METABOLIC SYNDROME AND RELATED DISORDERS REVIEW

Volume 9, Number 2, 2011

ª Mary Ann Liebert, Inc.
Pp. 85–89
DOI: 10.1089/met.2010.0090

Set-Point Theory and Obesity

Maria Magdalena Farias, M.D.,1 Ada M. Cuevas, M.D., M.Sc.,2 and Fatima Rodriguez, M.P.H.3

Abstract
Obesity is a consequence of the complex interplay between genetics and environment. Several studies have
shown that body weight is maintained at a stable range, known as the ‘‘set-point,’’ despite the variability in
energy intake and expenditure. Additionally, it has been shown that the body is more efficient protecting against
weight loss during caloric deprivation compared to conditions of weight gain with overfeeding, suggesting an
adaptive role of protection during periods of low food intake. Emerging evidence on bariatric surgery outcomes,
particularly gastric bypass, suggests a novel role of these surgical procedures in establishing a new set-point by
alterations in body weight regulatory physiology, therefore resulting in sustainable weight loss results. Con-
tinuing research is necessary to elucidate the biological mechanisms responsible for this change, which may offer
new options for the global burden of obesity.

Introduction The set-point theory suggests that the body has an internal
control mechanism that is a set-point located in the lateral

O besity is becoming a global epidemic as the body mass

index (BMI), an indicator of relative weight for height
[weight (kg)/height (m)2], continues to increase among all age
groups1 in most of the developed and developing countries.2
Health expenditures of morbidly obese people (defined as a
BMI >40) are estimated to be 81% higher than those for
nonobese adults.3 Similarly, obesity affects almost every organ
system in the body and is directly associated with increased
risk of diabetes, hypertension, dyslipidemia, cardiovascular
disease, osteoarthritis, cancer, and depression.4
Obesity is a consequence of the balance between energy
intake, energy expenditure, and energy storage. A better
understanding of how weight is regulated—how biological,
behavioral, and environmental factors interact to affect en-
ergy balance and body weight regulation—is necessary in
the development of strategies for the prevention and treat-
ment of obesity.5
Observations that body weight is maintained much more
stably over long periods of time than would be expected
from the wide variations in daily energy intake and that
obese people tend to have a rapid regain of lost weight
suggest that biological factors are important contributors to
body weight regulation.6 Further evidence indicates that
manipulating one component of energy balance produces
compensatory changes in other components (for example,
food restriction produces a decline in energy expenditure).7
hypothalamus, which regulates metabolism to maintain
weight at a predetermined level. Environmental changes in
diet or temperature may be detected by this set-point to
maintain fat stores at a certain level by promoting feedback
mechanisms.7 These mechanisms include roles and com-
plex interactions between appetite, nutrients, dietary com-
position, hormones, metabolic rate, neural pathways, brown
fat, and many neurotransmitters in the regulation of food
intake.8
Appetite Regulation
The hypothalamus is a processing center that integrates
signals from the brain, the peripheral circulation, and the
gastrointestinal tract to regulate energy intake and expen-
diture. Within the hypothalamus, the arcuate nucleus con-
tains peptide neurotransmitters associated with appetite.
Neuropeptide Y (NPY) and agouti-related peptide (AGRP)
are orexigenic (induce feeding), whereas propiomelanocortin
(POMC) and cocaine- and amphetamine-regulated transcript
(CART) are anorexigenic (inhibit feeding). Neurons expres-
sing these neuropeptides communicate with each other and
with many peripheral signals, including mechano- and che-
moreceptors; with nutrients such as glucose, amino acids,
and fatty acids; with gastrointestinal (GI) peptide hormones
(i.e., cholecystokinin and ghrelin); and with other hormones,

1
Department of Nutrition and Metabolism, Pontificia Universidad Catolica de Chile, Santiago, Chile.
2
Department of Nutrition, Clinica Las Condes, Santiago, Chile.
3
Harvard Medical School, Harvard University, Boston, Massachusetts.

85
86
including insulin, leptin, and adiponectin to influence ap-
petite level, feeding, and energy expenditure.9
The role of GI hormones in the regulation of appetite has
been reviewed. The GI tract is the largest endocrine organ in
the body. Gut hormones optimize the process of digestion
and absorption of nutrients by a local effect on GI motility
and secretion. Many of these gut peptides have shown to
influence energy intake. The most studied in this regard
are cholecystokinin (CCK), pancreatic polypeptide, peptide
YY, glucagon-like peptide-1 (GLP-1), oxyntomodulin, and
ghrelin. With the exception of ghrelin, these hormones act
to increase satiety and decrease food intake by different
mechanisms.
Local effects, such as the inhibition of gastric emptying,
might contribute to the decrease in energy intake. Activation
of mechanoreceptors as a result of gastric distension may
inhibit further food intake via neural reflex arcs. Circulating
gut hormones have also been shown to act directly on neu-
rons in hypothalamic and brain centers of appetite control.
The median eminence and area postrema in the brain are
characterized by a deficiency of the blood–brain barrier.
Extensive reciprocal connections exist between these areas
and the hypothalamic paraventricular nucleus, including
other energy-regulating centers of the central nervous system.
In this way, hormonal signals from the GI may be translated
into the subjective sensation of satiety. Additionally, many gut
peptides are both hormones and neurotransmitters. Peptides
such as CCK and GLP-1 are expressed in neurons projecting
both into and out of areas of the central nervous system crit-
ical to energy balance.10 As physiological mediators of satiety,
gut hormones represent an attractive mechanism involved on
weight regulation and energy balance.11
Energy Expenditure
Total energy expenditure (TEE) is the sum of resting en-
ergy expenditure (REE), thermic effect of food (TEF), and
physical activity–related energy expenditure (PAEE). The
majority of human energy expenditure occurs at rest condi-
tions, corresponding, in most of the people, to 70% of TEE.
Studies have also shown that by eliminating the sex differ-
ences that occur with the accumulation of adipose tissue, by
TEE per unit of ‘‘fat-free’’ or lean body weight, the values
between sexes for basal metabolism are essentially the same.7
REE is the energy required by the body to maintain basic
physiologic functions such as pumping blood, making hor-
mones, and maintaining body temperature. REE normally
increases in conditions such as trauma and infections and in
physiological conditions such as pregnancy, establishing a
‘‘new set-point’’ due to impact of the hypermetabolic state.8
TEE is regulated by the brain. Information from the body
periphery is carried by an affector to a central controller
located in the hypothalamus. The controller integrates and
transduces the information into an effect signal to correct any
deviation in body weight from its inherent set-point.7 The
primary efferent pathway regulating energy expenditure is
believed to be the sympathetic nervous system, which in-
nervates the thermogenic brown adipose tissue.8
Brown adipose tissue is important for TEE in the form of
thermogenesis (mediated by the ability to dissipate energy
by producing heat rather than storing it as triglycerides), due
the expression of the tissue-specific uncoupling protein-1
(UCP1). Brown adipose tissue affects whole-body metabo-
FARIAS ET AL.
lism, modifies susceptibility to weight gain, and may alter
insulin sensitivity. This tissue is present in rodents
throughout life. In humans, brown adipose tissue is found
primarily in infants and young children, and it has been
considered to be essentially nonexistent and without physi-
ologic relevance in adults. However, estimates suggest that if
it were present, as little as 50 g of maximally stimulated
brown adipose tissue could account for up to 20% of daily
energy expenditure in an adult human.12
Animal studies have suggested that expansion and/or
activation of brown adipose tissue counteracts diet-induced
weight gain and related metabolic disorders, such as type 2
diabetes mellitus. Despite its potential physiologic impor-
tance, methods to measure the mass and activity of brown
adipose tissue in humans have been lacking and controver-
sial. Recently, combined positron-emission tomography has
been used to identify brown adipose tissue in humans, for
whom this tissue could potentially be beneficial given its
association with both low BMI and low total adipose tissue
content.13 However, correlation of these findings with evi-
dence of UCP1 expression or metabolic impact has been
inconclusive.13–15
Obesity: Is There Low Energy Expenditure
in Obese People?
It has been hypothesized that obesity is caused by meta-
bolic or behavioral defects that result in a reduced energy
expenditure.16 Many studies have demonstrated that TEE is
elevated with increasing BMI. The TEE value for obese
people is estimated to be 40% higher than the TEE for non-
obese people.17 However, other studies have reported the
inability of some obese patients to respond to overfeeding
with the normal increase of energy expenditure.18
Evidence suggests that obese people may have individual
variations in energy expenditure; some obese patients have
increased energy expenditures whereas others have decreased
energy expenditures with similar caloric intakes. Therefore,
there is no established consensus on whether metabolic rates
are necessarily abnormal in obese individuals.16–19
Effect of Calorie Restriction and Regulation
of the Weight Gain
Studies in animals have shown that after weight loss from
calorie restriction, body weight is rapidly regained when
they are re-fed ad libitum. A proposed explanation for this
finding is that, in response to underfeeding, an adaptive
energy conservative mechanism emerges with subsequent
lowering of the basal energy expenditure. It has also been
reported that an adaptive increase in energy expenditure
occurs in rats with overfeeding. The reduction in energy re-
quired for maintenance is largely explained by a decline in
REE. These adaptations may serve to minimize fluctuations
in body weight, supporting the notion that body energy is
regulated around a ‘‘set-point.’’20
However, overfeeding results in fewer compensatory
changes in energy expenditure than food restriction,21 and
the degree of conservation is proportional to the degree of
underfeeding. Therefore, we can conclude that our organism
is better adapted to protect against weight loss compared to
weight gain, demonstrating the efficiency of food utilization,
particularly when food resources are scarce.22
SET-POINT THEORY AND OBESITY
In humans, some studies have shown similar results. After
a 10% weight gain, TEE is significantly higher. Similarly, TEE
is significantly lower at 10%–20% of weight loss. These ex-
pected changes in energy expenditure occurred during pe-
riods of weight changes.22 In addition, it has been reported
that during energy restriction there is a downregulation of
REE and sympathetic activity and a decrease of serum con-
centrations of thyroid hormones.23 It has also been reported
that there is a sense of extreme hunger that may accompany
weight loss, which, in turn, promotes calorie-dense food in-
take, further widening the gap between energy output and
intake.22
It is unclear whether the speed of the weight loss affects
the decrease in TEE, or how long the larger-than expected
decrease in TEE will persist after weight loss. Perhaps the
body will eventually adjust to the new weight and will be
able to preserve the reduced weight. Indeed, some investi-
gators have reported that, in sustained weight loss main-
tained for a long period, changes in energy expenditure
could eventually adjust, not leading to weight regain.23
Genetic Contribution
Results of many studies indicate that genetic factors play
an important role on the weight set-point. Metabolic studies
in monozygotic twins have demonstrated the importance of
genetic contributions to weight gain. Experiments have
shown that when unrelated individuals were similarly fed,
there was a large variation in the degree of weight gain.
However, the amount of weight gain was very similar when
monozygotic twins were compared. This finding suggests
that there is a significant genetic contribution to metabolic
efficiency and regulation of body weight.6
Researchers have elucidated some groups of genes that
code for proteins involved in the regulation of satiety and
food intake, such as leptin (Ob), the leptin receptor (Ob-R),
POMC, and the melanocortin-4 receptor (MC4R). Mutations
in some of these genes, although attributed to only few
families, have revealed the important role of some genes in
the neuronal control of satiety, leaving the food intake as the
prime driver in body weight regulation.6
Another line of evidence supporting the role of genetics in
body weight regulation has come from comparison of met-
abolic differences in individuals belonging to different eth-
nicities. In one study, a group of overweight women was
kept on a low-calorie diet until BMI decreased to <25 kg/m2.
When these age-, weight-, and BMI-matched women were
separated based on ethnicity (in this case African American
or white), differences in REE were apparent before and after
weight loss.24 It was attributed to some genetic factors
characteristic of African ancestry, suggesting that African
Americans may regulate weight at a lower ‘‘set-point’’ and be
at higher risk to regain the lost weight.18
Role of the Environment:
Moving on a ‘‘Set-Range’’
Weight appears to be maintained at a relatively stable
range for long periods of time. The major influence for
moving on this range is derived from an individual’s unique
environmental contributions. The impact of the environment
on weight seems to be unidirectional and promotes positive
rather than negative energy balance.21
87
The ‘‘settling-point’’ theory proposes that weight tends to
drift around the level at which the group of factors that de-
termine food consumption and energy expenditure achieve
an equilibrium. According to this view, weight would re-
main stable as long as there are no durable changes in any of
the factors that influence it. This theory casts a much wider
net than our ‘‘set-point’’ theory, which attributes weight
stability to specific physiological processes. Another differ-
ence is that ‘‘settling-point’’ theory suggests that if an obese
person makes long-term changes in eating or exercising, his
or her ‘‘settling-point’’ will drift downward without active
resistance from the body.6
Although we consistently believe that there are biological
systems that attempt to maintain energy balance, the ability
of such systems to defend body weight in the face of in-
creasing unidirectional environmental pressures is limited.
The fact that obesity rates have gradually increased might
suggest that people with high metabolic susceptibility ex-
perienced weight gain first as the environment became more
obesigenic.21
Food environment
We believe that is impossible to attribute the influences of
the environment on energy balance to a few factors; rather it
has been small changes in numerous environmental factors.
Our current food supply is high in fat, energy dense, and
high in sugar. Food is inexpensive and available in large
portions. Food is heavily advertised, and it has become ac-
ceptable to have food everywhere. These are factors that are
known to promote energy intake, with no strong biological
opposition.21
The role of diet composition on body weight will differ,
depending on whether subjects are in energy balance or
whether they are in positive or energy balance. During
negative energy balance, there is a little impact of altering the
fat-to-carbohydrate ratio of the diet. There seems to be sim-
ilar body weight and body fat loss with high- and low-fat
diets when total energy intake has fixed at a level below the
requirements. On the other hand, there are several reports of
differences in weight loss with high- and low-fat diets when
energy intake is not fixed, suggesting that body weight is
reduced slightly as dietary fat content of the diet is low-
ered.25,26 However, no differences between low-carbohydrate
and low-fat have been reported over a period of 1 year.27
Consequently, long-term exposure to a high-energy dense diet
represents a set-point deviation that is the price to be paid to
reach a new steady state of energy balance.28
Physical activity environment
The physical environment has changed due to techno-
logical advances that make it unnecessary to be physical
active in our daily lives. Most occupations no longer involve
physical activity for transportation. The development of
television, DVDs, computers, internet, and video games has
filled our leisure time with sedentary rather that physical
activity pursuits, especially for young people.18,21
Physical activity produces an obvious raise in TEE by
an increase on energy expenditure during exercise; but it
may also increase REE.21 Evidence suggests that the skeletal
muscle plays an important role in thermogenesis. Also,
variations of REE between humans have been explained by
88 FARIAS ET AL.

differences in body composition due to skeletal muscle may contribute to the effectiveness of the procedure and may
mass.8 explain why patients are more successful in maintaining the
As a result, individuals who have high levels of REE due weight loss over the long term after RYGB than after dietary
to high levels of physical activity have better capacity to restriction methods.33
regulate energy intake in a lower weight range compared to Studies in humans have failed to find a concrete associ-
those with lower levels of physical activity.21 ation between energy expenditure changes and RYGB. A
recent Chilean study showed that patients with an initial
lower REE tended to increase their REE after RYGB, and for
Is It Possible for Obese Individuals those with initially normal or increased REE, the REE after
to Change the Set-Point? the surgery did not change significantly, after adjusting for
The role of bariatric surgery free fat mass (FFM).34 With this information, we could
preliminarily conclude that weight loss after RYGB is not
Failure of conventional techniques for weight loss, par- associated with the compensatory reduction of REE that
ticularly in morbidly obese patients, has lead to 10-fold in- would be expected with lost weight by dietary therapy
crease in bariatric surgery procedures over the past decade.29 for obesity. These observations support the hypotheses
The three most popular bariatric surgery procedures are that nonmechanical factors contributing to weight loss
Roux-en-Y-gastric bypass (RYGB), sleeve gastrectomy, and may be a consequence of individual regulation of the new
gastric banding. Gastric banding and sleeve gastrectomy rely set-point.17,28
on purely restrictive procedures that limit the storage ca-
pacity of the stomach, resulting in early satiety. RYGB creates Discussion
a small stomach reservoir to restrict food intake as well, but
The body tends to regulate weight at a certain range,
also combines a malabsorptive component by bypassing a
known as the set-point, and our biology favors protecting
portion of the small intestine.30
against weight loss compared to weight gain by decreasing
RYGB has rapidly become the preferred surgical proce-
the energy expenditure in response to underfeeding.22 It
dure for the treatment of morbid obesity with very positive
seems appropriate to assume that the predetermined level at
outcomes.17 As compared to gastric banding or sleeve gas-
which body fat is maintained represents the equilibrium
trectomy, RYGB results in higher reduction of obesity-related
achieved by regulation of many biological parameters, in-
co-morbidities and more sustained weight loss.29,31
cluding genetic factors, nutrient balance, energy expenditure,
There is limited understanding of the precise mecha-
and neuroendocrine signaling and GI hormones, with im-
nisms by which RYGB induces and maintains substantial
portant environmental contributions.7 Physical inactivity
weight loss. Growing evidence suggests that the profound
and nutrition may be the most important environmental
changes in body weight and metabolism cannot be solely
determinants of weight regulation.33
explained by simple mechanical restriction or malabsorp-
Adipose tissue is the primary site of energy storage and
tive techniques of RYGB.31 Several groups have shown
plays a genuine role in the maintenance of body weight by
that RYGB affects hunger and increases or accelerates the
the release of hormones and cytokines that modulate whole-
experience of satiety after meals. RYGB has been shown to
body metabolism. Brown adipose tissue, on the other hand,
alter the release of various GI hormones, including ghrelin,
is important for energy expenditure. According to recent
GLP-1, peptide YY, and glucose-dependent insulinotropic
studies, the activity of brown fat tissue could be metaboli-
peptide, generating an endocrine response that results in
cally important in humans.14,15 Several possible targets that
dramatic appetite reductions and early sensation of satiety
may be useful for the expansion and/or activation of this
after meals.32
tissue by pharmacological means are to be identified. Whe-
It has long been recognized that the GI tract exerts sig-
ther or not brown adipose tissue will be useful in the battle
nificant neuroendocrine control over appetite, food intake,
against obesity remains to be seen.12
and glucose metabolism. It is possible that the rearrange-
Studies hypothesize that RYGB procedures are the most
ment of the GI tract induced by RYGB may significantly
effective treatment for long-term weight reduction in mor-
change this neuroendocrine function, leading to important
bidly obese people by creating a new ‘‘set-point.’’ RYGB has
alterations in body weight regulation. In addition, several
shown to alter the release of various GI hormones, generat-
clinical and animal studies have shown that glucose
ing an endocrine response that is consistent with a long-term
homeostasis is improved after RYGB and that this im-
decrease in body weight.33 In addition, animal models have
provement may result from weight loss–independent
demonstrated an increase on REE after surgery,29 and stud-
mechanisms. In fact, many patients present profound re-
ies in humans have demonstrated that weight loss after
duction of co-morbidities before significant weight loss is
surgery might not reduce the metabolic rate as would be
achieved, suggesting that physiological changes, including
expected with a diet restriction.34 These results suggest that
altered neuroendocrine signaling, may be important medi-
the surgery procedure acts by altering the physiology of
ators of the outcomes of RYGB.31,33
weight ‘‘set-point’’ regulation and not only through me-
On the other hand, an increase in energy expenditure after
chanical or malabsorptive mechanisms. Continuing research
RYGB has been observed in animal models of bypass sur-
on bariatric surgery is necessary to elucidate the biological
gery, with a fundamentally different metabolic response
mechanisms responsible for this change, which may offer
from the response to food restriction. In this study, the rats
new options for the global burden of obesity.
that were underfed to lose as much weight as RYGB-treated
rats appeared to recruit a compensatory mechanism (a de- Author Disclosure Statement
crease in TEE) to combat weight loss. In contrast, this energy-
conserving response was absent after RYGB. These changes No competing financial interests exist.
SET-POINT THEORY AND OBESITY
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Address correspondence to:
Maria Magdalena Farias, M.D.
Department of Nutrition and Metabolism
Pontificia Universidad Catolica de Chile
Marcoleta 367
Santiago, Region Metropolitana
Chile
E-mail: mmfarias@gmail.com