S P E C I A L F E A T U R E

C l i n i c a l R e v i e w

Regulation of Food Intake, Energy Balance, and Body

Fat Mass: Implications for the Pathogenesis and
Treatment of Obesity

Stephan J. Guyenet and Michael W. Schwartz

Diabetes and Obesity Center of Excellence and Division of Metabolism, Endocrinology, and Nutrition,
Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195

Context: Obesity has emerged as one of the leading medical challenges of the 21st century. The
resistance of this disorder to effective, long-term treatment can be traced to the fact that body fat
stores are subject to homeostatic regulation in obese individuals, just as in lean individuals. Because
the growing obesity epidemic is linked to a substantial increase in daily energy intake, a key priority
is to delineate how mechanisms governing food intake and body fat content are altered in an
obesogenic environment.

Evidence Acquisition: We considered all relevant published research and cited references that
represented the highest quality evidence available. Where space permitted, primary references
were cited.

Evidence Synthesis: The increase of energy intake that has fueled the U.S. obesity epidemic is linked
to greater availability of highly rewarding/palatable and energy-dense food. Obesity occurs in
genetically susceptible individuals and involves the biological defense of an elevated body fat mass,
which may result in part from interactions between brain reward and homeostatic circuits. In-
flammatory signaling, accumulation of lipid metabolites, or other mechanisms that impair hypo-
thalamic neurons may also contribute to the development of obesity and offer a plausible mech-
anism to explain the biological defense of elevated body fat mass.

Conclusions: Despite steady research progress, mechanisms underlying the resistance to fat loss
once obesity is established remain incompletely understood. Breakthroughs in this area may be
required for the development of effective new obesity prevention and treatment strategies. (J Clin
Endocrinol Metab 97: 745–755, 2012)

ver the course of industrialization, affluent popula- obesity epidemic can be traced to an increase in per capita
O tions have experienced an “epidemiological transi-
tion” characterized by an increased prevalence of certain
energy intake over the past 40 yr (Fig. 1) (4, 5), which in
turn is linked to changes in our collective diet, little is
disorders that are uncommon both in nonindustrial pop- known about the physiological mechanisms underlying
ulations and in wild animals (1). Among these, obesity is this trend. Particularly vexing is the question of why this
perhaps the most conspicuous. Affecting approximately disorder, once established, is so refractory to treatment.
one third of adults in the United States (with an additional Here, we review the mechanisms controlling food intake
one third falling into the overweight category) (2), obesity in the context of energy homeostasis (the biological pro-
has become a leading cause of morbidity, mortality, and cess that matches energy intake to energy expenditure over
reduced quality of life (3), a problem aggravated by the long time intervals), with a focus on obesity pathogenesis
limited efficacy of nonsurgical treatments. Although the and the dramatic recent increase in obesity prevalence.

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: AgRP, Agouti-related peptide; ARC, arcuate nucleus; BMI, body mass
Printed in U.S.A. index; CCK, cholecystokinin; DIO, diet-induced obesity; GLP-1, glucagon-like pep-
Copyright © 2012 by The Endocrine Society tide-1; GWAS, genome-wide association studies; HFD, high-fat diet; LHA, lateral hy-
doi: 10.1210/jc.2011-2525 Received September 9, 2011. Accepted December 8, 2011. pothalamic area; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; POMC,
First Published Online January 11, 2012 proopiomelanocortin; PYY, peptide YY; RYGB, Roux-en-Y gastric bypass.

J Clin Endocrinol Metab, March 2012, 97(3):745–755 jcem.endojournals.org 745

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746 Guyenet and Schwartz Regulation of Food Intake and Body Fat Mass J Clin Endocrinol Metab, March 2012, 97(3):745–755

planation for the experience of hunger and the decision

to commence eating is still awaited.
A popular notion in the lay literature merits comment.
Nearly 60 yr ago, Jean Mayer and his contemporaries
hypothesized that because hypoglycemia potently stimu-
lates appetite, hunger is normally triggered by sensing of
declining plasma glucose levels or rates of glucose utiliza-
tion by hypothalamic “feeding centers” (8). Decades of
subsequent research have demonstrated that to the con-
trary, meal onset is not causally related to preprandial
blood glucose (or insulin) levels within the normal phys-
iological range (9). Yet the notion that low glucose (or
FIG. 1. Per capita energy intake in the United States, 1970 –2009. elevated insulin) levels drive feeding behavior and pro-
According to U.S. Department of Agriculture (USDA) food
mote fat gain remains widely popular, due largely to the
disappearance data (corrected for waste), per capita daily energy
intake in the United States has increased 20% since 1970 (133). The marketing of commercial diet plans based on the glycemic
increase began shortly after 1980, closely paralleling the rapid index or reduced carbohydrate content. Among various
increment in obesity prevalence. Although USDA data are calculated scientific rationales that have been advanced for such diets
from food disappearance measurements, this recent increase is broadly
consistent with estimates calculated via other methods. is that excessive insulin secretion induced by rapidly di-
gested carbohydrate foods causes a subsequent, transient
Short-Term, Meal-Related Determinants of fall of plasma glucose levels; this, in turn, triggers excess
Food Intake feeding and ultimately causes obesity. Another idea pro-
poses that increased fasting and/or postprandial insulin
Because humans, like most mammals, consume food in levels induced by carbohydrate foods acts directly on adi-
discrete bouts (or meals), total daily energy intake is a pocytes to increase fat storage, promoting fat gain over
function of the size, frequency, and composition of
time. Although clinical trials have established that reduced
meals. The perception of hunger and the decision to
carbohydrate diets can safely induce modest long-term
initiate a meal involve complex and poorly understood
weight loss (10), the mechanisms typically advanced to
interactions between genetic, social, learned, environ-
explain this benefit have little in the way of experimental
mental, circadian, and humoral cues (6, 7). As such, this
support and are not informative with respect to the control
process is quite variable and, although several endoge-
of food intake. Moreover, reduced carbohydrate diets do
nous peptides have been identified with the ability to
stimulate feeding (6, 7), a unifying, physiological ex- not necessarily outperform diets with a higher carbohy-
drate content (e.g. the “Mediterra-
nean” diet) when outcomes are mea-
sured after 1 yr or more (10).
Once feeding commences, the amount
consumed is determined by factors in-
volved in satiety perception (Fig. 2). The
term “satiation” refers to the perception
of fullness that leads to meal termination,
whereas “satiety” describes the reduced
interest in food after a meal. These re-
sponses ensure that feeding is terminated
before gastric capacity is reached and
that an appropriate interval passes to al-
low the disposition of ingested nutrients
before the next meal begins (11). Unlike
hunger perception, these processes are
FIG. 2. Model for CNS regulation of food intake and body fat mass. The CNS is hypothesized
to regulate body fat mass via coordinated adjustments of both food intake and energy relatively well understood, involving
expenditure in response to afferent long-term and short-term signals of energy status. combined effects of gastric distention and
Environmental factors (e.g. the availability of highly palatable/rewarding foods, food the release of peptide signals from en-
composition, physical activity, etc.), genetic and developmental factors, hypothalamic
inflammation, and neuron injury collectively determine the biologically defended level of body teroendocrine cells lining the gastrointes-
fat mass. Brain image: Patrick J. Lynch. tinal tract (12).

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J Clin Endocrinol Metab, March 2012, 97(3):745–755 jcem.endojournals.org 747

Gastric distension is sensed by mechanoreceptor neu- ergy homeostasis (e.g. leptin) and project to the hindbrain,
rons in the stomach and relayed to the hindbrain via vagal where they modulate the sensitivity of NTS neurons to
afferent and spinal sensory nerves (13). The majority of satiety signals in a manner that compensates for changes
satiation-inducing gut peptides also mediate their effects of body fat mass (27).
via vagal afferent fibers, although some enter the brain
from the circulation and exert their effects directly (12).
Examples of satiation/satiety peptides released from in- Long-Term Regulation of Food Intake and
testinal enteroendocrine cells include cholecystokinin Energy Balance
(CCK), glucagon-like peptide-1 (GLP-1), oxyntomodulin,
peptide YY (PYY3–36), apolipoprotein A-IV, and en- The hormone leptin is secreted by adipocytes in propor-
terostatin (12). Additional satiety-inducing peptides re- tion to body fat mass and plays a key role in energy ho-
leased from the endocrine pancreas include pancreatic meostasis by informing the brain of changes in both energy
polypeptide, glucagon, and amylin (14 –18). CCK is a pro- balance and the amount of fuel stored as fat (Fig. 2) (28 –
totypic satiation peptide that is secreted by the duodenal 30). Leptin acts in the brain as a negative feedback regu-
and jejunal mucosa primarily in response to fat and pro- lator of adiposity, constraining fat mass by limiting energy
tein ingestion, and it decreases food intake rapidly but intake and supporting energy expenditure (28). Decreased
transiently via the activation of vagal afferents (12, 19, leptin signaling promotes increased food intake, positive
20). Meal size is increased by interventions that disrupt energy balance, and fat accumulation (28 –30). Although
CCK signaling, establishing a physiological role for this plasma leptin levels reliably reflect body fat mass under
peptide in satiation (21). GLP-1 and amylin are the only weight-stable conditions, they can also change in response
other satiation peptides shown to meet this criterion thus to short-term alterations of energy balance, well before
far (18, 22). significant changes of fat mass have occurred (31).
Ghrelin is an acylated peptide secreted from the gastric Leptin’s effects on energy balance are mediated via lep-
mucosa that, unlike satiety peptides, stimulates feeding tin receptors in hypothalamic areas such as the arcuate
and is implicated in meal initiation (6). Consistent with nucleus (ARC), paraventricular nucleus, ventromedial hy-
this concept, circulating ghrelin peaks just before meal pothalamic nucleus, and lateral hypothalamic area (LHA)
onset and declines rapidly during and immediately after (28). Many extrahypothalamic regions are also leptin-sen-
the meal (6, 12). However, because mice lacking a ghrelin sitive, including the NTS and midbrain regions central to
signal do not exhibit altered meal patterns (23), the con- reward and motivation (32). The ARC is a major site for
tribution of ghrelin to meal initiation relative to other fac- sensing and integrating peripheral energy balance signals,
tors remains uncertain. including hormones (leptin, insulin, and ghrelin) and nu-
Afferent signals involved in satiety are processed ini- trients (fatty acids, amino acids, and glucose) (28). These
tially in the hindbrain. The nucleus of the solitary tract effects are mediated by at least two distinct leptin-sensitive
(NTS) plays a particularly important role in the processing neuron subpopulations in the ARC. Neurons that express
of satiety-related input from vagal sensory fibers, and the proopiomelanocortin (POMC) synthesize and release
adjacent area postrema, being located outside the blood- melanocortin peptides such as ␣-MSH that are potently
brain barrier, can sense input from circulating peptides anorexigenic (inhibit food intake) and are stimulated by
directly (12). Evidence that hindbrain circuitry is itself leptin and insulin (28). Melanocortin signaling appears to
sufficient to regulate meal size stems from experiments in play a key physiological role to defend against excess fat
“decerebrate” rats, in which the hindbrain and forebrain gain, particularly during exposure to energy-dense, highly
are surgically disconnected (24, 25). Although these ani- palatable foods (33, 34).
mals are incapable of spontaneously initiating meals and Located adjacent to POMC cells are orexigenic neurons
rely on liquid food delivered directly into the mouth, they that express neuropeptide Y (NPY) and agouti-related
nonetheless terminate meals normally in response to gas- peptide (AgRP; an endogenous antagonist of the melano-
tric distention or satiation peptides such as CCK (24, 25). cortin-4 receptor). These cells are regulated in a manner
Because decerebrate rats fail to adjust meal size to com- reciprocal to POMC cells (28), and they play a key role to
pensate for changes in energy balance (26), however, com- enable/stimulate feeding behavior (35). NPY/AgRP neu-
munication between forebrain and hindbrain circuits rons are also GABAergic, and ␥-aminobutyric acid is im-
appears necessary for adaptive changes of meal size to plicated as an important regulator of feeding released by
occur in response to changing energy needs. The neuro- these neurons (36, 37). NPY/AgRP neurons synapse onto
circuitry involved in this integration includes hypotha- and inhibit POMC neurons, and both cell types regulate
lamic neurons that sense humoral input involved in en- energy balance via projections to brain regions that influ-

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748 Guyenet and Schwartz Regulation of Food Intake and Body Fat Mass J Clin Endocrinol Metab, March 2012, 97(3):745–755

aggressive marketing that in combination have undoubt-

edly helped drive the obesity epidemic over the past four
decades (4, 5).
Reward can be defined as the process whereby certain
behaviors are reinforced in response to specific environ-
mental stimuli. Animals and humans rapidly learn to as-
sociate olfactory, gustatory, and environmental cues with
food properties that, in turn, reinforce behaviors related to
the acquisition and consumption of rewarding food (39).
Relevant food properties include caloric density and tex-
ture as well as the content of fat, starch, simple sugars, salt
and free glutamate; under certain conditions, these factors
can influence food intake and body fatness (39 – 47). In
addition, a variety of other cues can be associated with
these factors and become rewarding over time, resulting in
acquired preferences (40, 41, 47). Palatability is defined as
the pleasure or hedonic value associated with food, and it
has been consistently shown to influence meal size in hu-
mans (48).
The “cafeteria diet” model of rodent obesity illustrates
the importance of food reward and palatability in appetite
regulation and obesity pathogenesis (49). In this model,
rodents are provided with an assortment of human com-
mercial “junk foods” in addition to standard unpurified
FIG. 3. Homeostatic regulation of body fat mass. A, Return of fat chow. The animals overconsume palatable foods at the
mass to baseline after short-term underfeeding or overfeeding. B,
Gradual increase in the defended level of fat mass with age in an expense of less palatable yet more nutritious chow, and
obese individual. The homeostatic response to fat loss induced by susceptible rat strains develop obesity rapidly (50). The
calorie restriction (CR) occurs in obese as well as lean individuals, impressive behavioral impact of food reward is illustrated
resulting in the recovery of lost fat.
by the observation that rats will voluntarily endure foot
shocks or extreme cold to obtain a cafeteria diet, even
ence motivation/reward, energy expenditure, hunger, and
when standard chow is freely available in unlimited
ingestive behaviors (28).
amounts (51, 52).
The adaptive response to fat loss induced by calorie-
Central nervous system (CNS) circuits involved in food
restricted diets illustrates how coordinate regulation of
reward are integrated with those governing energy ho-
ARC neurons participates in energy homeostasis. Nega-
meostasis to allow food-seeking behaviors to be adjusted
tive energy balance and loss of body fat lower plasma
according to energy needs. Although the mechanisms un-
levels of adiposity negative feedback signals (e.g. leptin
derlying this integration are not fully understood, hor-
and insulin) while also raising ghrelin levels. In response,
mones including leptin, ghrelin, PYY, CCK, and insulin
NPY/AgRP neurons are activated, whereas POMC cells
are inhibited, a combination that potently promotes hy- are implicated (32). The LHA is an important example of
perphagia (increased food intake), positive energy bal- an area that participates in both reward processing (53,
ance, and the recovery of lost fat (28). These responses to 54) and energy homeostasis (55), and hence may integrate
fat loss appear to be operative in obese as well as lean inputs pertinent to food reward with those involved in
individuals (Fig. 3). body fat mass regulation.
Numerous brain regions coordinately evaluate and re-
inforce the rewarding value of food (56 –58), including
corticolimbic, hypothalamic, and midbrain circuits in-
Food Reward and Palatability
volved in reward processing (e.g. dopaminergic neurons of
In the United States, fast food has increased from 2 to 18% the ventral tegmental area and substantia nigra) the insula,
of total food spending over the last 50 yr, whereas soft amygdala, striatum, nucleus accumbens, orbitofrontal
drink consumption has increased 3.5-fold (38). These cortex, and the LHA (58). Signaling by dopamine and
trends can be traced to increased food availability, sys- opioid peptides is particularly important in the reward and
tematic efforts to increase the reward value of food, and hedonic valuation of food, respectively (32, 58). Specifi-

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J Clin Endocrinol Metab, March 2012, 97(3):745–755 jcem.endojournals.org 749

cally, dopamine signaling is thought to contribute to the homeostasis system is presumed to have evolved to main-
“wanting” of food (e.g. motivational aspects), whereas tain the level of adiposity appropriate for each species’
opioids are implicated in the “liking” of food (e.g. hedonic ecological niche. There is general agreement that this sys-
value or palatability) (59). Consistent with this view, opi- tem responds robustly to reduced fat mass by increasing
oid receptor agonists strongly increase the intake of pal- both hunger and energy efficiency via a mechanism in-
atable food over standard chow in rodents, whereas opi- volving a low leptin signal, and that these responses are
oid antagonists decrease both the intake and the hedonic quite effective in returning fat mass to its original, prein-
value of palatable food (60, 61). Although the ␮-opioid tervention level (Fig. 3A) (71, 72).
receptor antagonist naltrexone was recently shown in clin- A more controversial question is the extent to which
ical trials to lower body weight in obese subjects when this homeostatic system defends against excess fat gain, a
combined with the norepinephrine-dopamine reuptake in- notion seemingly at odds with the steady increase of obe-
hibitor bupropion (62), efforts to obtain Food and Drug sity prevalence in affluent nations (57, 73, 74). Yet nu-
Administration (FDA) approval for this combination have merous studies suggest that both overweight and lean in-
thus far proven unsuccessful. The mechanism of action dividuals mount responses that resist excess fat gain and
may involve enhanced melanocortin signaling, consistent are able to lose most or all of the excess fat acquired during
with a role for opioid and dopamine signaling to influence periods of experimental overfeeding via a mechanism in-
energy homeostasis circuits (62). volving post-overfeeding hypophagia (Fig. 3A) (75–79).
The endocannabinoid system includes the ligands anan- This inherent resistance to fat gain in humans closely par-
damide and 2-arachydonlyglycerol that can act on either of
allels what is observed in rodents that are either overfed by
two cannabinoid receptor subtypes (CB1 and CB2). This
intragastric feeding or are exposed to refined highly pal-
system earned its name after confirmation that marijuana
atable food and subsequently returned to an ad libitum,
exerts its psychoactive effects primarily through CB1 recep-
low-palatability chow [although the degree of fat loss can
tor activation (63). Endocannabinoids are small lipophilic
vary (80 – 82)]. Combined with evidence that these adap-
molecules ubiquitously present in brain reward areas (64)
tive responses require intact leptin signaling (83), a phys-
and, whereas CB1 agonism selectively increases the con-
iological role for leptin to protect against pathological fat
sumption of palatable food (65) and is used to enhance
gain is implied.
appetite in the setting of cancer and other chronic disease
Obesity can therefore be viewed as a state in which the
states, antagonists of these receptors cause weight loss in
defended level of body fat is increased, analogous to in-
overweight humans and selectively suppress the consump-
tion of highly palatable foods in rodents (66, 67). The creased blood pressure in essential hypertension (Fig. 3B).
mechanism of fat loss is complex but includes reduced Yet obesity development is also clearly linked to reward/
food intake and enhanced leptin sensitivity and is primar- hedonic drives (57, 58), raising the possibility that reward/
ily mediated by CB1 receptors in the CNS (68 –70). De- hedonic circuits can impact homeostatic systems in a man-
spite unquestioned weight loss efficacy, the FDA has yet to ner that favors the defense of an elevated body fat mass
approve CB1 antagonists for human obesity treatment, (Fig. 2). This concept is strengthened by the extensive and
citing psychiatric side effects including an increased risk of reciprocal neuroanatomical connections involved in the
suicide (66). regulation of food intake and energy homeostasis that are
These findings collectively suggest that obesity can arise shared by these two systems (84, 85).
when animals or humans are confronted with foods whose Furthermore, interventions that alter CNS dopamine
palatability/reward value greatly exceeds that to which signaling can potently affect food intake and body fat
they are genetically adapted, and hence that interventions mass, although both the direction and magnitude of these
that inhibit food reward can prevent fat gain and promote effects depend on the brain areas and dopamine receptor
fat loss. In considering these hypotheses, it is important to subtypes involved (86 –91). As one example, variation at
bear in mind that obesity in both humans and animal mod- the dopamine D2 receptor gene locus can influence re-
els involves the biological defense of an elevated level of sponses to palatable foods in ways that predict subsequent
body fat mass (Fig. 3). A key issue, therefore, is to under- fat gain (91, 92), and D2 receptor availability in the stria-
stand how a change in the reward value of a diet impacts tum is reduced in obesity. These observations led to the
the energy homeostasis system. notion that obesity arises from a “reward deficit,” in
which affected individuals overeat to compensate for a
diminished perception of food reward (58, 93). However,
Obesity and Energy Homeostasis
this hypothesis is inconsistent with reports of increased
Because survival in a natural environment can be threat- food reward sensitivity in obese individuals (94), and it
ened by either too little or too much body fat, the energy predicts that low-reward food should cause compensatory

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750 Guyenet and Schwartz Regulation of Food Intake and Body Fat Mass J Clin Endocrinol Metab, March 2012, 97(3):745–755

overeating, which is not observed. To the contrary, food unclear, studies using pharmacological doses of CCK are
that is low in palatability and reward value can lower consistent with such a possibility (104). These findings
energy intake and body fat in ad libitum-fed obese rodents support the hypothesis that after RYGB, alterations in
and humans (81, 82, 95, 96). An alternative hypothesis reward processing, in conjunction with a more anorexi-
proposes that an inherited or acquired reduction of do- genic gut peptide profile and increased gastric distension,
pamine signaling via the D2 receptor in discrete CNS re- collectively support the defense of a reduced fat mass.
gions (perhaps accompanied by other dopaminergic alter-
ations) influences systems governing energy homeostasis
in a manner that favors the accumulation of body fat. The Genetic Factors
acquisition of this type of dopaminergic defect may in-
volve desensitization of specific dopamine circuits caused Although rare, single-gene mutations can cause obesity,
by overexposure to highly palatable/rewarding food (97) and much of what is known about energy homeostasis was
and/or the suppressive effect of elevated leptin and insulin discovered through the study of these monogenic obesity
on reward regions in obese individuals (32). syndromes. To date, all known nondysmorphic mono-
Bariatric surgery is an interesting case study in body fat genic obesity syndromes in humans arise from loss-of-
homeostasis. It is by far the most effective medical treat- function mutations in genes involved in the leptin signal-
ment for obesity, with the most commonly used proce- ing pathway (105).
dure, Roux-en-Y gastric bypass (RYGB), yielding an av- Although heritable factors (reflecting a combination of
erage approximately 60% loss of excess body weight in genetics and epigenetics) are estimated to explain 45 to
morbidly obese patients (98). In direct contrast to calorie 75% of body mass index (BMI) variability in human pop-
restriction, RYGB causes a reduction in hunger, reduced ulations (106), monogenic disorders account for only a
cravings for energy dense foods, and no alteration in cir- small fraction (⬍5%) of human obesity. Thus, obesity
culating thyroid hormones that would suggest a homeo- susceptibility may be a polygenic trait. Consistent with
static resistance to fat loss (99 –101). As such, it appears to this notion, genome-wide association studies (GWAS)
be the only well-characterized medical treatment that sub- have identified more than 40 common polymorphisms
stantially, reliably, and durably reduces the defended level that associate with BMI variability in humans (107, 108).
of fat mass. Although the mechanistic underpinnings of Their estimated collective contribution to BMI variability,
this effect remain poorly understood, plausible explana- however, remains quite small (⬍2%) (109), presumably
tions involving changes in gut-brain communication have because GWAS methodology does not detect gene-gene or
emerged. Studies using impermeable sleeves that cause lu- gene-environment interactions. Nevertheless, GWAS, like
minal nutrients to bypass the duodenum and proximal monogenic obesity syndromes, implicate altered hypotha-
ileum demonstrate that upper intestinal bypass per se is an lamic function in the pathogenesis of common obesity
important contributor to fat loss after RYGB (102). Thus, (107, 110).
simply excluding the duodenum and/or increasing nutri- In addition to genetic variability, developmental and
ent exposure of the ileum may favor the defense of a re- epigenetic factors are implicated in obesity risk. In animal
duced level of body fat mass. After RYGB but before sub- models, both in utero undernutrition and maternal over-
stantial fat loss, postprandial levels of PYY3–36 and GLP-1 nutrition increase subsequent obesity risk in offspring,
increase substantially, whereas ghrelin levels decrease in and children born to obese mothers are at an elevated risk
most (but not all) studies (103), changes that should be of obesity relative to those born to lean mothers (111).
anorexigenic and may therefore contribute to fat loss. Prepregnancy fat loss due to bariatric surgery attenuates
Neural signals arising from gastric distention also increase subsequent obesity risk in offspring (112), suggesting that
due to a surgically induced reduction of stomach volume, independent of genetic predisposition, developmental fac-
and this may enhance the inhibitory effect of gut peptides tors contribute meaningfully to the transgenerational
on appetite and food intake. In addition, the duodenum, transmission of obesity risk.
bypassed in RYGB, participates in nutrient sensing in- Growing evidence suggests that interacting genetic
volved in reward processing (56), so removing it from (113) and possibly developmental factors play an impor-
contact with luminal nutrients may diminish food reward tant role to determine obesity susceptibility when human
valuation. Indeed, several studies have reported altera- populations are confronted with an obesogenic environ-
tions in reward functions after RYGB, consistent with a ment (Fig. 2). Relevant environmental factors include not
role for altered reward processes in the fat loss observed only the types of foods available, but factors that affect
(101). Although the extent to which food reward is influ- food choice, such as education level, income, and related
enced by gastrointestinal or pancreatic peptides remains socioeconomic variables (114). From this perspective,

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J Clin Endocrinol Metab, March 2012, 97(3):745–755 jcem.endojournals.org 751

dramatic, recent increases of obesity prevalence in West- ticulum stress, an upstream activator of these signaling
ern societies can be viewed as resulting in large part from pathways. Suppressor of cytokine signaling 3 and protein
ever-increasing exposure of a genetically susceptible pop- tyrosine phosphatase 1B are molecules downstream of
ulation to highly palatable, energy-dense foods. NF-␬B activation that inhibit leptin (and insulin) signaling
and are induced in the hypothalamus of animals with DIO
(127, 128). A deficiency of either of these genes confers
Leptin Resistance: Cause or Effect of resistance to DIO in mice (121, 123, 124), supporting a
Obesity? link between inflammatory signaling, CNS leptin and in-
sulin resistance, and the development of obesity in this
Obesity is characterized by increases of both fat mass and model. Another potential mediator of neuronal resistance
circulating leptin levels (72, 115, 116), suggesting a state to leptin (and insulin) is protein kinase C-␪, a serine-thre-
of leptin resistance in which elevated leptin levels are re- onine kinase that is induced in the hypothalamus by in-
quired to overcome a defect in the leptin signaling cascade. tracellular accumulation of fatty acid metabolites (129,
Unlike in states of insulin resistance, in which a healthy 130), analogous to its role as a mediator of free fatty acid-
pancreas can simply secrete more insulin as needed, in- induced insulin resistance in skeletal muscle (131).
creased body fat mass is required to maintain hyperlep- Very recent work reveals evidence of neuron injury oc-
tinemia. Leptin resistance, therefore, offers a plausible curring rapidly in the ARC of rats and mice placed on a
mechanism to explain the defense of an elevated homeo- HFD, accompanied by microglial and astroglial responses
static “set point” for body fat mass. In support of this that may (at least initially) be neuroprotective in nature
hypothesis, fat loss induced by caloric restriction elicits (132). The onset of hypothalamic injury during HFD feed-
compensatory responses in obese individuals that pro- ing in rats and mice occurred before obesity onset, and an
mote the recovery of lost fat (including increased hunger increased gliosis signal was detected in the hypothalamus
and metabolic efficiency) (72, 115, 116), which can be of obese humans using magnetic resonance imaging, sug-
suppressed by restoring plasma leptin concentrations to gesting that a similar process may operate in humans. Al-
pre-fat loss levels (72). though the implications of this work await further study,
The hypothesis that leptin resistance contributes to acquired injury of neurons in a brain area central to energy
obesity pathogenesis is supported by evidence that rodents homeostasis offers a plausible mechanism for both hypo-
fed a purified, high-fat diet (HFD) acquire a striking loss thalamic inflammation and the defense of an elevated level
of leptin sensitivity in ARC neurons (117, 118). Because of body fat in obese individuals (Fig. 2) (132).
targeted deletion of leptin receptors from any of several Although these and related observations offer impor-
hypothalamic neuronal subpopulations is sufficient to tant insight into the pathogenesis of DIO, many pieces of
cause obesity in mice (119, 120), the acquisition of hypo- the puzzle are still missing. Among these are cohesive ex-
thalamic leptin resistance is a plausible explanation for the planations for the mechanisms underlying hypothalamic
defense of elevated body fatness in animal models of diet- inflammatory signaling and injury during HFD feeding
induced obesity (DIO). Genetic interventions that prevent and translational studies that address the hypothesis
hypothalamic leptin resistance also protect against DIO mechanistically in humans.
(121–125), suggesting that the former is required for the
latter to occur. Moreover, leptin resistance is detectable in
ARC neurons even after relatively short periods of HFD Conclusion
feeding, before substantial fat gain (118). At the cellular
level, inflammatory signaling has emerged as a potentially Although substantial progress has begun to identify neu-
important mediator of leptin resistance (Fig. 2) (126). An rohumoral mechanisms underlying obesity, nonsurgical
induction of proinflammatory cytokines and other mark- obesity treatment has improved little over the years. If
ers of inflammation is clearly evident in the hypothalamus obesity involves the biological defense of an elevated level
of rodents with DIO (122, 126) and, just as inflammation of body fat, as current evidence suggests, advice to simply
in peripheral tissues contributes to obesity-induced insulin “eat less, move more” cannot be expected to remedy the
resistance, cellular inflammatory signaling also potently problem. This is because interventions that reduce body
inhibits leptin signal transduction in neurons (122, 125). fat stores without a corresponding decrease in the de-
Among several cellular mechanisms implicated in obe- fended level of fat mass elicit compensatory responses that
sity-associated hypothalamic inflammation are activation promote the recovery of lost fat and are difficult to con-
of JNK (126) and IKK-NF-␬B (122) signal transduction sciously override. Because these responses constitute per-
pathways, possibly as a consequence of endoplasmic re- haps the single largest obstacle to effective obesity treat-

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752 Guyenet and Schwartz Regulation of Food Intake and Body Fat Mass
ment, breakthroughs in understanding the biological
defense of elevated body fat mass may be required to en-
able the development of effective new obesity prevention
and treatment strategies.
Acknowledgments
Address all correspondence and requests for reprints to: Michael
W. Schwartz, M.D., Diabetes and Obesity Center of Excellence,
University of Washington at South Lake Union, 815 Mercer
Street, N334, Box 358055, Seattle, Washington 98109. E-mail:
mschwart@u.washington.edu.
This work was supported by a National Institutes of Health
(NIH) Fellowship Training Program Award (T32DK007247),
an NIH National Research Service Award (F32DK091989), the
NIH-funded University of Washington Nutrition Obesity Re-
search Center and Diabetes Endocrinology Research Center, and
NIH Grants DK068384, DK083042, and DK052989 (to M.S.).
Disclosure Summary: S.G. has nothing to declare. M.S. has
previously consulted for Orexigen and Pfizer.
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