Review
Our stolen figures: The interface of sexual differentiation, endocrine disruptors, maternal programming, and energy balance
- Under a Creative Commons license
Open Access
Highlights
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- Endocrine disruptors are ubiquitous in the environment and affect energy balancing systems.
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- Energy balancing phenotypes are sexually dimorphic.
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- Endocrine disruptors interfere with sexual differentiation.
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- Maternal programming and other epigenetic effects disrupt similar processes.
Abstract
This article is part of a Special Issue “Energy Balance”.
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
influence 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 influences, 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 influence global changes in
energy balancing traits.
Keywords
- Adiposity;
- Ingestive behavior;
- Obesity;
- Food intake;
- Bisphenol A;
- Diethylstilbestrol
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, Flegal et al., 2002, Flegal et al., 2010, Ogden et al., 1997, Ogden et al., 2006 and Ogden et al., 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 significant changes in obesity prevalence
in youth or adults between 2003–2004 and 2011–2012. 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 and Ogden et al., 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 influences,
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
energy-balancing 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 significance 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 defined 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 and 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 and Vom Saal et al., 2012).
Third, 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 and Wajchenberg, 2000).
Fourth, endocrine disruptors have masculinizing effects on sexually
dimorphic phenotypes, and might also act through other defined
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 and Tracey et al., 2013), and their potential for unmasking cryptic genetic variation (Ledon-Rettig et al., 2008, Ledon-Rettig et al., 2009 and Ledon-Rettig et al., 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.