Hormones and Behavior 66 (2014) 104119

Contents lists available at ScienceDirect

Hormones and Behavior

journal homepage: www.elsevier.com/locate/yhbeh

Review

Our stolen gures: The interface of sexual differentiation, endocrine

disruptors, maternal programming, and energy balance
Jill E. Schneider a,, Jeremy M. Brozek a, Erin Keen-Rhinehart b
a
b

Lehigh University, Department of Biological Sciences, Bethlehem, PA 18015, USA

Susquehanna University, Department of Biological Sciences, Selinsgrove, PA 17870, USA

a r t i c l e

i n f o

a b s t r a c t

Available online 28 March 2014

This article is part of a Special Issue Energy Balance.

Keywords:
Adiposity
Ingestive behavior
Obesity
Food intake
Bisphenol A
Diethylstilbestrol

The prevalence of adult obesity has risen markedly in the last quarter of the 20th century and has not been
reversed in this century. Less well known is the fact that obesity prevalence has risen in domestic, laboratory,
and feral animals, suggesting that all of these species have been exposed to obesogenic factors present in the
environment. This review emphasizes interactions among three biological processes known to inuence energy
balance: Sexual differentiation, endocrine disruption, and maternal programming. Sexual dimorphisms include
differences between males and females in body weight, adiposity, adipose tissue distribution, ingestive behavior,
and the underlying neural circuits. These sexual dimorphisms are controlled by sex chromosomes, hormones that
masculinize or feminize adult body weight during perinatal development, and hormones that act during later
periods of development, such as puberty. Endocrine disruptors are natural and synthetic molecules that attenuate or block normal hormonal action during these same developmental periods. A growing body of research
documents effects of endocrine disruptors on the differentiation of adipocytes and the central nervous system
circuits that control food intake, energy expenditure, and adipose tissue storage. In parallel, interest has grown
in epigenetic inuences, including maternal programming, the process by which the mother's experience has
permanent effects on energy-balancing traits in the offspring. This review highlights the points at which maternal
programming, sexual differentiation, and endocrine disruption might dovetail to inuence global changes in
energy balancing traits.
2014 Published by Elsevier Inc. This is an open access article under the CC BY-NC-SA license
(http://creativecommons.org/licenses/by/3.0/).

Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Genes, poor diet, and sedentary behavior cannot explain obesity . . . . .
Introduction to endocrine disruptors . . . . . . . . . . . . . . . . .
Endocrine disruptors, ingestive behavior, energy balance, and obesity . . .
Sexual dimorphisms of the energy balancing traits . . . . . . . . . . .
Sex chromosomes and energy balance . . . . . . . . . . . . . . . . .
The organizational hypothesis and energy balance . . . . . . . . . . .
The aromatization hypothesis, multiple critical periods, and energy balance
Endocrine disruptors, sexual differentiation, brain, and behavior . . . . .
Endocrine disruptors, sexual differentiation, and peripheral factors . . . .
Linking peripheral metabolism to brain and behavior . . . . . . . . . .
Maternal programming of adult energy balancing traits . . . . . . . . .
Epigenetics and transgenerational effects on energy balance . . . . . . .
Summary, conclusions, and future directions . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Corresponding author at: Department of Biological Sciences, 111 Research Drive, Bethlehem, PA 18015, USA. Fax: +1 610 758 4004.
E-mail address: js0v@lehigh.edu (J.E. Schneider).

http://dx.doi.org/10.1016/j.yhbeh.2014.03.011
0018-506X/ 2014 Published by Elsevier Inc. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by/3.0/).

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J.E. Schneider et al. / Hormones and Behavior 66 (2014) 104119

Introduction
A global rise in the incidence of adult obesity has occurred over the
past 150 years, with a slow and steady increase prior to 1970 and a
sharp rise between the years 1970 and 2000 (Bundred et al., 2001;
Flegal et al., 1998, 2002, 2010; Ogden et al., 1997, 2006, 2007). In spite
of well publicized government guidelines, medical advice, and a proliferation of diet books, weight-watcher's programs, prescription diet
pills, fat-burning herbs, and appetite suppressing supplements
(Taubes, 2007), the prevalence of obesity remains high. Despite recent
reports by the news media that childhood obesity has decreased significantly in the last decade (e.g., Tavernise, 2014), the Centers for Disease
Control and Prevention (CDC) concludes that Overall, there have been
no signicant changes in obesity prevalence in youth or adults between
20032004 and 20112012. Obesity prevalence remains high and thus
it is important to continue surveillance. This quote is from the same
CDC report that provoked the optimistic news media headlines about
the putative decrease in childhood obesity (Ogden et al., 2014). Thus,
more than a decade into the 21st century, the high incidence of obesity
has not reversed (Ogden et al., 2013, 2014).
The relatively rapid rate of increase in body weight and the failure to
reverse the high incidence of obesity present a challenging puzzle with
many missing pieces. Some of the important pieces of this puzzle are in
place, whereas others have yet to be fully appreciated and integrated
with the other pieces.
For many years, the focus has been on three factors: Genetic inuences, diet, and sedentary behavior. This review will emphasize three
overlapping biological processes that interact with these factors: Sexual
differentiation, maternal programming, and endocrine disruption. We
begin with a very brief review of the role of genes, diet, and exercise,
noting that global obesity patterns are not explained by these factors
alone. Other evidence suggests the existence of widespread environmental obesogen acting on humans, laboratory rodents and nonhuman
primates, domestic animals, and even feral animals. We therefore
discuss endocrine disrupting compounds, natural and synthetic molecules from the environment that interfere with endocrine processes, including energy balance and ingestive behavior (Auwerx, 1999). A clear
understanding of their mechanism of action, however, requires that we
understand sex differences in energy-balancing systems. In most species including our own, males differ from females in many energybalancing characteristics. Some of these sexual dimorphisms are behavioral in that they involve caloric intake, diet preferences, the rewarding
aspects of food, and central nervous system circuits that control these
behaviors. Other sexual dimorphisms are morphological and physiological; they involve the distribution of adipose tissue, adipocyte differentiation, glucose homeostasis, and other peripheral systems. We discuss
the signicance of these sex differences and the importance of understanding how these differences come about. This brings us to the process of sexual differentiation, the process whereby physiological traits
are either masculinized or feminized by sex chromosomes, hormones
secreted perinatally, hormones secreted during other critical periods
of development (e.g., puberty), and interactions among these factors.
Reproductive biologists have dened multiple mechanisms involved
in sexual differentiation and experimental designs that discriminate
among them, but few have been employed in obesity research. Some
of these mechanisms involve fetal steroid receptor action, and endocrine disruptors act on these same receptors. Thus, experimental approaches used in sexual differentiation research will be critical in
understanding the effects of endocrine disruptors on obesity.
Using a few well-designed studies as examples, we connect four new
pieces of the obesity puzzle. First, endocrine disruptors are ubiquitous in
the environment (Baillie-Hamilton, 2002; Colborn et al., 1993;
Simonich and Hites, 1995). Second, they affect energy balancing systems (Heindel, 2003; Mackay et al., 2013; Manikkam et al., 2013;
Newbold et al., 2005; Oken and Gillman, 2003; Ruhlen et al., 2008;
Skinner et al., 2013; Tracey et al., 2013; Vom Saal et al., 2012). Third,

105

energy balancing phenotypes are sexually dimorphic in humans, with

the masculine phenotype most closely linked to metabolic diseases
such as type II diabetes and heart disease (Bonora, 2000; Kotani et al.,
1994; Lemieux, 2001; Macotela et al., 2009; Wajchenberg, 2000).
Fourth, endocrine disruptors have masculinizing effects on sexually dimorphic phenotypes, and might also act through other dened mechanisms of sexual differentiation (e.g., Mackay et al., 2013). We also
explain how peripheral changes in lipogenesis, lipolysis, and fuel oxidation bring about changes in ingestive behavior. The remainder of the review examines the consequences for future generations. New
information on the epigenetic effects of endocrine disruptors, their
overlap with fetal programming (Manikkam et al., 2013; Skinner et al.,
2013; Tracey et al., 2013), and their potential for unmasking cryptic genetic variation (Ledon-Rettig et al., 2008, 2009, 2010) provides plausible
basis for hypothesizing that endocrine disruptors are responsible for the
rapid increase in obesity at the end of the last millennium. Finally, we
summarize and propose new research frontiers.
Genes, poor diet, and sedentary behavior cannot explain obesity
There is no doubt that genetic inuences determine many aspects of
energy balance, but does this mean that the rapid, sharp rise in human
obesity can be explained by natural selection for obese phenotypes?
We know of many single gene mutations that can inuence various
aspects of metabolism and ingestive behavior (Campeld et al., 1995;
Farooqi et al., 1998; Geary et al., 2001; Halaas et al., 1995; Heine et al.,
2000; Pelleymounter et al., 1995; Vaisse et al., 2000). Yet, point mutations or major genes cannot account for a large proportion of the
variance in body weight (Garver et al., 2013; Hinney and Hebebrand,
2008; Rankinen et al., 2006). Human body weight is controlled by many
genes that inuence various aspects of body composition, eating behavior, and energy expenditure (Chaput et al., 2014). The sharpest rise in
human obesity spans only a few decades. Given the large population
size, long generation time, and a lack of a strong selective advantage for
obesity in humans (Speakman, 2006), it seems unlikely that changes in
gene frequencies alone can explain the recent sharp rise in global obesity.
Even studies aimed at documenting genetic inuences on human
obesity nd strong evidence for the effects of diet and energy expenditure on body weight. The Quebec Family Study (QFS) was designed to
estimate the extent of familial and genetic effects on energy balance
using data from more than 700 families assessed between 1979 and
2002. The authors conclude that, Unhealthy diet and physical inactivity
are thus the two major factors for obesity . The inuence of these
traditional risk factors for obesity has been largely documented,
including in the QFS. (Chaput et al., 2014).
Diet alone is not a good explanation for the recent global rise in
obesity because many individuals fail to gain weight on putative
obesogenic diets. In human or nonhuman animal populations, some
individuals are predisposed toward body fat accumulation when
exposed to obesogenic diets or after they end a period of calorie restriction, whereas other individuals are resistant to body weight gain under
the same conditions (e.g., Akieda-Asai et al., 2013; Blundell and Cooling,
2000; Jackman et al., 2006; Ji and Friedman, 2007; Ji et al., 2005; Levin
et al., 1987; Mutch et al., 2011; Pierce et al., 2010; Schemmel et al.,
1970; Schmidt et al., 2013; and reviewed by Astrup, 2011; Blundell and
Cooling, 1999; Levin, 2009). One explanation is genotype environment
interaction (e.g., Bouchard and Tremblay, 1990; Garver et al., 2013; Levin,
2009; Madsen et al., 2010; Martinez et al., 2003; Novak et al., 2006). Yet,
in many populations, even those individuals on the lower end of the
body weight spectrum are beginning to gain weight (Lustig, 2006).
Thus, if there is a susceptible phenotype, we must ask, Is the incidence
of this susceptible phenotype on the rise, and if so, why?
In this regard, it is important to note that rises in the rates of obesity
are not restricted to human populations, but also include domestic cats,
dogs, horses, and laboratory rodents and nonhuman primates (German,
2006; Klimentidis et al., 2011; Raffan, 2013; Thatcher et al., 2009). It is

106

J.E. Schneider et al. / Hormones and Behavior 66 (2014) 104119

DES, , DDT, PCBs, BPA, TBTs, Phytoestogens

Phthalates

ER

DDT

GH

GHR
ER !

AR

ER
GR

FFAs
Lukotrienes
Prostaglandins

PPAR

RXR

TBTs
high dose

TBTs low dose

Fig. 1. A diagram of a hypothetical cell illustrating loci where endocrine disruptors (from
outside the cell membrane) interfere with processes within the cell.
Adapted from Grun and Blumberg (2007).

safe to assume that these nonhuman animals are not victims of corporate marketing. Furthermore, the rises in obesity include laboratory
animals fed the control diets that formerly did not support current
rates of body weight gain. It might be argued that pet and lab animal
obesity is accounted for by a sedentary existence in small, conned
spaces. This, however, does not explain the next piece of the puzzle:
obesity in wildlife. Recent data have emerged documenting obesity in
feral animals that are not conned to cages or homes, but are free to
roam (Klimentidis et al., 2011; Wingeld, 2008). This suggests that
there might be agents in the environment that have widespread
obesogenic effects on many different species.
Introduction to endocrine disruptors
The book Our Stolen Future brought world-wide attention to the fact
that many natural and synthetic molecules interfere with endocrine
processes acting as toxins to animals that come in contact with them
(Colborn et al., 1997). These endocrine-disrupting compounds typically
bind to hormone receptors, thereby mimicking or blocking hormone
action. The best-known example might be the devastating effects
of DDT (dichlorodiphenyltrichloroethane) on populations of bald
eagles (Bowerman et al., 1995; Colborn, 1991). In this case, a synthetic
molecule from a commonly used pesticide caused a rapid decline in
reproductive success, largely by mimicking the action of estrogens
binding to estrogen receptors (ERs). After four decades of study, it is
clear that there are many different endocrine disruptors that interfere
with estrogen, androgen, thyroid, or glucocorticoid action, with related
effects on steroid biosynthesis, steroid sensitive neurotransmitter
systems, hormone degradation and/or elimination, reproductive
development, and behavior (Fig. 1, reviewed by Gore, 2008). Estrogenic
compounds include polychlorinated biphenyls (PCBs), components of
coolants, insulators, plasticizers and ame-retardants. Similarly,
phytoestrogens such as genistein, pesticides like DDT, and compounds
that leech from plastic containers such as bisphenol A (BPA) are estrogenic. Phthalates, used as plasticizers, tend to be androgen receptor
(AR) antagonists, although some are clearly estrogenic. These are just
a few of many examples. Effects of endocrine disruptors on the mammalian reproductive system include but are not limited to inhibited
spermatogenesis and ovulation, cryptorchidism, hypospadias, decreased semen quality, premature ovarian failure, polycystic ovary syndrome (PCOS), endometriosis, accelerated puberty, masculinized
genitalia in genetic females, feminized yolk production (vitellogenesis)

in males, initiation of mitosis in estrogen sensitive breast cancer cells,

disrupted hypothalamicpituitarygonadal function, altered sex and
social behavior, and these have been reviewed previously (Balabanic
et al., 2011; Frye et al., 2012; Gore, 2008, 2010; Gore and Patisaul,
2010; Nordkap et al., 2012; Ottinger and Dean, 2011; Ottinger et al.,
2001, 2005, 2008; Patisaul, 2005, 2013; Patisaul and Polston, 2008).
Each of these individual effects on reproductive processes can have negative fertility outcomes that diminish population size and threaten entire species, and the cumulative effects are often devastating.
Endocrine disruptors come from many and varied sources (BaillieHamilton, 2002; Colborn et al., 1993; Simonich and Hites, 1995). They
are found in organic pesticides, perfumes, and solvents that are released
into the air. They include molecules in industrial efuent. They include
chemicals used to make containers like plastic water and baby bottles.
These containers leech their endocrine disrupting byproducts into the
ingestible contents of those containers. In addition, many different
cleaning products, paints, and glues contain molecules that act as endocrine disruptors (reviewed by Baillie-Hamilton, 2002; Balabanic et al.,
2011; Crews et al., 2000; Gore, 2010; Gore and Patisaul, 2010; Khanal
et al., 2006). Some endocrine-disrupting compounds are simply steroid
hormones, for example, humans and livestock excrete natural and
prescription steroids and other pharmaceutical products that make their
way into water supplies, and at concentrations above the natural levels,
these steroids bind to mammalian hormone receptors altering physiology
and development (reviewed by Frye et al., 2012; Gore, 2010). Endocrine
disrupting compounds also include natural isoavones from soy and
other plants that are eaten by adults, children, and infants (reviewed
by Patisaul, 2005, 2013). These many and varied sources can make it difcult to estimate the contribution of any one endocrine disrupting compound to changes in reproduction and energy balance, but this difculty
does not diminish the importance of understanding the mechanisms.
There is general agreement that increasing exposure of humans and
wildlife to endocrine-disrupting compounds is a major societal problem
that requires a concerted interdisciplinary focus that includes cooperation among behavioral neuroendocrinologists, reproductive biologists,
conservation biologists, clinicians, epidemiologists, ecologists, evolutionary biologists, molecular biochemists as well as scientists and
policy-makers in other disciplines (Balthazart and Levine, 2014; Crews
and Gore, 2011; Gore et al., 2014; Vandenberg et al., 2013; Zoeller
et al., 2012). We argue that this interdisciplinary focus must include
scientists that specialize in neuroendocrinology of ingestive behavior,
energy balance, and obesity.
Endocrine disruptors, ingestive behavior, energy balance, and obesity
The idea that endocrine disruptors affect energy balance is not new.
An insightful review by Baillie-Hamilton points out that in the 1970s
and 80s, a plethora of endocrine disrupting agents were found to induce
body weight gain, although they were categorized by toxicologists as
nontoxic, even at high doses (Baillie-Hamilton, 2002). The number
of these obesogenic agents is astounding, but largely unknown because
the body weight data are not mentioned in the abstracts (they are
reported only within the article). In fact, in some of these articles, the
fact that the compounds promoted body weight gain was cited as
evidence that the compounds promoted good health (reviewed by
Baillie-Hamilton, 2002).
Evidence is accumulating that endocrine-disrupting compounds
inuence many aspects of energy balance, and in some cases, these
affected traits are known to lead to obesity and/or diabetes (reviewed
by Gore, 2010; Heindel, 2003; Newbold et al., 2005; Vom Saal et al.,
2012). Increases in body weight and body fat content, altered adipocyte
differentiation, disrupted glucose homeostasis, obesity and insulin
resistance all result from perinatal treatment with endocrine disruptors
such as the synthetic estrogen, diethylstilbestrol (DES), the soy isoavone,
genistein, or the ER-binding molecule known to leach from plastics and
paints, BPA (Masuno et al., 2002; Newbold et al., 2005; Ruhlen et al.,

J.E. Schneider et al. / Hormones and Behavior 66 (2014) 104119

2008; Sakurai et al., 2004). The variety of effects and mechanism of action
on energy balance are as varied as those on reproduction.
The effects of endocrine disruptors differ with different stages of
development. The most pronounced effects, at the lowest concentrations, occur during fetal development, when endocrine disruptors
make permanent changes that determine adult physiological and
behavioral function. Endocrine disruptors cross the placenta, i.e., they
are transferred across the fetalmaternal blood barrier and are present
in breast milk (Alleva et al., 1998; Bordet et al., 1993; Jacobson and
Jacobson, 1996). In some cases, transient exposure to endocrinedisrupting compounds during fetal development affects reproductive
traits in adults, which persists and leads to obesity in successive (e.g.,
the F3) generations, even though the endocrine-disrupting compound
is no longer present in the environment (Manikkam et al., 2013;
Skinner et al., 2013; Tracey et al., 2013).
Perinatal effects of endocrine disruptors are likely to interfere with
key steps in the development of sex differences. Endocrine disruptor
action involves the perinatal action of androgens, estrogens, and
glucocorticoids on their cognate receptors. Understanding the natural
process of sexual differentiation has been key to understanding the
effects of endocrine disruptors on development of the sexually dimorphic reproductive system. Because energy-balancing traits are sexually
dimorphic, understanding sexual differentiation is likely to be critical
for understanding endocrine disruptor effects on energy balance.
Sexual dimorphisms of the energy balancing traits
Sexual dimorphisms in energy balance are not just an interesting
aside or incidental tangent to the study of energy balance. Sexual differentiation is an essential puzzle piece that must be integrated into the
bigger picture of energy balance. We have known about sex differences
in body composition since the beginning of behavioral endocrinology
(Berthold, 1849), and we know that these differences are in part due
to the effects of testicular androgens on body fat storage and muscle development (Pasquali, 2006; Siegel et al., 1981; Symeon et al., 2010).
These effects, however, are not explained by activational effects of
adult hormones in all species. For example, in cattle, it is clear that
peripubertal androgens increase growth and muscle development
(Tucker and Merkel, 1987), yet castrated bulls (steers) grow faster
than adult females (heifers), and there are species differences in the
sexual dimorphism. The adult presence of androgens vs. estrogens
cannot explain these phenomena. These sexual dimorphisms in growth
and morphology are of great interest in the meat and dairy industry, and
have revealed a plethora of sexual dimorphisms, such as those found
in growth hormone concentrations, insulin-like growth factor, and
somatotrophin release-inhibitory factor (reviewed by Gatford et al.,
1998). Sexual dimorphisms and their link to reproductive success will
be central to understanding the difference between healthy energy balance and unhealthy energy balance.
Androgens, adiposity, and disease are interrelated, particularly in
humans. Men, on average have higher circulating androgen concentrations and are larger than women. What is more important, they tend
to accumulate white adipose tissue (WAT) in the visceral, abdominal
region, whereas women tend to accumulate WAT subcutaneously, particularly in the gluteofemoral region, i.e., the hips and thighs (Kotani
et al., 1994). This is reected in the waist-to-hip ratio, which is signicantly higher in men than in women. Male-typical (android) but not
female-typical (gynoid) WAT distribution is linked to many negative
health consequences (Wajchenberg, 2000), even in the absence of
obesity, including insulin and leptin resistance (Bonora, 2000; Lemieux,
2001; Macotela et al., 2009), type II diabetes (Lundgren et al., 1989),
cardiovascular disease (Kissebah et al., 1982; Krotkiewski et al., 1983),
hypertension (van Lenthe et al., 1998), and inammation (Lemieux
et al., 2001). The gynoid WAT distribution is not associated with these
negative health consequences. This is partially because subcutaneous
WAT, more prevalent in females, has a very different cytoarchitecture

107

than the visceral WAT, more prevalent in males. Subcutaneous WAT

and visceral WAT also differ in lipid ux and storage capacity (Power
and Schulkin, 2008), and furthermore, visceral WAT accumulation is
linked to elevated inammation (reviewed by Bloor and Symonds,
2014). The link between android, masculine obesity and disease has
moved researchers to venture beyond the body mass index (BMI, a
measure of body weight as a function of height) to look in more detail
at adipose tissue distribution and morphology.
Unlike android WAT, the gynoid WAT distribution is critical for successful lactation because breast milk production is fueled by fatty acids
released from lipids stored in the mother's gluteofemoral WAT. In fact,
the hormones secreted prior to lactation promote the growth of
gluteofemoral WAT; the hormones secreted during lactation promote
the breakdown of those lipids and the release of fatty acids used in
breast milk production (Rebuffe-Scrive et al., 1985). At least some investigators agree that the size of the gynoid WAT is not associated with
negative health consequences, even in women whose BMI places
them squarely in the obese range of the BMI population distribution
(Bjorntorp, 1988; Despres, 1993; Gillum, 1987; Macor et al., 1997;
Marin and Bjorntorp, 1993; Power and Schulkin, 2008; Van Gaal et al.,
1988). In fact, subcutaneous gluteofemoral WAT might be
cardioprotective (Van Pelt et al., 2005), and this protection might
wane along with a rise in visceral fat accumulation with age or with
the number of years past menopause (Kotani et al., 1994; Lovejoy et al.,
2008). Related to these cardioprotective and prolactational effects, the
sexual dimorphisms in WAT distribution might have played a role in
mate selection during human evolution. In support of this idea, crosscultural studies show that men tend to rate women as more attractive
if they have a low, rather than a high waist-to-hip ratio, regardless of
body weight (Jasienska et al., 2004; Singh, 1993, 1994a,b,c, 2002). Nevertheless, we can no longer afford to overlook the association of these sex
differences in adipose tissue distribution with sex differences in disease.
If sex differences in body fat composition and distribution are due to
sex differences in adult gonadal hormones, it would be expected that
visceral obesity and its metabolic sequelae could be ameliorated by
adult treatment with gonadal hormones. To the contrary, exogenous
treatment with testosterone in adult men has yielded disappointing
results with regard to levels of circulating triglycerides, glucose
tolerance, insulin sensitivity, and visceral abdominal obesity (i.e., there
was either no effect or a positive effect on endocrine proles) (Wu
and von Eckardstein, 2003). Thus, it is unlikely that negative effects of
sex hormones on metabolic parameters can be explained by differences
in adult hormone concentrations. This reiterates the need for more
attention to peripubertal and perinatal hormone effects on energy
balance.
In addition to the above-mentioned sex differences, there are
well documented sex differences in energy expenditure, orosensory
physiology (which affects the taste and smell of food), and normal
and disordered ingestive behaviors (reviewed extensively by Asarian
and Geary, 2013). In most vertebrates, males differ from females in
daily food intake (Wade and Gray, 1979), preference for sweet and
creamy avors (Bartoshuk, 1978; Prutkin et al., 2000; Zucker, 1969),
binge eating (Klump et al., 2013), susceptibility to diet-induced obesity
(Jones et al., 1986), energy restriction-induced hyperphagia (Nohara
et al., 2011; Shi et al., 2008), energy restriction-induced decreases
in energy expenditure (Nohara et al., 2011; Shi et al., 2008), resistance
to leptin- and insulin-induced hypophagia (Clegg et al., 2006), resistance to ghrelin-induced hyperphagia (Clegg et al., 2007), glucoor lipoprivation-induced hyperphagia (Sandoval et al., 2012),
proopiomelanocortin (POMC) gene expression in the arcuate nucleus
of the hypothalamus (ARH) (Nohara et al., 2011), seasonal food intake
responses to energetic challenges and leptin (Clarke, 2001; Clarke
et al., 2001), the tendency to develop obesity in response to exposure
to high-intensity sweeteners (e.g., saccharin) (Swithers et al., 2013a,
b), and many other traits (reviewed by Asarian and Geary, 2013; Shi
and Clegg, 2009; Shi et al., 2009). These data suggests that we examine

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XX

XY

No Sry

Sry

Ovary

Testis

*
*
*

*
*

Feminized and
demasculinized
ingestive behavior and
WAT distribution

Masculinized and
defeminized ingestive
behavior and WAT
distribution

Fig. 2. A diagram of the steps of sexual differentiation, illustrating the steps where endocrine disruptors are known to interfere. Points of endocrine disruption are noted with an asterisk.

the sexual differentiation of energy balancing traits with the same rigor
that we examine sexual differentiation of reproductive traits.
Furthermore, these data pique a number of important questions.
Which came rst, the unmanageable appetite and overeating, the increased visceral WAT accumulation, or the decreased energy expenditure? Are these effects rooted in the origins of sex differences? Are
these traits also inuenced by endocrine disruptors?
Sex chromosomes and energy balance
Investigators interested in the origins of obesity will be aided by
a better understanding of the process of sexual differentiation
(Fig. 2). Sex differences arise by genetic, hormonal, and environmental
effects and the interaction among these factors (reviewed by Lenz
et al., 2012).
The initial steps are related to the presence or absence of genes on
the Y chromosome. The undifferentiated genital ridge, for example,
develops into the testis in the presence of the Sry gene and into the
ovary in its absence. Aspects of body weight and energy metabolism

are affected directly by genes on the Y chromosome and indirectly by

hormones secreted by the testis (Chen et al., 2013).
With regard to energy balancing characteristics in mammals, genes
on the X and Y chromosomes are important. The presence of sex
chromosomes can act independently of gonadal hormones to inuence
adiposity, food intake, fatty liver disease, and glucose homeostasis, and
at least some of these effects are mediated by differential gene dosage
that results from X chromosomes that escape inactivation (Arnold
et al., 2012; Chen et al., 2012). Experimental techniques are available
for producing mice that are gonadally male (they have functional
testes) with the female sex chromosome complement (XX) and mice
that are gonadally female (with functional ovaries) with the male sex
chromosome complement (XY). Mice of either gonadal sex with two
X chromosomes have signicantly greater body weight, adiposity, and
food intake during the light portion of the day compared to those with
only one X chromosome. Consistent with this result, XXY mice are
heavier, fatter, and more hyperphagic than XO mice. The mechanism
whereby X chromosome dosage inuences these traits is under investigation and appears to involve the orexigen, growth hormone (GH)

J.E. Schneider et al. / Hormones and Behavior 66 (2014) 104119

(Bonthuis and Rissman, 2013). Gonadal females with 2 X chromosomes

have higher levels of GH gene (Gh) expression in the brain compared to
gonadal females with 1 X chromosome and to gonadal males (XY). Furthermore, Gh expression in the brains of mice with 2 X chromosomes is
signicantly correlated with body weight. Acute infusion of GH into the
brain region of GH receptors causes signicant increases in food intake
in normal (XY) males. This information about the mechanisms that underlie the effects of X-chromosome dosage on adiposity and food intake
might be critical to understanding environmental effects on obesity, as
GH is a potential target for endocrine-disrupting compounds (Elango
et al., 2006).
The organizational hypothesis and energy balance
In addition to X chromosome-mediated sex differences, some sexually
dimorphic energy-balancing-traits are inuenced by hormones secreted
perinatally, including thyroid hormone, glucocorticoids, and gonadal
steroids. The organizational hypothesis of sexual differentiation posits
that sex differences arise in two signicant endocrine steps (Fig. 2). In
the rst step, fetal hormones permanently organize the brain and
periphery. In the second step, peripubertal and adult increases in
hormones activate these masculinized substrates. This was rst demonstrated in mammalian genital development (reviewed by Blaschko
et al., 2012). It is important to note this two-part process because
adult exposure to testosterone will have different effects on the brain
and body, depending on the level of perinatal exposure to testosterone.
Thus, early masculinization or feminization (or X chromosome dose)
prepares or primes the tissue to respond to gonadal hormones during
later periods of development.
Following experiments that demonstrated prenatal organization of
the genitalia, classic experiments from the 1960s and 70s revealed that
sexual dimorphisms in rodent sex behavior are organized neonatally
and activated in adulthood by hormones secreted beginning at the
time of puberty (Feder et al., 1966; Grady et al., 1965; Pfaff and
Zigmond, 1971; Phoenix and Chambers, 1982; Phoenix et al., 1959;
Phoenix et al., 1983). This moved the study of sexual differentiation
out of the genitals and into the brain and behavior.
In parallel with the research on sexual differentiation of reproductive
behavior, this two-part process was found to underlie sex differences in
food intake and body weight. Just as male-typical sex behavior is more
prevalent in male than in female rats, body weight and food intake are
greater in male rats (Aschkenasy-Lelu and Aschkenasy, 1959). In rats,
male-typical sex behavior, food intake, and body weight are all
decreased by adult castration and the effect is reversed by testosterone
replacement. Furthermore, adult gonadectomy signicantly decreases
the incidence of sex behavior and increases body weight and food intake
in females and has the opposite effects in males (Gentry and Wade,
1976; Kakolewski et al., 1968). Analogous to male-typical sex behavior,
adult food intake is more responsive to the stimulatory effects of adult
testosterone treatment in males and neonatally androgenized females
than in nonandrogenized females (Bell and Zucker, 1971). In addition,
adult food intake is less responsive to the suppressive effects of estradiol
in males and neonatally androgenized females than in nonandrogenized
females (Gentry and Wade, 1976). This early work lays the foundation
for perinatal androgens and their masculinizing effects on the neural
circuits that control food intake and body weight and for the study of
sexual differentiation for the energy balancing system.
The masculinizing effects of perinatal androgen treatment have been
compared to perinatal exposure to endocrine disruptors, but the second
step is often omitted (i.e., adult response to steroid treatment is not
tested). It will be instructive to determine whether perinatal exposure
to endocrine disruptors organizes or primes the brain to respond
to adult hormones. This pattern of perinatal steroid organization of
behavior and physiology underlies many aspects of sexual, social, cognitive, and ingestive behaviors in vertebrates (Arnold and Gorski, 1984;
MacLusky and Naftolin, 1981; Morris et al., 2004; Negri-Cesi et al.,

109

2004, 2008; Wu et al., 2009). The concepts of sexual differentiation of

the gonad apply to brain and behavior, including food intake and body
weight, yet, relatively few ingestive behavior and obesity researchers
have employed experimental designs used in the study of sexual
differentiation.
The aromatization hypothesis, multiple critical periods, and energy
balance
In more recent years, the organizational hypothesis has been
augmented to include the aromatization hypothesis, the idea that testosterone masculinizes brain and behavior only after it is aromatized to estradiol in the brain (Davidson et al., 1968; Vagell and McGinnis, 1997).
One tenant of the aromatization hypothesis is that females are normally
protected from the masculinizing effects of their mother's estradiol by
molecules that bind estradiol, such as alpha fetal protein (in the case of rodents) and sex-hormone binding globulin (in the case of primates)
(Bakker et al., 2006). Thus, the sexual dimorphism in the prenatal circulating steroid prole (high testosterone in males but not in females) results
in estradiol action in male but not in female rodent brains. Females lack
these high levels of prenatal androgens, and are protected from the action
of circulating estradiol. According to the synaptocrine hypothesis (part of
the aromatization hypothesis) the presence of aromatase at only some
critical synaptic junctures confers the ability to control brain function
via estradiol action in some brain nuclei while simultaneously conferring
other functions via androgen action in other brain nuclei (Remage-Healey
et al., 2011; Saldanha et al., 2011).
Another revelation was that the perinatal period was not the only
time when the brain is permanently organized, and that full expression
of female-typical behaviors requires active feminization by hormones. It
was at rst tempting to refer to the female as the default sex, given the
fact that feminization and demasculinization require an absence of
androgens. This is incorrect, however, since full feminization and/or
demasculinization also requires estradiol action, albeit at a different
time period and in smaller amounts (Bakker et al., 2002). In other
words, the absence of testosterone is not enough to produce a female;
females are not merely the default sex.
The perinatal period is not the only time window that is critical for
permanent organization of sexually dimorphic characteristics. Adult
female-typical sex behaviors are restored in mice lacking aromatase
by treatment with low levels of estradiol during postnatal days 15 and
25, but not before postnatal day 15 (Brock et al., 2011). Thus, complete
feminization requires not only the absence of testosterone perinatally,
but also the action of estradiol prepubertally. There is mounting evidence that complete sociosexual development requires gonadal steroid
action peripubertally in many mammalian species including our own
(Juraska et al., 2013).
At least two examples from the energy balance literature support
the idea that there are multiple critical periods in which hormones organize energy-balancing traits (Fig. 2). First, there is a sexual dimorphism
in the eating response to decits in metabolic fuel availability in rats.
Decits in metabolic fuel availability are induced by treatment with
mercaptoacetate (MA), an inhibitor of fatty acid oxidation. Males, but
not females show signicant increases in food intake in response to
MA treatment (Swithers et al., 2008). Adult ovariectomy fails to ameliorate the sex difference, whereas peripubertal ovariectomy masculinizes
the food intake response to MA treatment. Treatment of prepubertallyovariectomized females with estradiol reverses the effects of ovariectomy (Swithers et al., 2008). These experiments identify the peripubertal
period as an additional time window when sexual dimorphic ingestive
behaviors are established.
Does the aromatase hypothesis apply to ingestive behavior development? There is a sexual dimorphism in the tendency to overeat and gain
weight when exposed to high-intensity sweeteners, such as saccharin.
Male rats, whether they are obesity prone or not, readily become hyperphagic and overweight in response to saccharin relative to glucose

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supplemented diets. Female rats that are not obesity-prone are resistant
to the hyperphagia and weight gain induced by the saccharin supplement (Swithers et al., 2013a). Adult ovariectomy fails to ameliorate
the sex difference in resistance to hyperphagia in response to the
high-intensity sweetener. However, the sex difference is abolished by
adult treatment with aromatase, suggesting that the normal, obesityresistant female is actively feminized by local estrogen action. There
might also be some pubertal programming of the response to highintensity sweeteners because when the ovaries are surgically removed
prior to the onset of puberty, females are masculinized; i.e., females are
not resistant to obesity and overeating induced by the high-intensity
sweetener (Swithers et al., 2013a). The results suggest that the female
tendency to be resistant to the obesogenic effects of high-intensity sweeteners is actively feminized peripubertally and involves the conversion of
testosterone to estradiol in localized cells in adulthood (Fig. 2).
Endocrine disruptors, sexual differentiation, brain, and behavior
Since the classic experiments on the prenatal organization of body
weight and food intake in the 60s and 70s, many sex differences in
ingestive behavior have been noted, yet relatively few of these have
been traced to organizational effects. Even fewer have been examined
with reference to perinatal aromatization, synaptocrine action, or active
feminization.
Recent attention has turned to the effects of perinatal gonadal
steroids on the neural circuitry of ingestive behavior. Male mice have
a signicantly higher daily food intake than female mice throughout
life. In addition, they show higher levels of postfast hyperphagia and a
higher sensitivity to leptin-induced hypophagia compared to female
mice (Nohara et al., 2011), and these behavioral sex differences have
been linked to sexual dimorphisms in the arcuate nucleus of the hypothalamus (ARH).
The ARH has received a great deal of attention as a primary controller
of ingestive behavior in response to metabolic fuel availability, insulin,
leptin, and ghrelin (reviewed by Barsh and Schwartz, 2002; Crowley
et al., 2001; Schwartz and Porte, 2005; Zigman and Elmquist, 2003).
Despite this intense focus, it should be mentioned that ingestive behavior is known to be controlled by a distributed neural network that
includes peripheral sensors of metabolic fuel availability and nutrient
intake, the caudal brain stem, midbrain, hypothalamus, and other
areas including the nucleus accumbens, ventral tegmental area, and
amygdala (reviewed by Grill, 2010; Grill and Hayes, 2009). In the
ARH, however orexigenic effects of neuropeptide Y (NPY) and agoutirelated protein (AgRP) are thought to be counterbalanced by the anorectic peptides: cocaine and amphetamine-regulated transcript
(CART) and alpha-melanocyte-stimulating hormone (-MSH), a cleavage product of the proopiomelanocortin (POMC) gene. Metabolic challenges tend to increase NPY and AgRP gene expression and secretion
while simultaneously decreasing these parameters in POMC cells.
These changes can be reversed by re-feeding or by treatment with the
adipocyte hormone leptin (reviewed by Schwartz and Porte, 2005;
Zigman and Elmquist, 2003). Peripheral hormones affect not only the release of neuropeptides but also the synaptic input into NPY/AgRP and
POMC/CART cells (reviewed by Briggs and Andrews, 2011; Eckel, 2011;
Gao et al., 2007; Gyengesi et al., 2010; Zigman and Elmquist, 2003).
Relevant to the topic at hand, there is a sexual dimorphism in the
number of ARH cells that contain NPY, AgRP, and POMC (Nohara et al.,
2011). Male rats show signicantly lower POMC gene expression and
neuronal projections from POMC cells to the ARH compared to females.
Perinatal androgens masculinize the sexually dimorphic circuits of the
ARH. The daily food intake, postfast hyperphagia, and POMC gene expression and projections are fully masculinized in females treated with
either testosterone or dihydrotestosterone (DHT), both of which act via
the ARs. This is consistent with the organizational hypothesis, the idea
that testosterone masculinizes the energy balancing system during
early development via action on AR in the ARH (Nohara et al., 2011).

What about the aromatization hypothesis and ARH circuitry? There is

a sexual dimorphism in the eating response to leptin treatment. Males are
less resistant than females to leptin-induced hypophagia. Females
neonatally treated with testosterone or estradiol, but not DHT, are
not masculinized, but are instead ultra-feminized; they show higher
resistance to leptin-induced hypophagia (Nohara et al., 2011). Leptininduced hypophagia appears to be actively feminized by estradiol. These
data support the aromatization hypothesis and conrm that different aspects of the energy balancing system are masculinized or feminized by
different steroid hormones acting on different steroid receptors (Fig. 2).
Missing from these studies are data that address the questions, How
do neonatal steroids prime the animals to respond to adult estradiol and
testosterone? The mice in the above-mentioned experiments were not
gonadectomized in adulthood and were not treated with controlled
levels of gonadal steroids in adulthood. Are these ARH systems analogous to those that control lordosis, i.e., Do perinatal hormones program
these ARH systems to respond to peripubertal and adult hormones? Are
the effects on the ARH and ingestive behavior secondary to the changes
in body fat accumulation that were induced by the steroid treatment?
Are there sexual dimorphisms outside the ARH?
These patterns are not limited to rodents. The body weight, insulin
sensitivity, POMC, and AgRP systems are also sexually dimorphic in
sheep. Males are larger, are more prone to develop insulin-resistance,
and show a higher number of AGRP-immunoreactive (ir) cells compared to POMC-ir cells. Prenatal testosterone inhibits growth of the
fetal lamb, leading to postnatal catch-up growth (Manikkam et al.,
2004) and decreased insulin sensitivity in adulthood (Recabarren
et al., 2005). Prenatal testosterone masculinized the ARH nucleus of
the adult ewe (Sheppard et al., 2011). Adult ewes that had received prenatal testosterone treatment showed a signicantly higher number of
AgRP-ir cells compared to POMC-containing cell bodies and bers in
the median ARH. The effects of testosterone treatment were mimicked
by prenatal treatment with DHT and prevented by co-treatment with
an antagonist to AR. Perinatal androgen treatment also increased
the density of AgRP ber-ir in the preoptic area, paraventricular
nucleus of the hypothalamus (PVH), lateral hypothalamus (LH), and
dorsomedial hypothalamus (DMH). These data show that in sheep,
the cells that contain AgRP and their projections are masculinized
during prenatal development by androgens acting on the AR. These effects in sheep are similar to the effects of neonatal testosterone in mice,
except that, in mice, androgens were acting on the POMC rather than on
the NPY/AgRP system (Nohara et al., 2011).
In Sheppard et al.'s (2011) study, all ewes were ovariectomized and
treated with a consistent dose of estradiol in adulthood, thus controlling
for any possible secondary effect of neonatal treatment on endogenous
ovarian function. It is not known, however, whether prenatal testosterone primes the brain to respond to adult hormones in sheep. In addition,
we do not know whether there is active feminization of the adult
response to ovarian steroids in sheep. Again, we do not know whether
effects in the ARH are secondary to changes in body composition.
The relevance of sexual differentiation research to understanding
human health and disease is not in doubt. For example, prenatal androgens masculinize body fat distribution, insulin resistance, and ingestive
behavior. By measuring traits in opposite sex twins compared to samesex twins, researchers can estimate the extent of exposure to prenatal
androgens (Culbert et al., 2013). Females from opposite-sex twin pairs
are exposed to more prenatal testosterone from their male twin.
Women with a male twin have a signicantly higher BMI and rate of
dyslipidemia compared with women with a dizygotic female twin
(Alexanderson et al., 2011). A similar conclusion is drawn from studies
that use nger length ratio to estimate prenatal androgen exposure. The
length of the index nger (the second digit) to the length of the ring
nger (the fourth digit) is sexually dimorphic; males and prenatally
androgenized females have a lower second to fourth digit ratio
(a.k.a., 2D:4D) (Brown et al., 2002; Gobrogge et al., 2008). As would
be expected if prenatal androgen exposure masculinizes the body fat

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distribution, 2D:4D ratio is negatively correlated with waist-to-hip ratio

in humans (Fink et al., 2003).
In addition, sex differences in disordered eating are inuenced by
prenatal androgens in human beings. Men tend to score lower than
women on psychological scales that measure the tendencies toward
disordered eating. When tested during puberty, females from
opposite-sex twin pairs showed more masculinized levels of disordered
eating than females from same-sex twin pairs. These associations with
the twin were independent of other variables, such as BMI and anxiety
levels, since binge eating can occur at extremes in body weight (both in
women with anorexia nervosa and with obesity). These data are consistent with the idea that prenatal androgens masculinize some aspect of
the energy balancing system so that men are to some degree buffered
from, but women are at a higher risk for developing eating disorders
(Culbert et al., 2013).
A few studies have emerged demonstrating that endocrinedisrupting compounds can masculinize or feminize energy balancing
traits. For example, perinatal exposure of rats to BPA masculinizes
some aspects of the energy balancing neural circuits via ER, but has
other effects that are not masculinizing and might be independent of
ER (MacKay et al., 2013). This suggests that the sexual dimorphisms in
rat energy balance are partially explained by the aromatization hypothesis. This effect is mimicked by perinatal exposure to BPA. Pregnant and
lactating mice fed diets that contained either a low or a high dose of BPA,
a vehicle, or the estrogenic endocrine disruptor, DES, were allowed to
grow to adults and their energy balancing traits were examined in detail. Offspring were weaned initially onto a normal laboratory chow
diet, then as adults they were exposed to either a normal or an
energetically-dense diet (MacKay et al., 2013). Females exposed to the
high dose of BPA, but not those exposed to DES show a masculinized
propensity for diet-induced obesity, with increased levels of body
weight, WAT gain, and increased levels of food intake compared to untreated females fed the same high-energy diet. Furthermore, BPAtreated but not DES-treated females on a high-energy diet show masculinized plasma leptin concentrations, ARH POMC projections, and ARH
ER expression i.e., signicantly increased plasma leptin concentrations,
reduced POMC mRNA expression in the ARH, and increased ER expression in the ARH. By contrast, males exposed to the high dose of BPA, but
not those exposed to DES show impaired glucose tolerance on both
high-energy and low-energy diets. They also show reduced ARH
POMC projections to the PVH. When exposed to energetically-dense
diets, BPA treated males show greater NPY/AgRP expression in the
ARH. In sum, exposure to BPA but not to DES hypermasculinizes males
masculinizes females and these effects appear to be independent of ER
(Fig. 2). In addition, BPA has other effects that cannot be described as
masculinizing, but these experiments did not manipulate the response
to adult hormones (testosterone vs. estradiol plus progesterone)
(Mackay et al., 2013). Furthermore, there is still a question as to whether changes in the ARH are secondary to or independent of changes in
lipid accumulation or other peripheral factors.

Endocrine disruptors, sexual differentiation, and peripheral factors

Most work on prenatal steroids, endocrine disruptors, and obesity is
focused on peripheral factors, especially glucose homeostasis, lipid
proles, adipose tissue distribution, and adipocyte differentiation,
which can presumably lead to differences in overall energy expenditure
and body fat distribution. In rats, perinatal androgen exposure, for
example, increases body weight and visceral adiposity; serum insulin,
triglyceride, and cholesterol concentrations; hepatic triglyceride content; and in some studies increased insulin resistance (Demissie et al.,
2008). Similar treatments lead to impaired insulin sensitivity and secretion and increased visceral adiposity in monkeys (Bruns et al., 2004;
Eisner et al., 2003), and reduced birth weight and impaired insulin resistance in sheep (Fig. 2, Recabarren et al., 2005).

111

Again, BPA serves as a prime example of an endocrine disruptor that

inuences body weight, adipocyte differentiation, and adipocyte accumulation in specic tissues via action on the ER (Chamorro-Garcia
et al., 2012; Kendig et al., 2012; Lalles, 2012; Liu et al., 2012; Marmugi
et al., 2012; Nadal, 2013; Polyzos et al., 2012; Ronn et al., 2013; Shankar
et al., 2012; Taxvig et al., 2012; Trasande et al., 2012; Vom Saal et al.,
2012; Wang et al., 2012a, 2012b; Wens et al., 2013; Zhao et al., 2012
and reviewed by Vom Saal et al., 2012).
The data are not conned to nonhuman animals. In human populations there is a positive correlation between levels of urinary BPA and
obesity across gender, race, and ethnicity, independent of potential
confounding factors including, smoking, alcohol consumption, and
serum cholesterol levels (Shankar et al., 2012).
Studies in laboratory animals suggest a mechanism of action.
Endocrine disruptors appear to affect growth of preadipocytes,
undifferentiated cells that will eventually develop the gene expression
patterns and metabolic characteristics of an adipocyte, such as the
ability to store triglycerides in lipid droplets. One ER-binding molecule,
for example, 4-nonylphenol, inhibits this process, whereas BPA stimulates this process. The effects of BPA differ depending on the timing of
fetal exposure to those compounds and the energy availability via the
mother's energy balance (Masumo et al., 2002). Nevertheless, these
changes in the adipocyte lead to changes in energy expenditure, storage,
and intake are increased or decreased.
Once the WAT and other cell types (muscle, liver, and brown adipose
tissue (BAT)) are formed, energy expenditure in those cells can be
inuenced by many different transcription factors, including estrogen,
androgen, thyroid, and glucocorticoid receptors. Transcription factors
are molecules that interact with DNA to change which genes are
transcribed and how often. For example, ER- is a ligand-dependent
transcription factor that binds to a segment of DNA on genes known
as the estrogen-receptor-response element (Iwase, 2003; Muramatsu
and Inoue, 2000). The number of known ligand-dependent transcription factors is growing to the point that they have been grouped together as a superfamilya group of approximately 150 members encoded by
at least 48 unique human genes (Brinkmann, 2011; Clark and Belvisi,
2012). Those with particular relevance are the retinoic acid receptors
(retinoic acid receptors, RARs and retinoid X receptors, RXRs), and the
peroxisome proliferator-activated receptors (PPARs), and numerous
orphan receptors (Kliewer et al., 2001; Redonnet et al., 2001). PPARs,
for example, are activated by fatty acids and fatty acid metabolites
(Reddy and Hashimoto, 2001). PPAR and its agonist stimulate hepatic
peroxisome proliferation in response to high levels of dietary lipid, and
PPAR directs adipocyte differentiation (Reddy and Hashimoto, 2001).
RARs, RXRs, and PPARs add another layer to the effects of endocrinedisrupting compounds and provide a link between peripheral metabolism and ingestive behavior (Auwerx, 1999).
How can adipocyte differentiation result in changes in ingestive
behavior? Adipose tissue is not simply one uniform organ, but rather
has at least three types based on the concentration of mitochondria.
WAT has a low concentration of mitochondria in the cytoplasm, hence
its white color. BAT has the highest concentration of mitochonodria,
and beige or gray adipose tissue has an intermediate concentration of
these cellular organelles. The relative proportions of these adipocyte
types determine the metabolic rate and overall energy expenditure;
the more gray and brown fat, the higher the level of fuel oxidation
(reviewed by Bloor and Symonds, 2014). In addition, different types of
adipose tissue are distributed into the different regions of the body.
The WAT around the visceral organs has direct circulatory communication with the gut, liver, pancreas and reproductive organs, is prone to
proliferate during the development of insulin resistance, and produces
more inammatory cytokines. BAT and gray fat is located in subcutaneous depots, and is not associated with symptoms of metabolic syndrome. Thus, PPAR, by virtue of its role in directing adipocyte
differentiation and whether or not the cells become white, brown, or
beige, can potentially control the adult body fat distribution, the rate

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of accumulation of visceral fat, limits of fatty acid oxidation, and other

metabolic sequelae of body fat distribution.
Steroids and endocrine disruptors act via ligand-dependent
transcription factors, such as PPAR, to inuence energy balance and
obesity. For example, tributylin chloride (TBT) is a member of a class
of compounds known as organotins, tetravalent tin compounds found
in marine paints and industrial water works. Its mode of action differs
with dose. At low doses, TBT can activate RXR and PPAR to directly
modulate the activity of genes involved at multiple stages of adipocyte
differentiation. At high doses, TBT can inhibit aromatase activity and
thereby decrease estradiol synthesis and down-regulate ER in some
tissue, while upregulating aromatase in other tissues. At doses that fall
between these high and low doses, TBT inhibits the activity of corticosteroid 11--hydroxysteroid dehydrogenase, leading to decreased inactivation of cortisol, thereby increasing local glucocorticoid levels (Figs. 1
and 2). Elevated glucocorticoid levels, acting at late stages of fetal development can alter adipocyte differentiation (Grun and Blumberg, 2006).
In Mus musculus, TBT is a ligand for RXR and PPAR, promotes adipogenesis in the murine 3T3-L1 cell model, and perturbs key regulators of
adipogenesis in vivo. Prenatal exposure to TBT increases lipid accumulation in newborn mice and these effects persist into adulthood leading to
larger gonadal fat pad weights. In Xenopus laevis, treatment with TBT,
RXR, or PPAR increases the accumulation of gonadal fat (Grun and
Blumberg, 2006). These clear effects of TBT via RXR, PPAR, and steroid
signaling pathways illustrate multiple routes of endocrine disruption
leading to obesity (Figs. 1 and 2).
Linking peripheral metabolism to brain and behavior
It might seem that these peripheral effects of endocrine disruptors
are independent of their central effects on the ARH circuits that control
ingestive behavior. It is possible, however, that effects of steroids and
endocrine disruptors on central feeding circuits are secondary to
peripheral changes in energy expenditure, fuel oxidation, and
lipogenesis. There is solid evidence that increased hunger for food and
overeating can be affected by peripheral events that increase body fat
storage and fuel oxidation (Friedman, 1990, 1998, 2008; Ji et al.,
2005). Furthermore, hunger and food intake are largely controlled by
a metabolic sensory system, or an energostat, that monitors the overall
availability of metabolic fuels, which in turn is a consequence of the ux
of fuels into and out of storage (Friedman, 2008). Food intake can be
reliably increased by decits in the cellular availability of fuels for
oxidation, the process that provides energy for cellular work. Cellular
fuel decits can occur during starvation but also occur in the face of
abundant food availability and/or high levels of body fat storage. An
example occurs in diabetic rats fed a carbohydrate diet. Diabetic rats
are hungry and hyperphagic because without insulin, they are unable
to transport carbohydrate-derived fuels (glucose) into cells where
they can be oxidized. The energostat registers a decit in oxidizable
fuels. This idea is supported by the fact that diabetic rats' hunger and hyperphagia are prevented when they are fed a high fat diet, which provides an alternative fuel (free fatty acids) that can be readily oxidized
in the absence of insulin (Friedman, 1990, 1998, 2008). Similarly, in
obesity-prone individuals in whom body fat is accumulating, the increase in lipogenesis sequesters oxidizable fuels by transforming them
into a chemical form that cannot be oxidized for cellular work (i.e., triglycerides stored in lipid droplets in adipocytes). In obesity-prone individuals therefore, a high proportion of fuels locked in storage
and decreased fatty acid oxidation can lead to intense food craving
and overeating of energy-dense foods. It is hypothesized that obesityprone individuals do not oxidize fat fuels as readily as obesityresistant individuals, and as a result tend to use these fuels in lipogenesis. The slow rate of fat oxidation in obesity-prone individuals leads to
excessive accumulation of dietary fat in adipose tissue, which in turn
leads to overeating in an attempt to compensate for the decreased availability of oxidizable fuels. This hypothesis has been supported by

experiments in which obesity-prone and obesity-resistant rats were

fed high-fat, obesity-inducing diets and treated with fenobrate, a
PPAR agonist that increases fatty acid oxidation (Staels et al., 1998).
This treatment signicantly decreases food intake and body weight in
obesity-prone, but not in obesity-resistant rats, suggesting that the
treatment ameliorated the low fatty acid oxidation characteristic of
obesity-prone rats (Ji et al., 2005). This example provides one of the critical links between altered peripheral lipid disposition and central events
that lead to changes in ingestive motivation and behavior. Whenever
organizational effects of perinatal hormones on ingestive behavior are
discovered, it is important to ask whether or not the effects are secondary to changes in energy expenditure and adipocyte morphology. This is
not so much a chicken and egg question as a testable hypothesis.
Maternal programming of adult energy balancing traits
Another piece of the obesity puzzle is the large body of research on
epigenetics and maternal programming of metabolism and cardiovascular health. The explosion of research in this area gives the impression
that this is a new eld of research, but in reality, it dates back to the mid
20th century. During the devastating famine that resulted from the
German occupation of Holland in World War II known as the Dutch
Hunger Winter, mothers who experienced starvation during the rst
two trimesters of pregnancy gave birth to sons with a signicantly
higher incidence of adult obesity compared to those of well-fed mothers
(Ravelli et al., 1976). Subsequently, other physicians and scientists
noted effects of 1) adolescent nutrition on adult health, 2) maternal
undernutrition on offspring health, and even 3) grandparents' nutrition
with transgenerational effects on their grandchildren's adult health
(Barker, 1997; Forsdahl, 1978; Lumey and Stein, 1997). Most of these
latter studies concerned cardiovascular health and diabetes, but they
set the stage for examination of maternal programming of body weight
and adiposity.
Using laboratory rats as a model system, Jones and Friedman, 1982
and Jones et al. (1984, 1986) tested the hypothesis that maternal food
restriction during the rst two weeks of pregnancy programs obesity
in the offspring. They found that male, but not female offspring of
food-restricted mothers gained weight and became obese as adults,
whereas the females showed disordered adipose tissue cellularity. Obesity was exaggerated in male offspring fed a calorically dense diet, and
diet-induced obesity occurred without increased caloric intake, implicating changes in energy metabolism and lipogenesis. These results
from behavioral endocrinology experiments of the 1980s are rarely recognized by researchers in the elds of obesity, diabetes, and cardiology,
but now, we know from many subsequent studies that energy metabolism is profoundly inuenced by the experiences of the mother, including her diet, exercise requirements, ambient temperature, and many
other environmental stressors. In rats, mice, and sheep, prenatal calorie
or protein restriction leads to low birth weight, usually followed by a period of rapid catch-up growth and body fat deposition, followed by
adult obesity (Armitage et al., 2004; Bol et al., 2009; Bouret, 2010; de
Oliveira et al., 2012; Holemans et al., 2003; McMillen et al., 2005; Ross
and Desai, 2005; Symonds et al., 2004; Vickers et al., 2003). Prenatal undernutrition in pregnant women leads to low birth weight newborns. If
these babies are allowed to eat as much as they want, they gain weight
rapidly during lactation. Catch-up growth is exaggerated in formula-fed
compared to breast-fed babies, and both groups from undernourished
mothers are prone to develop metabolic syndrome, insulin resistance,
cardiovascular disease, and obesity as adults (Desai et al., 2005, 2007;
Eriksson et al., 1999).
In some, but not all model systems, the effects on obesity and
cardiovascular disease occur in offspring of both undernourished and
overnourished mothers (Armitage et al., 2004; Symonds and Gardner,
2006; Vickers et al., 2000). In nonhuman primates such as the
Japanese macaque, mothers fed a high fat diet overeat, gain body fat,
and give birth to offspring that develop altered expression of genes

J.E. Schneider et al. / Hormones and Behavior 66 (2014) 104119

that encode putative orexigenic and anorectic peptides, increased circulating cortisol concentrations, and increased proinammatory signals.
Furthermore, as adults the offspring develop preferences for high fat
diets (reviewed by Wilson et al., 2014). Furthermore, the obesity of offspring of overnourished mothers can inuence the subsequent generations (Lumey and Stein, 1997; Sullivan et al., 2014; Taylor and Poston,
2007). It might seem paradoxical that both undernutrition and overnutrition have a similar effect on offspring. This is less surprising when we
remember that some organisms that are predisposed to excess lipogenesis also experience a decit in the availability of oxidizable fuels that
can lead to overeating. As explained earlier in this review (see the section on "Linking peripheral metabolism to brain and behavior), having
an abundance of adipose tissue and lipids stored inside adipocytes is
not the same as having an abundance of oxidizable fuels readily available for cellular work.
This line of research is promising, yet, we seem to have lost sight of
the original nding in rats (Jones and Friedman, 1982), which included
a profound sex difference: The susceptibility to diet-induced obesity in
rats occurred mainly in the male pups of mothers food restricted during
the rst two weeks of pregnancy, whereas in female pups, there were
changes in adipocyte architecture but not in the propensity for dietinduced obesity. This suggests that the eld of maternal programming
must meld with the study of sexual differentiation.
In fact, adult exposure to a calorically-dense diet in adulthood, perinatal androgen exposure, and maternal undernutrition all have similar
effects on cardiovascular health embodied by what is referred to as
the metabolic syndrome; all three produce enlarged mesenteric
adipocytes, an atherogenic lipid prole, insulin resistance, hyperglycemia, and a predisposition to overeat a calorically-dense diet (Demissie
et al., 2008; Manikkam et al., 2004). Furthermore, maternal energy
balance and prenatal testosterone interact to amplify the masculinization of the luteinizing hormone-surge system (Steckler et al., 2009).
Thus, it is important to ask whether maternal energy availability interacts with prenatal hormones to change adult energy balance.
Understanding the mechanisms of sexual differentiation will be
imperative to understanding maternal programming, because these processes overlap. Just as energy balancing characteristics can be
programmed by perinatal steroid action, they can be similarly affected
during perinatal development by other hormones originating from the
fetus. Some of these hormones respond to the availability of oxidizable
fuels or modulate the availability of those fuels, including leptin (Bouret
et al., 2004b). Animals homozygous for mutations in the gene that encodes leptin (Lepob/Lepob mice) are hyperphagic, obese, and diabetic.
Lepob/Lepob mice lack the spike in leptin secretion that normally occurs
during the rst week after birth of wild type mice, and develop decits
in the hypothalamic neural projections from the ARH to the PVH, DMH,
and LH. When Lepob/Lepob mice are treated with leptin during a critical
window of ARH development (postnatal days 412), the decits in ARH
projections are fully reversed and the obesity is ameliorated (Bouret
et al., 2004b). The same treatment in adult Lepob/Lepob mice fails to affect
ARH projections, suggesting that leptin acts neonatally as a neurotrophic
factor to determine the fate of these particular neural structures involved
in adult energy balance. If the process whereby leptin organizes ARH projections is analogous to the process whereby gonadal hormones organize
the neural substrates for male- and female-typical sex behaviors, then
perinatal leptin surges might render the brain more sensitive to adult effects of leptin, and this effect might be sex-specic. This has not been directly tested to the best of our knowledge. In fact, in the above-mentioned
study, it is not clear whether the subjects were male or female. In the online supplementary material it is specied that males were used in the
control group, but the sex of the experimental animals was not
specied. In a parallel study, males and females were not different, and
were thus combined into age groups in order to characterize the temporal
sequence of development of ARH projections. In another part of the study
aimed at understanding ARH activation in response to leptin treatment,
the sexes were not shown separately (Bouret et al., 2004a).

113

A
Maternal
programming

Sexual
differentiation
D
B

Endocrine
disruptors

Fig. 3. A Venn diagram of the interface of sexual differentiation, endocrine disruptor

action, and maternal programming of energy balancing traits. At interface A, perinatal
hormones program fetal energy balance, and the effects of hormones differ with the
mother's energy balance. Furthermore, both maternal programming and sexual differentiation might have different effects depending on the genetic sex of the fetus. At interface
B, both endogenous hormones and endocrine disruptors that mimic hormones, bind to
steroid receptors and either masculinize, defeminize, or actively feminize energy
balancing traits. At interface C, endocrine disruptors enter the mother and cross the
placenta to alter effects of the mother's energy balance on the fetus. At the three-way
interface D, there are many possibilities, e.g., both estradiol and leptin are secreted by
the fetus and the mother, and both can act via STAT3 signaling to organize energy
balancing circuits perinatally, and being vulnerable to estradiol, these circuits might also
be vulnerable to estrogenic endocrine disruptors such as DES, DDT, or BPA. One interesting
question is whether altered sexual differentiation by endocrine disruptors differs with
maternal energy availability. Figure by Jay Alexander.

We now know that organizational effects occur in adults. In adult

brains, short-term reversible effects involve restructuring, death, and
rebirth of neurons (Kokoeva et al., 2005; McNay et al., 2012). This is
true with regard to hormonal remodeling of putative energy balancing
systems of the ARH. In adult mice, for example, central leptin treatment
can rapidly rewire the POMC circuitry in terms of the ratio of excitatory
to inhibitory synapses on neuropeptide Y and POMC-containing cells in
the ARH (Pinto et al., 2004). What's more, and relevant to this review,
these rapid rewiring effects are mimicked by estradiol, even in Lepob/
Lepob mice. Like the effects of leptin, the effects of estradiol on synaptic
rewiring occur via STAT3 signaling (Gao et al., 2007). This provides a
quantiable locus for investigation, i.e., a structural component of the
nervous system where estradiol, leptin, and energy availability interface
during sexual differentiation/fetal programming. Furthermore, it
implicates estradiol as an agent capable of acting in the absence of leptin
but via the STAT3 system to rewire circuits in the ARH (Fig. 3).
These experiments provoke other interesting questions. Can perinatal leptin ameliorate obesity in ER knockout mice? How does prenatal
leptin action affect later response to adult leptin, ghrelin, testosterone,
estradiol, or progesterone? Is perinatal leptin acting as an active feminizing agent in the manner of postnatal estradiol, or as a masculinizing
agent in the manner of prenatal estradiol and testosterone? Which
comes rst, organization of the brain or periphery? Do early hormonal
effects produce energetic decits similar to those produced by maternal
food restriction? Does maternal food restriction cause changes in perinatal hormones or sensitivity to hormones?

Epigenetics and transgenerational effects on energy balance

Effects of natural transcription factors and endocrine disruptors can
have transgenerational effects, i.e., outcomes that are inherited from
parent to offspring in successive generations. Two ways that this
might occur are by imprinted germline epimutations and by genetic

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J.E. Schneider et al. / Hormones and Behavior 66 (2014) 104119

accommodation, two processes that can change population phenotypic

distribution without changing DNA (deoxyribonucleic acid) sequences.
Epigenetic transgenerational effects are inherited via germline
epimutations, a change in gene expression that does not alter the basepair sequence of the DNA (reviewed by Skinner et al., 2011). These
changes in gene expression are passed from parent to offspring and
can lead to adaptive or maladaptive changes in physiology and
behavior. As with the endocrine-disrupting compounds discussed
already, those that cause epigenetic transgenerational effects have sexspecic effects that depend on the developmental stage of the subject.
The mechanisms involve sex-specic DNA methylation. Thus, endocrine
disruptors that mimic ligand-dependent transcription factors might
have germline epigenetic effects on energy balancing traits, which
might ultimately increase the rate of phenotypic change over generations. For example, fetal exposure to TBT (with endocrine disrupting potential via PPAR) increases adipose tissue weight, adipocyte number,
and adipocyte size, reprograms multipotent mesenchymal stromal
stem cells to favor the adipogenic lineage at the expense of the osteogenic lineage, induces hepatic lipid accumulation, and upregulates the expression of genes involved in lipid storage, transport, and lipogenesis in
the F1F3 generation offspring to TBT treated mothers (ChamorroGarcia et al., 2013). In another study, fetal exposure to a mixture of
BPA and two other estrogenic plastic-derived endocrine disruptors,
bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP), caused
obesity and testis disease in males, and primary ovarian insufciency and
polycystic ovaries in the F3 generation female offspring (Manikkam et al.,
2013). These effects were sex- and generation-specic. The incidence of
testis disease in males and the ovarian disease in females was highest in
the F3 generation. Obesity was signicantly increased in the F3
generation females descended from the endocrine-disruptor treated
subjects, but in F3 males this only reached the level of a statistical
trend. Furthermore, female obesity was not observed in the directly
exposed F1 generation, but only in the F3 generation (Manikkam et al.,
2013). In summary, transient exposure to these agents during a brief
perinatal time window had marked effects on the F3 generation.
Another process that induces transgenerational population change
is known as genetic accommodation, a process that is generally adaptive
(West-Eberhard, 2003). It has long been suspected that novel environmental stressors initiate the transcription of heretofore untranscribed
genes, thereby increasing genetic variability that has been hidden in
the previous, less stressful environment. Hidden or cryptic genetic variation is genetic variation that is absent when measured under natural
conditions, but is revealed under special circumstances, e.g., when a
population runs out of its usual food source and survives by eating a
novel food. When new variation is revealed, new opportunities emerge.
Newly revealed genetic variation provides the fresh possibility that at
least some of the new phenotypes will be adaptive for consuming the
novel resource. If one or some of the newly revealed phenotypes are
adaptive, selection can shift the frequencies of the phenotype rapidly
in a process known as genetic accommodation (West-Eberhard,
2003). Thus, the unmasking of cryptic genetic variation can lead to
rapid phenotypic changes over only a few generations.
Now there is evidence that genetic accommodation can happen with
regard to energy balancing traits, and that genetic accommodation can
be mediated by changes in diet and/or increases in stress hormones
(Ledon-Rettig et al., 2010). Tadpoles of spadefoot toads of the genus
Spea have been used to demonstrate the presence of cryptic variation.
Ledon-Rettig et al. (2010) hypothesized that environmental changes,
such as the availability of a particular macronutrient, can increase glucocorticoids or its receptors, induce novel patterns of gene transcription, increase genetic variability, and create changes in gene frequencies that
underlie phenotypes related to ingestive behavior (e.g., gut length, developmental speed, and growth rate). They noticed that most species
of spadefoot toad subsist entirely on plants and detritus, whereas
other, newer species catch and eat live animal prey, and wondered
whether the change to a carnivorous diet might have involved genetic

accommodation. Genetic variability in a suite of ingestive traits was compared in different groups of plant/detritus-eating tadpoles. Broad-sense
heritabilities (amount of total genetic variance) were compared in 1)
tadpoles fed ancestral (plant/detritus) diets, 2) tadpoles fed carnivorous
diets, or 3) tadpoles fed the ancestral diet and treated with exogenous
corticosterone. In the species used as a proxy for the ancestral species,
Scaphiopus couchii, the carnivorous diet and corticosterone treatment
signicantly increase the genetic variance in traits related to ingestion.
Thus, both the new diet and the increase in stress hormones can unmask
genetic variation in a population, presumably allowing transgenerational
changes that would not have occurred otherwise.
Though both treatments increased genetic variation, the nature and
direction of the change in genetic variation differed between these two
treatments. One possibility to explain the difference between the carnivorous diet and the corticosterone treatment is that hormonal effects
differ depending on the energetic or nutritional background. Hormonal
interaction with energy availability might have played a critical role in
rapid population changes over generations (Ledon-Rettig et al., 2010).
If diet changes and glucocorticoids can unmask cryptic genetic
variation in toads, might changes in human diets and exposure to endocrine disruptors over the course of evolution also induce new genetic
variability leading to rapid changes in energy balancing phenotypes?
Can endocrine disruptors acting through glucocorticoid or other receptors also unmask cryptic variation? Alternatively or in addition, have
endocrine disruptors had widespread transgenerational epigenetic
effects that led to rapid population changes in energy balancing phenotypes? It is plausible that endocrine disruptors are altering or guiding
the rate of change in traits related to diabetes and obesity. The startling
implication is that might underlie the sharp increase in the incidence of
obesity and metabolic syndrome, not by acting on adults, but by acting
on the developing offspring, changing gene expression, exposing hidden genetic variation, thereby accelerating the rate of phenotypic
change over generations.
This might also provide a partial explanation for the nding that
laboratory rodents that were switched from traditional laboratory diets
containing high levels of phytoestrogens to a phytoestrogen-free diet become obese (Ruhlen et al., 2008). Until recently, all commercial laboratory
chow diets are produced with soy as the primary ingredient, which contains high levels of phytoestrogens. Scientists interested in the effects of estradiol on various physiological and behavioral traits have recently
switched to phytoestrogen-free diets in order to control for steroid exposure in their experimental and control groups. The unexpected result,
however, was the development of obesity and various reproductive abnormalities in the control animals fed the phytoestrogen-free diets. This phenomenon suggests that, as soy-based laboratory rodent chows have
become the norm, laboratory populations of animals have become adapted
to regular exposure to endocrine disrupting phytoestrogens, and thus,
when experimenters attempt to exercise control of estrogenic exposure
by feeding phytoestrogen-free diets, their animals experience abnormalities related to energy balance and reproduction. The ubiquity of soybased products in standard laboratory chow occurred in a relatively
short time frame (by evolutionary standards), but the phenomenon of
transgenerational epimutations and genetic accommodation provides
a mechanism that might account for these rapid population shifts.
The focus by Ledon-Rettig on genetic variation in characteristics
of the gut may be prescient in that it encompasses new data demonstrating effects of gut ora on energy balance (Turnbaugh et al., 2006).
Endocrine disruptors and perinatal steroids can inuence the favorability
of the gut environment for proliferation of obesogenic versus
obesoresistant microorganisms (Lalles, 2012). Adaptation of laboratory
species to phytoestrogen-containing diets might involve changes in
populations of microorganisms that inhabit the gut and inuence
energy storage and expenditure.
The above considerations are admittedly speculative, but more
importantly, they lead to valuable hypotheses that can be tested
if we merge the concepts of sexual differentiation to the study of

J.E. Schneider et al. / Hormones and Behavior 66 (2014) 104119

epigenetics/maternal programming of energy balance by dietary,

energetic, and environmental endocrine factors.

Summary, conclusions, and future directions

We have provided evidence that genetics, diet, and sedentary
behavior cannot fully explain the sharp rise in human obesity that
occurred in the last century, and bring attention to the interface of endocrine disruptors in the environment, maternal programming, and
sexual differentiation as a factor that underlies the rising incidence of
obesity (Fig. 3). The foundation for this assertion is based on four
main pieces of evidence. The presence of endocrine disrupting compounds has been on the rise since the end of Word War II; these compounds are now ubiquitous in the environment (Baillie-Hamilton,
2002; Colborn et al., 1993; Simonich and Hites, 1995); and they have
a plethora of effects on energy balancing systems (Heindel, 2003;
Mackay et al., 2013; Newbold et al., 2005; Oken and Gillman, 2003;
Ruhlen et al., 2008; Vom Saal et al., 2012). Furthermore, energy
balancing phenotypes are sexually dimorphic in humans, and the
masculine phenotype is most closely linked to metabolic diseases such
as type II diabetes and heart disease (Bonora, 2000; Kotani et al., 1994;
Lemieux, 2001; Macotela et al., 2009; Wajchenberg, 2000). Finally, endocrine disruptors have masculinizing effects on sexually dimorphic
phenotypes, and might also act through other dened mechanisms of
sexual differentiation, such as active feminization.
The inextricable link between energy balance and reproduction is well
known and has been the topic of many reviews in the past three decades
(Schneider et al., 2012; Schneider et al., 2013; Wade and Jones, 2004;
Wade and Schneider, 1992). If endocrine disruptors interfere with processes involved in reproduction, it follows that they might interfere
with those involved in energy balance. Each endocrine disruptor is likely
to have different effects depending on whether it agonizes or antagonizes growth hormone, estrogen, androgen, or glucocorticoid receptors
(Figs. 1 and 2). These in turn might occur via the different types of steroid action: classical, genomic; nonclassical, nongenomic; and nonclassical, genomic hormone actions. In fact, in this review, we provided a
few concrete examples demonstrating that the effects of endocrine
disruptors on energy balancing traits involve masculinization, active
feminization, aromatization, and hormone action at multiple critical
periods.
Investigators that study the effects of endocrine disruptors on
peripheral processes often work in isolation from investigators that
study the neural circuits for ingestive behavior. Examples were
provided in this review to illustrate that peripheral changes, such as
agonism of PPARs, lead to changes in ingestive behavior (Ji et al.,
2005). Future work should take up the search for the energostat, and
design experiments to determine whether endocrine disruptors might
inuence the development of hyperphagia, high caloric diet-induced
obesity, and metabolic syndrome via ligand-dependent transcription
factors involved in fatty acid oxidation and lipogenesis.
New information on the epigenetic effects of endocrine disruptors,
their overlap with fetal programming, and their potential for unmasking
cryptic genetic variation provide a plausible basis for hypothesizing that
endocrine disruptors are responsible for the rapid increase in obesity at
the end of the last millennium. This perspective melds ideas from the
sciences concerned with the most proximate with those concerned
with the most ultimate causes of physiology and behavior. Leaders in
the eld of neuroendocrinology agree that understanding the signicance of endocrine disruptors requires collaborative efforts that blend
the knowledge and expertise of many biological disciplines and government agencies (Balthazart and Levine, 2014; Crews and Gore, 2011;
Gore et al., 2014; Vandenberg et al., 2013; Zoeller et al., 2012). The authors of this review concur with this perspective and extend it to include experts in neuroendocrinology of ingestive behavior, energy
balance, and obesity.

115

Acknowledgments
The authors gratefully acknowledge gures drawn by Jay Alexander,
inspiration from conversations with Jon Levine, and the insightful
comments on the manuscript from Mark I. Friedman, Deborah Clegg,
Samantha Hanna, and Melynda Dalzon. This work was supported by
research grant IOS-1257876 from the National Science Foundation.

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