 2.3%
had a BMI ⬎ 40. Concerning as these statistics may be, the enormity of the problem
may be underestimated since the most pronounced trends in body weight are seen in
children, adolescents and young adults [1]. Although the degree to which prepubertal
obesity tracks to adult disease remains controversial, it is likely that by the age of 11 obe-
sity is established [1]. Moreover, recent data from a large prospective study demonstrate
that weight gain during early adulthood confers a particularly high risk of developing
type 2 diabetes (T2D) [2]. The more costly obesity-related complications evolve slowly,
becoming more evident and demanding more resource with increasing age and there-
fore the health burden is set to rise even if the prevalence of obesity were to stabilise [3].

Management of Obesity

Management of obesity in its broadest sense can be summarised in four steps: Step 1:
Prevention; Step 2: Weight management; Step 3: Prevention of complications; Step 4:
Management of complications.

Step 1: Prevention

Prevention of obesity is the public health holy grail. It is self-evident that energy and
resource need to be dedicated to what is rapidly becoming the most pressing public
health issue worldwide. In a BMJ review, Anjali Jain articulated the problem facing pub-
lic health policy makers: ‘The high rates of obesity do not allow us to wait for treatments
to be proved effective by the standards of evidence-based medicine. In other words,
something must be done soon, but we don’t know what.’ [4]. Public health measures are
both aimed to reduce the new incidence of obesity, and to limit the pace of weight gain
amongst overweight and obese individuals. Strictly speaking, there are therefore both
preventative and weight management (step 2) aspects to a program devised for the gen-
eral population. Furthermore, the health benefits of both weight loss through lifestyle
intervention, and altered diet without weight loss are disproportionately beneficial, and
therefore public health measures may also be considered as a component of step 3 –
limiting the development of complications [5]. Success might be defined as by achiev-
ing a fitter, if not thinner population, and it remains to be seen whether the governmen-
tal rhetoric will be followed by a proliferation in public facilities for exercise, cycle lanes
and so forth. However, the evidence base for effective large-scale interventions is lim-
ited [6, 7], and this area is largely outside the scope of this review.

Step 2: Weight Management

Behind the statistics, however, a growing number of individuals are experiencing the
medical complications, the reduced function and quality of life, and also the social and

230 Aylwin · Al-Zaman

workplace disadvantage, all of which conspire to magnify the burden of morbid obe-
sity [8]. The next approach is therefore to focus on the individual, recognise either the
presence or risk of related complications and intervene by aiming to reduce weight
with a form of weight management. The best combination lifestyle interventions in a
primary care setting only achieve a weight loss of up to 5% in fewer than half of indi-
viduals (43% of study-compliant patients in the Counterweight program) [9]. It is here
that the overwhelming effort of the pharmaceutical industry is primarily targeted,
attempting to develop new agents that will effectively reduce individual weight.
Presently, surgical strategies offer the best chances of clinically relevant weight loss, but
the capacity, let alone desirability, of treating large numbers of young individuals with
surgical procedures is doubtful, except for the minority with severe obesity.

Step 3: Prevention of Complications

Recognizing the limitations of existing non-surgical treatment, we might aim for

damage limitation, and since the principal cause of mortality, particularly in visceral
obesity, is ischaemic heart disease, focus on the management of other cardiovascular
risk factors. In addition, an emerging paradigm is to limit the natural history of the
condition, aiming to reduce the risk of complications notably T2D. At present, there
are no large-scale studies that have demonstrated that a pharmaceutical strategy has
any effect on mortality, although the SCOUT study using sibutramine is designed to
address this issue. In contrast to the management of hypertension, diabetes and
hyperlipidaemia, we have few data that address endpoints of obesity other than the
surrogate endpoint of weight, and these are long overdue.

Step 4: Treatment of Complications

Most of the medical cost of obesity is attributable to the management of the compli-
cations, and in this aspect the evidence base for specific complications is broad. It
should be emphasised that the ‘complications’ of obesity include the loss of individual
income, increase in social security benefits and also the secondary consequences if a
severely obese individual ceases to provide a carer role through their own disability.
Paradoxically, the management of the complications of obesity – particularly in rela-
tion to prevention of the complications of T2D – may in fact involve sacrificing the
primary goal of weight loss to address the greater evil of hyperglycaemia.
Analysis of preventative measures against obesity, behavioural and dietary inter-
ventions and the management of established complications are outside the scope of
this chapter [for review, see 10]. We will focus on the treatment of the obese adult
individual. A central theme will also be to evaluate the effectiveness of interventions
not merely in terms of weight but with equal emphasis on the improvement and

Emerging Concepts in the Medical and Surgical Treatment of Obesity 231

remission of obesity-related co-morbidities. This article will examine existing thera-
pies, their efficacy in terms of weight and weight-related complications; it will address
the recent research in both surgical and medical approaches, and will briefly provide
an obesity assessment tool for clinical practice (table 1).

The Role of Medical and Surgical Intervention in the Management of Obese States

Obesity matters because it represents a predisposition to the development of obesity-

related medical and psychosocial complications. Broadly speaking, the complications
of obesity can be divided into three overlapping categories:
Category A, related to total fat mass: conditions arising as a consequence of total
fat mass, including psychosocial and functional disturbance.
Category B, related to visceral adiposity: conditions associated with visceral adi-
posity, largely the constellation of cardiovascular risk factors that make up the meta-
bolic syndrome (MetS).
Category C, complicating unrelated chronic diseases: where obesity is a significant
exacerbating factor for morbidity and disability.
These conditions are graphically illustrated in figure 1.

Complications Related to Total Fat Mass

The medical complications attributable to total fat mass (category A) are principally
those that place medical strain on the musculoskeletal system and cause morbidity by
pain or disability. In addition, the psychosocial factors including body image dysphoria,
relationship difficulties, poor workplace achievement and economic handicap through
the requirement for assistance in activities of daily living appear to be related to the
degree of total obesity, although in one study, abdominal circumference also contributed
to disability [11]. Certain other conditions occur too infrequently (e.g. idiopathic
intracranial hypertension, IIH, obesity-related cardiomyopathy, glomerulopathy) to
clearly establish their aetiology in relation to total or visceral fat. The procoagulant ten-
dency that remains a risk factor for venous thromboembolism and arterial occlusion
may be related both to visceral and total adiposity. In general, the use of BMI and WHO
definitions stratifies the risk of these conditions effectively and they tend to occur at
higher degrees of obesity. BMI is therefore a reasonable surrogate marker of risk.

Complications Relating to Visceral Fat Mass

BMI in isolation is less convincing as the best marker for risks associated with visceral
obesity, and other co-morbidities in category B. Although the gold standard for the

232 Aylwin · Al-Zaman

measurement of visceral adiposity requires axial CT or MRI scan, a useful approxi-
mation can be obtained by the simple measurement of waist circumference obtained
at the level of the iliac crest [12]. Although BMI remains tightly related to T2D in a
population basis, at lower levels of obesity, consideration of anthropomorphic indices
relating to fat mass distribution becomes relevant [13]. Insulin resistance and the
attendant risks of T2D are more closely related to visceral adiposity than overall obe-
sity, and increasingly evidence indicates that subcutaneous fat is metabolically neu-
tral. Indeed, in the rare syndromes of partial lipodystrophy with absent subcutaneous
fat caused by monogenic defects in the lamin A/C and PPAR␥ genes, extreme MetS
derangements occur despite, or actually because of a lack of subcutaneous fat. The
modest metabolic disadvantage of subcutaneous fat is further emphasised by the lack
of effect of large-volume abdominal liposuction, which did not improve metabolic
parameters of insulin resistance, levels of inflammatory mediators or other risk fac-
tors for coronary artery disease [14]. Decreasing subcutaneous adipose tissue alone
does not achieve the metabolic benefits of visceral weight loss.
Although in severe obesity (BMI ⬎ 40), visceral fat is normally present in excess,
measurement of BMI alone risks misattributing individuals at both high risk and low
risk of T2D and MetS in lower categories (BMI 30–40), and in these circumstances,
assessment of visceral obesity is appropriate [12].
The association of visceral adiposity with features of MetS is now formalised in
both the International Diabetes Federation and National Cholesterol Education
Program definitions [15]. The global epidemiological Interheart study has also
highlighted that worldwide, visceral adiposity measured by waist-hip circumference,
is a powerful predictor of cardiovascular disease and probably better than BMI [16].
Individuals with visceral fat have a greater risk of commonly measured cardiovascu-
lar risk factors, and waist circumference represents an additional independent risk
factor. Similarly, MetS has a high prevalence amongst patients attending cardiac reha-
bilitation [17]. In older individuals (over 65 years) in the prospective Cardiovascular
Health Study, increasing BMI in fact had a significant protective effect, whereas
visceral adiposity was associated with increasing mortality [18]. A recent systematic
review failed to demonstrate an increased risk for coronary heart disease progression
in relation to BMI, indeed, reported improved outcome in patients in the overweight
and mildly obese groups [19].

Conditions Exacerbated by Obesity

Finally, in category C there are a number of conditions where obesity compounds the
morbidity of medical diseases, notably reducing the functional capacity of patients
with angina, congestive cardiac failure and asthma where modest weight loss may be
beneficial [20]. Intriguingly, there are circumstances where obesity confers a statistical
advantage: obese patients on dialysis programmes appear to have reduced mortality.

Emerging Concepts in the Medical and Surgical Treatment of Obesity 233

Table 1. King’s obesity
Criterion Stage 0
staging criteria
A Airway Normal, and
/apnoea Epworth score ⬍10

B BMI and w.c ⬍35 (WHO I) and

w.c. ⬍102 cm (M)
⬍88 cm (F)
C CVD risk ⬍10% over 10 years

D Diabetes Normal

E Economic No effects
complications

F Functional status No limitation

and musculoskeleal
G Gonadal and Normal sexual and
reproductive axis reproductive
function
H Health status Follows
(perceived) behavioural
and stages of recommendations
change ‘Maintenance phase’
I Body No concern
image/eating Normal eating
behaviour pattern
Good quality diet
O Other No other
medical complication
© 2007 King’s College Hospital NHS complications
Foundation Trust, London SE5 9RS,
UK. All rights reserved; permission CCF ⫽ Congestive cardiac failure; IFG ⫽ impaired fasting glucose;
requests should be addressed to CVD ⫽ cardiovascular disease.
Dr. Simon Aylwin.

Following cardiac artery bypass grafting, but not percutaneous revascularisation,

obese subjects also have an improved prognosis [21].
Defining obesity in terms of BMI provides a common terminology that enables
demographic comparison between populations and over time, and is a reasonable
means of describing the participants in a clinical trial. However, defining overweight

234 Aylwin · Al-Zaman

Stage 1 Stage 2 Stage 3

Epworth score ⱖ10 Uses CPAP Cor pulmonale Obesity

Apnoea-hypopnoea Apnoea-hypopnoea hypoventilation syndrome
index 5–20 index ⬎20
35–40 (WHO II) or 40–50 (WHO III) ⬎50 (superobese)
w.c. ⱖ102 cm (M) ⱖ88 cm (F)

ⱖ10% over 10 years Stable established Severe angina, or

ischaemic heart disease,
or CCF NYHA I–II
IFG/IGT, or previous T2DM
GDM, or HOMA-IR ⬎3.0
Financial impact of Workplace
obesity (travel, clothes) disadvantage
Limitation on work or 3rd party assistance for
recreation ADL or for dependents
PCOS Infertility
Low testosterone (men) Impaired sexual
function
Just started or Adequately informed
preparing for lifestyle and concerned about
change future ‘Contemplative’
‘Preparation/action’
Comfort eating Severe body image
Inappropriate eating dysphoria
cues Night eating disorder
Mild body image dysphoria Mild-moderate depression
Complications with Significant morbidity
low degree of from additional
morbidity complications
CCF NYHA III–IV
Uncontrolled T2DM, or
insulin-requiring
Unemployed, or
financial effect on 3rd
party, or receiving benefits
Housebound or wheel
chair dependent
Marital/relationship
breakdown due to obesity
Indifferent
No willingness for change
‘Precontemplative’
Binge eating disorder
Bulimia
Severe depression
Life or independence
threatened (e.g. IIH)

IGT ⫽ impaired glucose tolerance; GDM ⫽ gestational diabetes mellitus; w.c. ⫽ waist circumference;

and obesity merely in terms of BMI, and evaluating intervention on the basis of
change in weight alone is inadequate in categorizing individual risk and treatment
response. In brief, although we may have an increased repertoire of agents to deploy,
it will become ever more important to define those where greatest impact can be
achieved.

Emerging Concepts in the Medical and Surgical Treatment of Obesity 235

 Complications of obesity
A Related to total fat B Related to visceral fat

Osteoarthritis T2D
Disability Dyslipidaemia
OSA
Poor economic status Hypertension
thrombosis
Body image dysphoria PCOS
Obstetric complications NASH

C Obesity exacerbating unrelated disease

Congestive cardiac failure
Asthma

Fig. 1. Complications of obesity. Complications of obesity can be segregated into those that relate to
total fat mass (A), visceral fat (B), and those that represent an exacerbating effect of obesity on other
co-existing medical conditions (C).

Pharmacological Therapy for Obesity

Is There a Magic Bullet?

Proof beyond doubt that severe obesity can arise from organic disease is evident in
those with structural hypothalamic disease, in whom hyperphagia and severe weight
gain can occur. The recognition of a series of monogenic disorders involving appetite
regulatory pathways serves to further emphasise that excess body weight is not
merely founded in a lack of conscious restraint [22]. The astonishing reduction in
obesity demonstrated with leptin treatment for the handful of individuals with
monogenic leptin deficiency provides powerful proof of principle that biological
processes underpinning obesity can be manipulated [23]. For the vast majority of obese
individuals, however, the pathogenesis of obesity reflects a multi-factorial individual
predisposition coming into collision with an increasingly unsuitable environment,
where genetic and epigenetic factors, intrauterine adaptation, early life feeding,
learned attitudes to eating and social customs define the at-risk individual [8]. Unlike
the correction of congenital leptin deficiency, and like a number of other disease
states, monotherapy is insufficient in a polygenic disorder, and the nihilism that sur-
rounds the medical management of obesity is in part due to the fact that with only a
few agents, effective combination therapy has not yet been achieved.
The first prerequisite for any drug is that it should not cause harm, the second is
that it should have some effect, and the third that it should confer some meaningful

236 Aylwin · Al-Zaman

benefit on the patients that take it. In the ‘hall of fame’ of therapies for obesity there
are many good ideas that fell foul of the first proposition. Thus the use of thyroid hor-
mone, amphetamine derivatives, the centrally acting appetite suppressants dexphen-
fluramine, and the combination of fenfluramine with phentermine (fen-phen)
achieved a degree of weight loss but with unacceptable side effects and were never
demonstrated to impact usefully on hard endpoints. Phentermine can still be pre-
scribed in the USA but its potency is limited as a single agent and can only prescribed
for short-term use. Examination of extinct pharmacological approaches is not within
the scope of this article, and the reader is referred to the excellent review by Weigle [24].
We will concentrate in this section on the currently available treatments for medium-
to long-term treatment and their impact on weight.

Orlistat

Arguably the only widely used obesity therapy to have been specifically designed for
its purpose, orlistat is an intestinal lipase inhibitor that limits the amount of dietary
fat that can be converted into an absorbable form as a mono- or di-glyceride. Orlistat
has been shown to have a significant benefit over placebo and after 12 months,
patients treated with orlistat in addition to lifestyle intervention achieved a weight
reduction of 8.4% compared to 2.6% with placebo [25]. Later studies confirmed an
effect of orlistat superior to placebo, but only a third of patients achieved a 5% weight
loss at 12 months [26]. Once the benefits of intensive dietary support are removed in
a primary care setting, the use of orlistat with brief counselling effected a 4.8-kg
weight loss at 6 months, compared to 3.8 kg with drug alone and 1.7 kg with brief
counselling alone; although no significant differences were present at 12 months [27].
However, if we can ignore the statistical violation of continuation on the basis of early
response, results are more interesting, and patients randomised to either 500- or
1,000-kcal deficit diets, after initial success of 5% weight loss at 3 and 6 months,
achieved weight loss of over 10 kg at 1 year [28]. In a similar study, 3-month weight
loss of ⬎5% also predicted 11.9% loss at 2 years [29]. In the absence of any a priori
determinant of response, weight loss at 3 months appears to be of benefit in identify-
ing those patients who might achieve meaningful change in the longer term.

Sibutramine

Sibutramine was developed as a potential anti-depressant and combines serotonin

and noradrenaline re-uptake inhibition, but was recognised as having a weight loss
side effect. The STORM study subsequently demonstrated an effective role for sibu-
tramine in an experimental paradigm where patients were administered active com-
pound for 6 months in conjunction with intensive dietary intervention and then

Emerging Concepts in the Medical and Surgical Treatment of Obesity 237

 104
102 Placebo

Body weight (kg)

100
98
96
94
92
90
88 Sibutramine

0 2 4 6 8 10 12 14 16 18 20 22 24
a Month

Weight loss Weight maintenance

Year 2
Year 1 Placebo/placebo
20 mg of rimonabant/placebo
Placebo 20 mg of rimonabant/20 mg
5 mg of rimonabant of rimonabant
20 mg of rimonabant

Change from baseline (kg)

Change from baseline (kg)

0 0
⫺2 ⫺2
⫺4 ⫺4
⫺6 ⫺6
⫺8 ⫺8
⫺10 ⫺10
0 12 24 36 52 52 60 68 76 84 92 104
b Weeks Weeks
Patients
Placebo/placebo 292 284 254 247 233 222 216
Patients 20 mg of rimonabant/ 323 315 301 277 261 240 225
Placebo 590 496 413 347 309 placebo
5 mg of rimonabant 1191 1004 833 711 619 20 mg of rimonabant/ 328 319 297 286 272 263 256
20 mg of rimonabant 1189 1017 863 750 672 20 mg of rimonabant

Fig. 2. Recidivism after pharmacological weight loss. Following weight loss achieved through
pharmacological intervention, cessation of therapy is followed by a return to baseline weight.
a Sibutramine: following induction of weight loss with hypocaloric diet and sibutramine, subjects
were randomised to sibutramine or placebo [30]. b Rimonabant: weight loss induced by rimonabant
(left panel) is superior to placebo. After 12 months, re-randomisation to active compound or placebo
(right panel) demonstrates the effect of rimonabant on weight loss maintenance [99].

randomised to sibutramine or placebo. Forty-three percent of the patients respond-

ing to the initial period, and randomised to sibutramine, maintained ⬎80% of weight
loss [30]. This paper reaffirmed that obesity treatment can be effective in those
demonstrating early response, but also graphically illustrated that even amongst
responders, cessation of therapy would lead inexorably back to baseline (fig. 2a).
Combining sibutramine as a follow-up to weight loss with a very low calorie diet is
also to be considered, but only 30% of subjects maintained weight loss at 18 months

238 Aylwin · Al-Zaman

compared to 20% with placebo [31]. In contrast, intensive adjuvant support (30 group
sessions) with sibutramine is far more effective than drug treatment alone [32].
Similar to orlistat, initial response of 4-kg weight loss at 3 months amongst partici-
pants in the STORM study was a good predictor for later results [33].

Rimonabant

Rimonabant, a selective cannabinoid receptor type 1 antagonist, was developed as a

treatment for smoking cessation, but was noted to induce weight loss, and is the most
recent agent to be licensed in Europe for weight loss in obese patients. In four simi-
larly designed trials in the RIO program, with a total study group of over 6,000
patients, subjects were randomised to either 5- or 20-mg doses of rimonabant or
placebo [see review in 34]. Study populations were selected on the basis of obesity or
overweight alone (RIO-North America and RIO-Europe), or in the presence of co-
existing T2D or dyslipidaemia. In the Obesity-Lipids (RIO-Lipids) study, rimonabant
treatment at a dose of 20 mg was associated with increased HDL-C, and reduced
triglycerides, as well as significant weight loss compared to placebo with a mean
weight loss of 6.7 kg. Similar results were found in RIO-North America, where
patients in the active treatment group were re-randomised to receive either placebo
or rimonabant, and patients who were shifted from rimonabant 20 mg to placebo
experienced weight regain (fig. 2b). The return to baseline after cessation of therapy
appears to be a feature of all the major pharmacological interventions for obesity. It
remains to be determined how effective and well-tolerated rimonabant will be out-
side the context of pharmaceutical studies, since concerns have arisen with regard to
the development of depression in patients with a previous history.

Metformin

Although never proposed as a ‘diet pill’, metformin has long been recognised as hav-
ing at least a neutral effect on weight in comparison to sulphonylureas in the manage-
ment of T2D. Amongst obese diabetic subjects in the United Kingdom Prospective
Diabetes Study, metformin was the only treatment that was not associated with
weight gain. Although a neutral effect on weight is hardly headline-grabbing, this is
undoubtedly beneficial when seen in comparison to sulphonylurea and insulin therapy.
Metformin was associated with a significant reduction in any diabetic-related event,
diabetic-related death and all cause mortality and 39% reduction in myocardial
infarction [35]. Metformin has also been proven of value in the prevention of T2D: in
the Diabetes Prevention Trial metformin reduced the new incidence of diabetes and
was associated with greater weight loss (mean 2.1 kg) compared to placebo. Although,
first and foremost a treatment for T2D, conceptually at least, metformin has a broad

Emerging Concepts in the Medical and Surgical Treatment of Obesity 239

and intriguing role in the management of overweight and obesity. With reference to
the principles set out in section 1, metformin can be recognised as having beneficial
effects in relation to weight management (step 2), complication prevention (step 3)
and complication management (step 4).

Combination of Pharmacotherapy for Obesity

Intentional weight loss is followed by a counter-regulatory response to increase

appetite, conserve energy and restore homeostasis. In this circumstance, manipulation
of the pathway at two or more points offers the theoretical possibility of undermining
the feedback loop. The combination of fenfluramine and phentermine in a previous
era was undoubtedly an effective strategy, achieving weight loss of 10–15% [36], and
arguably represented the only medical therapy to date that allowed sufficient weight
loss for a clinically apparent effect. Unfortunately, reports of valvular heart disease and
pulmonary hypertension [37] in patients taking the combination phen-fen led to its
withdrawal, and were followed by evidence that these side effects were not uncommon
[38]. Nevertheless, the theoretical advantage of combing agents was demonstrated.
Disappointingly, both clinical practice and trial data do not support the combina-
tion of orlistat and sibutramine. In a short (12 weeks) randomised open-labelled trial
involving 86 obese subjects, sibutramine combined with orlistat was found to be
equally effective as either drug alone [39] and this lack of effect has been replicated.
At present, there are no data that have evaluated the effect of rimonabant in combina-
tion with either sibutramine or orlistat.

Surgical Treatment

Defining Success

The surgical literature has a lexicon that is different from that used by the rest of the
medical community. Obesity is typically defined as excess weight in relation to the
actuarial concept of ideal body weight at a BMI of 22. Hence, an individual with a
BMI of 33 has 50% ‘excess weight’, and one of 44, 100%. Whereas pharmacological
treatments might consider the proportion of patients losing 5 or 10% total weight as a
useful outcome measure, surgical reviews consider a weight loss of less than 10% as
being failure and 20% as being poor.
Surgical procedures (fig. 3) for obesity aim either to restrict the amount of foods that
can be ingested, or to reduce the effective surface area of the gut available for absorption,
and are referred to as ‘restrictive’ and ‘malabsorptive’, respectively. A further category of
procedures combines both of these elements, and is sometimes referred to as ‘hybrid’.
Although the first recognised surgical procedure for obesity was the jejuno-ileal bypass

240 Aylwin · Al-Zaman

 Malabsorptive procedures

a b c
Restrictive procedures

d e f

Fig. 3. Bariatric surgical procedures. a–c Malabsorptive bariatric procedures. a JIB. b BPD. c DS.
d–f Restrictive bariatric procedures. d VBG. e LAGB. f RYGB. Reproduced with permission from the
Endocrine Society [100].

(JIB), this procedure resulted in an unacceptable rate of complications, and restrictive

operative approaches developed that avoided the potential for protein-calorie malab-
sorption. More recently, there has been an increase in the popularity of procedures that
have a milder degree of malabsorption, such as the Roux-en-Y gastric bypass (RYGB).

Restrictive Bariatric Surgery

After the disappointment and bad press that followed the JIB (see the section below),
focus shifted to restriction of the gastric pouch rather than risking the long-term
effects of iatrogenic malabsorption. A variety of techniques emerged, most notably
the vertical banded gastroplasty (VBG), or ‘stomach stapling’ in the vernacular. This

Emerging Concepts in the Medical and Surgical Treatment of Obesity 241

procedure – in which a smaller stomach pouch is created with a staple line and a silas-
tic band forms an artificial distal stomach sphincter – has largely been superseded by
laparoscopic adjustable gastric banding (LAGB or Lap Band). In the LAGB, a small
silastic ring encircles the proximal stomach leaving an effective gastric pouch of
15 ml, the band being connected to a subcutaneous port in the abdominal subcuta-
neous fat that can be used to subsequently tighten the band by the introduction of
saline. Correct positioning of the band is crucial to achieving optimal results, and
although the remainder of the stomach remains in continuity with the gastric pouch,
the upper portion of the stomach is richly innervated with vagal afferent fibres that
respond to stretch and transduce the sensation of fullness [40]. The LAGB procedure
is relatively straightforward, does not risk malabsorption and the degree of restriction
can be readily adjusted. Increasingly, LAGB is performed as a day-case procedure
increasing the capacity of bariatric units. The principal disadvantage is the need for
continued follow-up and adjustment of the band tension, and variability in results
amongst units probably reflects accurate positioning and dedication to follow-up.
Particularly in Europe, however, the LAGB has become the most commonly per-
formed procedure.

Malabsorptive and ‘Hybrid’ Procedures

The original prototype malabsorptive procedure, the JIB was first pioneered in the
1950s. In this operation, the jejunum is divided and the proximal limb anastomosed
directly to the last portion of the ileum (fig. 3). Pancreatic and biliary secretions remain
in the newly fashioned tract, but a long segment of ileum remained as a blind loop. The
JIB was undoubtedly effective, but whilst many patients benefited, the side effects even-
tually led to its becoming discredited and abandoned. In addition to protein-calorie mal-
nutrition and fat malabsorption with its attendant vitamin deficiencies, increased oxalate
levels led to a polyarthritis, crystal nephropathy and poorly understood cirrhosis.
Newer techniques combine an element of malabsorption and restriction. The
Scopinaro procedure, or bilio-pancreatic diversion (BPD) and duodenal switch (DS)
are the modern descendants of purely malabsorptive operations, although they may
be additionally combined with a reduction in gastric volume. In both procedures, the
alimentary limb remains short, but the pancreatic and biliary secretions drain into
the redundant ileal limb. Diversion of the secretions has two effects: firstly to reduce
the mixing of food with digestive juices, and secondly to avoid the consequences of a
blind loop of intestine. Whilst treading a fine line between adequate weight loss and
clinical malnutrition – the surgical equivalent of a narrow therapeutic window – per-
formed by experienced practitioners these procedures are remarkably effective,
achieving a 40% weight loss in a typical bariatric patient.
Currently, the most widely used hybrid procedure is the RYGB. In this technique,
the jejunum is divided and the distal limb anastomosed to the stomach remnant of

242 Aylwin · Al-Zaman

20–30 ml. The remaining stomach, duodenum and proximal jejunum form the ‘Roux’
limb that is re-connected to the alimentary tract. Uniquely, this provides a relatively
long common limb; malabsorption is held to a minimum and is not usually clinically
evident. Despite minimal metabolic disruption, the RYGB achieves a degree of excess
weight loss that is consistently greater than purely restrictive procedure, and is the
leading bariatric operation worldwide [41].

Effect of Bariatric Procedures on Weight Loss

In the most comprehensive meta-analysis (22,094 patients) exploring weight loss

after bariatric surgery, it was shown that the mean percentage of excess weight loss
was 47.5% for LAGB, 68.2% for RYGB and 70.1% for BPD/DS [42], although there is
a lack of randomised studies and after longer-term follow-up the differences may be
less marked [43]. A recent study has reported the effect of bariatric surgery in patients
with lesser degrees of obesity than the typical bariatric patient, randomizing patients
to LAGB or combined behavioural and medical therapy [44]. At 2 years, subjects with
a pre-operative BMI of 30–35 had lost 21.6% of total weight compared to 5.5% in the
medical group [44].
The Swedish obese subjects trial (SOS) study, at least, provides long-term outcome
data with a carefully matched control group that had elected not to undergo surgery,
and demonstrated a gradual return of lost weight, but at 10 years surgical subjects
remained with 16.1% total weight loss (equivalent to 34.7% excess weight loss), com-
pared to a weight gain of 1.6% in the medically treated group [45]. This study, how-
ever, included a large number of patients undergoing restrictive procedures including
the fading VBG, and is at the lower end of the true treatment effect of modern
bariatric surgery. At present, the main determinants of surgical referral are patient
preference and surgical availability, since the capacity to treat patients remains lim-
ited, particularly outside North America [41].

Complications of Bariatric Surgery

As with any surgical procedure, the risks of the operation include those of any general
anaesthetic, and early and late consequences of the specific operation in question.
Evidently, obese subjects pose certain generic anaesthetic problems with airway
management and a higher risk of thrombotic complications. LAGB involves the
introduction of a foreign body into the peritoneum, and as well as the potential for
infection (rare) the band may on occasion lead to erosion through the upper stomach.
The most feared early complication of other surgical procedures is anastomotic leakage,
which may be difficult to diagnose promptly due to the difficulty in clinical examination
of the obese abdomen. Later complications include excessive capacity for ingestion,

Emerging Concepts in the Medical and Surgical Treatment of Obesity 243

or the consequences of malnutrition, including vitamin and trace metal deficiency.
Rarely, weight loss may be excessive, with reversal leading to a syndrome of re-feed-
ing oedema [unpubl. obs.]. The loss of fat mass may be so substantial, that despite
body image dysphoria being a major driver for surgical intervention, redundant skin
folds may require extensive secondary correction.
In a review of 64 studies of LAGB and 57 VBG or RYGB, short-term mortality for
LAGB was 0.05%, for VBG 0.31% and for RYGB 0.50% [43]; morbidity rates were
higher at 11.3, 25.7 and 23.6% respectively. Risk-adjusted data evaluating 30-day
morbidity estimates from a multi-centre, prospective study, showed that LAGB
(7.0%) led to fewer complications than open gastric bypass (14.5%) [46]. The above
data may underestimate the mortality of surgical procedures, and in the 10-year fol-
low-up of the SOS study, there was no survival advantage for those undergoing
bariatric surgery compared to matched medically treated controls [45]. Recent data
from the SOS study have illustrated an advantage in favour of surgery amongst all
subjects, including those with pre-existing cardiovascular disease, representing a
milestone – demonstrating that the excess mortality from obesity can be modulated
by a specific therapy [101].

Treatment for Obesity and the Effect on Co-Morbidities

Overwhelmingly, investigations into the efficacy of intervention in the management

of obesity have been initially evaluated in relation to their effects on weight. Although
BMI and visceral adiposity (waist circumference) are useful markers for obesity-
related complications, the MetS and T2D, they remain surrogate markers. Once
proof-of-principle is established in terms of weight loss, however, it is also relevant to
evaluate therapies on the basis of their effect on co-morbidities. In this regard, surgi-
cal treatments have a far greater evidence base, although ‘placebo’-controlled trials
are essentially impossible with surgical intervention. Studies using established med-
ical therapies have also begun to address their efficacy in relation to more pertinent
endpoints that reflect the morbidity of severe obesity.

Type 2 Diabetes

In addition to their effects on weight loss, currently available weight loss treatments
are effective in improving glycaemic control amongst patients with T2D. The Xendos
trial demonstrated a reduction in the new incidence of T2D amongst orlistat-treated
obese patients treated with impaired or normal fasting glucose. The RIO-Diabetes
study demonstrated approximately 0.5% reduction in HbA1c in patients treated with
rimonabant. Similar improvements in glycaemic control have been observed with
sibutramine [47].

244 Aylwin · Al-Zaman

 In an idiosyncratically titled paper – ‘Who would have thought it? An operation
proves to be the most effective therapy for adult-onset diabetes mellitus’ –, Walter
Pories rattled the cages of the medical diabetes community with his series of 608
patients – with a remarkable ⬎97% follow-up – undergoing RYGB in whom diabetes
remission was seen amongst 82.9% of 146 patients with diabetes at long-term follow-
up [48]. Other single centre studies and meta-analyses have demonstrated a high
proportion of patients with T2D going into effective remission after RYGB and BPD.
A pooled meta-analysis of 22,094 patients undergoing variety of bariatric procedures
demonstrated diabetes resolution in 76.8% [42]. Similarly, in the case-controlled SOS
study, where the majority of patients underwent restrictive bariatric procedures, rates of
remission were 72% at 2 years. However, at 10-year follow-up this had dropped to 36%.
Whereas improvement in insulin resistance alone might be anticipated after
weight loss, restored islet cell function can also be demonstrated after bariatric
surgery. Following BPD, Polyzogopoulou et al. [49] documented restoration of first-
phase insulin response to an intravenous glucose tolerance test in patients with T2D,
formerly considered a hallmark of the beta cell defect of the diabetic state. Although
it remains an attractive hypothesis and the suspicion of many observers, a specific effect
– over and above weight loss – of RYBG and/or BPD in resolving T2D and preserving
euglycaemia is still unproven.

Metabolic Syndrome

Dyslipidaemia improves with both sibutramine and orlistat, whereas blood pressure
falls amongst patients treated with orlistat. Rimonabant has beneficial effects on
components of the MetS. Consistent with the total weight loss, visceral adipose fat
mass has been shown to be reduced after bariatric surgery [50]. Improvements in
components of the MetS have also been observed consistently following bariatric
surgery, although they are less spectacular than the effects on diabetes. In the SOS
study, patients with hypertriglyceridaemia improved after surgical treatment com-
pared to controls, although there were only trends towards improvement in hyperc-
holesterolaemia at 10 years and no significant improvement in hypertension. In a
randomised controlled clinical trial comparing the effect of treating mild to moderate
obesity with LAGB to intensive medical program for 24 months there was a signifi-
cant improvement of the MetS [44]. Although potentially beneficial, these differences
fall short of the effects of specific lipid-lowering medications.

Hepato-Biliary Disease

Fatty liver, non-alcoholic steatohepatitis or non-alcoholic fatty liver disease (NAFLD)

are interchangeable terms that describe the excess fat deposition that may accompany

Emerging Concepts in the Medical and Surgical Treatment of Obesity 245

obesity and specifically insulin resistance and visceral adiposity, progressing to fibro-
sis and portal hypertension. In a recent double-blind randomised placebo-controlled
trial on 52 patients with NAFLD, orlistat was shown to improve serum transaminase
levels and steatosis on ultrasound in NAFLD patients [51]. In a prospective, histolog-
ical study examining subjects undergoing gastric bypass, reduced fat content and the
expression of factors associated with inflammation was demonstrated but there was
no effect on fibrosis itself [52]. At present, no hard outcome measures are available in
relation to retarding the natural history of NAFLD.

Obstructive Sleep Apnoea

Obstructive sleep apnoea (OSA) is a common complication of obesity, and its inci-
dence may be underestimated. In a recent open-labelled, uncontrolled cohort study,
10% weight loss with sibutramine was associated with a reduction in the severity of
OSA, with improvement in the Respiratory Disturbance Index and Epworth score (a
measure of sleepiness) over a 6-month period [53]. Most of the available data show a
reduction in the severity of OSA after bariatric surgery; in a prospective study, Dixon
et al. [54] showed improvement in the apnoea/hypopnoea index, Epworth score and
the need for assisted ventilation after LAGB.

Idiopathic Intracranial Hypertension

IIH is a well-recognised but relatively uncommon complication of obesity, although

data regarding the influence of dietary weight loss on IIH are scanty. Gastric bypass
has been shown to improve cerebrospinal fluid pressure and headache [55]. The
authors suggested that bariatric surgery should be the long-term procedure of choice
for severely obese patients with a higher rate of success than cerebrospinal fluid-
peritoneal shunting reported in the literature, although no comparative studies between
bariatric surgery and specific medical or surgical treatments have been undertaken.

Infertility and Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS) is a complex metabolic disorder that is defined by

irregular or anovulatory cycles, excess circulating androgens and morphological
changes that are recognised as structural polycystic change within the ovary. A large
body of evidence has arisen that demonstrates that PCOS is accompanied by insulin
resistance and subjects with PCOS are at higher risk of T2D and premature coronary
artery disease. In addition to the effects on fertility in relation to PCOS, obese subjects
have additional independent risk for infertility and pregnancy-associated complications.

246 Aylwin · Al-Zaman

 Demonstration of the effects of metformin on hyperinsulinaemia, ovarian
steroidogenesis and as an adjunct to clomiphene in the management of subfertility
established a role for metformin in PCOS [56]. Metformin appears to be safe to the
fetus when taken for the purpose of inducing fertility [57]. Improving insulin resis-
tance either through behavioural means or metformin appears to have similar benefi-
cial effects on the reproductive axis. There are few data regarding the effect of other
modalities of weight loss through pharmacological or surgical treatment. Essentially,
weight loss through medication as a means of treating PCOS is a largely unexplored
area. According to self-reporting, some previously subfertile women appear to have
achieved successful pregnancy after surgical weight loss [reviewed in 58], and several
series have reported reasonable perinatal outcomes after bariatric surgery in a popu-
lation known to be at risk of obstetric complications.

Psychiatric Co-Morbidity and Quality of Life

Psychiatric co-morbidity is common amongst obese individuals seeking specialist

management for obesity, with approximately 50% reporting symptoms of depression
and anxiety. In unselected population studies, increasing weight is associated with
reduced HRQL particularly in relation to physical functioning [59]. Successful weight
loss through behavioural interventions has proved valuable in short-term studies
with very low calorie diets [60]. Predictably, the degree of benefit after longer-term
follow-up is related to the maintenance of weight loss [61]. Medical treatment with
sibutramine amongst patients with T2D did not independently lead to improved
HRQL when compared to placebo, but patients that lost weight in either active or
placebo groups did benefit [62]. A crude estimate suggests that a 10–15% weight loss
is required to reap relevant improvement, and since relatively few patients succeed in
maintaining this degree of weight loss through either behavioural or medical strate-
gies, it is difficult to advocate such approaches on the basis of improving psychologi-
cal functioning or HRQL.
In contrast, numerous studies have demonstrated a positive effect for patients
undergoing bariatric surgery [42], and bariatric surgery is regarded as cost-effective
when considering outcome in terms of quality of life adjusted years. The SOS study
demonstrated an improved quality of life following bariatric surgery when compared
to matched obese subjects undergoing non-surgical management [63]. In a recent
randomised controlled trial specifically designed to evaluate comparing adjustable
gastric banding to intensive medical program for the treatment of mild to moderate
obesity, it was shown that the surgery group was associated with significant improve-
ment in the quality of life after 24 months of the trial [44]. We explored the relation-
ship between the change in eating behaviour and quality of life and proposed that the
specific effects of bariatric surgery brought about a shift in the perception of control
over eating contributing to an overall improvement in health status [64].

Emerging Concepts in the Medical and Surgical Treatment of Obesity 247

Advances in Bariatric Surgery

Arguably, the success of bariatric surgery owes more to serendipity than to science.
Drug discovery proceeds with an orderly and regulated progression through phase I
to phase V clinical trials. In contrast, surgical procedures evolve, building on the suc-
cess and adverse events of earlier procedures, and the mechanisms of weight loss are
somewhat obscure. Two observations have defined recent advances in this area: (1) a
reduction in appetite accompanies weight loss and (2) resolution of T2D appears to
occur prior to significant weight loss.

Effects of Bariatric Surgery on Appetite Reduction

The reduction in appetite after bariatric surgery has been long recognised but not
extensively studied. In a prospective study design, our group demonstrated that fol-
lowing RYGB, the sensation of fullness and a reduction in hunger was evident imme-
diately after a test meal and was maintained for 180 min. This effect was observed at
1 month and persisted at least to 6 months, despite a reduction in circulating leptin and
insulin and an increase in ghrelin that would be expected to increase hunger [65]. We
further demonstrated that the reduction in appetite was accompanied by an increase
in the negative experience of eating, which can be interpreted as either a conscious
adaptation to a smaller stomach or evidence for a restoration of negative feedback [64].
As early as 1982, researchers began to examine a possible humoral effect of the then
popular JIB. In a rarely cited paper, Atkinson and Brent demonstrated in a rodent
model of the JIB that serum derived from rats undergoing JIB had anorectic properties
when injected into control animals [66]. With the advent of radioimmunoassay for gut
peptides, patients who had undergone JIB were found to have elevated levels of peptide
YY (PYY) and enteroglucagons – a composite of products of the pre-pro-glucagon
gene. These observations became more significant once interest was reignited with the
growing body of evidence that gut peptides might contribute to appetite regulation. In
brief, a number of peptide hormones: peptide YY, glucagon-like peptide 1 (GLP-1),
pancreatic polypeptide and oxyntomodulin (OXM) have been shown to have
inhibitory effects on food intake in human and rodent studies, whereas the acylated
peptide hormone ghrelin is unique in stimulating food intake and appetite [67].
Shortly after the isolation of ghrelin from the stomach and the demonstration of its
orexigenic effects on meal size in man and adiposity in rodents, Cummings et al. [68]
showed that patients that had undergone RYBG had completely suppressed ghrelin
levels. This study provided the provocative notion that alterations in the levels of a gut
hormone might mediate the effects of malabsorptive bariatric surgery. A flotilla of
similar studies followed that had conflicting results, with ghrelin levels being
unchanged, decreased or even increased after RYGB. Variability of assays, surgical
techniques and experimental protocols may all contribute to the variability in results,

248 Aylwin · Al-Zaman

 50
After bypass
40 Lean controls
Obese controls
PYY (pM) 30 After banding

20

10

0
⫺30 0 30 60 90 120 150 180
Time point (min)

Fig. 4. PYY increase after bariatric surgery. PYY response to a test meal amongst obese and lean
controls, and patients undergoing RYGB or LAGB, demonstrating the exaggerated PYY response
after RYGB [74].

but overall it is unlikely that changes in circulating ghrelin represent a major contrib-
utor to the appetite-reducing effects of bariatric surgery [69].
Greater impetus to the effect of gut hormones on appetite regulation arose when
Batterham et al. [70] showed that peptide YY3–36 (PYY) limited meal size in lean
human volunteers and obese subjects. PYY null mice develop central adiposity that
may be reversed with exogenous treatment. Of particular interest, obese subjects are
not resistant to the effects of PYY, but exhibit a relative deficit that requires a larger
meal size to achieve an equivalent PYY response. Our group demonstrated that fol-
lowing RYBG, formerly obese patients had a greatly amplified PYY response to a
small test meal (fig. 4) [71]. This effect was not observed in patients who had lost sim-
ilar weight after LAGB, demonstrating that the effect was not simply a consequence of
weight loss. We further demonstrated in a prospectively designed study, a progressive
rise in PYY after RYGB over 6 months [65], maintained at least until 24 months
[unpubl. data]. Other groups have confirmed these results in both cross-sectional and
prospective designs with remarkable consistency [72].
The gut hormone response to a meal is not restricted to PYY and ghrelin. GLP-1,
better known for its incretin effects (see below), also has an effect on satiety. GLP-1
and other members of the enteroglucagon family are released in excess after RYBG,
and we have shown that enteroglucagon and GLP-1 are released in increased amounts
after RYGB [65]. See Aylwin [69] for a comprehensive review of the effects of bariatric
surgery on gut hormones.
Further work from Le Roux and colleagues [unpubl. data] has shown that suppres-
sion of the post-prandial PYY response with a somatostatin analogue increases meal size
and reduces satiety. Whilst these data do not specifically implicate PYY in mediating the

Emerging Concepts in the Medical and Surgical Treatment of Obesity 249

enhanced satiety after RYBG since somatostatin suppresses the release of other hor-
mones, they provide compelling evidence that gut hormones have a role in mediating
the reduction in appetite and food intake observed post-operatively in RYBG patients.
Taken together, the current data indicate a pleiotropic endocrine response to
RYGB that probably accounts for a significant component of its effectiveness. In con-
trast, purely restrictive procedures have little effect on the enteric endocrine system.
Dixon et al. [40] recorded post-prandial satiety in obese subjects who had undergone
LAGB, and randomly assigned them in a cross-over design to have different degrees
of band tightening by varying the amount of saline injected into the device. Although
the subjects may not have been entirely blind to the band tension, they reported
increased satiety with narrower band aperture in a dose-dependent manner. The
proximal portion of the stomach is richly innervated by vagal fibres that send signals
to the nucleus tractus solitarus that in turn relays information to the hypothalamus.
Although evidence is lacking, it is a promising hypothesis that interruption, a change
in pulse frequency or hyperstimulation of vagal afferents might account for the
anorexigenic effects of restrictive bariatric procedures.

Effects of Bariatric Surgery on Diabetes

Debate continues as to whether the improvement or even cure of T2D after bariatric
surgery arises as a consequence of weight loss alone or due to some ‘magic’ from the
procedure. In an animal model it was shown that the bypass of the duodenum and
jejunum could improve post-prandial glucose excursion in rats prone to diabetes,
independent of an effect on weight loss [73]. In human subjects undergoing BPD,
recovery of first-phase insulin release in patients with T2D became progressively
apparent over a 12-month period: impressive evidence that the pathological hallmark
of T2D could be reversed.
Potential mechanisms for these effects have been proposed to involve an increase
in the islet cell trophic incretin hormones, GLP-1 and gastric insulinotrophic peptide,
thought to be respectively either reduced or less effective in T2D. Both RYGB and
BPD increase GLP-1 secretion both during fasting and after meal, a consequence of
L-cell stimulation by early arrival of nutrients in the distal ileum [65, 74]. The secre-
tion of GLP-1 promotes insulin release, influences glucose metabolism by inhibiting
glucagon secretion, delaying gastric emptying and stimulating glycogenesis and
GLP-1 has also been shown to inhibit pancreatic islet cell apoptosis. The potential for
stimulation of insulin release after RYGB has been highlighted by the development of
post-prandial hypoglycaemia amongst formerly obese subjects who had previously
undergone RYGB and the development of nesidioblastosis has been observed [75].
The unwanted hypoglycaemia may be an unusual side effect of RYGB but it is strong
circumstantial evidence that RYGB somehow induces an exaggerated insulin
response that might be mediated by increased release of GLP-1 [74].

250 Aylwin · Al-Zaman

Potential New Pharmacological Strategies

Centrally Acting Agents

In many cases, agents have been developed for other indications, and an effect on
body weight observed as a side effect during phase II/III development. It is worth
noting that both sibutramine and rimonabant owe their current indications to a sim-
ilar provenance. The following are examples of each class and the available data on
their proposed effect in the management of obesity. For an exhaustive account of
agents under evaluation, see Foster-Schubert et al. [76].

Antidepressants: Fluoxetine/Sertraline and Bupropion

Fluoxetine and sertraline are selective serotonin reuptake inhibitors and have effects
beyond their antidepressant actions, and have been used to treat both binge eating dis-
order and night eating syndrome which are associated with severe psychological mor-
bidity and depression. Night eating syndrome was shown to respond to sertraline in a
small double-blind trial that demonstrated improved symptoms and modest weight loss
[77]. The use of fluoxetine may also improve psychopathology and depressive symp-
toms in subjects with binge eating disorder, although weight loss was not enhanced and
cognitive behavioural therapy is more potent in reducing bingeing [78]. The data avail-
able on the effect of fluoxetine on achieving body weight reduction remain conflicting.
In a meta-analysis including 13 studies, fluoxetine was shown to induce weight loss
ranging from 14.5 kg to a weight gain of 0.4 kg in studies lasting at least 12 months [79].
Bupropion is an atypical antidepressant that inhibits the neuronal uptake of nora-
drenaline, serotonin and dopamine and is currently indicated for the treatment of
depression and smoking cessation. In one randomised double-blinded clinical trial,
which involved 400 obese individuals with depressive symptoms, sustained release
bupropion was shown to induce more weight loss (average of 4.2 kg) than placebo
(1.7 kg); interestingly, resolution of depressive symptoms was more pronounced in
those who lost ⬎5% weight regardless of treatment category [80]. Similarly,
Anderson’s group reported a randomised double-blind control trial on 327 obese sub-
jects in which bupropion induced a net 5.1% weight loss over placebo.

Anti-Seizure Agents: Topiramate, Zonisamide

The anti-epileptic agent topiramate has been investigated as an anti-obesity agent follow-
ing the recognition that patients using the drug for epilepsy had unintentional weight
loss. In a randomised double blind study of 385 patients, topiramate reduced weight by
6.3% compared to 2.6% in the placebo arm [81]. Adverse effects of topiramate include
somnolence, cognitive dysfunction and transient amnesia leading to withdrawal in 21%,
although arguably better tolerated than other currently marketed obesity agents. A

Emerging Concepts in the Medical and Surgical Treatment of Obesity 251

recently reported multi-centre double-blind study amongst patients with T2D demon-
strated 6.5% weight loss compared to placebo (1.7%), with 0.6% reduction in HbA1c [82].
Zonisamide is another agent used in the treatment of partial epilepsy with
dopaminergic and serotonergic effects that has been investigated for obesity treat-
ment with promising early data.

Agents Affecting the Leptin-Melanocortin Pathway

The discovery of leptin initiated an avalanche of research into appetite regulation that
proceeded to define the interface of peripheral hormones and the hypothalamus, out-
lined in the chapter by Wren [this vol., pp. 165–181]. In brief, the system includes an
orexigenic (EAT!) pathway initiated in a low-insulin/low-leptin state, by activation of
NPY and AgRP expressing hypothalamic neurones, and an opposing anorexigenic
(DON’T EAT!) pathway via leptin’s stimulation of POMC expression acting at the
melanocortin receptor MC4R. Experimental mouse models demonstrate that both
sides of the system are required for normal functioning, and human subjects with
congenital mutations [22] testify to the importance of this system in extreme mono-
genic obesity. To what extent appetite regulatory mechanisms are relevant to more
common forms of human obesity remains to be established.

Leptin
To the far-from satiated pharmaceutical industry, the discovery of leptin – a hormone
produced by adipocytes that circulated in proportion to fat mass, crossed the blood
brain barrier and influenced satiety [83] – seemed almost too good to be true.
Although a handful of individuals have been found to have congenital leptin defi-
ciency, in the vast majority of obese subjects leptin levels are increased. The higher
level of leptin suggests either (1) a state of relative leptin resistance, where the anorex-
igenic effect of rising leptin concentration eventually overcomes the refractory cen-
tral sensor and reaches a steady state set at a high body weight; or (2) that leptin
is merely an anti-starvation hormone, relevant only in deficiency where low levels
promote an overwhelming drive to eat, but higher concentrations have no effect
beyond a threshold level.
In the first randomised double-blind dose-ranging controlled trial with recombi-
nant leptin, obese subjects lost up to 7.1 kg after 24 weeks at the highest dose
compared to 0.7 kg for placebo [84]. The effect, however, was non-specific, being
dependent on doses that achieved levels 20- to 40-fold higher than at baseline. In a
further study using a pegylated form of leptin in which levels of total serum leptin
were increased twofold, in 30 obese men over a 12 week period, there were no differ-
ences on weight loss, percent body fat or respiratory quotient between pegylated leptin
and placebo. Leptin treatment has, however, been shown to undermine the homeostatic

252 Aylwin · Al-Zaman

response to weight loss in the reduced-obese state and may yet have a role in weight
maintenance after behavioural weight loss.

Recombinant Variant Ciliary Neurotrophic Factor

Overcoming leptin resistance or augmenting the effect of circulating leptin represents
an appealing strategy for drug development. Ciliary neurotrophic factor (CNTF) is an
endogenous neuroprotective protein present in Schwann cells and astrocytes that was
found unexpectedly to induce marked weight loss in a study of patients with motor
neurone disease. CNTF activates the STAT3 2nd messenger system utilised by leptin,
and animal studies showed that CNTF could induce weight loss in both diet-induced
obese and leptin-deficient animal models [85], with initial blinded studies showing a
short-term effect. More intriguing are the apparently durable effects of CNTF beyond
the treatment period, recently demonstrated to be due to a trophic effect on POMC
neurones that participate in mediating an anorexigenic effect [86]. Alone amongst med-
ical strategies for the treatment of obesity, these early data suggest that CNTF might
offer a treatment that is not required on an open-ended basis to maintain its effect.

NPY/AgRP
The roles of NPY in the regulation of food intake and energy expenditure are highly
complex, due to the number of receptors (Y1–Y6) and their widespread expression. A
Y5R antagonist was demonstrated to suppress weight gain in rodents but in a large
double-blind study of 1,661 subjects, the Y5R antagonist MK-0557 had no clinically
relevant effect [87].

Gastrointestinal Hormone Agonists and Antagonists

Whilst leptin, and to an extent insulin, provide information about the state of avail-
able energy stores, a parallel system exists to inform the organism about the nutri-
tional value of recently ingested meals, and a growing number of peptides have been
identified that are released from the gastrointestinal tract in response to food intake.
Hormones released in the periphery that have an influence on central appetite regu-
lation make obvious and attractive targets for the treatment of obesity.

Amylin (Pramlintide)
Amylin is a peptide secreted by the pancreas in response to nutrients and other
insulinogenic stimuli; pramlintide is a subcutaneously administered synthetic ana-
logue of amylin. Amongst severely obese subjects (BMI ⬎ 40), pramlintide resulted
in significant reduction in weight (⫺3.2 kg placebo corrected) at 26 weeks with

Emerging Concepts in the Medical and Surgical Treatment of Obesity 253

favourable effect on glycaemic control [88]. Whilst this degree of weight loss in
severely obese individuals is unlikely to reap any additional benefit other than the
improvement in glycaemic control, this should be contrasted against the likely weight
gain were those subjects to have been treated with increasing insulin doses.

Cholecystokinin
Cholecystokinin (CCK) was the first gut peptide recognised to have anorexigenic
effects. CCK is released from the proximal small bowel into the circulation and its
effects on gall bladder contraction are well established. CCK also acts at as an agonist
at the CCKA receptors (alternately named CCK1R) present on peripheral vagal affer-
ents. Peripheral CCK administration has been shown to increase satiety and reduce
food intake acutely in man [89], although the effects of CCK are short-term and
chronic administration has not been shown to have a sustained effect [90].

Ghrelin
In contrast to other gastrointestinal hormones, ghrelin remains the only known circu-
lating orexigenic peptide. Ghrelin was initially identified as the ligand for the formerly
orphan G-protein-coupled growth hormone secretagogue GHSR1a receptor, but its
principal effects are to co-ordinate a protective response to energy depletion both
through peripheral effects on intermediary metabolism and a central effect on feeding,
augmenting calorie intake in man [91]. Ghrelin antagonism therefore represents an
obvious potential strategy in the management of obesity. Proof-of-principle for the
validity of ghrelin antagonism has been demonstrated with the use of polyethylene gly-
col stabilised RNA oligonucleotides (Spiegelmers) that have been demonstrated to
inhibit the orexigenic properties of ghrelin [92]. The oligonucleotide NOX-B11-2 had
caused reduced intake and weight loss in diet-induced obese mice with chronic treat-
ment [92]. Whether such agents can be deployed in human studies is far from clear,
but it is likely that other antagonists of ghrelin will be actively pursued.

Oxyntomodulin
OXM is a member of the enteroglucagon family of polypeptides, which includes
glucagon and glucagon-like peptides GLP-1 and GLP-2, products of the pre-
proglucagon gene. OXM is part of a co-ordinated ileal satiety response and its actions
are similar to PYY and GLP-1, and it is also released from the same cells [93]. OXM,
given pre-prandially by subcutaneous injection three times a day in a parallel blinded
study design, resulted in a mean weight loss of 2.3 kg over 4 weeks compared to 0.5 kg
in the placebo group [94]. The precise mechanism of action of OXM is not known,
but its effects can be inhibited by a central GLP-1 antagonist and abolished in a GLP-1
receptor knockout model, suggesting that it acts via GLP1 receptors. The development

254 Aylwin · Al-Zaman

and use of GLP-1 agonists should allow experimental approaches to determine
whether there is an additive effect of OXM in conjunction with GLP-1.

GLP-1 Agonists
The development of the long-acting GLP-1 analogue exendin-4 (exenatide) represents
the first incursion of a gut hormone into the mainstream pharmacopoeia. Exenatide is
resistant to degradation by dipeptidyl peptidase IV, has a longer half-life than the
native peptide and is now established as a therapy for T2D. In addition to its effects on
glycaemic control, exenatide has the additional advantage of weight loss, mean 4.0 kg
at 1.5 years [95]. Future studies are awaited in normoglycaemic obese human subjects.

Peptide YY
PYY was originally identified as modulator of gastrointestinal motility, released from
the L-cells of the small bowel and may have a role in delaying gut transit in malab-
sorptive conditions. The principal active form of PYY, PYY3–36 acts at the inhibitory
Y2 (NPY) receptor expressed by NPY neurons in the arcuate nucleus and has been
shown to act as an inhibitor of food intake. Recent data with an intranasal formula-
tion, however, have failed to demonstrate weight loss over a 12-week period [96].

Perspective

Public health initiatives, research into the aetiology of obesity, drug development and
establishing an increased capacity for bariatric surgery all have a role to play in the
future handling of obesity, but probably not in that order. It is becoming obvious that
increasing energy supply is closely associated with the increase of overweight and
obesity in western countries [97], and simply praying for a plateau rather than expect-
ing a reversal of the underlying trend may be more realistic.
The explosive pace of research into the adipose-hypothalamic and entero-
hypothalamic axes that have emerged as the principal homeostatic co-ordinators of
body weight will continue to offer opportunities for drug discovery. In this arena,
combination treatments have been slow to emerge, although it should be noted that
the combination of fenfluramine with fluoxetine has been shown recently to be
almost as potent as the now discredited fenfluramine-phentermine combination [98].
Medical therapy for obesity is very much in its infancy in comparison to other
chronic disorders, but it would be a fair bet to predict that treating individuals with
severe obesity will more resemble multi-drug treatment of hypertension rather than
the one-size-fits-all approach to hyperlipidaemia.
Management of the obese individual must extend beyond the boundaries of weight
management, and interventions need to be judged by their effects on co-morbidities.

Emerging Concepts in the Medical and Surgical Treatment of Obesity 255

We have developed a shorthand holistic assessment tool (King’s obesity staging criteria)
to categorise obese patients in a 10-dimensional matrix that enables us to assess inter-
ventions against a range of metrics in a given individual (table 1). We have chosen to
combine both medical and psychosocial co-morbidities, since this provides a more
complete guide to assessing and advising an individual. Just as treatment for a specific
cancer is tailored to suit the stage and grade of disease, so the management of obesity
can range from watchful waiting to palliative. In its broadest sense, both medical and
surgical strategies are essentially a means to cause a ‘down-staging’ of disease. One fun-
damental premise to our approach is that individuals up to obesity WHO grade I may
have no evidence of any complications of obesity (i.e. all criteria in stage 0), and under
these circumstances it is highly questionable whether either short- or long-term med-
ical intervention might be considered appropriate. Individuals with co-morbidities in
stage 1 are candidates for intervention, whether it might be a statin to reduce cardiovas-
cular risk, or behavioural support to move their ‘stage of change’ from preparation
through to action and maintenance. Most of the co-morbidities that fall under the func-
tional and psychosocial categories, and being relatively weight-loss resistant, may be
good indications for surgical intervention. It should be emphasised that our staging sys-
tem approach only represents a strategy for individual assessment, and does not repre-
sent a means of either stratifying overall risk or specifying a treatment. It is hoped that
over time, more obesity interventions will be evaluated against a broad range of criteria,
later facilitating the development of the model, and providing the data to recommend
interventions likely to be of benefit to patients with specific sets of complications.
At the time of writing, surgical treatment remains the gold standard for the man-
agement of severe obesity, and the progressive analysis of the mechanisms responsible
for the success of these procedures will continue to offer not only scope for more
refined procedures but also insight into the pathophysiology of morbid obesity in an
unusual interpretation of reverse pharmacology – understanding the disease through
examination of its treatment. It remains to be seen when or indeed whether medical
strategies will compete for supremacy.

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Front Horm Res. Basel, Karger, 2008, vol 36, pp 260–270

The Sociology of Obesity

Annika Rosengrena ⭈ Lauren Lissnerb
a
Department of Medicine, Sahlgrenska Universital Hospital/Ostra,
and bDepartment of Public Health and Community Medicine,
Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

Abstract
The current obesity epidemic is largely driven by environmental factors, including nutritional transition
towards refined and fatty foods with the growing production of energy-dense food at relatively low cost,
increased access to motor vehicles, mechanisation of work and sedentary lifestyles. These influences in
modern society are modified by individual characteristics. Ultimately, energy intake in excess of caloric
expenditure causes obesity, but why this occurs in some but not all individuals is not known. Obesity is
more prevalent in the lower socioeconomic classes but even so, there is a varying relation of socioeco-
nomic status with obesity between countries at different stages of development and, even in the
Western world, socioeconomic gradients with respect to obesity are both heterogeneous and in transi-
tion. Potential mechanisms for an effect of obesity on subsequent social status have been proposed, the
most obvious being related to the stigmatisation experienced by the obese. Obesity seems to be
causally related to mood disturbances, whereas there is no conclusive evidence that the reverse is true.
When considering psychological aspects of obesity, depressive symptoms are more likely to be conse-
quences, rather than causes of obesity. Copyright © 2008 S. Karger AG, Basel

While there is, by now, little doubt that the current obesity epidemic is largely driven by
environmental factors, it is equally clear that these influences in modern society are
modified by individual characteristics. There is a growing literature on sociological and
psychosocial factors in relation to obesity. In this chapter, we describe psychosocial cor-
relates of obesity from a societal, as well as from an individual, perspective.

Societal Factors

Obesity is ‘man-made’ and the current obesity epidemic is a sociodemographic phe-

nomenon. The remarkable recent changes in the prevalence in obesity worldwide,
coupled with the large geographical variation, bear witness to this. The obesity
Table 1. Causes of decreased
Separation of work, housing and shopping necessitating
energy expenditure in urban
society mechanised transportation
Increased automation at work
Increasing availability of home entertainment (computer, television)

pandemic was first apparent in the US, subsequently spreading to the rest of the west-
ernised world. With the urban transition in the developing countries in the world,
obesity is now rapidly increasing worldwide. Many developing countries are currently
affected by high rates of overweight that often surpass underweight as a public health
nutrition problem. In the case of urban Africa, recent analyses of national data on
body mass index (BMI) from women showed that prevalence of BMI ⱖ25 exceeded
that of BMI ⬍18.5 in 17 of 19 countries [1]. By 2020, two thirds of the global burden
of disease is estimated to be attributable to chronic non-communicable diseases, most
of them strongly associated with overnutrition [2]. The causes of the obesity epidemic
are multifactorial, including nutritional transition towards refined and fatty foods
with increased production of energy-dense food at relatively low cost, access to
motorised transport, mechanisation of work, and sedentary lifestyles. This increas-
ingly ‘obesogenic’ environment, reinforced by the cultural changes associated with
globalisation and urbanisation, makes the adoption of healthy lifestyles difficult. At
the same time undernutrition, while an uncommon problem in high- and middle-
income countries, still prevails in large segments of the population in low-income
countries.
On a societal level, decreasing daily physical activity is one of the important dri-
ving forces behind the obesity epidemic (table 1). Separation of work, housing and
shopping, often over long distances, necessitates the use of motorised transporta-
tion. Contemporary city structures strive to accommodate cars, buses and trams, but
not walking or cycling. Within the work environment, increased automation has led
to a lower workload with less physical exhaustion and with lower caloric expendi-
ture. During leisure, substantial portions of time are taken up by watching television
and using the computer. All these separate influences add up in expending less
energy, with obvious consequences for the net energy balance. It has been estimated
that a positive daily energy imbalance of 100 kcal/day results in slightly less than 1 kg
of weight gain per year, which is close to the actual weight gain observed in some US
populations [3]. The steady decline in physical activity is probably a major contribu-
tor to the rising prevalence of obesity. Small changes in behaviour, such as 30 min
per day of brisk walking or eating less at each meal, might contribute to arresting the
obesity epidemic [4]. Using terminology from a classic epidemiological triad (host,
vector, environment), it has been proposed that the contributions of physical inac-
tivity to the obesity epidemic may be attributed to combined effects of machines that
enable us to reduce the energy cost of everyday activities (‘disease vectors’) and other

The Sociology of Obesity 261

aspects of the physical environment that promote sedentary living patterns in the
‘host’ [5].
At the same time, dietary patterns represent the other side of the positive energy bal-
ance equation, and may also be considered as potential vectors in the obesity epidemic.
According to Swinburn and Egger [5], the main candidates for food-based vectors of
passive overconsumption of total energy are energy-dense foods (usually high in fat and
low in water and fibre), energy-dense drinks (usually high in sugar) and large portion
sizes. As the price of food relative to income has decreased, inadequate calorie intake is
now rare in most Western societies. Overconsumption of energy is induced by abun-
dant availability of inexpensive and energy-dense food. Food production has moved
away from the home to wholesale and marketing by large corporations. In restaurants,
servings have become increasingly larger. The social and commercial environments are
conducive to eating more, with increasing energy intake. The types of foods consumed
have also changed, for instance, with a rise in refined carbohydrates such as soft drinks,
which may balance out decreases in fat intake. Commercial policies and other environ-
ments influencing food prices and availability affect the choices people make in select-
ing healthy versus unhealthy food. Calorie-dense food is often less expensive than low
calorie dense bulky foods. Again, using the epidemiologic triad metaphor, food-based
vectors interact with obesity environments and cultural practices to produce obesity in
the host. The combined influences of increasingly obesity promoting agents and envi-
ronments produce a situation in which positive energy balance is accelerated whereas
forces that inhibit this development are overwhelmed [6].
Whereas obesity has primarily been considered to result from individual choices
against a background of genetics, it is becoming increasingly clear that the current
obesity epidemic is driven by an environment that promotes obesity, by affecting
individual lifestyle in the context of society. The rapid increase in obesity over the
past few decades, during which the environment has changed markedly, will obvi-
ously not be explained by major changes in genetic make-up. While studies of genetic
factors may improve our knowledge of the pathogenesis of obesity, we also need to
know more about societal changes that drive the changes in the prevalence of obesity.
A recent study demonstrated that local area is an important predictor of adult BMI in
women but not in men, supporting the need to focus on improving local environ-
ments to reduce socioeconomic inequalities in overweight and obesity [7]. This illus-
trates that individual lifestyle choices are constrained by societal factors, hampering
to a varying degree the individual’s ability to change lifestyle.
Nevertheless, while societal changes are what probably drives the obesity epidemic
overall, there is still scope to examine which individual determinants cause obesity in
a given individual. The health hazards of being obese have been abundantly docu-
mented, but, in contrast, individual determinants for obesity are not well understood.
Ultimately, energy intake in excess of caloric expenditure causes obesity, but why this
occurs in an increasing number of men and women is not known, nor do we know
why this occurs in some, but not all, individuals.

262 Rosengren · Lissner

Socioeconomic Status and Obesity

Is it relevant, when discussing individual determinants of obesity, to consider the

common assumption that specific psychological and/or risk factor profiles are
causally related to obesity? The reverse question must also be asked: what is the evi-
dence that psychological and socioeconomic characteristics are not the conse-
quences, but rather the causes, of the obese state?
There has been a strong interest in studying the relation between socioeconomic
status (SES) and obesity. Previous studies have shown that the association between
SES and obesity may vary by population, sex and age [8, 9]. However, a person’s body
weight status may also affect his/her education and occupational opportunities,
which subsequently affect his/her SES. A good understanding of the association
between obesity and SES has many important public health and policy implications,
particularly for the prevention and management of obesity. It is well known that obe-
sity is more prevalent in the lower socioeconomic classes and that this pattern is more
common among women than men. Even so, there is a varying relation of SES with
obesity between countries at different stages of development [10].
A landmark review of studies published prior to 1989 on SES and obesity proposed
that obesity in the developing world would be essentially a disease of the socioeco-
nomic elite [11]. However, in a recent review [12] on studies conducted in adult pop-
ulations from developing countries, the authors concluded from the studies they had
reviewed that obesity in the developing world is no longer a disease of groups with
higher SES. Additionally, the burden of obesity in each developing country tends to
shift towards the groups with lower SES as the country’s gross national product
increases. They also concluded that the shift of obesity in women with low SES appar-
ently occurs at an earlier stage of economic development than it does for men.
Socioeconomic gradients with respect to obesity, even in the Western world, are both
heterogeneous and in transition. For example, it has long been accepted that in the US
population, groups with low SES are at greater risk to be obese than people of high SES.
This perception, however, was challenged in a recent study [13]. Based on nationally
representative data collected in the National Health and Nutrition Examination Surveys
from American adults since the 1970s, the findings indicated an overall trend of a weak-
ening association between SES and obesity, with differing patterns across ethnic groups.
In a study of children and young people grouped by race, sex, and age, different results
were observed in the association between overweight and SES. Between 1988–1994 and
1999–2002, the ratio in the prevalence of overweight in adolescent boys with a low or
high SES decreased from 2.5 to 1.1 and from 3.1 to 1.6 in girls (fig. 1) [14]. Consistently
across almost all SES groups, the prevalence of overweight was much higher in blacks
than in whites, indicating highly complex patterns in the association of SES and over-
weight [14]. The authors speculated that television viewing might have been the pri-
mary type of inactivity in poor adolescents during the early part of the period they were
studying, whereas computers and computer games became more widely accessible and

The Sociology of Obesity 263

 20 Low SES
Boys Medium SES
Girls

Prevalence of overweight (%)

High SES
15

10

2
5

4
00

00
97

98

99

97

98

99
–2

–2
–1

–1

–1

–1

–1

–1
99

99
71

76

88

71

76

88
19

19
19

19

19

19

19

19
Fig. 1. Prevalence trends in the disparity of overweight in American adolescents 10–18 years
(1971–2002) in the low, medium, and high SES groups. Overweight was defined as a BMI ⱖ95th per-
centile. Adapted from [14].

affordable during the more recent part of the observation period, especially in high SES
groups. Accordingly, the energy intake and expenditure patterns of all adolescents
regardless of SES, particularly for white adolescent boys, became more similar, resulting
in smaller economic disparities of the proportion of overweight subjects. Similarly, data
from the US show that in the 70s there was as much as a 50% relative difference in obe-
sity prevalence among those with less than high school education, compared to people
with college education, but by 1999–2000, the difference had decreased to 14% [13].
Similar observations of a decreasing socioeconomic gradient in obesity were reported
in one Swedish study of young adults [15]. These findings underline that individual
characteristics are probably not the main cause of the current obesity epidemic. In addi-
tion, changing patterns of consumption and of physical activity directly affect socioeco-
nomic differences in a way that is not always predictable.
The other side of the obesity-SES association is whether obesity can be shown to be a
risk factor for subsequent changes in SES. Among the first studies indicating that obe-
sity might affect social mobility was based on a Swedish population-based sample of
women examined in the late 1960s showing that the shift toward higher socioeconomic
level since childhood was more common in normal-weight than in overweight women
[16]. However, this study did not establish which subjects were already overweight
as children. One US study, which classified adolescents and young adults as being
overweight or normal at baseline, found that the overweight group, 7 years later, were
less often married, had lower income and had completed fewer years of education.

264 Rosengren · Lissner

These prospective findings were independent of initial SES, suggesting that obesity cre-
ated a situation of downward social mobility, and, in addition, more often occurring in
women than in men. Thus, in addition to the physical health consequences of obesity,
obese people, particularly obese women, suffer from social stigmatization, prejudice,
and discrimination [17]. In a Swedish longitudinal study, no social difference in over-
weight was observed at age 16 years but at 30 years educational level was associated with
overweight, reflecting the cumulative influence of multiple adverse circumstances expe-
rienced from adolescence to young adulthood [18].
Potential mechanisms for an effect of obesity on subsequent social status have
been proposed, the most obvious being related to the stigmatisation experienced by
the obese. Leanness is often equated with beauty, success, fitness and self-control.
Obesity, on the other hand, is considered as undesirable as leanness is desirable, for
reasons that are more often related to cosmetic concerns than to actual or potential
medical complications. Specific examples for discrimination may be seen in the areas
of marital, employment and educational opportunities. If obesity has both social
causes and effects, a self-perpetuating cycle may be created that reinforces the rela-
tionship between low SES and obesity.

Stigmatisation in Obesity

When considering psychological aspects of obesity, it is widely believed that most

psychological disturbances are more likely to be consequences, rather than causes, of
obesity. One of the most compelling illustrations was reported in the early 1990s,
based on 47 patients who were, on average, 66 kg overweight before surgery for mor-
bid obesity, who lost 45 kg or more subsequently and who successfully maintained
weight loss for at least 3 years [19]. As a group, they perceived their previous morbid
obesity as having been extremely distressful. Most patients said that they would pre-
fer to be normal weight with a major handicap (deaf, dyslexic, diabetic, legally blind,
very bad acne, heart disease, one leg amputated) than to be morbidly obese. All
patients said they would rather be normal weight than a morbidly obese multi-mil-
lionaire. Thus obesity, as perceived by obese individuals themselves, is an extremely
serious handicap, although not always perceived as such by others. A recent review
summarised that extreme obesity is associated with significant psychiatric morbidity
and impaired health-related quality of life that in many cases imposes a greater bur-
den of suffering than the physical complications of obesity [20].
A second issue is how the obese individuals are treated by others. Negative atti-
tudes are prevalent, and exacerbated by idealisation of thinness in many Western cul-
tures. There are numerous examples of obesity-related discrimination, including how
children perceive overweight and obese peers, among employers, students’ ideas
about suitable spouses [21]. In a classic study on childhood stereotypes, young chil-
dren associated overweight in children with being lazy, dirty, stupid, cheats and liars

The Sociology of Obesity 265

[22]. The perception of obesity as a self-inflicted condition creates little sympathy for
the obese. Studies of morbidly obese patients show that in many instances they feel
that they are treated disrespectfully by the medical profession because of their weight,
that people look critically at them and their shopping cart when they go shopping,
and that their spouses and children do not like them to accompany them to social
functions because of their weight [23]. At the workplace, they often feel that they are
placed out of sight of the public and they may be passed over for promotion. When
the 47 patients studied by Rand and Macgregor [19] were asked the same questions
after gastric bypass surgery which they had answered before the surgery, their
responses were dramatically different showing a much more positive view of their
own position. Therefore, these perceptions are reversible, following efficient treat-
ment of obesity. This demonstrates that the obese suffer not only from negative atti-
tudes but, in addition, also from frank discriminatory behaviour [21].
Unsuccessful dieting may have negative psychological consequences, due to a sense
of distress, failure and self-blame assumed to accompany the visible consequences of
weight gain. The data supporting this are, however, mixed. In severely obese subjects,
the number of previous dieting attempts was associated with mood disturbance and
anxiety, and was a strong predictor of obesity-related psychosocial problems in women.
In contrast, an evaluation of young women before and after treatment at a weight clinic
did not detect any significant effect of one cycle of weight loss and regain on mood [24].

Obesity, Mood and Well-Being

In studies of the general population, early studies showed few consistent patterns with
respect to psychosocial distress and obesity, partly due to small samples and varying
assessment tools [21]. The relationship between BMI, smoking status, and depressive
symptoms was studied in a large US national sample, using validated instruments.
The investigators found that the relationship between obesity and depression varied
by sex. Among women, but not men, greater BMI was weakly associated with ele-
vated reports of depressive symptoms. This relationship remained significant after
controlling for age, years of education, and smoking status, indicating that relative
body weight is weakly related to psychological distress among women but not men
[25]. Another US study sought to test the relationships between relative body weight
and clinical depression, suicidal thoughts and suicide attempts in an adult US general
population sample comprising over 40,000 people. Outcome measures were past year
major depression, suicidal thoughts and suicide attempts. Among women, increased
BMI was associated with both major depression and suicide ideation. Among men,
lower BMI was associated with major depression, suicide attempts and suicidal
thoughts. There were no racial differences [26].
Studies of clinical populations have used psychometric instruments for assessment
of mental health and psychological functioning in obese individuals and compared

266 Rosengren · Lissner

them with healthy reference populations. In a much-cited Swedish study [27],
severely obese men and women reported distinctly poorer current health and less
positive mood states than the reference subjects, a situation that was worse in women
than in men. Anxiety and/or depression on a level indicating psychiatric morbidity
were more often seen in the obese, again more often in women. The obese subjects
rated their mental well-being worse than chronically ill or injured patients, for exam-
ple patients with rheumatoid arthritis, cancer survivors with no recurrence and
spinal-cord injured persons several years after injury. These symptoms improved
with subsequent weight loss from bariatric surgical treatment, providing further sup-
port for the idea that obesity was driving the psychological impairment.
In contrast to the widely accepted view that much of the observed psychopathol-
ogy associated with obesity is secondary to the obesity itself, one line of research sug-
gests that psychosocial stress induces central obesity and the metabolic syndrome
[28]. Originally suggested by Björntorp and colleagues, subsequent research has been
hampered by largely cross-sectional designs and lack of prospective data. However, a
recent study found that the effect of job strain on subsequent weight change was
dependent on baseline BMI in men but not in women [29]. In the leanest quintile
(BMI ⬍ 22) at baseline, high job strain and low job control were associated with
weight loss, whereas among those in the highest BMI quintile (⬎27), these stress
indicators were associated with subsequent weight gain. No corresponding interac-
tion between baseline BMI and weight change was seen among women. Furthermore,
the metabolic syndrome, with abdominal obesity as an important determinant, was
recently demonstrated to be closely related to cumulative exposure to work stressors
over 14 years, independent of other relevant risk factors [30]. Employees with chronic
work stress (three or more exposures) were more than twice as likely to have the syn-
drome compared to those without work stress. Altered adrenocortical function
induced by stress might influence hepatic lipoprotein metabolism and insulin sensi-
tivity at target organs, providing a partial explanation for the social inequalities in
obesity and obesity-related disorders. However, given the recent development with
decreasing socioeconomic differences in obesity seen in the US this is obviously a
complex issue.
Other than the conventional view of obesity as a condition carrying both medical
and psychosocial disabilities to the individual, obesity may also been viewed as a socio-
logical problem deriving from current cultural norms of beauty, normality and socially
acceptable behaviour. In other cultural contexts, where food was less plentiful, obesity
was often considered beautiful. On the other hand, a negative attitude towards obesity,
with stigmatisation of obese individuals, is not entirely a recent phenomenon, with
ascetism and self-denial idealised in many Western societies throughout the centuries.
One of the views driving the stigma of obesity is the notion that it is self-inflicted, with
the cardinal sins of sloth and gluttony emanating from low morals and poor character.
Despite increasing knowledge about the importance of heritability in obesity, and the
societal changes behind the obesity epidemic, these attitudes still prevail.

The Sociology of Obesity 267

 The growing stigma attached to all degrees of overweight reflects a society with a
contemporary ideal of extreme leanness. There is a belief that this attitude is setting
the stage for an epidemic of dieting and eating disorders.
One of the repeating themes emerging from research on psychosocial aspects of
obesity is the necessity for a gender perspective. Medically, due to the greater likeli-
hood of central adiposity in men, obesity may be said to confer a greater risk among
males. However, there is much evidence suggesting that the psychological and social
consequences of obesity are far worse for women. Even so, it should be noted that
increased prevalence of body dissatisfaction is occurring in both men and women.
Is there an association between obesity and depression? In Western society, being
overweight has been associated with increased risk for low self-esteem and depres-
sion. It has, however, not been quite clear whether obesity increases the risk of
depression, or if depression increases the risk of obesity, or if there is a reciprocal rela-
tion such that the obese are at increased risk of depression and the depressed are at
increased risk of obesity. Roberts et al. [31] summarised 11 studies studying this asso-
ciation using cross-sectional or prevalence study designs, with seven of these finding
some evidence of greater risk of depression among the obese. But while seven of these
studies found support for the proposition that the obese are at a greater risk for
depression, evidence was not uniformly robust, and the temporal relation between
obesity and depression was unclear. In their own study of 2,123 adults age 50 and
older, participants reported their height, weight and depressive symptoms during
interviews in 1994 and 1999. Subjects who were obese in 1994 had twice the risk of
becoming depressed in 1999 than subjects who were not obese in 1994. They did not
find any support for depression predicting subsequent obesity, after adjusting for
baseline obesity, or limiting the analyses to the non-obese at baseline. Accordingly, to
date, there is little conclusive evidence that obesity is caused by depression, whereas
obese people do seem more prone to develop future depression.

Conclusions and Implications

The obesity epidemic is driven by societal changes, as detailed above, but on an indi-
vidual level there is little evidence that psychosocial factors are causally related to obe-
sity. The socioeconomic influences are complex and variable; even in some of the
developing countries obesity is now becoming increasingly more associated with low,
not high, SES, whereas in the US, socioeconomic gradients may be decreasing. Obesity
seems to be causally related to mood disturbances, whereas there is no conclusive evi-
dence that the reverse is true. Although this has not been systematically investigated, it
seems plausible that negative and stigmatising attitudes towards obesity play a role in
the obesity-depression link. The low self-esteem in which many overweight and obese
people hold themselves secondary to the prevalent attitudes in society is probably also
important. In this respect, there are key areas in which these negative consequences

268 Rosengren · Lissner

should be mitigated. Current public attitudes towards ideal body weight need to be
examined, although there is a conflict in that a healthy body weight with respect to the
development of cardiovascular disease probably is in the low-normal range. In addi-
tion, longevity has been linked to reduced calorie intake in several species [32].
However, on balance, there is no clear health benefit from the extremely lean aesthetic
ideal propagated by advertisements, magazines and films. Discrimination and preju-
dice against the obese are inexcusable, particularly by health professionals, and should
be put on an equal level as discrimination based on race, sex or religion.

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Front Horm Res. Basel, Karger, 2008, vol 36, pp 271–286

Obesity in Art – A Brief Overview

Rosalind Woodhouse
Department of Endocrinology, Barts and the London, Queen Mary’s School of Medicine and Dentistry,
University of London, London, UK

Abstract
This brief overview of obesity in art will look at how fatness has been depicted in Western art and its
antecedents from classical times to the present day; what, if anything, this can tell us about how preva-
lent obesity was in previous centuries, and how the meanings attached to being fat may have altered
over the years. Copyright © 2008 S. Karger AG, Basel

The earliest sculptural representations of the body all show it as female, large-but-
tocked, obese even, although the smooth contours of the Venuses of Willendorf (c.
30,000–22,000 BC; fig. 1), and Lespugue (c. 34,000–29,000 BC; fig. 2) contrast with
the lumpy obesity of the Venus of Laussel (c. 25,000–20,000 BC; fig. 3). Nigel Spivey,
writing about the emphasis on ‘fatness and fertility’ in primitive art, offers neurosci-
entist Vilanyur. S. Ramachandran’s theory that
‘in technical terms these [excessively fleshy] features amount to hypernormal stimuli that acti-
vate neuron responses in our brain . . . something that comes naturally to us because our brains
are hard-wired to concentrate perceptive focus upon objects with pleasing associations, or those
parts of objects that matter most. For palaeolithic people, the female parts that mattered most were
those required for successful reproduction: the breasts and pelvic girdle. The circuit of the palae-
olithic brain, therefore, isolated these parts and amplified them’ [1].
Spivey argues that the tendency to distort images of the body recurs across many
cultures and periods of history. In other words:
‘The drift of all popular art is towards the lowest common denominator, and there are more
women who look like a potato than the Cnidian Venus. The shape to which the female body tends
to return is one which emphasises its biological functions . . .’ [2].
Other theorists have denied the element of exaggeration in prehistoric art, pointing
instead to the ‘relative linearity of warm-dwelling peoples, and the relative globularity of
cold-dwelling ones’ at least as far back as the Palaeolithic era, so that, even allowing for
some artistic licence, the figurines probably bear some credible relation to the models
1 2 3

Fig. 1. Venus of Willendorf (c. 30,000–22,000 BC). Naturhistorisches Museum, Vienna. © Naturhistori-
sches Museum, Vienna. Photo: Alice Schumacher. With kind permission.
Fig. 2. Venus of Lespugue (c. 34,000–29,000 BC). Musée de l’Homme, Paris. Reproduced with kind
permission from the Musée de l’Homme, Paris.
Fig. 3. Venus of Laussel (c. 25,000–20,000 BC). Musée d’Aquitaine, Bordeaux. © City of Bordeaux.
Photo J.M. Arnaud. With kind permission.

who posed for them, and the archaeological evidence can therefore be assumed to
establish ‘an empirical record as well as a merely aesthetic one’. This is particularly likely
in view of the fact that the most globular of the figures were found at sites which must
have been the coldest at the time they were sculpted, while the more linear figures have
tended to be uncovered at more southerly or warmer sites [3].
Ancient Greek and Roman sculpture and pottery art tended to portray the human
body in an idealised though still naturalistic way, a corollary of the ancient concept of
anthropomorphism – the belief that deities took human shape – but also perhaps as
further evidence of the influence of climate on body shape. However, in the interest
of aesthetics it was quite usual to attenuate the limbs, particularly the legs, and to
downplay or omit any deformity or sign of ageing or disease, even in portrait sculp-
ture. True obesity, as opposed to bulky muscularity, is notably absent in surviving
examples: excessive fat tended to produce a too solid ‘line’, rather than the more desir-
able qualities of fluidity and movement.

272 Woodhouse
 Because Greek civilisation laid down that pleasure was to be moderated for the
civic good, overindulgence, whether in food or other sensual pleasures, was seen as
ugly and improper. Hippocrates, father of Greek medicine, viewed fat as a disease [4],
and Plato, believing that excessive eating led to illness, recommended what in mod-
ern times has become known as the ‘Mediterranean diet’ of mainly cereals, vegetables,
fruits and fish, with strictly limited meat, alcohol and sweet things [5]. Fat people,
perceived as flawed, were marginalised by Greek society; the obesus, or stock fat char-
acter in Greek comedies by Aristophanes and others, was a sponger, drunkard, glut-
ton or idler, far from the contemporary ideal; a figure of mockery with the additional
function of flattering the spectator’s sense of superiority.
If the Greeks sought to moderate pleasure in eating, Christians sought to extin-
guish it altogether. Food was seen by some theologians as a distraction from religious
duties, as ‘external’ and polluting; preoccupation with food was viewed as the gateway
to worse sins, sloth and lust [6] and so over centuries, the Church evolved a complex
set of rules controlling when certain foods and drink could be consumed;
Wednesdays, Fridays and the period of Lent became by custom meatless, fasting days,
and by the later mediaeval period, it is thought there were between 140 and 160 des-
ignated fast days per year [7].
The early mediaeval painters shared the same overall idea of linkage between body
shape and moral character that the Greeks did, but with a completely different con-
cept of the value of the body: whereas to the ancients its form had been shared with
the gods and was essentially admirable, to Christians the flesh had been seen as a
cause of shame and humiliation since the Fall of Man in the Garden of Eden – and
therefore as implicitly sinful and not to be flaunted. Individual portraiture as we
know it today was unknown; one legacy of the Jewish foundation of Christianity had
been the belief that images of the human form could be construed as the breach of the
2nd Commandment (to make no graven images). Rulers were often depicted on a
larger scale than ordinary people; saints and lay people all tended to be shown as slim
or even emaciated, perhaps reflecting the great emphasis in the Early Church on
asceticism, fasting and the overall denial of the flesh or maybe just mirroring a world
where consumption was restricted, for the mass of people, and hedged around by reli-
gious prescription even for the prosperous few.
By contrast, clerical exemplars of gluttony seem to have been confined to fiction
(Friar Tuck in the legend of Robin Hood, and Chaucer’s monk, who ‘liked a fat swan
best, and roasted whole’) [8]. As with Classical painters and sculptors, though, it was
generally only those at the margins of the painter’s vision – working people, such as
the wine taster depicted here, the old, the sick and wrong-doers, who were depicted as
obese (fig. 4). This resonates with contemporary experience that in the West, it is the
lower socio-economic groups, with least disposable income, who are most prone to
obesity due to the cheapness of high-calorie foods.
Artistic realism, or at least the beginnings of it, is thought to originate with the
work of Jan van Eyck, claimed as the first real portrait painter [9], although the later

Obesity in Art – A Brief Overview 273

4 5
Fig. 4. Giotto, The Marriage at Cana (c. 1305–1313). Arena Chapel, Padua. Assessorato ai Musei.
Politiche Culturali e Spettacolo del Comune di Padova. With kind permission.
Fig. 5. Robert Campin, Portrait of a Stout Man, Robert de Masmines (c. 1425). Museo Thyssen-
Bornemisza, Madrid. © Museo Thyssen-Bornemisza, Madrid. With kind permission.

mediaeval convention of enacting great events of religious and secular history only by
stylised or idealised physical specimens went on for a long time – perhaps into the
mid-19th century [10]. Van Eyck’s contemporary, Robert Campin (c. 1375–1444),
could paint a realistic head and shoulders portrait of a stout aristocrat, Robert de
Masmines (fig. 5), but such realism was not extended to larger-scale works such as the
apocalyptic scenes of Hieronymous Bosch (c. 1450–1510) or the tableaux from peas-
ant life of his artistic heir Pieter Bruegel the Elder (1525–1569), which were intended
to portray character types rather than individual personalities.
But in one Bruegel painting, The Land of Cockaigne (1567; fig. 6), three plump
characters are depicted in a fairyland in which there is food in abundance (although
the winter of 1564 had been the coldest of the century, followed by harvest failure in
1565) [11]. Cockaigne or Luilekkerland, Dutch for ‘lazy-glutton land’, was a popular
fantasy in an age when food supplies were an obsessive concern. In addition to the
stock character of the greedy peasant, a soldier and a clerk have bedded down to sleep
after a feast. Beyond, a goose lies ready-cooked on a plate, a pig brings its own carving
knife with it, and the fence is made of sausages [12].
Cockaigne apart, there was a real dearth of images of body types at the extremes of
normal; shorter life expectancy may have contributed, because gross obesity, or con-
versely, emaciation, possibly suggesting serious disease states, would have been less

274 Woodhouse
Fig. 6. Peter Brueghel the Elder, The Land of Cockaigne (detail), 1576. Alte Pinakothek, Munich.
Reproduced with kind permission from the Alte Pinakothek, Munich.

sustainable in earlier times. On the other hand, there may have been less natural
variation in body type within localities – perhaps a corollary of restricted population
mobility, and greater consanguinity.
Obesity in the context of intermittent but unrelenting famines and plagues might
seem unlikely, but perhaps something to do with the repeated switching between
restricted and abundant fare, led to rebound weight gain like that observed in ‘yo-yo’
dieting today, especially as Western populations would have been largely of the
‘thrifty genotype’ variety. Also, the ever-present threat of food shortages, coupled with
the Church’s alternating seasons of feast and fast, may well have shaped people’s eat-
ing habits in ways difficult to imagine in affluent societies today; for instance, socially
sanctioned binge eating in times of plenty may have been the general rule, rather than
the exception [13]. There would have been an annual cycle of plenty in winter, when
the animals were slaughtered, and scarcity in spring and summer in the lead up to the
harvest, and people’s eating habits would have mirrored this, with excess at harvest
time and Christmas, and frugality during Lent.
Unpredictable food supplies may not have been the only stressor; long, cold win-
ters, and, for most people, extended periods of hard physical work with little time for
rest at harvest time, may have edged the population towards excess weight gain
related to relative sleep deprivation, which has recently been linked to up-regulation
of orexigenic ghrelin and down-regulation of anorexigenic leptin [14, 15].

Obesity in Art – A Brief Overview 275

Fig. 7. Antonio Moro, Catherine of Austria,
Queen of Portugal (c. 1552). Museo Nacional
del Prado, Madrid. All rights reserved. © Museo
Nacional del Prado, Madrid. With kind
permission.
Fig. 8. Frans Hals, The Banquet of the Officers of
the St George Militia of Haarlem, 1616. Frans
Hals Museum, Haarlem. (Nicolaes van der Meer
is shown in the centre foreground.)
Reproduced with kind permission from the
Frans Hals Museum, Haarlem.
Fig. 9. Frans Hals, Nicolaes van der Meer, 1631.
Frans Hals Museum, Haarlem. Reproduced
with kind permission from the Frans Hals
Museum, Haarlem. 7

Women’s body shape might have been more vulnerable to the prevailing condi-
tions than men’s, especially as women generally entered adulthood with a higher per-
centage of body fat than men. Menarche could be delayed if food supplies were
sparse, resulting, potentially, in fewer births before the menopause occurred. Again,
in theory, multiparous women would tend to lay down more body fat over the course
of their fertile lives (pregnancy itself being an obesogenic process) than the childless,
presumably leading to a greater difference in BMI, all other factors being equal,
between young, unmarried women, and older mothers, than between groups of men
of comparable ages. Social historian Peter Laslett has estimated the average number
of children per pre-1700 marriage in England as 5, or up to 8 provided that maternal
death did not supervene [16]. If the rich and powerful did became obese, though,
they could choose to disguise it with flattering clothing or flaunt it as a privilege of
rank, as in the many ‘swagger’ portraits of Henry VIII [17]. Antonio Moro’s painting
of Catherine of Austria, Queen of Portugal (fig. 7), though, is an example of the
Renaissance tradition of pregnancy portraiture, rather than a depiction of an obese
woman. Pregnancy portraits like these served both as a commemoration of the
important occasion of pregnancy and a visual ‘insurance policy’ in case the mother
did not survive: at the time of painting, Catherine of Austria was 45 years old, and as
a very elderly mother-to-be was probably at far greater risk from childbirth than a
younger woman.

276 Woodhouse
8 9

During the later mediaeval period, the introduction of calorie-dense food crops
from the New World, most importantly rice, maize and the potato [18], innovations
in the preservation of meat and fish by salting, and the weakening of religious embar-
gos on consumption, led to an enrichment of the common diet. At the same time, the
upheaval of the Reformation, urbanisation and the beginnings of capitalism, led to
big changes in who commissioned works of art and why. Church patronage of art
continued, but increasing numbers of lay people with the funds to engage artists often
chose from a wider range of secular and religious themes: the body ceased to be a
focus of shame, to be depicted modestly, in a stylised way, and started to be a mar-
ketable commodity, to be promoted by the sitter or the artist, depending on who held
the real power in the transaction.
By the early 17th century, Amsterdam had overtaken Antwerp as the great interna-
tional port of the north and the chief banking centre of Europe, and it was here, in the
Dutch Republic, that there was a great boom in portraiture, and evidence in these pic-
tures of the results of a more stable food supply and better diet. Art historian Kenneth
Clark wrote that we know more about what the 17th-century Dutch looked like than
we do about any other society, except perhaps the 1st-century Romans, and he singled
out Frans Hals’ work as the exemplification of this [19]. Interestingly, there is at least
one occasion where Hals (1582–1666) painted the same individual more than once,
enabling us to see his figure bulking up over the years: Nicolaes van der Meer, a

Obesity in Art – A Brief Overview 277

 This picture is available at
http://www.nationalgallery.org.uk.

Fig. 10. Emmanuel de Witte,

Adriana van Heusden and Her
Daughter at the New
Fishmarket in Amsterdam,
1661–1663. The National
Gallery, London. Photo
© The National Gallery,
London. With kind permission.

Fig. 11. Peter Paul Rubens,

Drunken Silenus and Satyrs,
1616–1617. Alte Pinakothek,
Munich. Reproduced with
kind permission from the
Alte Pinakothek, Munich.

278 Woodhouse
wealthy Haarlem brewer and burgomaster, depicted first, aged about 42 in 1616, in a
large group portrait, Banquet of the Officers of the St George Militia (fig. 8), and subse-
quently in a portrait of 1631 when he would have been around 57 years of age (fig. 9).
The well-fleshed appearance of people from all social strata in Holland reflected
the absence of the severe famines experienced elsewhere in Europe during this period
[20] and gives an air of bustling prosperity to genre paintings such as the market
scene by Emmanuel de Witte (c. 1616–1691/1692) (fig. 10). Allegedly it is with 17th-
century Dutch portraiture that breasts are seen as attractive for the first time: previ-
ously, unobtrusive, small breasts were to be preferred; large breasts being linked with
moral laxity and even witchcraft [21]: this novel voluptuousness gives another clue to
Holland’s being a well-nourished society.
A handful of prominent Flemish and Dutch artists stand out as advocates of the larger
body. Among the best known, Rubens (1577–1640) and Rembrandt (1606–1669) both
dwelt on the texture of flesh, but whereas Rubens concentrated on allegorical portraits or
tableaux featuring the legendary or the lusciously nubile (fig. 11, 12), Rembrandt, chron-
icler of life’s misfortunes, depicted all conditions of men and women, and was accused in
his day of seeking out the gratuitously unappealing (fig. 13). Later, Degas (1834–1917)
used a similarly wide range of (mainly female) subjects as Rembrandt for his mainstream
work, but it is in his less well-known brothel monotypes that he explores a very different
kind of nude: squat, short-necked (fig. 14) and very far from his pastel studies of ballet
dancers (fig. 15). Renoir’s (1841–1919) women ‘massive, ruddy … with the weight and
unity of great sculpture’ (fig. 16) [22] continue in the tradition of Rubens, rather than
emulating Degas’ realism. However, in both instances there was an emphasis on fleshi-
ness, either as a mark of sensuality or as a reflection of moral turpitude.
Heaviness and obesity had now been synonymous with wealth, success and ele-
vated social status, for centuries, but the link was soon to be put into reverse by a
complex blend of economic and social developments: by the later 19th century,
advances in agricultural methods, food processing and transportation, had brought a
varied, calorie-rich diet within the reach of all but the poorest, across much of Europe
and North America, opening up the possibility of fatness as a life ‘choice’ for the
many, for the first time ever. However, for the elites,
‘Slimness, together with speed, productivity and efficiency, were beginning to be advocated as a
new aesthetic and cultural model. A new Puritanism, which shared obvious traits with traditional
Christian penitence, re-launched the image of a lean, slender and productive body; the bourgeois
body which ‘sacrifices itself ’ to the production of goods and wealth’ [23].
For the privileged minority, eating to excess as a way of displaying wealth and priv-
ilege was gradually being replaced by other forms of conspicuous consumption: the
concept of overweight being a hindrance to living a newer, more fluid kind of ‘good
life’ dawned first with those at the top of society, and diffused downwards [24].
In the early stages of this transformation, slimness would have been seen as a novelty
(just as obesity had once been) for the majority of people. Fleshiness was still linked to
prosperity in the collective mind, and thinness was often associated with tuberculosis

Obesity in Art – A Brief Overview 279

Fig. 12. Peter Paul Rubens,
The Three Graces, 1636–1638.
Museo Nacional del Prado,
Madrid. All rights reserved.
© Museo Nacional del Prado,
Madrid. With kind permission.

Fig. 13. Rembrandt van Rijn, Seated Female Nude

(c. 1631). British Museum, London. © The Trustees
of the British Museum, London. With kind
permission.

280 Woodhouse
and chronic ill health [25]. It was only at the very end of the 19th century that slimness,
rather than obesity, began to be seen (first in the United States) as a desirable standard
for all, heralded by a dramatic increase in the numbers of advertisements for diets, and
editorials in the popular and medical press on the dangers of excess weight [26].
Suggested reasons for why disapproval of obesity gained ground so quickly have
included deliberate manipulation by an emergent diet industry, an increased middle-class
interest in athleticism (manifested by the bicycle craze of the 1880s and 1890s), both
perhaps springing from accelerating industrialisation and urbanisation, and an overall
speeding up of the pace of life for everyone. Now, to aspire to slimness meant to stand
out from the crowd, just at a time when most people had managed to achieve the req-
uisite standard of living to be plump. In addition, photographic portraiture was
becoming increasingly accessible and revealing to its subjects their true, three-dimen-
sional shape for the first time. More reliable methods of contraception were becoming
generally available; women could more easily limit family size, and so reduce the
amount of weight they put on during their fertile years. In this new ‘machine age’, car-
rying excess weight might become a hindrance to ‘staying ahead’ [27].
Once the connection between slimness and social advantage had been formed, it
was just a short step to obesity becoming socially undesirable, stigmatising even: by
the early 20th century, this had been reinforced by insurance companies’ promoting
ideal body weight to height tables [28], showing that the medical establishment was
now ‘on board’ also.
During the century since then, the desirability of slimness over heaviness has been
accepted more or less unchallenged by Western societies: its cachet has increased as
the average Western citizen has become fatter and the population profile has aged –
slimness now being associated with youth. ‘Super-sizing’ of the human body in art
has continued, but has been reserved for monumental sculpture such as the socialist
realist statuary of countries of the former Soviet bloc, for surrealist interpreters of the
human form or for artists with agendas involving humour, social comment, or a
voyeuristic take on the outsized.
Lucien Freud (b. 1922), speaking about his model for Benefits Supervisor Resting,
admitted that he ‘had perhaps a predilection towards people of unusual or strange pro-
portions’ and had become aware of ‘all kinds of spectacular things to do with her size,
like amazing craters and things one’s never seen before’ [29]. (Indeed, one art historian
found her body proportions to be identical to those of the Willendorf Venus [30]).
Jenny Saville (b. 1970) was well-known for her massive, uncompromising canvases
of naked, obese women even before the controversial 1997 ‘Sensation’ exhibition at
the Royal Academy, where she shared billing with others similarly engaged with
mutilated and abnormal forms. She started painting in the 1980s when ‘everyone was
obsessed with the body – it was all about dieting, the gym, the body beautiful.
Pornography and AIDS were the big debates’ [31]. Her huge images were always
female, ‘massive as the Eiger’, ‘daunting’ and ‘confrontational’ [32]. Sponsored by
Charles Saatchi, she spent part of 1994 in New York observing and photographing

Obesity in Art – A Brief Overview 281

plastic surgery procedures, subsequently expanding her repertoire with studies of
liposuction, bariatric surgery, and transgendered bodies (fig. 17).
James Gillray (1756–1815) and Thomas Rowlandson (1756–1827; fig. 18), popular
and successful satirists, underlined the foibles of British society by means of exagger-
ated body types for stock characters such as the obese country squire or rector, the
skinny doctor and the plump young woman ‘on the make’, and it was usually the fat
characters who were the most comical and lampooned. This was especially true for
Gillray, whose political cartoons made much of ‘Prinny’s’ (the future King George
IV’s) corpulence, and linked this with his supposed moral and intellectual torpor.
Napoleon was similarly dismissed in his cartoons as a quarrelsome, squat dwarf.
Beryl Cook (b. 1926) has continued the humorous tradition, depicting benevolent
endomorphs in a style blending surreal and naive. Comparisons have been made with
Gillray, Hogarth and Pieter Bruegel. Cook admits to going out to clubs, bars and other
likely settings for her paintings and covertly making sketches to work from – she has
described herself as being an introvert – not as at all as her characters appear – and so
her pictures involve a sometimes voyeuristic, but never sleazy, take on everyday plea-
sures. Her figures are invariably rotund and so she may be the artist who best repre-
sents the recent upward trend in BMI. In fact, this could be one factor in her
popularity.
Fernando Botero’s characters share the same pneumatic body type as Beryl Cook’s,
but his subject matter is wider ranging, encompassing religious and political themes
and still life as well as genre scenes. Botero (b. 1932) emigrated from South America
to Europe, studying the old masters before arriving at his now familiar style by the
mid-1960s: figurative, but not realistic; inflated, balloon-like figures against back-
drops of similarly voluminous objects. Perhaps influenced by growing up in
Colombia during a time of civil unrest, some of his pictures show a critical awareness
of political realities. In Botero’s Official Portrait of the Military Junta the implicit men-
ace and violence of the military subjects depicted are here at variance with the style of
their depiction, as plump, sometimes childlike figures. Unfortunately, the image can
not be reproduced here, on the grounds that ‘Mr Botero objects to any usage of his
work in connection with health or weight issues. This is not the message that his work
is designed to send’ [33].
Mariana Hanstein, writing about Botero’s style explained it thus:
‘Whatever theme he takes up, his eccentrically expansive style robs it of harshness, viciousness,
extremism . . . his exaggerated volumes are precisely the magic wand with which he transforms life
and the world and transports them into a floating unreality [34].
Others have seen his subject matter as ‘tamed to death’ representing a created
world ‘enormously fat and complacent’ [35], although Botero himself has explained
his use of obese forms as ‘ the expression of abundance’ and claimed that ‘in art, as
long as you have ideas and think, you are bound to deform nature. Art is deformation’.
Returning to the question of whether obesity was more or less prevalent compared
with our own times, it is of course, impossible to be sure. Moderate and extreme

282 Woodhouse
Fig. 14. Edgar Degas, The Customer,
1876–1877. Musée d’Orsay, Paris. Reproduced
with kind permission from the Musée d’Orsay,
Paris.

Fig. 15. Edgar Degas, Dance Lesson, 1872. Musée d’Orsay, Paris. Reproduced with kind permission
from the Musée d’Orsay, Paris.

Obesity in Art – A Brief Overview 283

16 17

Fig. 16. Pierre-Auguste Renoir, The Great Bathers (The Nymphs), 1918–1919. Musée d’Orsay, Paris.
Reproduced with kind permission from the Musée d’Orsay, Paris.
Fig. 17. Jenny Saville, Plan, 1993. Gagosian Gallery, New York, N.Y. © Jenny Saville. Courtesy of
Gagosian Gallery, New York, N.Y. Photograph by Robert McKeever.

obesity as we understand it today in industrialised societies, whether at first hand, or

via the media, seems much less prevalent in the artworks of previous centuries, what-
ever type of person is being represented, across all social strata. But it is always diffi-
cult to determine how far paintings and sculpture revealed the painter’s aspirations
for his sitters (and the sitters’ for themselves) rather than how things actually were in
reality. (Kenneth Clark has commented that in art, the instinctive desire is ‘not to imi-
tate but to perfect’ [36]). Imagery is culturally determined and these images should be
read, not as straightforward documents, but within a framework of contemporary
artistic practices.
Certainly, gender differences in how obesity was depicted run through the whole
history of Western art: women were depicted nude more often then men, and hence it
is much easier to assess the amount of fat they carry. Anne Hollander, costume histo-
rian, has written that the naked body is rendered in art as if it retains the imprint of its
dress – that though clothing has been removed, the nude body has been cast in its
mould [37]. Fashion has probably always influenced how the body was represented:
what was currently unfashionable at any time may have been simply ‘edited out’.
It does seem likely, though, that once being fat had ceased to be a life-saving tac-
tic for the mass of people, there came to be an innate sense of what was acceptable
for the body in terms of size – a ‘happy medium’ where the body had enough
padding for warmth and protection, but not sufficient to get in the way of everyday

284 Woodhouse
Fig. 18. Thomas Rowlandson, A Little Tighter,
1791. British Museum, London. © The Trustees of
the British Museum, London. With kind
permission.

activities [38]. In other words, once the daily business of survival ceased to be a
struggle, conspicuous markers of success other than extreme obesity would have
been sought. Even so, from the evidence, the ideal weights for both men and women
would probably have been heavier than present day ones for most of the period
under consideration.
The trim, athletic body proportions of classical art were feasible in the context of
stable, prosperous, mercantile societies with good and varied food supplies and a
warm climate, but when, subsequently, contentious northern European civilisations
operating in colder climates became pre-eminent, the depicted ideal was replaced by
a stockier, less elegant model. From early modern times until just over a century ago,
excess weight had positive associations with wealth, success, physical strength and
health, and none of its current negative associations with sudden death, chronic dis-
ease, shorter life expectancy and ‘loser’ social status. Intimations that excess weight
might have drawbacks coincided with a ‘democratisation’ of obesity, as a high-calorie
diet came within the reach of the majority, and led to slimness soon replacing heavi-
ness as a mark of social distinction, initially just for women, but subsequently for men
as well.
Fat in art could no longer be so ‘mainstream’, once the body ideal had shifted, but
still remained as an important theme in painting, particularly in naive art. The para-
dox now is that while thinness has become ever more valued, in real life and in the
media, the prevalence of obesity in society has soared, and even Saville and Freud
nudes no longer outscale everyone around them.

Obesity in Art – A Brief Overview 285

References
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2 Clark K: The Nude. London, Penguin Books, 1964, p 87.
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10 Clark K: Civilisation. London, BBC & John Murray
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13 Pleij H: Dreaming of Cockaigne: medieval fantasies
of the perfect life. New York, Columbia University
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17 Klein R: Eat Fat. New York, Vintage Books, 1996, pp
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Blackwell, 1994, pp 101–104.
Rosalind Woodhouse, BA Hons
Department of Endocrinology
Barts and the London, Queen Mary’s School of Medicine and Dentistry, University of London
Charterhouse Square, London EC1M 6BQ (UK)
Tel. ⫹44 20 7882 6238, Fax ⫹44 20 7882 6197, E-Mail rosalind.woodhouse@sth.nhs.uk
Copyright. The author and the publisher have made every effort to obtain permission for all copyright-protected
material. Any omissions are entirely unintentional. The publisher would be pleased to hear from anyone whose rights
unwittingly have been infringed.
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19 Clark K: Civilisation. London, BBC & John Murray
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20 Schama S: The Embarrassment of Riches: An Inter-
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24 Featherstone M, Hepworth M, Turner BS: The Body:
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Woodhouse
 Author Index

Ahima, R.S. 182 Lissner, L. 260

Al-Zaman, Y. 229
Armitage, J.A. 73 McPhee Chapman, I. 97
Aylwin, S. 229 Morton, N.M. 146

Beales, P.L. 37 Osei, S.Y. 182

Beedle, A.S. 61
Parton, L.E. 118
Clarke, I.J. 107 Poston, L. 73
Cota, D. 135
Raubenheimer, D. 61
Farooqi, I.S. 1 Rosengren, A. 260
Rutter, G.A. 118
Gluckman, P.D. 61
Goldstone, A.P. 37 Sabin, M.A. 85
Grossman, A.B. VII, 198 Seckl, J.R. 146
Shield, J.P.H. 85
Hanson, M.A. 61 Stumvoll, M. 12

Kiess, W. 12 Taylor, P.D. 73

Kola, B. 198
Korbonits, M. IX, 198 Weaver, J.U. 212
Körner, A. 12 Woodhouse, R. 271
Kovacs, P. 12 Wren, A.M. 165

287
Subject Index
Adipokines, see also specific adipokines
functional overview 182, 183, 189, 190
types and functions 184, 185
Adiponectin
AMP-activated protein kinase interactions
190
functional overview 184
levels in obesity 189
receptors 190
structure 189
Adipsin, functional overview 185
Aging, see Elderly
Agouti-related peptide (AgRP)
antagonist therapy 253
appetite regulation 109, 139, 169
Albright’s hereditary osteodystrophy (AHO),
features 42, 43
Alström syndrome (ALS), features 40, 41
AMP-activated protein kinase
adiponectin interactions 190
adipose tissue metabolism role 201, 202
AMP activation mechanisms 199
endocrine pancreas effects 202
functional overview 198, 199
hypothalamus function 202
insulin secretion control 119, 126
leptin targeting 187
liver metabolism role 201
metabolic hormone mediation 203
obesity activity
animal models 203–205
288
humans 206, 207
skeletal muscle metabolism role 199–201
whole body metabolism regulation 207
Amylin, therapeutic potential 253, 254
Anandamide, endocannabinoid system 137,
138
Angiotensin II, adipokine activity 186
Animal models, obesity
AMP-activated protein kinase activity
203–205
appetite regulation in large animals and
birds 108–110
epigenetic effects 115
genetic models in livestock 112
insulin dynamics in ruminants 111
leptin effects 111, 112
livestock advantages over rodents 107, 108
natural models of adiposity changes
hibernation 115
migratory birds 114, 115
reindeer 114
predisposition studies 113
Apoptosis, fatty acid induction in ␤-cells 122,
123
Appetite
aging effects 98, 99
agouti-related peptide regulation 109, 139,
169
bariatric surgery effects 248–250
cholecystokinin satiety signaling 172
ghrelin regulation 109, 110, 168, 169
 leptin regulation 109 DNA microarray analysis 124, 125
melanocortin system regulation 110 fatty acid-induced apoptosis 122, 123
neuroendocrine control 68 genetics 120–122
neuropeptide Y regulation 109, 110, 139, glucolipotoxicity 122
169 mitochondrial oxidative metabolism
regulation in large animals and birds 125, 126
108–110 peroxisome proliferator-activated
2-Arachidonoylglycerol (2-AG), receptor-␥ 124
endocannabinoid system 137, 138 signaling processes 125
Area postrema (AP), peripheral signals of SREBP1c 123
energy balance 167 loss in diabetes 119
ARNT, expression in diabetic ␤-cells 124 microRNA regulation of function 127
Art, obesity representations stimulus-secretion coupling 118, 119
ancient Greece and Rome 271–273 Body mass index (BMI)
18th century 279 children 86–88
famine and plague 275 classification 73, 229
medieval period 273–277 elderly 97, 98
19th century 279, 281, 283 Börjeson-Forssman-Lehmann syndrome
prospects 285 (BFLS), features 52
17th century 277–280 Bupropion, obesity management 251
20th century 281, 282, 284
women’s body shape 276, 284 Candidate gene
Association analysis, genetic dissection of approach for genetic dissection of complex
complex diseases 16 diseases 14
diabetes type 2 risk genes
Bardet-Biedl syndrome (BBS) CDKAL1 26
association studies 40 CDKN2A 26
clinical features 37–40 genome-wide scans 25, 26
obesity 40 IGFBP2 26
Bariatric surgery TCF7L2 24, 25
appetite reduction effects 248–250 gene-gene interactions 26, 27
childhood obesity management 94 obesity risk genes
complications 243, 244 ENPP1 21, 22
diabetes type 2 response 245, 250, 251 FTO 22, 23
elderly patients 104, 105 INSIG2 20, 21
gut hormone response 179, 248–250 peroxisome proliferator-activated
malabsorptive and hybrid procedures 242, receptor-␥ 18–20
243 Cannabinoids, see Endocannabinoid system
metabolic syndrome response 245 Cardiovascular disease, AMP-activated
non-alcoholic fatty liver disease response protein kinase role 207
246 Carpenter syndrome, features 42
obstructive sleep apnea response 246 Catecholamines, thyroid hormone
restrictive bariatric surgery 241, 242 interactions 216
success criteria 240, 241 CDKAL1, diabetes type 2 candidate gene
weight loss outcomes 243 26
Beta-cell CDKN2A, diabetes type 2 candidate gene
AMP-activated protein kinase activation 26
effects 202 Children
diabetes type 2 defective insulin secretion genetic dissection of complex diseases 17
mechanisms growth importance on long-term health
dense core vesicle exocytosis 126, 127 85, 86

Subject Index 289

 obesity SREBP1c 123
causes 88, 89 loss 119
consequences candidate genes
cardiovascular complications 90 CDKAL1 26
metabolic syndrome 90 CDKN2A 26
non-alcoholic fatty liver disease 91 genome-wide scans 25, 26
respiratory complications 90, 91 IGFBP2 26
type 2 diabetes 89, 90 TCF7L2 24, 25
definition 86–88 childhood obesity effects 89, 90, 230
management 92–94 maternal effects on offspring 76, 77
prevalence 88 obesity treatment response 244, 245, 250
prevention 91, 92 Pima Indian studies 17, 18
Cholecystokinin (CCK) Diet-induced obesity mouse, AMP-activated
energy balance signaling 166 protein kinase activity 204
satiety signaling 141, 172
therapeutic potential 254 Elderly
Ciliary neurotrophic factor (CNTF), obesity aging effects
management 253 body composition
Cohen syndrome (CS), features 41, 42 fat stores 99
Cortisol sarcopenia 99, 100
cortisone therapy 150 body weight 98, 99
levels in obesity 148, 149 food intake and appetite changes 98
Cushing’s syndrome obesity
causes 220, 221 causes 100
clinical features 147, 220 consequences
diagnosis 222, 223 beneficial effects 102
epidemiology 221 morbidity 102
11␤-hydroxysteroid dehydrogenase mortality 101
defects, see 11␤-Hydroxysteroid management
dehydrogenase lifestyle modification 103, 104
obesity mechanisms 222 medications and surgery 104, 105
pseudo-Cushing’s syndrome 221, 222 rationale 102, 103
prevalence 97
Depression, obesity comorbidity 266–268 Endocannabinoid system (ECS)
Developmental origins of health and disease, cannabinoid receptors
see Fetal environment; Maternal obesity agonists and antagonists 138
Diabetes type 2 antagonist therapy for obesity 142,
beta-cell 143
defective insulin secretion mechanisms overview 136, 137
dense core vesicle exocytosis 126, endocannabinoid types 137, 138
127 energy balance regulation
DNA microarray analysis 124, 125 hypothalamus 139
fatty acid-induced apoptosis 122, peripheral metabolism 140, 141, 144
123 reward system 140
genetics 120–122 obesity role 141, 142
glucolipotoxicity 122 ENPP1, obesity candidate gene 21, 22
mitochondrial oxidative metabolism Epidemiology, obesity 74, 147, 165, 198
125, 126 Epigenetics
peroxisome proliferator-activated complex diseases 27, 28
receptor-␥ 124 environmental factor studies in livestock
signaling processes 125 115

290 Subject Index

 mechanisms of nutritional programming
66, 67
Exercise
AMP-activated protein kinase response 206
see also Lifestyle modification
Exocytosis, defects in diabetic ␤-cells
125–127
Fat deposition
aging effects 99
patterns 62, 63
polycystic ovarian syndrome patterns 218,
219
Fat intake, maternal role in developmental
origins of health and disease 80, 81
Fatty acid synthetase (FAS), Pima Indian
polymorphisms 18
Fen-phen 237, 240
Fetal environment, see also Maternal obesity
developmental origins of disease 63, 75–77
fetal size constraints 69
mechanisms of nutritional programming
epigenetics 66, 67
glucocorticoids 67
metabolic partitioning 67
neuroendocrine control of appetite 68
overnutrition effects 66
thrifty phenotype model 64
Fluoxetine, obesity management 251
Food intake, see Appetite
Fragile X syndrome, features 52
FTO, obesity candidate gene 22, 23
Gastric surgery, see Bariatric surgery
Genetics of Obesity Study (GOOS) 1, 2
Gestational diabetes, offspring outcomes 78
Ghrelin
appetite regulation 109, 110, 168, 169
bariatric surgery response 248, 249
growth hormone regulation 168
long-term energy homeostasis role 170,
171
polycystic ovarian syndrome levels 220
pre-prandial hunger contributions 169, 170
processing 168
receptor 168, 171
therapeutic targeting 171, 172, 254
Glucagon-like peptide-1 (GLP-1)
bariatric surgery response 249
processing 176
receptor 178
Subject Index
satiety signaling 176
therapeutic potential 177, 179, 255
Glucocorticoids
levels in obesity 148, 149
mechanisms of nutritional programming 67
metabolism, see 11␤-Hydroxysteroid
dehydrogenase
polycystic ovarian syndrome role 219
Glucolipotoxicity, ␤-cell dysfunction 122
GLUT2, expression in diabetic ␤-cells 124
GLUT4, AMP-activated protein kinase
regulation of expression 199
Growth hormone
Cushing’s syndrome levels 223
ghrelin regulation 168
thyroid hormone interactions 216
Heritability, obesity 1
Hexokinase II, AMP-activated protein kinase
regulation of expression 199
11␤-Hydroxysteroid dehydrogenase
glucocorticoid metabolism 149, 150
isoforms 149, 150
polycystic ovarian syndrome levels 219
type 1 enzyme
ApoE combination transgenic mouse
phenotype 154, 155
circulating substrate levels 150, 151
functional studies
adipose tissue 152
liver 151
regulation in obesity 152, 153
knockout mouse phenotype 155, 156
therapeutic targeting 158
transgenic mouse model of metabolic
syndrome 153, 154
type 2 enzyme transgenic mouse 156–158
Hypothalamic-pituitary-adrenal axis,
glucocorticoid levels 147, 148
Hypothalamus
AMP-activated protein kinase function 202
central hypothyroidism 223–225
energy balance regulation 139
peripheral signals of energy balance
166–168
Hypothyroidism
central hypothyroidism 223–225
clinical features 213, 214
epidemiology 213
thyroid hormone, see Thyroid hormone
weight gain mechanisms 215, 216
291
Idiopathic intracranial hypertension (IIH),
obesity treatment response 246
IGFBP2, diabetes type 2 candidate gene 26
Infant nutrition
effects in later life 66
mechanisms of nutritional programming
epigenetics 66, 67
glucocorticoids 67
metabolic partitioning 67
neuroendocrine control of appetite 68
INSIG2, obesity candidate gene 20, 21
Insulin
resistance, see Diabetes type 2; Metabolic
syndrome
ruminant dynamics 111
secretion, see Beta-cell
Interleukin-6 (IL-6), adipokine activity 185
Intraflagellar transport (IFT), Bardet-Biedl
syndrome defects 38–40
Isolated populations, genetic dissection of
complex diseases 16, 17
Leptin
AMP-activated protein kinase
activity in knockout mice 205
targeting 187
appetite regulation 109
deficiency
clinical phenotypes 3, 4
therapy responses 3–5
endocrine and reproductive effects in
livestock 111, 112
functional overview 184, 187
gene polymorphisms in livestock 112
immune function 188, 189
levels in obesity 183
mechanisms of action 187, 188
mutations 2
polycystic ovarian syndrome levels 219,
220
receptor
isoforms 183, 185
mutations 2
signaling 184, 186
tissue distribution 187, 188
therapeutic potential 252, 253
thyroid hormone interactions 216
Lifestyle modification
childhood obesity management 92, 93
elderly 103, 104
societal factors in obesity 260–262
292
Linkage analysis, genetic dissection of complex
diseases 14, 15
Livestock, see Animal models, obesity
Macrosomia, obesity, macrocephaly, and
ocular abnormalities (MOMO), features 53
Maternal obesity
developmental origins of health and
disease
maternal obesity and fat intake role
80, 81
programming vectors 78–80
gestational diabetes outcomes 78
offspring effects
animal studies 75, 76
complications 82
observational studies 75
type 2 diabetes 76, 77
Maturity-onset diabetes of the young (MODY),
gene mutations 120, 121
MCT-1, expression in diabetic ␤-cells 125
Melanocortin receptor MC4R
Albright’s hereditary osteodystrophy
mutations 43
deficiency in obesity 7–9
Melanocortin system, appetite regulation
110
␤-Melanocyte-stimulating hormone (␤-MSH),
mutations in obesity 6
Metabolic syndrome
childhood obesity sequelae 90
11␤-hydroxysteroid dehydrogenase type 1
therapeutic targeting 158
transgenic mouse model 153, 154
obesity treatment response 245
Metformin
clinical trials in obesity 239, 240
polycystic ovarian syndrome response
247
MicroRNA, ␤-cell function regulation 127
Mismatch pathway
evolutionary perspective 68, 69
fetal overnutrition effects 66
mechanisms of nutritional programming
epigenetics 66, 67
glucocorticoids 67
metabolic partitioning 67
neuroendocrine control of appetite 68
overview 62
mTOR pathway, inhibition by AMP-activated
protein kinase 200
Subject Index
Neuropeptide Y (NPY) therapeutic potential 255
antagonist therapy 253 Peroxisome proliferator-activated receptor-␥
appetite regulation 109, 110, 139, 169 (PPAR-␥)
receptors 172, 173 ␤-cell dysfunction role in diabetes 124
Non-alcoholic fatty liver disease (NALFD) obesity candidate gene 18–20
childhood obesity 91 Phentermine 237
obesity treatment response 245, 246 PHF6, Börjeson-Forssman-Lehmann
Nucleus of the solitary tract (NTS), peripheral syndrome mutations 52
signals of energy balance 167 Pima Indians, type 2 diabetes studies 17, 18
Plasminogen activator inhibitor-1 (PAI-1),
Obesity complications, see also specific adipokine activity 185
complications Polycystic ovarian syndrome (PCOS)
classification 232–235 appetite-regulating hormone levels 219,
prevention 231 220
treatment 231, 232 clinical features 217, 218
Obesity staging, King’s College criteria 234, diagnostic criteria 217
235 epidemiology 217, 218
Obstructive sleep apnea (OSA), obesity fat distribution patterns 218, 219
treatment response 246 glucocorticoid roles 219
Orlistat metformin response 247
childhood obesity management 93 obesity treatment response 246, 247
clinical trials in obesity 237 Population attributable fraction (PAF),
diabetes type 2 response 244 genetic dissection of complex diseases
elderly patients 104 15, 16
non-alcoholic fatty liver disease response Positional cloning, genetic dissection of
246 complex diseases 14, 15
sibutramine combination therapy 240 Prader-Willi syndrome (PWS)
Oxyntomodulin association studies 50
processing 176 chromosome deletions
receptor 178 1p36 50, 51
satiety signaling 176, 177, 254 2q37 51
therapeutic potential 177, 178, 254, 255 6q16 50
9q34.3 51
Pancreatic polypeptide (PP) chromosome 14 maternal uniparental
appetite effects 176 disomy 51
long-term energy homeostasis role 175 clinical features 43–45
post-prandial satiety role 175 functional neuroimaging studies 50
receptors 172, 173 genetics 45, 46
secretion 175 hypothalamic abnormalities 49
Paraventricular nucleus (PVN), Prader-Willi obesity 46, 47
syndrome defects 40 peripheral appetite signals 47–49
Peptide YY (PYY) Pramlintide, see Amylin
bariatric surgery response 248, 249 Prevention
dietary manipulation 179 obesity 230
energy balance signaling 166 obesity complications 231
forms 173 Prohormone convertase 1 (PC1), mutations in
long-term energy homeostasis role 174 obesity 6, 7
mechanism of action 174, 175 Proopiomelanocortin (POMC)
post-prandial satiety role 173, 174 complete deficiency 5
receptors 172, 173 haploinsufficiency 5, 6
secretion 173 mutations in obesity 6

Subject Index 293

Psychiatric comorbidity, obesity
obesity treatment response 247
overview 266–268
Quality of life, obesity treatment response 247
RAB23, Carpenter syndrome mutations 42
RBP4
functional overview 185, 191, 192
receptor 192
Resistin
functional overview 184
secretion 191
structure 190
Rimonobant
childhood obesity management 93
clinical trials in obesity 143, 239
Rubinstein-Taybi syndrome, features 43
Sarcopenia, aging 99, 100
Sertraline, obesity management 251
Sibutramine
childhood obesity management 93
clinical trials in obesity 237–239
elderly patients 104
obstructive sleep apnea response 246
orlistat combination therapy 240
Single nucleotide polymorphism (SNP), genetic
dissection of complex diseases 15, 16
Sleep apnea, see Obstructive sleep apnea
Societal factors, obesity causes 260–262
Socioeconomic status (SES), obesity
association studies 263–265
SREBP1c, ␤-cell failure role in diabetes
123
Stigmatization, obesity 265, 266
Surgery, see Bariatric surgery
TCF7L2, diabetes type 2 candidate gene 24, 25,
121, 122
⌬9-Tetrahydrocannabinol (THC), food intake
effects 135
Thrifty genotype hypothesis 12, 13, 63
Thyroid hormone
hypothyroidism, see Hypothyroidism
interactions
catecholamines 216, 217
growth hormone 216
leptin 216
mitochondrial actions 217
receptors 215
types 214, 215
Topiramate, obesity management 251, 252
Trends, obesity 74
Tropomyosin-related kinase B (TrkB),
mutations in obesity 9
Tumor necrosis factor-␣ (TNF-␣), adipokine
activity 185
Vaspin, adipokine activity 192
Visfatin
functional overview 186, 191
secretion 191
Weight management, compliance 231
Zonisamide, obesity management 251, 252
Zucker rat, AMP-activated protein kinase
activity 204

294 Subject Index