Er 2017-00111

SCIENTIFIC STATEMENT
Obesity Pathogenesis:
An Endocrine Society Scientific Statement
Michael W. Schwartz,1 Randy J. Seeley,2 Lori M. Zeltser,3 Adam Drewnowski,4 Eric Ravussin,5 AFFILIATIONS
1Diabetes Institute, University
Leanne M. Redman,5 and Rudolph L. Leibel3,6 of Washington, Seattle,
Washington 98109
Downloaded from https://academic.oup.com/edrv/article/38/4/267/3892397 by guest on 08 November 2023

2
Department of Surgery,
University of Michigan,
ABSTRACT Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest Ann Arbor, Michigan 48109
3Naomi Berrie Diabetes Center
that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is
and Department of Pathology
concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective and Cell Biology, Columbia
options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully University, New York,
complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included New York 10032
4Center for Public Health
evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding
Nutrition, University of
mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the Washington, Seattle,
tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the Washington 98195
5John S. McIlhenny Skeletal
biological process that maintains weight stability by actively matching energy intake to energy expenditure
Muscle Physiology Laboratory,
over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than Pennington Biomedical Research
simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms Center, Baton Rouge,
underlying this “upward setting” or “resetting” of the defended level of body-fat mass, whether inherited or Louisiana 70808
6Division of Molecular Genetics,
acquired. The ongoing study of how genetic, developmental, and environmental forces affect the energy Department of Pediatrics,
homeostasis system will help us better understand these mechanisms and are therefore a major focus of this Columbia University, New York,
statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public New York 10032
policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic
consequences. (Endocrine Reviews 38: 267 – 296, 2017)
Definition Genetic factors: evidence for and against Impact of diet composition on
Rationale for a scientific statement on Interactions between genes, obesity risk
obesity pathogenesis development, and environment Roles of sedentary behavior, exercise,
ENERGY HOMEOSTASIS AND THE Role of epigenetic modifications and nonexercise activity thermogenesis
PHYSIOLOGICAL CONTROL OF Developmental factors: evidence for Other factors
BODY-FAT STORES and against Smoking cessation
General principles Roles of parental body weight or diet Infectious factors
Background Undernutrition Mechanisms for biological defense of
Leptin and energy homeostasis Overnutrition/obesity elevated body-fat mass
Fuel partitioning, insulin, and obesity Modes of transmission CONCLUDING REMARKS AND FUTURE
Neurobiology of energy homeostasis Role of EDCs DIRECTIONS
Background PFCs The two distinct components of obesity
Hypothalamic neurons controlling BPA pathogenesis
energy balance Modes of transmission of endocrine Developmental determinants of the
Hindbrain circuits and the parabrachial disrupting chemical effects biologically defended level of body-fat mass
nucleus GI factors, bariatric surgery, and the Interactions between genetics, ISSN Print: 0163-769X
Developmental considerations microbiome epigenetics, developmental influences, ISSN Online: 1945-7189
Integrative physiology of energy Insights from bariatric surgery and the environment Printed: in USA
homeostasis The gut microbiome and other Future directions for EDC research Copyright © 2017
Determinants of feeding behavior GI factors Lessons learned from the weight- Endocrine Society
Determinants of energy expenditure Social and economic factors reduced state Received: 11 May 2017
MECHANISMS OF OBESITY Diet composition, lifestyle, and The gut–brain axis Accepted: 12 May 2017
PATHOGENESIS obesity risk Dietary influences First Published Online:
26 June 2017
doi: 10.1210/er.2017-00111 https://academic.oup.com/edrv 267

Stratification of obesity outcomes Identifying and mitigating

Unraveling mechanisms linking the environmental risk factors
environment to defense of elevated Translating basic science into more
body weight effective pharmacotherapy
ESSENTIAL POINTS
· Obesity pathogenesis involves two related but distinct processes: (1) sustained positive energy balance (energy intake .
energy expenditure) and (2) resetting of the body weight “set point” at an increased value. The latter process explains
why weight lost through changes of diet and/or lifestyle tends to be regained over time, a major obstacle to effective
obesity treatment.
· How the increased body weight comes to be biologically defended remains uncertain, although ongoing research is
beginning to shed some light on underlying mechanisms. Therapeutic strategies that target these mechanisms have the
potential to reset the defended level of body weight at a lower, more normal value.

· The impact of diet on obesity risk is explained largely by its effect on calorie intake, rather than by changes of either energy
expenditure or the internal metabolic environment. Stated differently, "a calorie is a calorie.” Thus, habitual consumption
of highly palatable and energy-dense diets predispose to excess weight gain irrespective of macronutrient content.
· Beyond diet, environmental factors ranging from socioeconomic status to chemical exposures to sedentary lifestyle can
confer obesity risk. How these inputs interact with genetic, epigenetic and developmental factors that predispose to
obesity is a key question for future research.
T he need to integrate molecular, genetic, de-

velopmental, behavioral, and environmental
factors highlights the substantial challenge inherent in
between these values to be “overweight.” The degree of
obesity can be further subcategorized into class  (BMI
of  to ,), class  (BMI of  to ,), and class 
achieving a comprehensive understanding of obesity (BMI of .) (). Assessing BMI in children requires
pathogenesis. Mechanistic formulations must draw adjusting for both age and gender.
from disciplines that include: the neuroscience of BMI satisfies our need to estimate body-fat mass at
feeding behavior; the psychology of food reward; the a population level and thus gauge a group’s susceptibility
metabolic impact of specific nutrients and changes of to complications of obesity. However, it is not a reliable
physical activity; as well as genetics, epigenetics, and clinical tool for assessing individual body fatness, because
developmental biology relevant to energy balance variations in skeletal muscle and other lean-body-mass
control, and the influence of exposure to environ- components create substantial variations in total body
mental variables ranging from endocrine-disrupting mass. For example, a heavily muscled individual with
chemicals (EDCs) to socioeconomic factors. When increased body weight relative to height will have a BMI
processing this information, one must also be mindful value that can erroneously place them into the over-
that although there are many interventions that can weight or even obese category. Additionally, there are
cause obesity in an experimental setting, the key significant racial/ethnic differences in how BMI associ-
question is whether they do cause obesity in a natu- ates with adverse medical consequences. (For addi-
ralistic environment. In this statement, we focus on tional information, see the companion Endocrine Society
factors for which compelling evidence exists that Scientific Statement titled “Obesity Management: Past,
implicates them in the pathogenesis of either the Present, and Future; Science and State of the Art.”)
accumulation or maintenance of excess body fat mass.
Rationale for a scientific statement on
Definition obesity pathogenesis
Obesity is broadly defined as an excess of body- For most endocrine disease, researchers have estab-
fat mass. Reliable fat-mass quantitation requires lished effective therapeutic treatments based on un-
sophisticated tools that are not widely available (e.g., derlying disease mechanisms. This is not the case with
magnetic resonance imaging or dual energy X-ray obesity; unlike most other endocrine disorders, we
absorptiometry), and this has hampered efforts to have a very limited understanding of its pathogenesis,
arrive at a more specific definition. Consequently, an despite decades of research and billions of dollars
elevated body mass index (BMI), which expresses body spent each year on its treatment. This gross expen-
weight (in kilograms) as a function of body height diture of time and money is undoubtedly linked to the
(in meters) as a surrogate measure of body fatness, extraordinarily high prevalence (affecting one-third of
is the most widely accepted definition of obesity. the adult United States population) (), ease of de-
Population-based actuarial studies place the upper tection, and stigma associated with obesity. These
limit of normal BMI in adults at  kg/m, define factors conspire to create an enormous demand for
obesity as a BMI .  kg/m, and designate a BMI weight-loss products and services that continue to
268 Schwartz et al Obesity Pathogenesis Endocrine Reviews, August 2017, 38(4):267–296

flourish, despite being largely ineffective, sometimes presidential address was given in , the same year
dangerous, and almost entirely unregulated (). that insulin was discovered.)
This situation is not unlike the medical practice of Clearly, we need a well-defined, generally accepted
a century ago in which “glandular extracts” were cleverly set of physiological, developmental, and environ-
marketed for a multitude of diseases, generating robust mental principles regarding body weight homeostasis
sales and profits for their manufacturers despite a lack of that will inform strong research and therapeutic
efficacy or safety data (, ). It was largely in response to strategies regarding obesity pathogenesis. The current
the rise of this practice (termed “organotherapy”) that lack of consensus regarding obesity pathogenesis has
the Endocrine Society chose a different path. In the resulted in competing and poorly justified claims both
third year of its existence, the Endocrine Society elected from within and outside of the scientific community.
Sir Harvey Cushing as President. In his presidential These inconsistencies erode public trust and confi-
address, he advocated strongly in favor of adopting the dence in the scientific process as it pertains to obesity
scientific method and abandoning empiricism to better and its treatment, which only further supports non-
inform the diagnosis and treatment of endocrine disease scientific ideologies and products. To break this vi-

(). In doing so, Cushing helped to usher in the modern cious cycle, and to identify effective treatments, we
era of endocrinology and with it, the end of organo- need to establish clearly defined and reliable data
therapy. (In an interesting historical footnote, Cushing’s regarding obesity’s underlying causes.
Energy Homeostasis and the Physiological mixed body tissue) per year (, kcal total) is
Control of Body-Fat Stores equivalent to a .% positive caloric balance. Thus, we
infer that such individuals are .% accurate in
General principles matching energy intake to expenditure. There are caveats
to such calculations relating to the fact that increased
Background body mass increases energy expenditure (further re-
At its most basic level, the pathogenesis of obesity ducing the balance error), but from a thermodynamic
seems simple: Calories are consumed in amounts that perspective, it is clear that obesity is generally the
exceed ongoing energy expenditure. Based largely on consequence of small, cumulative imbalances of energy
this concept, most people have historically perceived intake and expenditure. Although the causes of these
obesity as the result of negative personal traits, such as imbalances can involve innumerable genetic, de-
gluttony, sloth, self-indulgence, laziness, and lack of velopmental, and/or environmental factors, once in-
will power. However, growing evidence indicates that dividuals who are obese and individuals who were never
obesity pathogenesis involves processes far more obese achieve their “customary” body weights and
complex than the passive accumulation of excess compositions, they tend to maintain and defend those
calories. It is this complexity that lies at the heart of weights by identical mechanisms.
why obesity is so difficult to treat. Fundamentally, Studies investigating the adaptive responses of
humans have an “evolutionary physiology” that is normal-weight humans and animals to changes in
predisposed to conserve body fat as a factor of survival. body weight support the concept of a physiologically
This evolutionary physiology in today’s climate of easy important energy homeostasis system. Weight loss
access to virtually unlimited calories has created a large induced by caloric restriction, for example, results in
segment of humanity that appears to be biologically both an increased drive to eat and a reduction of
predisposed to excessive weight gain. Hence, we see energy expenditure. These responses both resist fur-
upward trends of adiposity in developed and de- ther weight loss and favor recovery of lost weight,
veloping communities. and they can persist for years, provided that body-
How does the energy homeostasis system bear on fat stores have not returned to baseline (). These
this issue? We see clear evidence of a properly op- adaptive responses to weight loss are reported in both
erating energy homeostasis system in the remarkable individuals who are obese and lean individuals (),
body-weight stability of individuals who are not therefore suggesting that obesity pathogenesis involves
obese over long periods of time. Evidence from an the physiological defense of a higher level of body fat.
observational study of , healthy Swedish women This perspective offers a plausible explanation for the
() indicates that participants were, on average, very frequent regain of lost weight that confounds
..% accurate in their annual matching of energy most forms of obesity treatment (, ).
intake to expenditure for  consecutive years of Conversely, normal-weight subjects respond to
observation. To better understand the implications experimental weight gain (induced by “forced over-
of this observation, consider that a healthy adult feeding”) by increasing energy expenditure and
weighing  pounds can be expected to gain .. reduced hunger. Once forced overfeeding is dis-
pounds in a year if they expend  fewer calories per continued, a combination of decreased drive to eat and
day than they consumed. During  years of adulthood increased energy expenditure tends to restore body
[assuming a caloric intake of  kcal/day (. M kcal weight to normal (). Indeed, such overfeeding studies
total)], a weight gain of  pound (~ kcal/pound show that it is surprisingly difficult for normal-weight

individuals to achieve and sustain experimentally in- neurocircuits may be related more to preventing loss
duced weight gain (). Individuals who are obese also of body fat (communicated to the brain by a decrease
resist excess weight gain induced by forced overfeeding of leptin signaling) than to defending against its in-
(). Therefore, their elevated levels of body-fat mass crease (conveyed by increased leptin levels). In this
appear to be similarly subject to biological defense. formulation, genetics, development, and even envi-
Stated differently, individuals who are obese and in- ronmental factors can influence the level of leptin
dividuals who are not obese appear to use the same signaling (“threshold”) below which compensatory
homeostatic mechanisms to defend different levels of increases in food intake and reductions in energy
body-fat mass. This observation suggests that dysfunc- expenditure occur. Accordingly, this theory holds that
tion of the energy homeostasis system is both necessary leptin circuitry is more sensitive to decreases than to
and sufficient for the biological defense of elevated body increases in the circulating leptin level, with the limited
weight in individuals who are obese (). What remains response to leptin concentrations above the lower
unclear is how this dysfunction is linked to factors that threshold offering a potential explanation for what some
enable excess weight gain, such that excess body-fat mass refer to as leptin resistance. The apparent resistance in

comes to be biologically defended. This issue is central to this formulation is simply a reflection of the circuitry’s
obesity pathogenesis and therefore a central focus of this design (, ). More work in this area is clearly needed.
scientific statement.
Fuel partitioning, insulin, and obesity
Leptin and energy homeostasis General perspectives on obesity pathogenesis have
The adipocyte hormone leptin, which circulates at swung from early conceptualizations of obesity as
concentrations proportional to body-fat mass, plays a storage disease of adipose tissue (analogized pre-
a significant role in the relationship between obesity and sumably to some of the earliest identified inborn errors
energy homeostasis. A deficiency of leptin causes severe of metabolism by Garrod) to more recent brain-centric
hyperphagia and obesity in both humans and animals models, in which the brain, by virtue of its operational
(), with physiological leptin replacement ameliorating control of food intake and energy expenditure, im-
both the hyperphagia and obesity in leptin-deficient poses excess calories on passive adipocytes. Sometimes
individuals (). Therefore, there can be no question referred to as “pull” and “push” models, respectively,
that normal body-weight maintenance in humans re- each makes very different predictions regarding both
quires intact leptin-regulated neurocircuits. underlying molecular mechanisms and how we should
However, these observations do not indicate that approach obesity prevention and treatment. Embed-
genetic deficiencies of leptin or its cognate receptor ded within this debate is the extent to which adipocyte-
are important causes of human obesity. Although autonomous processes can pull substrate molecules
such individuals exist, they are rare (). In contrast, preferentially into adipocytes, and by “partitioning”
most individuals who are obese have elevated plasma calories in this way cause higher fractional deposition
leptin levels (in proportion to the increase of body-fat of calories as fat. A key prediction of this model is that
content), raising the possibility that common forms of some individuals who consume a diet in which caloric
obesity are associated with “leptin resistance” (i.e., that intake and energy expenditure are matched (e.g., an
supraphysiological plasma leptin levels are required to isocaloric diet) will preferentially deposit ingested
overcome tissue resistance to leptin and thereby enable calories as fat at the expense of their lean tissue mass,
energy intake and energy expenditure to match one thereby becoming relatively fatter without entering
another). Because adipocytes secrete leptin in proportion a state of positive energy balance per se (see the section
to body-fat content, the only way to raise plasma leptin titled “Impact of diet composition on obesity risk”).
levels in this setting is to become obese. Although it is possible that variations in body
These considerations would seem to point to composition among individuals of the same body
a causal role for leptin resistance in the pathogenesis of weight reflect (to some extent) the consequences of
common forms of obesity, but the matter remains such processes, achieving clinical obesity in this
unsettled. For one, there is no uniformly agreed-upon manner must be rare, because most individuals who
definition for leptin resistance (), and the presence are obese have absolute increases of both lean and fat
of hyperleptinemia per se cannot be taken as evidence mass. Nevertheless, when leptin-deficient ob/ob mice
of its presence. Indeed, recent data suggest that are pair-fed the same amount of food consumed by
the cellular response to leptin (e.g., activation of in- normal controls, they gain more mass (due to reduced
tracellular STAT signaling) is preserved in obese, energy expenditure) and preferentially deposit that
hyperleptinemic rodents (). The circulating leptin mass as fat, leading to an absolute and relative de-
concentration needed to fully engage central nervous ficiency of lean mass in these animals (). Although
system responses likely differs among individuals the mechanism underlying this partitioning effect
based on the influence of genetics, development, and must relate to developmental and/or intercurrent ef-
possibly diet. Thus, some individuals who are obese fects of leptin (perhaps involving interactions with
may simply require more leptin (and hence body fat) insulin as well), the precise biology is not clear ().
to fully engage relevant neurocircuits (). The hypothesis that leptin plays a direct role in these
Given the evolutionary considerations alluded to processes is supported by evidence of its direct effects
above, the primary role played by leptin-responsive on lipid partitioning in skeletal muscle ().

Lipoprotein lipase (LPL), an enzyme that hy- consumption is matched between diets) (). This is
drolyzes circulating apolipoprotein-bound acylgly- not to say that diets high in refined carbohydrate and/
cerides at the surface of many cell types (including or fructose (soft drinks) do not predispose to obesity,
adipocytes and myocytes), also appears to affect the but the underlying mechanism is likely to involve
partitioning of fatty acids in ways that affect both excessive intake of calories, rather than nutrient-
absolute and relative fat mass. Although mice specific or hormonal effects on substrate partitioning.
overexpressing LPL in skeletal muscle accumulate Collectively, these data suggest that diet compo-
triglyceride in muscle and are resistant to increases sition per se (relative quantities and specific types of
of adipose tissue mass during overfeeding (), carbohydrates, sugars, and fatty acids, as distinct from
overexpression of LPL in adipocytes does not affect caloric content) contributes far less to the etiology of
body weight or adiposity in mice (). Restoration of obesity than do contributions made by the net im-
muscle LPL in mice that otherwise lacks the enzyme balance of intake and expenditure. It therefore follows
creates animals functionally lacking LPL in adipose that although variations in diet composition can
tissue; surprisingly, these mice are characterized powerfully affect palatability and hence hedonically

by normal body-fat mass, apparently because of motivated feeding, whether it can also influence food
a compensatory increase of fatty acid synthesis in intake via secondary metabolic consequences (e.g.,
adipocytes (). Expression of LPL varies widely by effects of insulin on circulating nutrient levels) remains
depot in humans, and it might account for differ- a highly controversial topic that seems unlikely to be
ences in adipose tissue distribution in some in- resolved without clinical studies that will be costly and
dividuals. As insulin increases the synthesis and challenging to undertake.
activity of LPL (while also stimulating adipocyte
uptake of fatty acids and glucose), intrinsic differ- Neurobiology of energy homeostasis
ences in insulin-mediated molecular processes
could (in theory) play a determinative role in body- Background
fat content and/or distribution. In this context, More than  years ago, to account for evidence that
however, it is important to note that humans lacking body weight is biologically defended, Kennedy
LPL on a genetic basis have normal fat mass due to () proposed that body-fat mass is regulated by an
the ability of adipocytes and muscle to take up “adiposity negative feedback” system. Specifically, he
circulating free fatty acids in quantities sufficient to suggested that circulating signals inform the brain
allow adequate aclyglyceride formation in adipose regarding the amount of body fuel stored in the form
tissue or oxidation in muscle (). Therefore, al- of fat. In response, the brain makes compensatory
though local activity of LPL (in adipocytes and adjustments to both food intake and energy expen-
muscle) could play a role in partitioning of fat diture so as to promote weight stability. Compelling
among tissues, it appears to be neither necessary nor support for this hypothesis has emerged in the decades
sufficient for the uptake of fatty acids into adipose since, including the identification of neurocircuits and
tissue. signaling molecules that sense, integrate, and trans-
Several investigators have proposed that the effect duce humoral input relevant to body-fuel stores into
of specific diet components on insulin secretion or adaptive changes of energy balance. Because a credible
action contributes to obesity pathogenesis through formulation of obesity pathogenesis depends on
effects on calorie deposition in adipocytes, rather than a comprehensive understanding of how food intake
(or in addition to) effects on energy balance per se. and energy balance are controlled, we explore this
Essentially, carbohydrates in general (and refined and topic in detail here.
possibly naturally occurring sugars in particular) are Motivational aspects of feeding behavior provide
proposed to promote hyperinsulinemia that in turn a useful context within which to introduce the topic
drives glucose and fatty acids into adipose tissue (). of energy balance neurocircuitry. Both “metabolic
Accordingly, this process is proposed to cause obesity need” and “food reward” have long been considered
by both direct effects on adipocytes that favor fat key drivers of feeding. The former involves a desire to
deposition and by lowering circulating metabolic alleviate the discomfort associated with inadequate
substrates (and/or exerting effects on hepatic meta- food availability (“drive reduction”), whereas the
bolism) that subsequently stimulate food intake. Addi- latter describes the anticipation of a rewarding ex-
tional “lowering” effects on energy expenditure by perience and subsequent fulfillment of that experi-
these dietary components are proposed to exacerbate ence (). Recent advances in neuroscience have
the tendency toward increased fat deposition (). As enabled the identification of neuronal substrates
we discuss in greater detail in a later section (“Diet implicated in these distinct but complementary
composition, lifestyle, and obesity risk”), this hy- sources of motivation.
pothesis remains controversial and has yet to receive
the level of support needed for broad acceptance. Hypothalamic neurons controlling energy balance
Among several concerns is that differences in diet Perhaps the best studied subset of neurons involved
composition have yet to be convincingly shown to in feeding behavior are those that co-express neuro-
cause differences in body composition when provided peptide Y (NPY), agouti-related protein (AgRP) (an
in an isocaloric manner (such that total calorie antagonist of melanocortin signaling), and the inhibitory

neurotransmitter, g-aminobutyric acid (GABA); as a positive or a negative experience may therefore

henceforth referred to as AgRP neurons, because they depend on whether food is available.
are the only neurons that express AgRP. Located in an Situated adjacent to AgRP neurons in the ARC are
area of the mediobasal hypothalamus known as the neurons that express pro-opiomelanocortin (POMC)
arcuate nucleus (ARC), AgRP neurons are activated in and release the anorexic neuropeptide a-melanocyte–
conditions of negative energy balance and weight loss stimulating hormone. Food intake is reduced following
(e.g., fasting), in part because such conditions reduce the activation of melanocortin  receptors expressed
plasma concentrations of leptin and insulin, hormones on “downstream” target neurons in the paraventricular
that tonically inhibit these neurons (). Because this hypothalamic nucleus and other brain areas, and leptin
inhibitory input becomes quiescent during fasting, stimulates POMC neurons (). In conditions of nega-
AgRP neurons are activated and increase the drive to tive energy balance and leptin deficiency, therefore,
eat. POMC neurons are inhibited, whereas AgRP neurons
What evidence causally links AgRP neuron acti- are activated (). This combination drives feeding in
vation to increased food intake? Thanks to recent the same way that a car is propelled forward by stepping

advances in optogenetics and related neuroscience on the accelerator pedal (AgRP neuron activation) while
methods, researchers have been able to investigate also removing one’s foot from the brake pedal (POMC
responses triggered by the selective activation or in- neuron inactivation).
hibition of uniquely identified neuronal subsets in Just as leptin’s ability to reduce food intake and
conscious, freely moving animals. This work has con- body weight requires an intact melanocortin system,
vincingly revealed the powerful hyperphagic response mutations that impair the melanocortin system cause
elicited by selective AgRP neuron activation (). hyperphagic obesity in both humans and rodent
Combined with evidence that AgRP neurons are models (). POMC neurons are also targets for the
activated across a variety of states of metabolic need action of certain anorexic agents, including seroto-
that drive hyperphagic feeding (e.g., fasting, un- nergic drugs (). Because the degree of hyperphagia
controlled diabetes, genetic leptin deficiency, and and obesity induced by defective melanocortin sig-
hypoglycemia), researchers have suggested a causal naling is greatly enhanced by consuming a highly
role for their activation in the associated hyperphagia palatable diet, the melanocortin system appears to play
(). This possibility received direct support fol- a physiological role to limit reward-based feeding ().
lowing the demonstration that experimental silenc- Additionally, a recent study reported that adjacent to
ing of AgRP neurons prevents hyperphagia elicited AgRP and POMC neurons in the ARC is a distinct and
by fasting (). previously unrecognized subset of excitatory neurons
Recent work has identified several unique and that, when activated, powerfully and rapidly inhibit
unanticipated properties of AgRP neurons. Using feeding (). How these neurons fit into the bigger
cell type–specific in vivo calcium imaging in con- picture of energy homeostasis will undoubtedly be the
scious, free-moving mice, Knight et al. () docu- subject of intensive additional study.
mented that although AgRP neurons are activated in A relevant consideration here is that food intake
fasted mice, as expected, they cease firing upon the regulation involves distinct components operating
sight of food, prior to feeding onset. Although across very different time periods. Some neurohu-
originally interpreted to suggest that activation of moral mechanisms exert very rapid effects of short
AgRP neurons merely prepares animals to eat, duration (e.g., a single meal), whereas others are more
rather than driving feeding behavior per se, the same modest but sustained over long time intervals. Yet
group showed that if food is made available only each is somehow integrated to enable the precise long-
after activation of AgRP neurons ceases, intake still term constancy of body weight mentioned above, and
increases markedly (as long as food is made available each can respond in an integrated manner to per-
within  minutes) (). Thus, activation of AgRP turbations of body weight, although not necessarily
neurons provides a robust stimulus to feeding that through reciprocal effects on the same processes.
continues throughout a meal, even though activity Delineating the mechanisms responsible for this
of these neurons ceases prior to meal onset. seamless integration is a critical issue for the future
Whether activation of these neurons increases study of the biology of energy homeostasis. Related
intake by enhancing the rewarding properties of issues are how homeostatic and hedonic drivers of
food or whether it motivates feeding through drive energy intake interact, how this interaction is woven
reduction (a desire to alleviate the discomfort as- into long-term control of energy balance, and whether
sociated with not eating) is an active and somewhat defects in this integration contribute to obesity
controversial area of study. Sternson et al. () pathogenesis.
suggested a key role for the latter mechanism, im-
plying that AgRP neuron activation is aversive when Hindbrain circuits and the parabrachial nucleus
food is not available, and that feeding ameliorates Because experimental activation of POMC neurons is
this effect. Conversely, Knight et al. () reported not associated with rapid or potent feeding inhibition,
that as long as food is available, animals perceive the melanocortin system does not appear to be im-
AgRP neuron activation as being highly rewarding. portant for meal termination under physiological
Whether animals perceive AgRP neuron activation conditions. The latter process involves meal-induced

secretion of gut-derived peptides, such as glucagon- satiety. Despite its inherent complexity, further re-
like peptide  and cholecystokinin, that, following their search in this area could lead to novel therapeutic
release by enteroendocrine cells in the gastrointestinal agents for obesity.
(GI) tract, play a physiological role to promote satiety
by activating an ascending visceral sensory circuit (). Developmental considerations
This circuit originates with vagal afferent neurons that Identifying the contribution of developmental in-
convey GI signals to hindbrain areas, including the fluences to obesity risk is a daunting challenge because,
nucleus of the solitary tract. Some of these hindbrain as noted above, neurons regulating energy homeostasis
neurons project to the parabrachial nucleus, which is are distributed throughout the brain (, ), and our
a central node in this ascending pathway. Of particular understanding of the ontogeny and plasticity of these
relevance are calcium gene-related peptide expressing circuits is incomplete. Nevertheless, available evidence
neurons in the parabrachial nucleus (CGRPPBN) suggests that developmental influences can and do
neurons located within the external lateral subnucleus contribute to obesity pathogenesis in adults.
of the parabrachial nucleus. A variety of stimuli In rodents, circuits regulating distinct aspects

linked to food consumption activate these neurons, of feeding behavior develop asynchronously. The
such as gastric distention, secretion of cholecystokinin, most basic types of feeding regulation are present
and glucagon-like peptide . Activation of CGRPPBN at birth, whereas the development of progressively
neurons is implicated not only in physiological satiety more complex systems extends into adolescence.
and normal meal termination, but also in anorexia The capacity to regulate food intake in response to
elicited by a variety of aversive stimuli. Because hy- short-term signals associated with meal termination
pothalamic AgRP neurons inhibit CGRPPBN neurons develops prior to the maturation of systems governing
(), activation of hypothalamic AgRP neurons ap- energy homeostasis. We can detect autonomic pro-
pears to stimulate feeding, in part, by inhibiting jections at birth that link rodent hypothalamus and
CGRPPBN neurons. brainstem to the stomach, and these projections
Unlike what is seen with POMC neurons, exper- continue to increase during the lactation period (,
imental activation of CGRPPBN neurons causes an- ). Food intake is suppressed in response to gastric
orexia that is rapid in onset, severe, and if sustained distension as early as postnatal day , but it is not
can lead to life-threatening weight loss (). Con- influenced by postabsorptive nutritional signals from
versely, inactivation of CGRPPBN neurons increases the gut until postnatal day  to  (, ). Ho-
meal size and blocks the satiating effects of chole- meostatic feeding circuits that sense, integrate, and
cystokinin and glucagon-like peptide , implicating relay information about the availability of short- and
these neurons as physiological mediators of meal long-term energy stores develop in the periweaning
termination (). However, because the increase of period (–). Projections from ARC neurons that
meal size induced by CGRPPBN neuron inactivation is convey nutritional (e.g., glucose and fatty acids) and
offset by a proportionate reduction in the number of hormonal (e.g., leptin and insulin) signals of energy
meals, net food intake does not change. Therefore, status to preautonomic components of the feeding
normal energy homeostasis does not appear to require circuitry form in the third week of life (), and re-
activation of these neurons, even though meal ter- sponsiveness to adiposity signals (such as leptin)
mination does (). Unlike what is observed in mice emerges  week after weaning (at  weeks of age) ().
with defective melanocortin signaling, CGRPPBN Finally, processes that control motivated/rewarding
neuron inactivation also does not increase intake aspects of feeding behavior are not established until
of a highly palatable diet, nor does it predispose to postingestive consequences can be reinforced by the
diet-induced obesity, whereas POMC neurons play actions of corticolimbic circuits, which mature in the
a physiological role to limit food intake over long time postweaning period (, ). Although the onset of
intervals. Therefore, CGRPPBN neurons provide an corresponding regulatory networks has yet to be
immediate and powerful brake to food consumption parsed in humans, individual patterns of food intake
during individual meals. are apparently established between  and  years of age
Importantly, note that although these observations (, ). In both species, therefore, maturation of
highlight relevant recent advances in the neurobiology feeding circuits continues during the transition to
of feeding, the substantial complexity inherent in food independent feeding of solid foods.
intake regulation cannot be reduced to a small set of Progress toward an understanding of develop-
interacting neurocircuits, and much remains to be mental events regulating the maturation of feeding
learned in this field. Adding to this complexity is circuits is hampered by the fact that neurons with
evidence that some of these neurons can affect feeding opposing effects on food intake are often interspersed
in unexpected ways. For example, CGRPPBN neurons within the same nucleus (). Furthermore, neurons
are implicated not only in the perception of satiety but with similar peptidergic identities (e.g., NPY, AgRP,
also in the transmission of aversive experiences that GABA, and POMC) can respond differently to the
can lead to fear conditioning and formation of threat same hormone and nutrient signals at different de-
memory (). It therefore seems somewhat surprising velopmental stages (), and they can also regulate
that activation of these same neurons during a meal feeding via projections to multiple downstream targets
plays a key role in the physiological experience of (). The origin of ARC feeding circuits involves

progenitor cells in the basal aspect of the third ven- of the pup-derived leptin surge (, ). Exposure to
tricle that differentiate into immature postmitotic maternal obesity or overnutrition during lactation
neurons at midgestation in rodents (, ) and by the can also reduce the number of neurons that express
end of the first month of gestation in primates (). In leptin receptors, with lasting impacts on leptin re-
mice, most of these immature ARC neurons initially sponsiveness (, ). Furthermore, the extent of
express the Pomc gene (), but during the course of axonal outgrowth from ARC neurons to their various
gestation and early part of lactation, Pomc expression is target sites appears to be influenced by both milk-
gradually extinguished in many of these cells. As this derived (insulin) and pup-derived (leptin) hormones
occurs, these neurons begin to express the combina- (, ). Finally, if undernutrition sufficient to limit
tion of neuropeptides and neurotransmitters that growth occurs during lactation, the maturation of
comprise the signaling outputs in the adult (e.g., NPY, systems that provide presynaptic (GABA) and post-
AgRP, and GABA). In AgRP neurons, this process synaptic (adenosine triphosphate–sensitive potassium
occurs progressively, with expression of NPY turning channels) inhibitory signals to AgRP neurons is
on first, followed by GABA, and finally AgRP. Axonal delayed (). The existence of multiple steps at which

outgrowth from ARC neurons to downstream targets ARC circuits can recalibrate to match the anticipated
begins at the end of the first postnatal week and is external environment likely underlies the extraordi-
largely complete by the end of lactation in the third nary capacity of these circuits to compensate for early
postnatal week (). In nonhuman primates, in developmental deficits ().
comparison, ARC projections develop during the third Although developmental influences on food in-
trimester of gestation (), consistent with the fact that take regulatory circuits could certainly impact obesity
the lactation period in rodents corresponds develop- susceptibility in adults, maternal programming of
mentally to late gestation in humans (). Conse- obesity susceptibility in rodents appears to arise more
quently, many neurodevelopmental processes that from reductions of resting () and activity-dependent
occur in utero in humans do not take place until after energy expenditure () than from persistent effects on
birth in rodents. food intake (). To better understand these effects,
Researchers have postulated a neurodevelopmental a brief focus on the ontogeny of autonomic nervous
role for the surge of plasma leptin levels that occurs in system neurocircuits regulating thermogenesis is
rodents at the end of the first postnatal week (). warranted. The components of energy expenditure
Although food intake is not sensitive to leptin at relevant to this discussion include heat produced ei-
this age, developmental processes (such as axonal ther in the service of thermoregulation or in response
outgrowth) apparently are (). Furthermore, during to food consumption (diet-induced thermogenesis).
lactation, AgRP neurons () require leptin to pro- The ontogeny of sympathetic circuits regulating non-
ject from the ARC to other areas, such as the shivering thermogenesis hinges on the coordinated
paraventricular hypothalamic nucleus (, ). Fol- development of both the nervous system and its target
lowing the transition to independent food intake at organ. In both neonatal rodents and humans, the
weaning, AgRP neurons begin to express adenosine primary means of heat generation is via activation of
triphosphate–sensitive potassium channels, which interscapular brown adipose tissue (iBAT) (–). In
enable a switch in the response to leptin from exci- humans, the iBAT depot appears to be maximally
tation to inhibition (). Presynaptic modulation of active during infancy, before the development of
AgRP neuronal activity develops with the same systems that increase or decrease core body tem-
temporal pattern as the postsynaptic systems outlined perature by shivering or sweating, respectively. In
above, with excitatory inputs to AgRP becoming fully rodents, iBAT remains the primary source of ther-
developed by the second postnatal week, whereas the moregulatory heat production throughout the life-
number of inhibitory synapses increases after weaning. span. This distinction between species is critical to
The onset of homeostatic regulation of feeding co- interpreting how rodent studies relate to human
incides with this final maturation step. These obser- physiology.
vations raise the possibility of a “developmental Whereas baselines of activity in feeding circuits are
window” for the maturation of energy homeostasis likely established by  to  weeks of age in rodents ()
neurocircuitry. We clearly need additional work in this and by  to  years of age in humans (), circuits
area to further elucidate these developmental factors. regulating resting energy expenditure (also referred to
Signals relevant to the external nutritional envi- as basal metabolic rate) appear to mature later. For
ronment (usually transmitted by the mother) can example, when a period of caloric restriction is im-
influence the maturation of ARC neurons. During posed on obese mice between  and  weeks of age, the
gestation, for example, the metabolic status of the result is a paradoxical (and maladaptive) increase of
dam (e.g., the presence of obesity-associated hy- resting energy expenditure (), implying incomplete
perinsulinemia) can influence the number of ARC maturation of circuits controlling this response.
neurons that adopt an anorexigenic POMC vs an Consistent with this observation, weight loss in young
orexigenic NPY cell fate (), and during lactation, children who are obese is not necessarily followed by
such influences appear to be magnified. For example, the compensatory decrease of circulating levels of free
differences in the availability or composition of milk triiodothyronine (the active form of thyroid hormone
during lactation can affect the onset and the strength that helps to determine basal metabolic rate) that

occurs in adults (). Teenagers appear to be hyper- Integrative physiology of energy homeostasis
metabolic compared with adults (), potentially
owing to higher endogenous brown/beige fat activity Determinants of feeding behavior
(–). In most mammals, food intake is organized into in-
Unlike what occurs in rodents and other small dividual bouts (meals), the frequency and size of which
animals, iBAT activity appears to decline with age in can vary greatly to accommodate the needs of the
humans (, , ). Thermogenic circuits develop in organism. For example, predatory hunters, such as
several distinct phases (). In both species, the iBAT lions and wolves, may eat only every couple of days,
depot is formed and produces key components of the provided that they can eat the entirety of their kill in
thermogenic machinery (e.g., uncoupling protein ) what amounts to a single meal. In contrast, most
during gestation, but it is not active until after birth. humans eat multiple meals per day, and each meal
An immature phase of brown adipose tissue (BAT) constitutes a modest fraction of total daily caloric
thermogenesis is induced both by hormones released intake, with the number and size of meals per day
at parturition (e.g., glucocorticoids and prolactin) and ranging widely across populations and cultures. Ul-

by factors released in response to the ketogenic diet of timately, however, moment-to-moment regulation of
lactation (e.g., FGF) (, ). Hypothalamic neu- intake serves the larger goal of maintaining adequate
rocircuits that project to the brainstem and modulate fuel stores to support life, and meal size and frequency
sympathetic nervous system output regulate the can be adjusted so as to meet this goal ().
mature phase of BAT thermogenesis; certain hor- The identification of neuromolecular mechanisms
monal signals (e.g., thyroid hormone) are also re- that integrate short-term and long-term control of
quired. In rodents, both sympathetic projections and feeding behavior, such that calorie intake precisely
sympathetic nervous system–dependent stimulation matches energy expenditure over long time intervals,
of BAT activity develop during the suckling period will almost certainly enable better preventive and
(–). therapeutic approaches to obesity. The origins of the
Sensitive periods for development of circuits reg- flexibility in meal size and frequency that serve this
ulating BAT thermogenesis are distinct from those goal can be traced to differences in the biological
that characterize the development of ARC feeding- underpinnings of meal initiation and meal cessation.
relevant circuits, in that neither maternal signals of Specifically, although researchers have proposed that
metabolic status (, ) nor maternal environmental changes in the internal milieu trigger meal initiation
exposures () during gestation influence the forma- (e.g., a decrease in circulating levels of glucose or an
tion of the iBAT depot or the expression of its as- increase of plasma ghrelin levels) (–), the de-
sociated thermogenic machinery. Nevertheless, leptin cision to begin a meal is also strongly impacted by
deficiency () or severe intrauterine growth retar- a wide range of external variables, including food
dation can cause diminished iBAT capacity in rodents availability and palatability, the cost and risk associated
(), and leptin administration early in the postnatal with acquiring food (e.g., threats from predators), and
period (postnatal days  to ) can reverse these effects. so forth.
Paradoxically, the same treatment leads to impaired In contrast to the considerable flexibility inherent
BAT thermogenesis and increased susceptibility to in meal onset, meal termination appears to be highly
diet-induced obesity when applied to wild-type mice regulated by postingestive feedback signals and
nourished normally (, ). other physiological variables. Accordingly, meal size
Circuits regulating iBAT thermogenesis remain is greatly increased when postingestive feedback is
plastic throughout the weaning period. For example, minimized, such as draining ingested food from the
weaning onto a high-fat diet (HFD) or during cold stomach (). One implication of this observation is
exposure leads to increased catecholaminergic in- that meal initiation and its associated consequences
nervation of iBAT (, ) with lasting impacts on (e.g., activation of oral taste receptors) are themselves
thermogenic capacity and sensitivity to diet-induced insufficient to elicit meal termination. However,
obesity (-). Environmental programming available evidence points to a host of afferent humoral
of the maximal capacity of iBAT thermogenesis is and neural signals arising from the interaction of
correlated with lasting effects on the number of food with the GI tract as primary determinants of the
iBAT-innervating neurons in the sympathetic size of individual meals (see the earlier section titled
ganglia (). In addition to upstream regulation of “Hindbrain circuits and the parabrachial nucleus”).
processes controlling sympathetic innervation, iBAT Both the time since the last meal and the status of
activation itself may alter the expression of neuro- intercurrent fat stores in the body can strongly in-
trophic factors that promote the outgrowth or survival fluence the capacity of these physiologic signals to
of innervating sympathetic neurons. This notion is terminate a meal. Consequently, when energy stores
predicated on established evidence that signals from (and therefore leptin levels) are low, these physiologic
peripheral targets influence innervation by sensory “satiety signals” are less capable of terminating a meal,
nerves, and an analogous system operating in ther- thereby resulting in larger meal size (). Such in-
mogenic circuits would provide a means of tuning teractions among signals arising from the GI tract and
neuronal outputs to match the anticipated need for those generated in proportion to stored fuel adjust
iBAT thermogenesis. ingestive behavior on a meal-to-meal basis, so as to

maintain stable body-fat stores. This process is fun- (nonresting energy expenditure, %). Overfeeding
damental to energy homeostasis, although it is in- raises energy expenditure in each of these compartments
completely understood. (due in part due to increases of both thyroid hormone
Beyond this physiological control system, varia- levels and sympathetic autonomic activity); conversely,
tions in both the type and amount of food available weight loss due to imposed caloric restriction reduces
and the environment in which it is eaten can alter how energy expenditure in each compartment.
much food is consumed at a single meal. For example, Net gain in stored energy cannot occur unless
delivery of the same food in the same form repeatedly energy intake exceeds expenditure. Cell-autonomous
can reduce consumption, a phenomenon known as characteristics of adipocytes and skeletal myocytes, the
“sensory-specific satiety” (). A more variable pre- chemical composition of the ingested calories, and the
sentation of the same food can reverse this effect, even hormonal responses to these factors may (in theory)
though overall diet composition is unaffected. Even influence the chemical composition of stored energy
factors such as the size of one’s plate, the type of (fat or lean mass). Although a low rate of resting
serving utensils, and the number of people in the room energy expenditure predicts subsequent weight gain in

can influence the number of calories consumed in some studies (), and despite growing interest in the
a single meal (). What has been harder to de- contribution made by brown and beige adipose tissue
termine is the extent to which such factors contribute to energy expenditure in humans (), the major
to sustained alteration of overall energy balance. Al- cause of the energy imbalance implicated in the
though meal-size variation does not by itself appear to current obesity epidemic is excessive food intake
have much impact on body weight (because changes in (relative to energy expenditure) in the context of
meal frequency can compensate for this to maintain sedentary lifestyles. It would be interesting to identify
stable caloric intake), few studies have investigated the different contributions that autonomic activity, the
the long-term consequences of changing meal sizes. thyroid axis, and brown/beige adipocytes make to
Ongoing investigation into the effects of restricted resting energy expenditure in individuals who are
feeding and intermittent fasting paradigms may prove preobese. However, it is unlikely that such differences
interesting in this regard. (if they exist) will account for a substantial amount of
risk variance in comparison with physical activity (for
Determinants of energy expenditure example). Furthermore, variations in energy intake
As noted earlier, in free-living adults, energy intake (driven by a complex mix of endogenous and exog-
and expenditure are tightly coupled over long time enous factors described earlier) typically have a much
intervals. A mismatch between intake and expenditure larger effect than variations in energy expenditure on
of as little as % can result in involuntary changes of overall energy balance. Another consideration is that
body weight amounting to several pounds per annum, therapeutic interventions that raise energy expenditure
which (over time) could result in profound obesity. sufficiently to cause weight loss eventually trigger
As weight increases, so does total energy expenditure. increased food intake as a compensatory response. For
Consequently, total energy intake must increase these reasons, the ability to influence and clinically
gradually over time for a fixed caloric excess to persist. manipulate energy intake is the more pressing goal
Although energy intake adjusts well to increased en- where obesity treatment is concerned.
ergy expenditure, this compensation appears to be less
accurate at low levels of energy expenditure, favoring
weight gain in sedentary individuals (). Similarly, Mechanisms of Obesity Pathogenesis
energy expenditure can compensate for a change
of energy intake, although the “coupling” may be Genetic factors: evidence for and against
stronger when weight is reduced vs when it is in- Concordance rates for obesity in studies of both twin
creased. Therefore, whereas weight loss resulting from pairs and in adopted children suggest that % to %
reduced caloric intake is strongly resisted by decreases of the risk for obesity is heritable (). Reasonable
of energy expenditure (both during and after weight arguments can be made on evolutionary grounds
loss), increases of energy expenditure induced by that the current Homo sapiens genome is enriched
overfeeding tend to be more modest and short-lived for “thrifty” alleles that conserve calories and resist
(). downward perturbations of weight that would—by
Although the mechanisms underlying these re- virtue of effects on fat mass—impair reproductive
sponses (and the metabolic/endocrine connections efficiency (). Others have argued that “predation
linking intake and expenditure) are of major clinical release” (the reduced threat of predation brought on by
importance, they are incompletely understood. In advances in social behavior, weapons, and the use of
sedentary individuals, the following factors are the fire) enabled more obese and therefore less agile
primary determinants of energy expenditure: cardio- hominids to escape predation, leading to changes in
respiratory activity and the maintenance of cellular ion population adiposity as a result of random mutations
gradients (resting energy expenditure, %); the di- and genetic drift (). These are not mutually ex-
gestion and initial distribution of food substrates (%); clusive formulations.
and both planned or voluntary activity and low- The search for the genetic basis of the apparent
level unplanned physical activity, including fidgeting “lipostat” for body fat led ultimately to the molecular

cloning of the ob and db mutations (in genes encoding presumably, be residue of earlier selection for phe-
leptin and the leptin receptor, respectively). These in notypes enabling predation avoidance, as we alluded to
turn led to the identification of a canonical molecular/ above. To the extent that these are hypomorphic al-
cellular signaling pathway: LEP → LEPR → POMC, leles, the genes could provide attractive targets for
AgRP → PC → MCR. inactivating drugs.
With the exception of MCR, obesity-causing
coding mutations in these genes are rare in hu- Interactions between genes, development,
mans. During the past  decades, genome-wide as- and environment
sociation studies (GWASs) and exome/genome Although genetic factors acting in isolation are un-
sequencing studies have identified a large number of likely to explain the rapid increase of obesity preva-
gene variants associated with more prevalent instances lence during the past  years, it remains quite possible
of obesity. It is disappointing that these strategies have that certain genetic factors enhance the risk of obesity
been able to account for only a small fraction (~% to conferred by environmental influences in ways that
% of interindividual variation) of the implied genetic favor positive energy balance (higher calorie intake,

risk variance for obesity. Sample size has been an issue less physical activity, or both) and/or result in the
with most candidate gene studies, but for some genes biological defense of increased fat mass. The long list
(e.g., MCR, ADRB, BDNF, and PC) the association of potentially relevant environmental factors includes
studies are convincing, especially because hypomor- changes of diet composition and lifestyle, environ-
phic alleles of each of these genes cause obesity in mice. mental toxins, infections, changes in the microbiome,
Since , GWASs of obesity have tested asso- and many others as well. Superimposed on these
ciations of millions of relatively common (.%) single influences are the potential roles played by maternal
nucleotide polymorphisms spaced more or less evenly obesity and diabetes. As discussed in the next section,
across the genome with obesity-related phenotypes the mechanisms responsible for transmitting such
such as BMI, body-fat content, waist/hip ratio, re- effects range from changes in maternal substrate
sponse to bariatric surgery, and other phenotypes. provision and endocrine factors to effects conveyed by
Most of the subjects in these studies have been white placental secretions into fetal circulation and effects on
adults. However, some studies included African milk provided during lactation. Vertical “transmission”
Americans, East Asians, and children, and associations of phenotype in this fashion could exacerbate (or
present in one adult population were generally present mitigate) shared genetic predispositions between
in others, as well as in children. mother and offspring while also affecting the phe-
GWASs have identified many loci of small effect notypes of progeny in the absence of primary genetic
size. Importantly, note that single nucleotide poly- predisposition. Factors such as these almost certainly
morphisms themselves simply implicate a genetic confound some of the efforts to quantify genetic risk
interval and do not necessarily identify the relevant for obesity and diabetes.
gene or allele, even if the single nucleotide poly- An example of interactions of genetic predis-
morphism is within the coding region of a gene. This position and lifestyle characteristics that influence
point aside, many of the ~ GWAS-implicated loci obesity risk can be found in how levels of physical
for obesity () are preferentially expressed in brain, activity and diet composition strongly influence the
consistent with the large amount of research sup- impact of obesity risk alleles of the FTO gene (which
porting primacy of the central nervous system in the encodes “fat mass and obesity-associated protein”)
control of energy homeostasis. Loci associated with (). Additionally, single base pair sequence varia-
body-fat distribution, in comparison, primarily mark tions in noncoding portions of the first intron of the
genes implicated in adipose tissue biology. FTO gene have the strongest association with obesity
The weak explanatory/predictive power of the in human populations yet detected (). The effect
alleles implicated by GWASs in obesity has led to the size is not large, but the susceptibility alleles are very
suggestion that other (as yet undiscovered) alleles frequent in the population. There are apparently
(genetic “dark matter”) exist that are of much lower several mechanisms by which these noncoding
frequency and higher phenotypic impact. Sequencing variants affect obesity risk, mediated by effects on
of the entire exomes of individuals has the potential to neighboring genes that influence brain development
address this possibility. An alternative explanation is and/or function, as well as the development of beige
that individual risk alleles do not act in isolation. adipose tissue ().
Rather, it is the interaction among different risk alleles Much of the sequence variation contributing to
or between these alleles and environmental factors that obesity risk will also likely be found in noncoding
results in increased obesity risk. Quantifying these portions of the genome. Unfortunately, our grasp of
interactions, however, is a far more daunting challenge the molecular genetics of noncoding DNA sequence
(requiring much larger sample sizes) that has yet to be variation (including epigenetic influences conveyed
met effectively (). by these sequences) is insufficient for a clear under-
Another area that has yet to be explored (mostly standing of how these factors might relate to human
due to difficulties finding suitable subjects) is whether disease susceptibility.
alleles of genes that protect against obesity exist Related to this issue and to the future identification
and can be identified. Such genes/alleles would, of obesity therapeutics is an apparent conceptual bias

regarding the biological consequences of sequence That maternal undernutrition increases obesity
variants implicated in these studies. The canonical risk only during the first trimester is consistent with
pathway identified above relates primarily to secreted a role for early epigenetic processes (). Methyl
peptides/neurotransmitters and their cognate recep- donor supplementation during rodent gestation can
tors. Even though interruptions of signaling can cause reverse adverse metabolic consequences programmed
acute changes of energy expenditure and intake, by undernutrition (, ), and methylation status
these pathways also affect hypothalamic structure/ in the periconception period is particularly sensitive
connectivity both during development and in post- to undernutrition. This is because high levels of
natal life (). Thus, the consequences of congenital or homocysteine (due to folate deficiency) suppress the
acquired disruption may be long-lived. A potentially expression of DNA methylase  (a key enzyme for
important example of a complex structure/pathway maintaining methylation during mitosis) (), and
exemplifying a likely combination of such effects is supplementation with either folic acid or methyl
the primary cilium of hypothalamic and other neurons donors during gestation can reverse these effects (,
that conveys both acute signaling and structural , ). Studies in both sheep and humans have

guidance in the development of circuits affecting food reported hypomethylation of imprinted genes (IGF)
intake (, ). and metastable alleles (POMC) when the subject is
These considerations highlight the possibility that severely undernourished early in gestation, but not
genes that contribute to obesity susceptibility through when undernourished only in late gestation (–).
direct effects on energy intake and expenditure Although early influences on the epigenetic modifi-
may also influence the response to developmental/ cation of metastable or imprinted alleles can persist to
environmental factors, such as intrauterine and adulthood, these changes do not correlate with later
perinatal exposures to “obesogenic” diets, toxins, and obesity risk within groups of similarly exposed in-
others. By such mechanisms, genes/alleles not impli- dividuals (, , ). Genome-wide epigenomic
cated in responses to earlier evolutionary factors analysis of children of underweight mothers has
might be implicated in responses to historically recent identified thousands of hypomethylated loci (), and
and novel factors. Future research regarding genetic some EDCs can induce hypomethylation that is re-
and environmental/developmental factors that affect versible with maternal methyl donor supplementation
obesity will need to consider these pathways and (). Future studies that clarify whether global hypo-
mechanisms. methylation results from impaired placental function
or nutrient transport may help to explain why so many
Role of epigenetic modifications different maternal exposures yield overlapping phe-
Epigenetic modification of genes typically involves notypic outcomes.
changes in how transcriptional complexes access Although studies have reported associations be-
regulatory elements in the genome and can occur tween adult obesity and methylation marks on can-
during development and throughout life. That sub- didate loci in either cord blood or peripheral blood
strates of intermediary metabolism convey some (, –), these findings are often either dis-
epigenetic modifications implies a sensitivity to nu- cordant with one another or inconsistent with dif-
tritional status (). Although examples exist in ferentially methylated loci identified in a genome-wide
which developmental methylation changes are tied screen (or both). Impacts of maternal obesity may
directly to obesity pathogenesis (, ), such effects therefore be conveyed via tissue-specific mechanisms
are the exception rather than the rule. Epigenetic that cannot be assessed in the analyses of global
changes can program phenotypes in adulthood by methylation patterns in blood samples.
affecting placental function, fetal growth rate, organ In some brain regions, as well as peripheral tissues
function, and the expression of metastable or (such as skeletal muscle and BAT), site-specific
imprinted genes involved in energy balance regulation. demethylation/remethylation driven by transcrip-
At fertilization, there is a near-global resetting of tional or neuronal activity reorganizes the methylome
the epigenome that accompanies the process of cel- (–). In tissues in which this remodeling is
lular differentiation from totipotent progenitors to relatively restricted to the postnatal period, epigenetic
specific cell identities that is mandatory for cell type marks reflective of the postnatal environment can
specification (). MicroRNAs also play a role in persist to adulthood (). For example, studies
reinforcing cell fate decisions that progressively restrict of several animal models of maternal overnutrition/
the potential cell fates of progenitor cells. One form of obesity reported CpG hypermethylation and increased
epigenetic modification involves methylation of CpG repressive histone marks on the Pomc locus, which
sites that are established during development, and persist to adulthood (–). These observations are
these can be inherited via semiconservative replication consistent with the idea that epigenetic marks on the
in progenitor cells. Once established, they are highly Pomc promoter underlie alterations in hypothalamic
stable in differentiated cells (). Some of these early feeding circuits that diminish leptin responsiveness
methylation events occur on metastable alleles or and consequently predispose not only to weight gain
imprinted genes, which can impart a lasting impact on but to biological defense of elevated body weight.
numerous tissues, whereas others are restricted to However, some studies involving maternal HFD
specific cell lineages. feeding reported hypomethylation of the Pomc locus,

as well as dopamine- and opioid-related genes (, increased risk of obesity (, , ), whereas
). Even if we can potentially explain these differ- exposure late in gestation or the persistence of limited
ences via complex interactions between the effects of nutrient availability after birth is often protective
maternal nutrition on early methylation patterns and against obesity. These observations are consistent with
the later influences of the postnatal and postweaning the theory that the undernourished fetus experiences
environments on the remodeling of these epigenetic changes in the energy homeostasis system that are
marks (, , ), they nevertheless challenge the adaptive when limited nutrient availability persists, but
reliability of epigenetic marks as a biomarker of future become maladaptive in a nutrient-rich environment
obesity risk. (, ). We have not yet identified the mechanism
Exposure to maternal obesity during gestation is underlying such a proposed change.
associated with both an increased risk of obesity in The observation that some of the adverse conse-
offspring and decreased methylation of a develop- quences of exposure to gestational undernutrition can
mental gene (Znf) that promotes adipocyte dif- be reversed by treatment with leptin () or folic acid
ferentiation (–). As this effect is associated with () during the neonatal (but not the peripubertal)

enhanced adipogenic potential of white adipose tissue period () supports the existence of discrete sensitive
(–), it could conceivably contribute to sub- periods (referred to as “critical windows”) during
sequent obesity risk. Although some early epigenetic which influences on developmental processes can have
marks are retained in adipose tissue, the adipose tissue a lasting impact on metabolic disease risk. Although
methylome is sensitive to changes in diet, exercise, and the early postnatal period in rodents likely represents
weight loss throughout life (–), perhaps owing one such window, whether corresponding processes
to the many different cell types represented in adipose occur in humans is unclear, especially because many
tissue. developmental processes that occur postnatally in
Collectively, this evidence supports the possibility rodents take place during late gestation in humans
of a causal link between the stable transmission of (). Although epidemiological studies suggest that
epigenetic marks, parental nutritional status in the maternal undernutrition predisposes to obesity in
periconception period, and programming of sub- offspring in humans (), we need additional in-
sequent obesity risk. However, this hypothesis has very formation to determine whether such a mechanism
limited experimental support and hence only modest contributes to the increased prevalence of human
potential to explain the complex biology observed obesity in recent decades, and, if so, whether there is
either in the laboratory or in human populations. a critical window during which the energy homeostasis
Going forward, promising avenues of research include system is impacted in ways that predispose to obesity
interdisciplinary approaches that combine epigenetic in adulthood.
and developmental approaches to clarify how specific Overnutrition/obesity. Although parental
epigenetic changes influence overall fetal growth and obesity is associated with an increased obesity risk in
tissue-specific developmental processes. Such studies offspring, parsing contributions made by develop-
are needed to delineate whether these processes mental exposure vs genetic or environmental factors
contribute to the impact of maternal undernutrition or is a difficult challenge. Studies in a genetically rela-
overnutrition on obesity risk in offspring. tively homogeneous population at high risk for obesity
(Pima Indians) point to a link between exposure to
Developmental factors: evidence for and against maternal (but not paternal) diabetes during gestation
During sensitive periods of development, ontogenic and an earlier onset of obesity (), whereas maternal
processes in both brain and peripheral organs can be weight loss due to bariatric surgery prevents the
modified so as to match anticipated environmental transmission of increased obesity risk (). Combined
conditions. Although many exposures during devel- with evidence that the strongest predictor of childhood
opment could potentially predispose to obesity in obesity is pregravid maternal BMI (, ), these
adulthood, we focus here on two that some researchers studies support the idea that an obese gestational en-
think contribute to the secular trends in obesity: pa- vironment programs susceptibility to obesity.
rental obesity and exposure to EDCs. In rodents, exposure throughout gestation and
lactation to maternal consumption of an obesogenic
Roles of parental body weight or diet HFD is correlated with persistent increases of adiposity
Undernutrition. The impact of developmental in offspring (, ). However, this effect appears to
exposure to reduced maternal food availability has be explained by exposure specifically during lactation,
been examined both in animals and in human pop- which leads to increased adiposity, irrespective of
ulations around the globe (). Although these whether offspring are weaned onto chow or an HFD
studies often report sustained effects on obesity risk, (, , ). Because the lactation period in rodents
outcomes tend to be somewhat variable and sensitive corresponds developmentally to late gestation in
to both the timing of developmental exposure and the humans, there are very few scenarios in which obesity
relative abundance of food in the postnatal environ- in human parents would be limited to only early
ment. Specifically, early gestational exposure to un- or late gestation. Thus, offspring will typically be
dernutrition followed by an abundant food supply in exposed throughout development. Whether the
the postnatal period is reliably associated with an amount or type of food consumed by the mother has

developmental consequences that predispose to obe- Maternal exposure to ECDs usually occurs via
sity independently of maternal obesity per se awaits ingestion of contaminated food or beverages, although
further study. contact with personal care items, plastics, or other
Modes of transmission. Although initial ef- products that contain these chemicals can also con-
forts to model developmental exposure were focused tribute. These chemicals can also be transmitted to the
on maternal transmission to progeny (F generation), fetus across the placenta or to an infant via breast milk
recent studies have also explored the possibility of both (). Compared with adults, relative levels of expo-
paternal (F) and transgenerational (F) transmission. sure as a function of body weight are higher for fetuses
Paternal obesity is reported to impair placental and and infants (), and exposure to low, environ-
fetal growth in mice (), but consequences for mentally relevant levels can program lasting effects
adiposity in offspring are variable (–). Although (,). Given that some EDCs can act directly on
paternal exposure to famine has been suggested to adipocytes to promote adipogenesis (–), the
program increased adiposity in humans (), the possibility that low levels of these chemicals might
contribution of paternal BMI to later obesity risk in program increased susceptibility to obesity later in life

broad-based population studies is weaker than the has been raised ().
maternal contribution (, ), as might be ex- The potential contribution to obesity risk of de-
pected. Although transgenerational transmission of velopmental exposure to EDCs has been extensively
obesity in humans has been suggested—through the reviewed, including two scientific statements pub-
paternal lineage in a largely homogeneous population lished by the Endocrine Society (the first in  and
of humans () or inbred rodents ()—such effects the second in ) (, ), a workshop sponsored
are difficult to quantify, owing to the influence of many by National Toxicology Program of the National
other variables that are difficult to control for. Institute of Environmental Health Sciences (), and
These data collectively support the notion that elsewhere in the scientific literature (, , ). Yet
developmental exposure to either undernutrition or unlike the consensus that exists regarding maternal
obesity can increase susceptibility to obesity in off- metabolic influences on obesity risk, links between
spring, and that the timing of exposure strongly in- EDC exposure and obesity risk are a focus of ongoing
fluences such effects. However, we need more evidence research, with many key questions remaining unan-
to conclude whether these developmental exposures swered. A brief comparison of how concern about the
have contributed to the increase of obesity prevalence impact of maternal influences vs EDC exposure on
in human populations in recent decades. obesity risk first came to light, and how the two re-
search areas developed thereafter, offers insight into
Role of EDCs the origins of some of this uncertainty.
Numerous studies link exposure to EDCs to a variety Compelling support for the involvement of ma-
of outcomes of potential relevance to obesity, internal influences in programming metabolic outcomes
cluding stimulation of adipogenesis and changes of first emerged from epidemiological observations in
insulin secretion, insulin sensitivity, and liver meta- humans. These observations led to the development of
bolism. A recent Endocrine Society Scientific State- animal models that have largely recapitulated these
ment provides a comprehensive review on this topic observations across multiple species, thereby creating
(). In many cases, however, the relevance of these a foundation upon which underlying cellular mech-
findings to obesity pathogenesis per se remains un- anisms can be investigated (for examples see earlier
certain. Our focus here is limited to evidence that sections on both epigenetics as well as developmental
specifically links EDC exposure to the accumulation factors). In comparison, evidence of a link between
and maintenance of excess body fat mass. EDC exposure and obesity risk began with in vitro
That the increase of human exposure to EDCs effects on master regulators of adipogenesis. These
parallels the rise in obesity rates in the United States observations generated justifiable concern regarding
(, ) raises the possibility of a causal link between risk to human populations and hence led to a search
the two. Many of these chemicals are classified as for evidence of a causal link through epidemiological
EDCs based on their capacity to mimic or alter re- studies and animal-based research, with mixed results.
ceptor signaling by endogenous hormones, including To illustrate the challenges inherent in transitioning
estrogen, testosterone, and thyroid hormone (). from in vitro studies to animal models that are sur-
Whereas some EDCs are chemically unstable [e.g., rogates for human exposure, we focus on two specific
bisphenol A (BPA) and pthalates], several are highly EDCs—PFCs and BPAs.
persistent in the environment and bioaccumulate.
These include brominated flame retardants; poly- PFCs
chlorinated biphenyls; organotins, such as tributyltin; PFCs are widely used to make products more resistant to
organochlorine pesticides, such as dichlorodiphenyl- stains, grease, and water. Because they break down in the
trichloroethane; and perfluorinated chemicals (PFCs) environment very slowly, they tend to bioaccumulate
(, ). Although most of the latter chemicals are and can therefore persist in human tissues for years
currently banned from use (with the exception of (). Some classes of PFCs can bind to and activate
flame retardants), low-level exposure is widespread in the nuclear receptors peroxisome proliferator–activated
human populations (). receptor a and/or peroxisome proliferator–activated

receptor g (a master regulator of adipogenesis), effects methodological and statistical concerns that may
that can promote adipocyte proliferation and differen- contribute to these discrepancies () and raised
tiation (, , ). These chemicals also have the awareness about the potential impact of differences in
potential to alter the methylation status of peroxisome experimental design that include diets, sex, species,
proliferator–activated receptor g or its target genes in strain and dose, duration, and route of exposure ().
ways that promote (or retard) adipocyte differentiation The same organization subsequently convened a fol-
(, ). Other evidence suggests that some PFCs can low-up workshop in  to reassess the state of the
alter thyroid function (), which can secondarily field and highlighted both continuing inconsistencies
impact both adipocyte biology and energy balance. Fi- in animal data and the need for better metrics of
nally, some PFCs increase glucocorticoid concentrations obesity (fat mass, adipose tissue cellularity, and re-
by inhibiting the degrading enzyme b-hydroxysteroid sponse to an HFD challenge), rather than relying solely
dehydrogenase  (), which also has the potential to on body weight ().
increase obesity risk. This workshop also recommended the need for
Another relevant consideration is that, as noted comparable dose-response information across studies

earlier, obesity risk in adults appears to be increased by to address peculiarities in the observed relationship
any intervention that results in a period of growth between BPA exposure and excessive weight gain. For
restriction in early development followed by sub- example, lower BPA-exposure levels often produce
sequent catch-up growth. Relevant to this issue is that more profound effects than are observed at higher
meta-analysis of  studies in rodents () and nine levels (, , ), and the dose of BPA ( mg/kg/
studies in humans () supports the hypothesis that d) associated with increased adiposity in rats ()
developmental exposure to PFCs reduces fetal growth. elicits reduced adiposity in mice (, ). Further
In some cases, therefore, the obesogenic effects of complicating matters are sexually dimorphic effects
PFCs may be secondary to nonspecific effects on fetal of BPA exposure, with increased body weight and liver
growth rather than involving direct effects (e.g., on weight but unchanged adiposity in males, and de-
adipogenesis) that predispose to obesity later in life. creased body weight, liver weight, and adiposity in
females (). Such effects may reflect actions of BPA
BPA on brown adipose tissue and physical activity, as well
As BPA is used in the production of polycarbonate as on white adipose tissue adipogenesis ().
plastics and epoxy resins, the main exposure route in Additional concerns pertain to the nonmonotonic
humans is via bottles, food-can linings, and food dose relationship between effects of BPA on liver vs
packaging. Maternal BPA is transported across the adipose tissue. Specifically, doses that promote adi-
placenta, with significantly higher concentrations in male posity typically have no effect on the liver, whereas
fetuses (). Young children can also be exposed through doses that impact the liver can have opposite effects on
human milk, as well as through bottle-feeding (). adipose tissue mass (, ). Based on these con-
There is little question that, unlike PFCs, BPA siderations, the consequences of developmental ex-
directly promotes adipogenesis in a peroxisome posure to any particular dose of BPA on growth
proliferator–activated receptor g-independent man- trajectories, body weight, and fat mass would appear to be
ner (). Although such an effect cannot, in and of influenced by the sum of its various effects on a variety of
itself, be assumed to cause or predispose to obesity, tissues. Metabolic and physiological outcomes can be
other potentially obesogenic effects of BPA include further influenced by changes of BPA exposure during
activation of estrogen receptor a (, ) or in- gestation vs during lactation and/or bottle-feeding.
creased glucocorticoid synthesis (through actions Efforts to extend these findings to the conse-
on b-hydroxysteroid dehydrogenase type ) (). quences of BPA exposure for human obesity risk have
BPA-induced estrogen receptor signaling is also encountered similar inconsistencies. For example,
associated with increased expression of histone- whereas evidence from cross-sectional studies shows
modifying enzymes that cause global increases in a link between urinary BPA concentrations and
repressive epigenetic marks (HK trimethylation) childhood adiposity (–), prospective studies
(, ) and changes of mitochondrial metabolism have reported reduced growth at birth or at  years of
resulting from altered DNA methylation (). There age (with a stronger effect in girls than boys) (, ),
is therefore little question as to whether BPA can have increased adiposity (), or no effect (, ). In
biologically relevant and potentially concerning effects comparison, a link between BPA exposure and be-
in vivo as well as in vitro. havioral disturbances in boys is a more consistent
Where obesity pathogenesis is concerned, how- finding in prospective epidemiological studies ().
ever, data from animal models of low-level BPA ex- Such effects seem worthy of investigation independent
posure have been inconsistent. Thus, whereas several of the impact of BPA exposure on obesity risk.
studies reported increased postnatal growth in rodents
exposed to low-dose BPA during development Modes of transmission of endocrine disrupting
(–), others reported no differences (–) chemical effects
or even reduced postnatal growth rates (,). In rodents, maternal exposure to organotins and
In , a review of the existing literature sponsored organochloride pesticides (dichlorodiphenyltrichloro-
by the National Toxicology Program identified ethane and methyloxychlor) is linked to increased

obesity risk in the F generation (–), despite speculate that this reduction of the defended level of
inconsistent effects on F offspring (). These ob- body-fat mass reflects a reversal of pathogenic pro-
servations raise the possibility of effects transmitted via cesses that led to obesity in the first place. However, it
epigenetic changes in the germline and transgenera- is also possible that the original pathological processes
tional transmission of exposure-specific epigenetic are not themselves altered by bariatric procedures, and
marks (). Should this interpretation prove correct, that, instead, a host of nonphysiological responses
a relevant consideration is that most rodent studies of collectively serve to lower the defended level of body
transgenerational transmission involve intercrosses be- weight. In either case, it is evident that the response of
tween offspring with the same developmental exposure, the gut–brain axis to these procedures can powerfully
a condition that is less common in humans. impact not only food intake but also the homeostatic
regulation of body-fat mass. Studies that clarify how
GI factors, bariatric surgery, and the microbiome this occurs are a high priority, as are studies to identify
cell types in the gut that convey these effects to the
Insights from bariatric surgery brain and the role of the liver as a potential in-

There is little question that bariatric surgical pro- termediary in these processes.
cedures can produce profound and long-lasting
effects on body weight. Chief among these pro- The gut microbiome and other GI factors
cedures are Roux-en-Y gastric bypass and vertical How might such information inform our un-
sleeve gastrectomy, each of which can produce derstanding of obesity pathogenesis? The importance
profound and sustained weight loss that cannot be of GI signals in meal termination, the potent effects of
reliably achieved by other means (). Although bariatric surgery on some of these signals, and the large
these effects have historically been attributed to sustained reductions in body weight from bariatric
either caloric restriction (converting the stomach surgery support the hypothesis that obesity patho-
into a small pouch) or malabsorption (the loss of genesis involves changes in the secretion or response
calories in the feces), neither explanation can ac- to GI signals related to the composition and quantity
count for the aggregate effects of these procedures. of food. Yet despite the large number of experiments
Of particular relevance is that patients report being measuring gut hormone responses to different types of
less (rather than more) hungry following these nutrients in individuals who are obese vs lean, a clear
procedures, even in the face of pronounced weight role for GI factors has yet to emerge, owing to both
loss. In comparison, weight loss due to restricted biological variation inherent in these responses and
food access or to conditions causing GI malab- issues related to study design that make it difficult
sorption clearly increases hunger, suggesting that to compare results across studies. Thus, one can find
these bariatric procedures suppress appetite even in examples of differences in almost any gut hormone
the face of greatly reduced energy stores—ordinarily, response between individuals who are obese vs lean
a potent stimulus to food intake. that are contradicted by examples where there are no
Among plausible mechanisms underlying the un- meaningful differences. That obesity risk alleles have
expected effects of Roux-en-Y gastric bypass and yet to be directly linked to GI signals by GWAS also
vertical sleeve gastrectomy on appetite is the possibility argues against a causal relationship between GI factors
that these procedures alter communication between and obesity pathogenesis ().
the GI tract and energy homeostasis neurocircuits The composition of the ~ pounds of gut bacteria
(referred to as the “gut–brain axis”). Researchers have in humans has also been linked to obesity risk ().
suggested that signals that might contribute to these Alterations in diet can profoundly affect the compo-
effects include: gastric hormones, such as ghrelin; sition of gut bacteria at multiple levels of the GI tract,
intestinal hormones, such as glucagon-like peptide- and obesity itself may also affect the composition of
and peptide tyrosine tyrosine; and alterations in the gut bacteria.
level and composition of bile acids and/or the in- In mouse studies, transferring bacteria into the GI
testinal microbiome (). These various mechanisms tract of germ-free mice causes weight gain, and the
are not mutually exclusive, and each may contribute to effect is modestly greater when the source is an obese
effects on food intake control that result from surgical donor vs bacteria from a lean animal (). These and
alteration of the GI tract. The larger point is that we similar observations raise the possibility that the
cannot attribute the effect of bariatric surgery on “obese” microbiome is capable of harvesting more
energy homeostasis to simple mechanical alterations realizable calories from ingested food than is the lean
of the physical capacity of the GI tract to ingest food microbiome. The problem with this explanation is that
or absorb nutrients. Rather, these bariatric surgeries simply increasing the energy harvested from ingested
appear to lower the defended level of body-fat mass, foods should elicit compensatory adjustments else-
presumably through effects involving the gut–brain where in the energy homeostasis system (e.g., reduced
axis. energy intake or increased energy expenditure) that
This conclusion is consistent with rodent studies in limit weight gain, as detailed above. An alternative
which animals subjected to bariatric surgery actively possibility is that gut bacteria generate biological
defend a lower body weight, even when this involves signals (such as butyrate and other short-chain fatty
increasing food intake (, ). It is tempting to acids) that impact the energy homeostasis system, and

that the composition of gut bacteria influences the able to track the patterns of social, racial, and resi-
nature of these signals (, ). dential segregation and their impact on body weight
Evidence linking specific gut microbiota to obesity and health. At the census tract level, obesity prevalence
falls well short of establishing a causal relationship. rates can vary from . to ., depending on where
Indeed, a recent analysis of available literature was people live. Analyses that accounted for variations in
unable to identify a reliable bacterial composition residential property values, education, and incomes
difference between humans who are lean and humans have accounted for % of the variance in census tract
who are obese across different studies and different obesity rates in Seattle/King County (). Such
populations (). Furthermore, a recent clinical trial geolocalized data provide a clear link (although not
found no evidence of a change of energy balance or necessarily causal) between social and economic fac-
other metabolic alterations arising from long-term tors and obesity risk at the level of individual
administration of antibiotics that profoundly im- neighborhoods (with the caveats noted above).
pacted the gut microbiome (). An additional Disparities in the types and amounts of food
concern is the reliance on germ-free mice as a main- consumed are obvious candidates to explain this as-

stay of basic research in this area. These animals at sociation. Low-cost foods are typically highly pro-
baseline have a lean, hypermetabolic phenotype and cessed, composed of refined grains with added sugars
are resistant to weight gain when exposed to a HFD; and added fats, inexpensive, and palatable. Such foods
the mechanistic basis for this phenotype remains combine low cost with high energy density and high
uncertain. Although these phenotypic features tend to reward value, are readily available in underserved areas
normalize following fecal microbiome transfer, the (), and tend to be preferentially selected by lower
body weight of the donor does not dramatically affect income groups (, ). Excess consumption of such
the outcome. This observation is consistent with fecal foods is linked to rising obesity rates (, ), and it
transfer experiments designed to supplement an or- has been suggested that (for some individuals) con-
ganism’s existing microbiome. Whether conducted in sumption of such foods mitigates the stress of daily life
rodents or humans, the effect on body weight tends to (–), thereby adding to their high inherent re-
be relatively small (). ward value.
One other experimental limitation that impacts the Studies that link diverse aspects of the built en-
link between obesity and the gut microbiome pertains vironment with diet quality metrics, reported physical
to differences between the microbiome of the large activity, and weight and health outcomes have iden-
intestine and that of the small intestine. Whereas the tified proximity to supermarkets, grocery stores, and
donated microbiome usually is almost exclusively other services, as well as access to parks and other
from fecal (or sometimes cecal) samples, variations in opportunities for physical activity as independent
the microbiome that affect energy balance by influ- predictors of obesity risk (, –). These and
encing signals from the GI tract are likely to involve other studies (–) collectively identified an as-
organisms in the small intestine as well as those in sociation between lower obesity rates and locations
the large intestine. These considerations highlight the that have pedestrian safety; low crime; attractive
many questions that must be answered before the streets; well-maintained parks; and homes within close
impact of the microbiome on obesity pathogenesis and physical proximity to supermarkets, parks, sidewalk
its role in future interventions for obesity prevention cafes, and landmark buildings. Conversely, locations
or treatment are understood. with physical disorder; poor sidewalk quality; close
proximity to bars, liquor stores, fast food, and con-
Social and economic factors venience stores; and the presence of garbage, litter,
There is little question that in the United States obesity and graffiti were associated with higher BMI in some
rates are linked inversely to socioeconomic status (–) but not other studies (–).
(SES), especially among women (–). Deducing Residential property values provide insight into
cause and effect is complicated by the difficulty in- variations in the wealth of an individual or area; they
herent in controlling for numerous potentially con- also offer a useful alternative metric with which to
founding variables (e.g., genetic or epigenetic factors assess the relationship between the built environment
and environmental exposures that impact develop- and obesity risk (, ). A Seattle-based study that
ment). The focus of this section, therefore, is not on examined the associations among perceived measures
whether obesity is caused by economic insecurity of the environment, residential property values, and
(which cannot be ascertained from the available evi- BMIs () found that for each $, increase in
dence) but rather on the extent to which highly property value, obesity prevalence was .% lower
prevalent social, economic, and cultural conditions (). Factors related to poverty or wealth may
influence obesity risk. Once we identify factors that therefore account for at least some of the link between
impart the greatest obesity risk, future studies can the built environment and obesity risk.
begin to investigate whether and how they impact the Access to healthy foods is one such measure. The
energy homeostasis system. concept of a “food desert,” defined as a low-income
Unlike obesity statistics at the national or county area in which the nearest supermarket is at least  mile
levels, which can obscure social disparities, new geo- away (), has become a focus of public health
localization and mapping approaches (–) are policies aimed at improving both diet and health (,

, ). Studies suggest that BMI tends to be lower adiposity. Studies that clarify how this occurs are a key
in areas where the consumption of vegetables and priority for the field.
fruits is higher (–). Researchers tend to gauge
a specific population’s access to healthy food and food Diet composition, lifestyle, and obesity risk
choices largely in terms of whether their neighborhood Although an increase of average energy intake relative
has a high density of (or long distance to) healthy food to energy expenditure during the past  to  decades
sources (–). Yet the risk of obesity is not reliably can be inferred from the mean increase of adult body
associated with distances between home and multiple weight (. kg) in the United States (), the relative
food sources (). Rather, it is the type of super- contributions of increased energy intake and reduced
market by price that is significantly associated with physical activity to this increase cannot be known with
obesity rates, even after adjusting for the distance to certainty, nor can the extent to which energy balance is
the store and other sociodemographic and lifestyle impacted by other variables [e.g., sleep deprivation,
variables. decreased variation in environmental temperature
Where obesity risk is concerned, therefore, access (owing to heating and air conditioning), drugs causing

to healthier foods might be associated more with weight gain, decreased smoking, and possible de-
economics than with distance from home. This pos- velopmental exposures discussed earlier] (). Al-
sibility highlights the need to focus beyond neigh- though data from Swinburn et al. (–) suggest
borhood geographic boundaries. One way to do this is that increased energy intake is sufficient to account for
to use GPS tracking methods that capture actual food recent population increases of body weight without
shopping behaviors (). Whether improved access invoking large decreases of physical activity, epide-
of low-income populations to healthy foods will re- miological evidence points to a concomitant increase
duce obesity prevalence is an important unanswered of sedentary behaviors. For example, Church et al.
question that the food desert formulation does not () reported that energy expenditure related to
completely address. occupation has drastically decreased over time, and
Studies in the United States (), United Kingdom that the associated reduction of energy expenditure
(), France (, ), Finland (), Belgium (), likely contributes to the increase of mean body weight
Ireland (), and Australia () have reported that in the United States.
diet quality is directly linked to SES. Studies on food
pattern modeling suggest that imposing a cost con- Impact of diet composition on obesity risk
straint leads to food choices that are energy-dense but The extent to which changes in diet composition drive
nutrient-poor, similar in composition to diets con- the obesity epidemic has been a matter of considerable
sumed by lower income groups (, ). Recent controversy for decades. To what extent does con-
economic analyses of empirical data from the United sumption of highly processed foods (especially snack
Kingdom provide a relevant example (). In the foods) with higher levels of sugars and fats (and rel-
wake of the economic recession of , more British atively low fiber) play a role? What about excess
consumers turned to foods with lower cost per calorie consumption of sugar-sweetened beverages, including
(), and obesity rates in the United Kingdom in- soda, juice-based drinks, and sports drinks? These are
creased dramatically in recent years; today they are the questions of great public interest, particularly where
highest in Europe (). We need additional studies to diets high in fat vs carbohydrate content are concerned
investigate the extent to which economically driven (, ).
dietary changes contributed to the observed increase of Diets of different macronutrient composition can
obesity prevalence. theoretically affect energy balance by altering overall
Overall, these observations support the testable caloric intake, energy expenditure, or both. However,
hypothesis that obesity risk increases among lower available data argue against major effects on accu-
income groups when their food budgets are in- mulation of body-fat mass, so long as energy intake is
sufficient to ensure access to a healthy diet. This held constant (discussed further below). For this
hypothesis points to the larger question of how such reason, the focus of the debate has shifted toward the
an effect ultimately causes not only weight gain but effects of diet composition on caloric intake.
also the biological defense of elevated fat mass—the Substantial debate surrounds the question of
two processes that define the obese state. To reiterate whether the effects of dietary lipids to increase both
a key point, factors that predispose to positive energy palatability and caloric density contribute to their
balance alone are insufficient to explain how obesity overconsumption (, ) or whether increased
persists, because individuals who are obese defend dietary carbohydrate content (and the associated in-
their body-fat stores as effectively as do lean insulin response, in particular) plays a uniquely im-
dividuals (), and switching to a “healthy” diet and portant role in obesity pathogenesis (, –). As
lifestyle is insufficient to restore elevated body weight noted earlier, researchers have suggested that dietary
to normal in the vast majority of individuals (). In carbohydrates—and refined sugars in particular—
addition to predisposing to weight gain, therefore, increase insulin secretion. This suppresses lipolysis and
dietary, behavioral, and other factors linking SES status the associated release of fatty acids from the adipose
to obesity risk must also affect the energy homeostasis tissue while also preferentially directing dietary fat
system in ways that raise the defended level of body toward storage. Some researchers propose that the

ensuing depletion of circulating fatty acids triggers difference was trivial and does not justify recom-
a state of “cellular starvation” for metabolically active mending one diet over the other for weight-loss
tissues, such as heart, muscle, and liver. Such changes purposes. Although low-carbohydrate diets have been
might then induce both an adaptive decrease of energy suggested to be helpful—by virtue of increased energy
expenditure () and an increase of food intake (, expenditure—for maintaining reduced body weight
, ) that together conspire to cause obesity. (), differences in protein content of the comparison
Extending this logic, replacing dietary carbohydrate diets confound this conclusion.
with fat should reduce insulin secretion while in-
creasing fat mobilization and the oxidation of circu- Roles of sedentary behavior, exercise, and
lating free fatty acids, effects that together protect nonexercise activity thermogenesis
against obesity. As mentioned earlier, the increasing global prevalence
A number of observations challenge this premise. of obesity may involve sedentary behavior in addition
For one, despite the known ability of insulin to inhibit to changes of food availability and/or diet composi-
adipocyte lipolysis, and despite the fact that in un- tion. Analyzing the contribution of physical activity to

controlled diabetes severe insulin deficiency causes total daily energy expenditure and obesity risk is
unrestrained lipolysis, there is little direct evidence that a complex challenge. Although originally described
insulin’s antilipolytic action is an independent de- as a single component of total daily energy expendi-
terminant of fat mass. Furthermore, the hyper- ture (in addition to basal metabolic rate and diet-
insulinemia of obesity is typically associated with induced thermogenesis), overall physical activity can
normal or elevated circulating glucose and fatty acid be subdivided into three distinct components: sed-
levels (), a combination inconsistent with a state of entary behaviors, nonexercise activity thermogenesis
insulin-mediated cellular starvation. (NEAT), and planned/structured activity (exercise).
The foregoing discussion raises the perennial Researchers estimate that during the past  years
question: Is a calorie a calorie? In other words, can reductions in occupational physical activity have de-
consumption of different types of foods predispose to creased total daily energy expenditure by . cal-
weight gain independently of the number of calories ories per day ().
consumed? To address this question, one study placed Physical activity is now widely accepted to be the
 volunteers who were obese or overweight on an most variable component of daily energy expenditure
isocaloric ketogenic diet (% carbohydrate) for  weeks. in people. Surprisingly, however, increased physical
This study revealed a marginal (~ kcal/d) but activity is largely ineffective as a stand-alone weight
statistically significant effect of the ketogenic diet to loss intervention, even though it should promote
increase -hour energy expenditure measured in negative energy balance as effectively as does dietary
a respiratory chamber (), but the effect waned over energy restriction (). The explanation for this
time and was not associated with significant loss of fat paradox is presumably that among those individuals
mass. This finding is consistent with other studies susceptible to obesity, the energy homeostasis system
showing that carbohydrate restriction does not increase compensates for increased energy expenditure (by
energy expenditure unless accompanied by an increase in increasing energy intake and thus resisting weigh loss)
protein content (as is the case in most low carbohydrate better than it compensates for increased energy intake
diets, but not the study described above) (–). (by increasing energy expenditure to protect against
When calorie intake is held constant, therefore, weight gain). Nevertheless, adherents to vigorous
body-fat accumulation does not appear to be affected physical activity programs are more likely to keep lost
by even very pronounced changes in the amount of fat weight off than are those who remain relatively in-
vs carbohydrate in the diet. With regard to obesity risk, active. For example, according to the National Weight
the clear implication is that the impact of a change of Control Registry, individuals who lose a substantial
diet composition is primarily due to the number of amount of weight and keep it off for an extended
calories consumed, with changes of energy expendi- period of time, on average, are those who engage in at
ture, fat oxidation, or other aspects of nutrient han- least  minutes per day of physical activity (). This
dling being less important. Given that diets high in effect of exercise may involve a partial reversal of the
simple sugars and processed carbohydrates tend to effects of weight loss to increase muscle work efficiency
be calorie-dense, low in satiety-promoting fiber and (). The key point is that although increased physical
other nutrients, affordable, widely available, and often activity has not proven effective as a stand-alone
heavily marketed, it is perhaps not surprising that such treatment of obesity, it can help to sustain weight
diets can favor an increase of overall energy intake. In loss achieved by other means.
comparison, mechanisms related to increased insulin In addition to structured activity, Levine et al. ()
secretion, nutrient partitioning, cellular starvation, reported that energy expended passively in activities of
or other internal processes do not appear to explain daily living is both a determinant of total daily energy
the putative benefits of low-carbohydrate or low- expenditure and an obesity risk factor. NEAT activities
glycemic index diets. Furthermore, a recent review are those that occur during normal daily life, rather
of weight-loss diets () reported that although low- than in structured bouts of exercise () (e.g., sitting;
carbohydrate, higher fat diets led to slightly greater standing; fidgeting; walking; computer work; house-
weight loss than did low-fat diets (~ kg), the overall related chores; activities associated with personal

hygiene, such as bathing; and occupation-related ac- balance and predispose to weight gain, a fundamental
tivities). Evidence that reduced NEAT contributes unanswered question is how elevated body-fat mass
independently to obesity pathogenesis stems from comes to be biologically defended in individuals who
the observations that NEAT tends to be lower in are obese. Under certain circumstances (e.g., mutation
individuals who are obese vs lean, and it does not of genes encoding leptin or POMC) we can predict
appear to change in response to either weight gain that the biologically defended level of body fat will
(in normal weight subjects) or weight loss (in subjects increase due to the direct, deleterious effects on the
who are obese) (). With regard to the magnitude energy homeostasis system. In the vast majority of
of this effect, a study of  individuals conducted in individuals who are obese, however, researchers have
the late s using a room calorimeter () found yet to identify a clearly definable energy homeostasis
that energy expenditure attributable to spontaneous defect (genetic or otherwise) to explain this phe-
physical activity averaged  kcal/d but varied from nomenon. Part of the experimental problem is that
 to  kcal/d between individuals. We need ad- subtle differences in energy intake and/or expenditure
ditional research to establish the extent to which can have large effects on adiposity over time, and once

variations in NEAT play a causative role in obesity an individual is in weight equilibrium, any etiological
pathogenesis. differences are no longer present.
A very modest but persistent energy balance
Other factors mismatch (~% to % more calories consumed than
expended per year) can explain the slow but contin-
Smoking cessation uous accumulation of additional body fat over many
Another potentially causative factor in the steady years that is characteristic of most humans who are
increase of obesity prevalence in the United States and obese. Although an acute increase of body-fat mass is
other Westernized societies is a substantial concom- often reversible, incremental, sustained increases of
itant reduction in rates of cigarette smoking. Smoking body fat typically end up becoming part of the total
cessation is reliably associated with weight gain (), body-fat mass that is biologically defended. It is for this
presumably owing to withdrawal of the pharmaco- reason that the weight loss induced by a change of diet
logical effect of nicotine to suppress food intake and or lifestyle (e.g., changes that might be expected to
weight gain. Nicotinic acetylcholine receptors are remedy an acquired defect in the energy homeostasis
found on hypothalamic POMC neurons, and activa- system arising from a maladaptive diet, sedentary
tion of these receptors can reduce food intake and behavior) is often ultimately regained, even in the face
body weight in animal models (). Although re- of adherence to a more healthy diet and lifestyle. These
duced tobacco use can therefore be expected to in- observations imply that although the mechanism
crease the average body weight of a population, obesity underlying the gradual increase in the defended level
nevertheless remains a problem among both current of body fat may have been triggered by one or more of
smokers and those who have never smoked. the many environmental exposures discussed earlier,
simple withdrawal of the offending exposure is un-
Infectious factors likely to reverse the increased body fat once it becomes
The emergence of obesity as a global pandemic has established. Instead, the energy homeostasis system
spurred interest in the hypothesis that one or more has been upwardly reset, so that the higher level of
infectious agents play a causal role. Consistent with body fat is relatively resistant to lifestyle interven-
this view, individuals who are obese have a reduced tions, similar to a genetically determined increase
immune response to some vaccines, raising the pos- of adiposity (although not necessarily by the same
sibility that susceptibility to infections could play a role mechanisms).
in the development of obesity. For example, infection How might such a change in the energy homeo-
with the AD- virus is reported to cause adipocyte stasis system be acquired? Although we still wait for
proliferation and increased body weight in a variety of definitive answers, recent work offers potential in-
preclinical models, and individuals who are obese have sights. In many tissues (including liver, skeletal muscle,
significantly higher antibody titers to this virus than do adipose tissue, and the vasculature) obesity is associ-
lean individuals (). However, without better evi- ated with activation of inflammatory processes marked
dence of a causal relationship between such infectious by the invasion of macrophages or related immune
agents and human obesity, this mechanism seems cells and an associated increase in the expression of
unlikely to be a major factor underlying the current proinflammatory cytokines, such as tumor necrosis
obesity epidemic. Should such evidence one day factor-a or interleukin- (). Because the onset of
emerge, it would profoundly impact current ap- this inflammation either coincides with obesity onset
proaches to obesity treatment and prevention. or occurs after obesity is established, it is likely
a consequence rather than a cause of obesity ().
Mechanisms for biological defense of elevated However, the hypothalamus is an exception. In
body-fat mass this region of the brain inflammation and tissue
Although the many intrinsic (e.g., genetic) and injury occur in discrete areas involved in energy ho-
extrinsic (e.g., diet composition, lifestyle, or SES) meostasis, and this effect is evident before obesity
variables discussed herein can favor positive energy develops. When rats or mice are placed on an HFD,

inflammatory markers become detectable in the hy- distinct from those responsible for the biological
pothalamic ARC within  to  hours, well before defense of excess fat mass. A key question, therefore,
body-fat mass has increased (). Moreover, this is how the energy homeostasis system comes to
inflammatory response is associated with expansion defend an elevated level of fat mass (analogous to
and activation of hypothalamic glial cells, a process the defense of elevated blood pressure in patients
referred to as “reactive gliosis” (the prototypical brain with hypertension). Answering this question re-
response to neuron injury). Specifically, switching quires an improved understanding of the neuro-
either mice or rats from standard chow to a HFD molecular elements that underlie a “defended” level
(which predisposes to diet-induced obesity) induces of body fat. What are the molecular/neuroanatomic
both microgliosis and astrogliosis (activation of predicates that help establish and defend a “set
microglia and astrocytes, respectively) in the ARC point” for adiposity? How do these elements reg-
within  week (, ). ulate feeding behavior and/or energy expenditure,
Although it is tempting to draw a causal link so as to achieve long-term energy balance? By what
between the evidence of injury to a key brain area for mechanisms is an apparently higher set point

energy homeostasis and defense of elevated body-fat established and defended in individuals who are
mass, we emphasize that neither the causes nor the obese?
consequences of this local hypothalamic reaction to Given that recovery of lost weight (the normal,
HFD feeding are known. Thus, the idea that the physiological response to weight loss irrespective of
defense of elevated fat mass results from this hy- one’s starting weight) is the largest single obstacle
pothalamic gliosis (by impairing the capacity of key to effective long-term weight loss, we cannot overstate
neurons to respond to input from leptin and/or other the importance of a coherent understanding of
pertinent humoral/neural signals) is a hypothesis that obesity-associated alterations of the energy homeo-
needs further testing. A working model posits that in stasis system.
susceptible animals or humans, an increase in the
consumption of saturated fat () and/or other Developmental determinants of the biologically
nutrients induces injury of hypothalamic neurons defended level of body-fat mass
involved in energy homeostasis, which in turn trig- By what means do intrauterine, perinatal, and later
gers reactive gliosis. Alternatively, the diet switch may developmental processes influence the defended
directly activate local microglia (a macrophage-like level of body fat or set point? How do these factors
cell found only in the central nervous system), a re- interact with underlying genetic determinants? Is
sponse that sets off a vicious cycle by causing neuron overnutrition during development associated with
injury and triggering more gliosis. In either case, it is premature maturation of feeding circuits? Can in-
not difficult to envision how this type of local reaction sight into key developmental influences be leveraged
might dampen the capacity of ARC neurons to re- into strategies to reset the defended level at a lower
spond to humoral (leptin) or neural inputs relevant value? Can these insights enable us to prevent the
to body weight control and thereby favor the defense homeostatic system from being reset at a higher
of elevated body-fat mass. It is noteworthy that level in the first place? Do these developmental
studies have reported radiological evidence of gliosis exposures act directly on energy balance neuro-
in the mediobasal hypothalamus in humans who are circuitry, or do such effects occur indirectly as
obese (, ), as well as in rodent models. What a result of nonspecific changes in rates of placental
distinguishes this type of mechanism from those or fetal growth that impact adult body weight and
discussed earlier is its potential to account for the composition? Answers to these questions will po-
defense of elevated body weight in acquired (envi- tentially help us develop maternal/prenatal in-
ronmental) forms of obesity. The extent to which it terventions that could protect against obesity in
does so is a key priority for future work. adulthood.
Interactions between genetics, epigenetics,

Concluding Remarks and Future Directions developmental influences, and the environment
Although many studies (e.g., those based on identical
In closing, we attempt to distill from foregoing sections twins reared apart) identify a major role for heritable
a set of key areas for possible further investigation. factors as determinants of obesity susceptibility,
GWAS data indicate that only a small fraction (~%)
The two distinct components of of obesity risk is attributable to identifiable allelic
obesity pathogenesis variants. One potential explanation for this discrep-
To be viable, theories of obesity pathogenesis must ancy is that nongenetic factors that contribute to
account not only for how excess body fat is acquired, heritability, such as epigenetic modification or de-
but also for how excess body fat comes to be bi- velopmental influences, make a major contribution to
ologically defended. To date, the preponderance of obesity risk. Another possibility is that interactions
research has focused on the former. However, we among risk alleles themselves and/or between risk
must consider the possibility that some (perhaps alleles, epigenetic factors, and developmental factors
even most) mechanisms underlying weight gain are play a role. Beyond these considerations, each of these

potential contributors to obesity risk can interact with regain (). It also reduces circulating leptin con-
environmental factors as well. In other words, many centrations in proportion to lost body fat, and (con-
heritable factors may increase obesity risk, not by sistent with the leptin threshold formulation described
causing obesity so much as by conferring susceptibility earlier) providing exogenous leptin in doses just
to obesogenic environmental factors. It seems plau- sufficient to restore circulating leptin to preweight loss
sible, for example, that certain obesity risk alleles concentrations relieves some of the autonomic, en-
expressed in the brain, perhaps through an interaction docrine, energy expenditure, and behavioral pheno-
with neurodevelopmental consequences of gestational types associated with the weight-reduced state (,
events, enable energy homeostasis neurocircuits to ). Whether such “physiological leptin replacement”
become reset around a higher level of body fat stores. strategies can protect against recovery of lost weight is
It is also possible that the likelihood of such an an important unanswered question.
outcome is maximized by consuming a diet that is Rather than viewing recovery of lost weight as
highly palatable, energy dense, and in abundant supply. a therapeutic failure or as evidence of noncompliance
Establishing suitable experimental models with which to with a prescribed treatment regimen, patients and

test such concepts is a necessity. practitioners alike should view this phenomenon as an
expected physiological response to weight loss. This
Future directions for EDC research perspective emphasizes the importance of identifying
Although available evidence suggests that EDCs can strategies to subvert these responses. It is likely that the
impact the function of genes important for the control pharmacology involved in maintaining the weight-
of energy balance and adipocyte function, human reduced state is different—qualitatively and quanti-
data and results from in vivo animal studies have yet tatively—from that relevant to the induction of weight
to clearly demonstrate an increased risk of obesity loss. The Food and Drug Administration should allow
conferred by developmental EDC exposure. Among for such differences in the licensing of pharmacologic
the confounding factors that may underlie this un- agents for the treatment of obesity.
certainty are differential developmental impacts of
EDC exposure on metabolically relevant organs (e.g., The gut–brain axis
liver and adipose tissue) (, ), variation stem- There are a number of key questions pertaining to the
ming from sex- and dosage-specific effects, and the gut microbiome. Does it influence the defended level
potential for combinations of EDCs to cause syner- of body-fat mass and, if so, to what extent? How do
gistic effects (, , , ). These concerns microbial influences interact with the energy ho-
highlight the need to focus animal research on those meostasis system? To what extent do host genetic or
exposures most closely linked to untoward impacts on other variables influence such effects? Is the micro-
child health. Meta-analyses of prospective epidemio- biome a potential target for obesity treatment? How
logical data may ultimately help to identify those do bariatric surgical procedures, such as Roux-en-Y
combinations and doses of EDC exposures that are gastric bypass or vertical sleeve gastrectomy, reduce the
most often associated with increased adiposity and biologically defended level of body-fat stores? Which
that are observed consistently across species. Studies specific signals emanating from the GI tract account
that define conditions in mice that recapitulate the for this phenomenon?
molecular and/or epigenetic signatures of EDC ex- Identifying the relevant signals and delineating
posure in humans will also be important (, ). how they influence energy homeostasis neurocircuitry
Given difficulties inherent in obtaining human tissue, will ultimately inform potential drug-therapy targets.
the identification of biomarkers for these effects (e.g.,
changes of liver function) may also help to accelerate Dietary influences
progress in this field. Lastly, the question of whether Growing evidence suggests that (for practical pur-
developmental EDC exposure increases obesity risk poses) the answer to the question, “Is a calorie a cal-
through nonspecific effects on fetal growth (), orie?” is “yes.” Calories derived from different dietary
rather than or in addition to direct effects on energy constituents (fats, carbohydrates, and proteins) do not
homeostasis system components, must be addressed. differ significantly in their inherent capacity to pro-
mote weight gain by affecting energy expenditure or
Lessons learned from the weight-reduced state nutrient partitioning, so long as total calorie intake is
The weight-reduced state is a distinct metabolic/ held constant (). From this we infer that the effects
behavioral condition created when body weight is of diet composition per se on metabolic variables
reduced below its biologically defended level. Studies suggested to contribute to obesity pathogenesis (e.g.,
during the past  years (, , –) have shown those related to plasma levels of glucose, insulin, or
that maintenance of a reduced body weight (e.g., % free fatty acids; inherent differences in the propensity
or more) is associated with reductions in energy ex- of adipocytes to store fat; or the gut microbiome) do
penditure (in part conveyed by increased contractile not play a clinically significant causal role unless they
efficiency of skeletal muscle) due to reduced sympa- promote increased calorie intake (). The thera-
thetic autonomic activity and circulating thyroid peutic potential of interventions primarily targeting
hormones. Reduced body weight increases hunger as these metabolic processes per se, therefore, seems
well, creating a “perfect metabolic storm” for weight limited.

Stratification of obesity outcomes influence obesity risk. Studies that delineate how in-
Given that not all individuals who are obese are subject teractions among these factors impact the energy
to the same level of risk of comorbidities, we need homeostasis system are critical.
improved strategies for identifying biomarkers pre-
dictive of these comorbidities (e.g., diabetes, hyper- Identifying and mitigating environmental
tension, dyslipidemia, and cardiovascular disease). risk factors
Similarly, strategies for identifying both predictors of Taking poverty again as an example, does an identi-
future obesity comorbidity risk (to enable effective fiable set of motivations, attitudes, and beliefs con-
preventive intervention) and responsiveness to a spe- tribute to obesity susceptibility? Which specific
cific therapeutic intervention (to improve outcomes by elements related to SES predispose not only to weight
identifying what intervention is best suited for each gain but to the biological defense of elevated body-fat
individual) are also a high priority. stores, and how might they be mitigated? Can such
mitigation efforts reduce obesity risk?
Unraveling mechanisms linking the environment

to defense of elevated body weight Translating basic science into more
A seemingly unlimited number of environmental effective pharmacotherapy
variables appear to predispose to weight gain. Poverty Can anatomic and functional imaging of the human
is a case in point. How does its influence on food brain be used, in combination with suitable behavioral
choices, behavior, and activity translate to increased measures, to translate cognitive, regulatory, and hedonic
obesity risk? How can we best account for the impact aspects of human feeding behavior into effective new
on obesity risk of differences in the racial and ethnic pharmacologic approaches to the treatment of obesity?
mix between low and higher SES communities? Do An improved understanding of those aspects of ingestive
developmental factors also contribute? behavior that are not driven directly by homeostatic
Disarticulating differences in genetic background mechanisms controlling body weight is critical to
from the impact of diet, lifestyle, and other environ- strategies for obesity prevention. Insight gained from
mental variables is a daunting challenge. That the animal models of these “hedonic” processes may
impact of low SES on obesity risk is greater among eventually identify relevant pathways and molecules.
women than men () points to poorly understood However, we will need better behavioral and imaging
interactions between environment and biology that tools to fully understand these phenotypes in humans.
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perinatally exposed to bisphenol A. Epigenetics. 2016;11: Ashkan Afshin of the Institute for Health Metrics and SmartMoms®, which are intensive weight management in-
489–500. Evaluation at the University of Washington for their helpful terventions delivered via mHealth technology. The remaining
333. Rosenbaum M, Murphy EM, Heymsfield SB, Matthews comments.
authors have nothing to disclose.
DE, Leibel RL. Low dose leptin administration reverses Address all correspondence and requests for reprints to:
Disclaimer Statement: The Endocrine Society develops
effects of sustained weight-reduction on energy ex- Michael W. Schwartz, MD, Department of Medicine, Uni-
Scientific Statements to assist clinicians by providing guid-
penditure and circulating concentrations of thyroid versity of Washington, UW Medicine at South Lake Union,
hormones. J Clin Endocrinol Metab. 2002;87:2391–2394. 850 Republican Street, Box 358055, Seattle, Washington ance and recommendations for particular areas of practice.
334. Rosenbaum M, Sy M, Pavlovich K, Leibel RL, Hirsch J. 98109. E-mail: mschwart@u.washington.edu. Clinicians and other users should not consider this Scientific
Leptin reverses weight loss-induced changes in regional This work was supported by National Institutes of Health Statement inclusive of all proper approaches or methods or
neural activity responses to visual food stimuli. J Clin Grants DK083042, DK090320, and DK101997 and by the exclusive of others. It cannot guarantee any specific outcome,
Invest. 2008;118:2583–2591. National Institute of Diabetic and Digestive and Kidney
nor does it establish a standard of care. It is not intended to
335. Kissileff HR, Thornton JC, Torres MI, Pavlovich K, Mayer Disease–funded Nutrition Obesity Research Center at the
LS, Kalari V, Leibel RL, Rosenbaum M. Leptin reverses University of Washington (to M.W.S.), R01 DK089038 (to dictate the treatment of a particular patient. The in-
declines in satiation in weight-reduced obese humans. L.M.Z.), DK52431 (to R.L.L.), DK076608 (to A.D.), DK072476 dependent judgment of health care providers and each
Am J Clin Nutr. 2012;95:309–317. (to L.M.R. and E.R.), and the Russell Berrie Foundation (to patient’s individual circumstances must determine treat-
336. Fothergill E, Guo J, Howard L, Kerns JC, Knuth ND, R.L.L.).
ment decisions. The Endocrine Society makes no warranty,
Brychta R, Chen KY, Skarulis MC, Walter M, Walter PJ, Disclosure Summary: M.W.S. receives research funding

Hall KD. Persistent metabolic adaptation 6 years after from and serves as a consultant to Novo Nordisk. R.J.S. re- express or implied, regarding this Scientific Statement and
“The Biggest Loser” competition. Obesity (Silver Spring). ceives research support from Ethicon/Johnson & Johnson, specifically excludes any warranties of merchantability and
2016;24:1612–1619. Novo Nordisk, Janssen/Johnson & Johnson, MedImmune, fitness for a particular use or purpose. The Endocrine Society
337. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Sanofi, and Boehringer-Ingelheim, and serves as a consultant/ shall not be liable for direct, indirect, special, incidental, or
Shulkes A, Kriketos A, Proietto J. Long-term persistence advisor to Ethicon/Johnson & Johnson, Novo Nordisk,
consequential damages related to the use of the information
of hormonal adaptations to weight loss. N Engl J Med. Orexigen, Daiichi Sankyo, Janssen/Johnson & Johnson,
2011;365:1597–1604. Novartis, Paul Hastings Law Firm, Zafgen, Takeda, and contained herein.
338. Rosenbaum M, Leibel RL. Models of energy homeostasis Boehringer-Ingelheim. A.D. has received grants, contracts,
in response to maintenance of reduced body weight. honoraria, and consulting fees from numerous food and Abbreviations
Obesity (Silver Spring). 2016;24:1620–1629. beverage companies and other commercial and nonprofit AgRP, agouti-related protein; ARC, arcuate nucleus; BAT,
339. Subramanian SV, Perkins JM, Ozaltin E, Davey Smith G. Weight entities with interests in diet quality and health. E.R. serves on brown adipose tissue; BMI, body mass index; BPA, bisphenol
of nations: a socioeconomic analysis of women in low- to the Scientific Advisory Board to the Nutrilite Health Institute
A; CGRPPBN, calcium gene-related peptide expressing neu-
middle-income countries. Am J Clin Nutr. 2011;93:413–421. with Amway, has a consultant contract with Janssen, serves
340. Bellissimo N, Akhavan T. Effect of macronutrient on the Scientific Advisory Board for the Institute of Car- rons in the parabrachial nucleus; EDC, endocrine-disrupting
composition on short-term food intake and weight loss. diometabolism and Nutrition in Paris, France, gives lectures at chemical; GABA, g-aminobutyric acid; GI, gastrointestinal;
Adv Nutr. 2015;6:302S–308S. the Open Academy in Venice, and is an advisor for the GWAS, genome-wide association study; HFD, high-fat diet;
Center for Medical Weight Loss. He has received research iBAT, interscapular brown adipose tissue; LPL, lipoprotein
grants or unrestricted gifts from Amway, Nestle, the Nu-
lipase; NEAT, nonexercise activity thermogenesis; NPY,
Acknowledgments trition Science Initiative, and Ethicon Surgery. L.M.R. serves on
We acknowledge science writer Eric Vohr for his contribution the Scientific and Medical Board Advisor to AdvoCare In- neuropeptide Y; PFC, perfluorinated chemical; POMC, pro-
to this scientific statement, and Drs. William Heisel and ternational, LP, and receives royalties for SmartLoss® and opiomelanocortin; SES, socioeconomic status.

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SCIENTIFIC STATEMENT

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Stratiﬁcation of obesity outcomes Identifying and mitigating

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T he need to integrate molecular, genetic, de-

268 Schwartz et al Obesity Pathogenesis Endocrine Reviews, August 2017, 38(4):267–296

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270 Schwartz et al Obesity Pathogenesis Endocrine Reviews, August 2017, 38(4):267–296

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neurotransmitter, g-aminobutyric acid (GABA); as a positive or a negative experience may therefore

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272 Schwartz et al Obesity Pathogenesis Endocrine Reviews, August 2017, 38(4):267–296

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Interactions between genetics, epigenetics,

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