YHBEH-03717; No. of pages: 6; 4C: Hormones and Behavior xxx (2014) xxx–xxx
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Editorial
Guest editor's introduction: Energy homeostasis in context Jill E. Schneider ⁎ Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015, United States
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Available online xxxx
This article is part of a Special Issue “Energy Balance”.
Keywords: Adiposity Body weight Energy expenditure Food intake Hibernation Ingestive behavior Migration Reproduction Sex behavior Sex differences
Energy homeostasis is achieved through neuroendocrine and metabolic control of energy intake, storage, and expenditure. Traditionally, these controls have been studied in an unrealistic and narrow context. The appetite for food, for example, is most often assumed to be independent of other motivations, such as sexual desire, fearfulness, and competition. Furthermore, our understanding of all aspects of energy homeostasis is based on studying males of only a few species. The baseline control subjects are most often housed in enclosed spaces, with continuous, unlimited access to food. In the last century, this approach has generated useful information, but all the while, the global prevalence of obesity has increased and remains at unprecedented levels (Ogden et al., 2013, 2014). It is likely, however, that the mechanisms that control ingestive behavior were molded by evolutionary forces, and that few, if any vertebrate species evolved in the presence of a limitless food supply, in an enclosed 0.5 × 1 ft space, and exposed to a constant ambient temperature of 22 + 2 °C. This special issue of Hormones and Behavior therefore contains 9 review articles and 7 data articles that consider energy homeostasis within the context of other motivations and physiological processes, such as early development, sexual differentiation, sexual motivation, reproduction, seasonality, hibernation, and migration. Each article is focused on a different species or on a set of species, and most vertebrate classes are represented. Energy homeostasis is viewed in the context of the selection pressures that simultaneously molded multiple aspects of energy intake, storage, and expenditure. This approach yields surprising conclusions regarding the function of those traits and their underlying neuroendocrine mechanisms. © 2014 Published by Elsevier Inc.
Introduction
“…rats and mice used in biomedical research are sedentary, obese, glucose intolerant, and on a trajectory to premature death” [Martin et al., 2010] For many years, energy homeostasis has been studied using methods that have afforded a great deal of experimental control but may have warped or limited our understanding. Most biomedical research is conducted in a small number of laboratory species housed under constant, standardized conditions, including static ambient temperature and day length, and widely-used commercial diets. The control groups are typically provided with an unlimited supply of food, and all subjects are housed in isolation from opposite-sex conspecifics or predators in relatively small, enclosed spaces. The underlying assumption seems to be that animals make decisions about when, what, and how
⁎ Department of Biological Sciences, 111 Research Drive, Bethlehem, PA 18015, United States. Fax: +1 610 758 4004. E-mail address: [email protected].
much to eat in the absence of potential mating partners, competitors, predators, and family members. Among the many studies of ingestive behavior published in biomedical journals, an overwhelming majority of those experiments used mice or rats housed under these conditions (Ebling, 2014; Martin et al., 2010). Furthermore, the subjects are most often male, with no consideration given to females (Beery and Zucker, 2011). The obvious advantages of these well-worn practices include 1) a high degree of experimental control over relatively inexpensive experimental subjects with short lifespans and generation times; 2) standardized conditions that minimize error variance and facilitate collaboration, cross-laboratory comparisons, and meta-analyses; and 3) the ability to identify many different hormones and neuropeptides that influence energy intake, storage, and expenditure. The benefits, however, can turn into liabilities if standardized, artificial conditions obscure the reality of hormone– behavior relations as they exist in nature. Furthermore, mice and rats housed in standard laboratory conditions with ad libitum access to laboratory chow are overweight, insulin resistant, hypertensive, hyperglycemic, hyperinsulinemic, and hyperleptinemic (reviewed by (Martin et al., 2010)). The question then is not “Why should we study other species in a more relevant context?” but rather, “Why are we still studying male
http://dx.doi.org/10.1016/j.yhbeh.2014.05.001 0018-506X/© 2014 Published by Elsevier Inc.
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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mice and rats living 24-7 at the all-you-can-eat buffet and calling them ‘the control group?’”. Regular readers of Hormones and Behavior are likely familiar with the limitations of studying animals confined to small enclosures. We need only remember the erroneous assumptions that were reinforced when female sex behavior was studied in rats or monkeys in small testing arenas with a single male conspecific, and the way that the dogma was shattered when females were housed in larger arenas with multiple conspecifics, and when female motivation was examined separately from that of the male (reviewed by Erskine, 1989; Wallen, 1990, 2001). A similar situation exists in the field of energy homeostasis, but we have not broken out of the traditional mode, and we are suffering the consequences. Despite enormous progress in identifying new neuropeptides and peripheral hormones that influence energy homeostasis (reviewed by (Schneider et al., 2013; Sohn et al., 2013), the global prevalence of obesity is still at its highest level in recent history (Ogden et al., 2013, 2014). It has been almost two decades since the watershed discovery of leptin, the adipocyte protein encoded by the ob gene (Zhang et al., 1994), and yet we still lack successful therapeutic treatments that ameliorate or prevent obesity. One obstacle to progress might be the erroneous picture that is painted by studying homeostatic variables in isolation from the selection pressures that molded them. The mechanisms and function of the traits involved in energy homeostasis appear in a new light when animals of both sexes are considered within the context of development, opposite-sex conspecifics, fluctuations in food availability, ambient temperature, and day length. Readers of this special issue are in for an upgrade if not a total transformation of their understanding of energy homeostasis. In these articles, energy intake, storage, and expenditure are viewed within the context of reproduction, seasonality, migration, and development, and in some cases the articles consider the interactions among these factors. Within these articles, there are representative species of mammals, birds, reptiles, amphibians, and fish. Mice and rats are not excluded, but where they are included, they are studied in relation to reproduction or sexual differentiation. The penultimate review article is concerned with sex differences in energy homeostasis, primarily white adipose tissue (WAT) distribution, in our own species. Each of these articles contains surprising conclusions about the mechanisms that underlie energy homeostasis. When viewed as a group, these articles compel us to face the true meaning of energy “homeostasis” and to more closely define the words “regulate” and “control.” The word homeostasis stems from the Latin words for staying “similar to,” not “the same as,” and thus it implies some degree of fluctuation as well as maintenance within a range of values (reviewed by (Friedman, 2008). These central points of equilibrium might change somewhat over the lifespan, during periods of growth, during different reproductive stages, and in response to changes in the environment. Examples of variables that must be maintained in relatively tight homeostasis include body temperature (in homeotherms), blood pH, and the intracellular availability of oxidizable metabolic fuels. Thermotaxis is controlled (not regulated) in service of regulating body temperature, i.e., maintaining body temperature homeostasis. If your body temperature were to rise above 107 °C (or your blood pH rises above 8.0) you would be in trouble. For you, the only alternative to tight regulation of these variables is death. By contrast, excess levels of food intake or a high percentage of WAT can be tolerated for months or years prior to any major effect. In fact, survival often depends on the ability to increase food intake and accumulate WAT stores. This is because all cellular processes require a continuous supply of metabolic fuels, but energy is not continuously available in the environment. Most animals evolved in habitats where energy was not continuously available (Bronson, 1989), and survival in such environments often required anticipatory overeating and WAT accumulation as a buffer against future energy shortages. Periods of food scarcity coupled with high-energy demands are accompanied by
hydrolysis and mobilization of fuels from lipids stored in WAT and loss of body weight and overall levels of body fat. To defend a particular level of body fat content in the face of low food availability and high energetic demand would be a fatal mistake. Survival requires that we allow the level of body fat to fall as we use the fatty acids derived from those fat stores to fuel essential cellular processes. Another fatal mistake would be to defend a particular level of body fat content instead of accumulating body fat in preparation for future food shortages or impending periods of high energy demand when feeding is not continuously possible; e.g., migration. This concern for future food scarcity might be hard for first-world academics to imagine, but it would not be an unusual scenario for most wild animals or for the early hominids from which we evolved (Brown and Konner, 1987; Pennington, 2001). This explains why this special issue concerns energy homeostasis, not body weight homeostasis. A common feature in vertebrates is that body fat content and food intake are controlled (not regulated) in service of the regulated homeostatic variable: the availability of oxidizable fuels (Friedman, 2008). In response to such realities, it has been suggested that we replace the term “homeostasis” with “rheostasis” or “allostasis” (McEwen and Wingfield, 2003; Mrosovsky, 1990). Perhaps the best example is the control of energy intake, storage, and expenditure in service of reproductive success. Review articles Energy homeostasis in the reproductive context In the first group of articles, we learn that energy intake, storage, and expenditure are controlled so the high energetic cost of female reproduction can be paid from the females' bank account or insurance policy. The bank account is often filled in advance of the metabolic challenge by increased food intake and the accumulation of body fat and/or external food caches. Instead of defending a low-medium body weight, females of many species will overeat or hoard food weeks or months in advance of mating. Furthermore, instead of maintaining some sort of homeostasis in food intake, females of many species increase their food intake, sometime three or more fold, during lactation (reviewed by (Schneider et al., 2013)) or posthatching (e.g., Koch et al., 2002, 2004; Ramakrishnan et al., 2007; Strader and Buntin, 2003). In times of food shortage or high energy demand, energy can be conserved for those processes necessary for survival, and thus, metabolic challenges can inhibit every aspect of the hypothalamic-pituitary-gonadal (HPG) system. The primary effect, however, is on the gonadotropinreleasing hormone (GnRH) pulse generator (reviewed by Wade and Schneider (1992)). In this way, the systems controlling energy homeostasis and reproduction are reciprocally linked. Virtually every hormone or neuropeptide that controls ingestive behavior also controls reproduction, and it is difficult to understand energy homeostasis except in the context of reproduction (reviewed by Schneider et al. (2013)). 1. Nicole Bellefontaine and Carol Elias review an excellent example of this link between energy homeostasis and female reproduction. Mice with mutations in the gene that encodes the adipocyte protein, leptin are both obese and infertile, and the obesity and infertility are ameliorated by treatment with leptin. In strains of mice that lack the functional leptin receptor, obesity and infertility are ameliorated with genetic restoration of leptin receptors restricted to neurons (reviewed by Donato et al. (2011)). This leads to an interesting question. Is the infertility secondary to the obesity? Members of the Elias laboratory answered this question using viral vector delivery and the Cre/loxP system. Whereas large body of data using traditional neuroanatomical methodologies has implicated kisspeptin cells in the arcuate as targets of leptin-induced effects on GnRH cells, the Elias laboratory refutes this idea. Rather, they demonstrate that leptin can reverse the effects of fasting on the HPG system via action in the ventral premammillary
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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nucleus (PMv). This is fascinating because this brain area is responsive to olfactory cues, and contains both estrogen and leptin receptor, and projects to GnRH cells. These and other findings reviewed by Bellefontaine and Elias open the door to unexplored possibilities. For example, future work might combine genetic manipulations with manipulations of metabolic fuel availability and/or energy expenditure. This work is so far restricted to the role of leptin control of the HPG system, but does not rule out direct control by the availability of fuels or by other hormones such as ghrelin. Given the importance of the PMv, it will be interesting to include observations of sex and courtship behavior, appetitive aspects of ingestion, and other olfactory mediated behaviors in ovariectomized females brought into estrous with exogenous hormone treatment. 2. Iain Clarke provides a heroic review of energy homeostasis and reproduction in ruminants with particular attention to sheep. His clear description of the ruminant HPG system illustrates the need to elucidate the basic biology of the estrous cycle in order to fully understand metabolic control of female reproduction. For example, we lack a clear understanding of the molecular and neurophysiological mechanisms that generate pulsatile GnRH secretion and mediate negative and positive steroid feedback on the brain and pituitary. Understanding these processes, particularly the role of kisspeptins (Kp) and gonadotropin-inhibiting hormone (GnIH), will be critical because changes in the availability of metabolic fuels influence GnRH sensitivity to steroid feedback , and Kp and GnIH, but not GnRH cells contain steroid receptors . It should be noted here, that whereas Bellefontaine and Elias restricted their review to leptin control of the HPG system, there is still reason to examine environmental control of the HPG system by metabolic fuel availability and other hormones using other model systems. One principle that arises from the Clarke review is that the so-called “appetite regulatory peptides” are not just for ingestive behavior any more. They are major players in control of reproduction. In this way, the metabolic control of reproduction in ruminants shares much in common with that of rodents and primates, but these large animals allow the experimenter to take the research a step further, to observe acute changes in pulsatile gonadotropin and GnRH secretion in response to environmental manipulations. For example, using these methodologies, the Clarke and Schneider laboratories discovered that in sheep food-resticted to the point of hypogonadotropism, restoration of the HPG system by re-feeding or infusion of metabolic fuels does not require an increase in circulating levels of leptin. 3. Scott Davies and Pierre Deviche review the metabolic control of reproduction in birds. Most of this work comes from an ecological perspective that highlights the allocation of energy toward reproductive success and survival in environments where energy supply and demand fluctuate. As in sheep and rodents, the HPG system in birds is dependent upon food availability, and body weight is not defended at low levels prior to the breeding season. To the contrary, a period of massive hyperphagia and body weight gain anticipate or accompanies the breeding season, such as during the well-known period of parental hyperphagia (Koch et al., 2002, 2004; Ramakrishnan et al., 2007; Strader and Buntin, 2001, 2003) . When wild populations are compared across years or within a year across habitats that differ with respect to environmental food availability, we find that this variable is significantly correlated with reproductive success. Davies and Deviche bring us up to date on the role of hormones and neuropeptides in mediating the effects of energy availability on reproduction in birds. This field of research is in its early stages, and there is room for more research on male and female reproductive physiology and behavior in response to manipulations of energy availability, photoperiod, and ambient temperature. In some of the above-mentioned review articles, both homeostasis and reproduction are placed in the seasonal context. In seasonal species,
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the day length often provides a reliable predictor of the coming increase in food availability in the environment, allowing these species to time their matings so that the offspring are born in an environment of energy abundance. This is currently of enormous importance because the data show that some populations have become increasingly out of synch with the availability of food for their young due to climate change. Energy homeostasis in the seasonal context Just as females must anticipate potential food shortages by overeating and storing body fat or food in their homes, caches, or burrows, so also must temperate zone animals of both sexes anticipate harsh seasons when food availability is low and energy demands for thermogenesis are high. Thus, the next two articles explore energy homeostasis in seasonal animals. 1. Fran Ebling, with exceptional clarity, reviews energy homeostasis in mammalian species that undergo natural seasonal cycles of over and under-eating and fat deposition and catabolism. We find that the Ebling and Barrett laboratory groups have made great strides toward understanding the central mechanisms that underlie these seasonal changes in physiology and behavior. Readers may be surprised to find that these mechanisms are distinct from the hypothalamic neuropeptide systems purported to control body weight and fat content in laboratory mice and rats. The Ebling and Barrett groups find no support for the idea that seasonal cycles of body weight and food intake are controlled by leptin receptors acting on orexigenic and anorectic neuropeptide systems in the arcuate nucleus of the hypothalamus. Not only are the key neuropeptides systems not in the arcuate nuclues, they are not even in neurons. In this unique and insightful review, Ebling predicts that when we gain an understanding of how altered thyroid milieu controls neurogenesis and plasticity, we will be able to envision new avenues of translational research aimed at preventing and reversing obesity. 2. Craig Willis and Alana Wilcox study energy homeostasis in the context of hibernation, periods of reduced body temperature and metabolic rate that can last from days to weeks. In the bat species that they study, mating occurs in the fall and early winter prior to hibernation, and females store the sperm or delay implantation of embryos until spring when they might become officially pregnant, an event that is stamped for approval by high levels of body fat. Entry and exit from hibernation or torpor are controlled by neuroendocrine mechanisms acting on many traits, including ingestive behavior, metabolic rate, and general activity. The hormones and neuropeptides involved in control of hibernation in bats include the usual suspects (e.g., leptin, melatonin, glucocorticoids). The surprises in this fascinating and well-written article include the fact that plasma leptin levels are not always positively correlated with body fat deposition; high levels of leptin and leptin sensitivity are not compatible with hibernation; and leptin may also be necessary for arousal from hibernation. Again, we see that when behavior and physiology cannot be explained by the expected relations among body fat levels, leptin concentrations, and food intake, the same old questions raise their heads: How are metabolic fuels measured? Where are they measured, and how do they change leptin sensitivity? How do changes in fuel availability uncouple plasma leptin and body weight gain? In addition, Willis and Wilcox discuss hibernation in bats from a conservation physiology perspective, specifically with regard to whitenose syndrome, an emerging infectious disease causing catastrophic mortality among hibernating bats in eastern North America. Energy homeostasis in a developmental and social context When should organisms “regulate” their food intake or body weight? If newly conceived animals chose to defend a “set point” of
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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body weight by decreasing their energy intake intake, they might never progress from embryo to infant. The same might be said about the transition from infant to juvenile or from juvenile to adult. Just as females must anticipate potential food shortages by overeating and storing body fat or food in their homes, caches, or burrows, so also must developing animals of both sexes anticipate the energetic consequences of pubertal and psychosocial development by accumulating body mass, neuroendocrine maturity, and body fat. Thus, the next articles explore energy homeostasis in the context of development and adult social behaviors. 1. Erica Crespi and Margaret Unkefer take a comparative approach to energy homeostasis in a developmental context. This unique review article compares and contrasts energy homeostasis during early life history stages in fish, amphibians, birds, and mammals. Amphibians, for example, pass through discrete stages of development in which physiological systems differ between early and late stage tadpoles and post-metamorphic adults. Although the morphological transitions between early and later life history stages are not as dramatic, all vertebrates experience similar transitions in energy balance homeostasis between early and later life history stages. For example, within each vertebrate group there are early life history stages in which eating is largely unrestricted to meet the energetic requirements of rapid growth and development. Thus, in neonates and larval forms, food intake is emancipated from effects of so-called “satiety” factors (e.g., leptin, melanocortins, corticotropin-releasing factor), and environmental effects. Recent studies of fish and amphibians demonstrate that many different hormones and their receptors have been conserved during vertebrate evolution. Crespi and Unkefer shows that there is much developmental plasticity in controls of food and stress responsiveness, and adult characteristics are highly dependent on early experience and the organizational effects of gonadal hormones. 2. Mark Wilson, Carla Moore; Kelly Ethun, and Zachary Johnson discuss energy homeostasis, especially food intake, in nonhuman primates. They illustrate that many of the hormones and neuropeptides that play a role in laboratory rodents have similar effects in adult nonhuman primates, and the effects of hormones and neuropeptides in nonhuman primates are programmed during early development. In primates, however, effects of hormones and diet on ingestive behavior differ according to social dominance status. These insights would not have been possible without Wilson's techniques used to measure food intake and foraging in free-ranging populations of nonhuman primates (usually monkeys) housed in social groups. Wilson's group finds that access to food and other resources is delayed in socially subordinate monkeys. Among other fascinating facts, Wilson's group reports that the inhibitory effects of estradiol on appetite can be reversed with a calorically-dense diet, and only socially subordinate females gain weight on calorically-dense diets. They have begun to examine whether these differences are due to differences in sensitivity to orexigenic or stress-related peptides. These results might applied to understanding the increased incidence of binge eating and body weight accumulation in some women in certain phases of the menstrual cycle or post menopause, and alert us to the possibility that the effects of hormones on ingestive behavior can vary with caloric density of the diet. 3. Michael Symonds discusses energy homeostasis in the context of the development of sex differences in Homo sapiens. He notes that women tend to develop a greater abundance subcutaneous WAT located mainly on the gluteofemoral region whereas men accumulate more WAT in the visceral abdominal area. The masculine pattern of adipocyte distribution is associated with negative health consequences, whereas the feminine pattern is associated with successful lactation. This review notes the link between adipocyte differentiation, sex differences in body fat distribution and inflammation, and the possible role of brown adipose tissue in these sex differences.
Readers of Hormones and Behavior might recall that a role for brown adipose tissue in the effects of ovarian steroids on body weight and adiposity has been ruled out in rats and hamsters (McElroy and Wade, 1987; Richard, 1986; Schneider et al., 1986), but Symonds introduces a new kind of adipose tissue, beige adipose tissue, which might be more prevalent in a wider range of species. Beige adipose tissue might be more closely linked to energy homeostasis in some species, particularly in our own. 4. Jill Schneider, Jeremy Brozek, and Erin Keen-Rhinehart review energy homeostasis in the context of maternal programming and the effects of environmental obesogens, in particular endocrine disruptors. We provide several lines of evidence suggesting that the sharp increase in global obesity that occurred since the end of World War II might be at least partially related to the increase in endocrine disrupting compounds in the environment. Obesity, for example, is not limited to human beings, but occurs in domestic and feral animals. As we learned from the Symonds review, aspects of energy intake, storage, and expenditure are sexually dimorphic, with the masculine phenotype most closely associated with negative health consequences. The most profound effects of endocrine disruptors are to disrupt the process of sexual differentiation, which in turn alters many physiological systems, including the system that control energy homeostasis. Thus, there is a potential for endocrine disruptors to have profound influence on early development and inheritance of obesity and metabolic disease. One of the most useful aspects of this review might be the exposition of how the mechanisms that control peripheral changes in lipogenesis, lipolysis, and fuel oxidation can bring about changes in the neural circuits that control ingestive behavior.
Data articles The importance of context is best illustrated in the data articles of the special issue of Hormones and Behavior. The first two articles examine energy homeostasis in a reproductive context. Using red-sided garter snakes, Deborah Lutterschmidt and Ashley Maine studied the role of glucocorticoids in mediating the preference for food odors vs. pheromones from opposite-sex conspecifics. Here the Lutterschmidt lab members show that the preference for food over sex is stimulated in response to a fall in endogenous glucocorticoids and also in response to treatments that decrease glucocorticoid synthesis and increase the number of NPY immunoreactive cells in brain areas homologous with the mammalian hippocampus and amygdala. Their clever experiments show that these effects of lower glucocorticoids (and possibly lower availability of metabolic fuels) appear to act on hunger motivation and are independent of the effects on sexual motivation. In a similar vein, Amir Abdulhay, Noah Benton (co-first authors), Candice Klingerman, Kaila Krishnamoorthy, Jeremy Brozek, and Jill Schneider examine the preference for food or potential mating partners in Syrian hamsters. We see that there is an interaction between energy availability and ovarian hormones such that when females live in an environment where energy is abundant, estrous cycle fluctuations in appetitive behavior are masked. By contrast, when energy demands are high (such as in the cold) or where energy availability is low (food restriction), appetitive sex behaviors are restricted to the periovulatory period when fertilization is most likely to result from mating, and the rest of the estrous cycle dominated by vigilant appetitive ingestive behavior (food hoarding). Both of the above-mentioned papers agree that energy availability interacts with steroid hormones to orchestrate the appetites for food and sex. After reading both of these papers, I can't help but wonder whether garter snakes in lower body condition would switch more rapidly from sexual to food preference, and whether Syrian hamsters preference for sex would be altered by treatment with glucocorticoid synthesis inhibitors.
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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The next three data articles are concerned with energy homeostasis in a seasonal context. Migratory species optimize reproductive success by first restricting their reproductive behaviors to the season and location where food is abundant, and then leaving for more hospitable habitats after the breeding season. Breeding and migration are both energetically costly and require anticipatory overeating and body fat deposition concomitant with reproductive recrudescence. Marilyn Ramenofsky and Zoltán Németh ask whether a short pulse of testosterone is both necessary and sufficient to regulate development and expression of the vernal traits. I won't give away the punch line, but these results begin to parse the organizational and activational effects of gonadal steroids in relation to annual change in photoperiod on the sequential steps of preparation for spring migration that involve prenuptial molt, fattening, mass gain, flight muscle hypertrophy, and expression of migratory flight or migratory restlessnessness . In the next data article, Sean Bradley and Brian Prendergast ask whether there is an interaction between photic cues (day length) and food cues to entrain circadian timed behavior in Siberian hamsters. They wonder whether the food entrainable oscillator is more sensitive when animals are housed in short day lengths that mimic winter conditions. The answer is interesting because it suggests one way that Siberian hamsters limit their exposure to cold for more efficient foraging during harsh winter conditions. Paul Heideman's laboratory might be the only group dedicated to determining which aspects of variation in the reproductive and energy balancing systems are heritable, and how these heritable differences determine the reproductive response to the environment. A large team of students led by Jordan White uses selectively bred lines of white-footed mice (Peromyscus leucopus) derived from a wild population. The selected lines therefore display phenotypes spanning the full range of variation observed in nature, and the variability between the selected lines raised in a common environment represents genetic variation. In this article, they tested for heritable variation in circulating levels of hormones involved in energy homeostasis. They compared mice selected for high and low photoresponsiveness provided with either high or low energy diets. Readers might be surprised to find which aspects of the HPG and energy balancing systems are heritable and which are not. Huidi Yang, Qian Wang, and Dehua Wang show that food deprivation increases the appetitive behavior, food hoarding, but not the consummatory behavior, food intake, in female gerbils. They explore the effects GABAA in the mesolimbic dopamine system and specific hippocampal areas. This represents a unique perspective on the plasticity and development of brain areas involved in appetitive behaviors, behaviors that provide a window into motivation. Finally, Kathryn Davis, Elizabeth Carstens, Boman Irani, Lana Gent, Lisa Hahner and Deborah Clegg tested whether G protein-coupled estrogen receptor 1 (GPER) is necessary to prevent hyperphagia and the premature development of obesity. Using a very thorough experimental design and attention to many different aspects of energy balance, they discovered interesting sexual dimorphisms in the role of GPER in control of body weight, energy expenditure, and adiposity. These results are yet another example of the link between energy homeostasis and the reproductive system, and also of the fact that nonclassical steroid hormone receptor action can alter the organization and activation of mechanisms involved in energy homeostasis. Summary and conclusions Together these articles illustrate that the function of energy balancing traits is revealed when those traits are viewed in contexts closer to those in which they evolved. From our day-to-day human perspective, it might seem that a large part of our lifespan is concerned with the maintenance of a stable body weight and body fat content. From the perspective of natural selection, however, energy balance must be in flux for most of the lifespan because energy
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demands are always increasing during periods of growth, and body fat content must be increased in anticipation of reproduction, migration, hibernation, and possible future food shortages. Females of most species are likely to spend their lives first in a period of rapid growth and development, then in a series of pregnancies, or fluctuating between reproductive inhibition when energy is scarce and reproductive activity when energy is abundant. The importance of body weight “regulation” is not obvious when females are viewed from this perspective. Environmental factors have molded an energy homeostasis system that requires a dynamic and responsive, not a static, stubborn mechanism for control of food intake and adiposity, particularly in females (McEwan and Wingfield, 2003; Mrosovsky, 1990). There may be specific cases in some species in which the primary function of energy homeostasis is to tightly regulate body weight and adiposity. It cannot be denied, however, that in most species, one very critical function of energy balancing traits is to optimize reproductive success in environments where energy supply and demand fluctuate (reviewed by Schneider et al., 2013). The vast information yielded from the studying animals housed alone with ad libitum food intake represents a major contribution, but it might be rendered even more useful when it is integrated with information generated by studying energy balancing traits in other contexts, i.e., in many different species representing the different vertebrate taxa, in different stages of life history, and in environmental conditions that are more closely related to the selection pressures that molded those species during their evolution. I encourage readers to enjoy all of these articles, so that they might glean for themselves the common themes that emerge and the new questions that arise from these different experimental designs and these different model systems. Just to illustrate one example: A thread that runs through many of these articles is that inhibition of the HPG system or stimulation of food intake can occur even when plasma leptin concentrations are very high or even at their peak (e.g., Willis and Wilcox, 2014; Crespi and Unkefer, 2014) , suggesting that the energetic state must affect leptin sensitivity or transport. In other cases, the HPG system is stimulated food intake is inhibited in the face of low circulating levels of leptin (e.g.,Clarke, 2014; Ebling, 2014) . This suggests that leptin is not providing information about body fat content, but rather, leptin is functioning in other capacities (reviewed by Londraville et al., 2014). One possibility is that alterations in the availability of oxidizable metabolic fuels are somehow detected and sent to the mechanisms that control leptin transport or leptin sensitivity. Future work might examine the nature of the detectors of fuel availability and how these alter leptin transport or sensitivity. This is just one of the many common threads running through the data from many of these different model systems and different experimental methodologies. Serving as guest editor for this special issue has been an exhausting pleasure. I extend my heartfelt thanks to all of the authors for their excellent contributions, their courageous scientific forays into the unknown, and their resistance to doing what everyone else is doing. I also thank the authors and the many unsung, anonymous reviewers for their dedication to clear communication and scholarship. Acknowledgments This introduction has been a collaborative enterprise. I am very grateful to all of the authors of the special issue for their feedback, and in particular, Jeremy Brozek, Noah Benton, Paul Heideman, Marilyn Ramenofsky, Erica Crespi, Pierre Deviche, Scott Davies, Carol Elias, and Craig Willis. I thank Melynda Dalzon for expert proof reading. A special “thank you” goes to Fran Ebling for critical insights, inspiration, information, and references. I sincerely appreciate the opportunity to serve as guest editor for this issue of Hormones and Behavior, and thank Kim Wallen, the associate editors, and the editorial board for the invitation, and Shamus O'Reilly, and Nithya Sathishkumar from Elsevier for their
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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assistance. I also send my warm appreciation to Denise Blake, journal manager, for tireless efforts, efficient management, and endless patience. The scholarship and research involved in this introduction and the special issue on Homeostasis in Context was supported by a grant from the National Science Foundation IOS 1257876. References Beery, A.K., Zucker, I., 2011. Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 35, 565–572. Bronson, F.H., 1989. Mammalian Reproductive Biology, 1st ed. The University of Chicago Press, Chicago and London. Brown, P.J., Konner, M., 1987. An anthropological perspective on obesity. Ann. N. Y. Acad. Sci. 499, 29–46. Donato Jr., J., Cravo, R.M., Frazao, R., Elias, C.F., 2011. Hypothalamic sites of leptin action linking metabolism and reproduction. Neuroendocrinology 93, 9–18. Ebling, F.J., 2014. On the value of seasonal mammals for identifying mechanisms underlying the control of food intake and body weight. Horm. Behav. (this issue). Erskine, M.S., 1989. Solicitation behavior in the estrous female rat: a review. Horm Behav 23, 473–502. Friedman, M.I., 2008. Food intake: control, regulation and the illusion of dysregulation. In: Harris, R.B., Mattes, R. (Eds.), Appetite and Food Intake: Behavioral and Physiological Considerations. CRC Press, Boca Raton, Florida, USA, pp. 1–19. Koch, K.A., Wingfield, J.C., Buntin, J.D., 2002. Glucocorticoids and parental hyperphagia in ring doves (Streptopelia risoria). Hormones and Behavior 41, 9–21. Koch, K.A., Wingfield, J.C., Buntin, J.D., 2004. Prolactin−induced parental hyperphagia in ring doves: are glucocorticoids involved? Hormones and Behavior 46, 498–505. Londraville, R.L., Macotela, Y., Duff, R.J., Easterling, M.R., Liu, Q., Crespi, E.J., 2014. Comparative endocrinology of leptin: Assessing function in a phylogenetic context. General and Comparative Endocrinology. Martin, B., Ji, S., Maudsley, S., Mattson, M.P., 2010. “Control” laboratory rodents are metabolically morbid: why it matters. Proc. Natl. Acad. Sci. U. S. A. 107, 6127–6133. McElroy, J.F., Wade, G.N., 1987. Short- and long-term effects of ovariectomy on food intake, body weight, carcass composition, and brown adipose tissue in rats. Physiol. Behav. 39, 361–365. McEwen, B.S., Wingfield, J.C., 2003. The concept of allostasis in biology and biomedicine. Hormones and Behavior 43, 2–15.
Mrosovsky, N., 1990. Rheostasis: the physiology of change. Oxford University Press. Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M., 2013. Prevalence of obesity among adults: United States, 2011–2012. NCHS Data Brief 1–8. Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M., 2014. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311, 806–814. Pennington, R., 2001. Hunter–gatherer Demography. University of Cambridge Press, Cambridge, UK. Ramakrishnan, S., Strader, A.D., Wimpee, B., Chen, P., Smith, M.S., Buntin, J.D., 2007. Evidence for increased neuropeptide Y synthesis in mediobasal hypothalamus in relation to parental hyperphagia and gonadal activation in breeding ring doves. Journal of Neuroendocrinology 19, 163–171. Richard, D., 1986. Effects of ovarian hormones on energy balance and brown adipose tissue thermogenesis. Am. J. Physiol. 250, R245–R249. Schneider, J.E., Palmer, L.A., Wade, G.N., 1986. Effects of estrous cycles and ovarian steroids on body weight and energy expenditure in Syrian hamsters. Physiol. Behav. 38, 119–126. Schneider, J.E., Wise, J.D., Benton, N.A., Brozek, J.M., Keen-Rhinehart, E., 2013. When do we eat? Ingestive behavior, survival, and reproductive success. Horm. Behav. 64, 702–728. Sohn, J.W., Elmquist, J.K., Williams, K.W., 2013. Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 36, 504–512. Strader, A.D., Buntin, J.D., 2001. Neuropeptide−Y: a possible mediator of prolactin −induced feeding and regulator of energy balance in the ring dove (Streptopelia risoria). Journal of Neuroendocrinology 13, 386–392. Strader, A.D., Buntin, J.D., 2003. Changes in agouti−related peptide during the ring dove breeding cycle in relation to prolactin and parental hyperphagia. Journal of Neuroendocrinology 15, 1046–1053. Wade, G.N., Schneider, J.E., 1992. Metabolic fuels and reproduction in female mammals. Neurosci. Biobehav. Rev. 16, 235–272. Wallen, K., 1990. Desire and ability: hormones and the regulation of female sexual behavior. Neurosci Biobehav Rev 14, 233–241. Wallen, K., 2001. Sex and context: hormones and primate sexual motivation. Horm Behav 40, 339–357. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J.M., 1994. Positional cloning of the mouse Obese gene and its human homologue. Nature 372, 425–431.
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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Editorial
Guest editor's introduction: Energy homeostasis in context Jill E. Schneider ⁎ Department of Biological Sciences, Lehigh University, Bethlehem, PA 18015, United States
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Available online xxxx
This article is part of a Special Issue “Energy Balance”.
Keywords: Adiposity Body weight Energy expenditure Food intake Hibernation Ingestive behavior Migration Reproduction Sex behavior Sex differences
Energy homeostasis is achieved through neuroendocrine and metabolic control of energy intake, storage, and expenditure. Traditionally, these controls have been studied in an unrealistic and narrow context. The appetite for food, for example, is most often assumed to be independent of other motivations, such as sexual desire, fearfulness, and competition. Furthermore, our understanding of all aspects of energy homeostasis is based on studying males of only a few species. The baseline control subjects are most often housed in enclosed spaces, with continuous, unlimited access to food. In the last century, this approach has generated useful information, but all the while, the global prevalence of obesity has increased and remains at unprecedented levels (Ogden et al., 2013, 2014). It is likely, however, that the mechanisms that control ingestive behavior were molded by evolutionary forces, and that few, if any vertebrate species evolved in the presence of a limitless food supply, in an enclosed 0.5 × 1 ft space, and exposed to a constant ambient temperature of 22 + 2 °C. This special issue of Hormones and Behavior therefore contains 9 review articles and 7 data articles that consider energy homeostasis within the context of other motivations and physiological processes, such as early development, sexual differentiation, sexual motivation, reproduction, seasonality, hibernation, and migration. Each article is focused on a different species or on a set of species, and most vertebrate classes are represented. Energy homeostasis is viewed in the context of the selection pressures that simultaneously molded multiple aspects of energy intake, storage, and expenditure. This approach yields surprising conclusions regarding the function of those traits and their underlying neuroendocrine mechanisms. © 2014 Published by Elsevier Inc.
Introduction
“…rats and mice used in biomedical research are sedentary, obese, glucose intolerant, and on a trajectory to premature death” [Martin et al., 2010] For many years, energy homeostasis has been studied using methods that have afforded a great deal of experimental control but may have warped or limited our understanding. Most biomedical research is conducted in a small number of laboratory species housed under constant, standardized conditions, including static ambient temperature and day length, and widely-used commercial diets. The control groups are typically provided with an unlimited supply of food, and all subjects are housed in isolation from opposite-sex conspecifics or predators in relatively small, enclosed spaces. The underlying assumption seems to be that animals make decisions about when, what, and how
⁎ Department of Biological Sciences, 111 Research Drive, Bethlehem, PA 18015, United States. Fax: +1 610 758 4004. E-mail address: [email protected].
much to eat in the absence of potential mating partners, competitors, predators, and family members. Among the many studies of ingestive behavior published in biomedical journals, an overwhelming majority of those experiments used mice or rats housed under these conditions (Ebling, 2014; Martin et al., 2010). Furthermore, the subjects are most often male, with no consideration given to females (Beery and Zucker, 2011). The obvious advantages of these well-worn practices include 1) a high degree of experimental control over relatively inexpensive experimental subjects with short lifespans and generation times; 2) standardized conditions that minimize error variance and facilitate collaboration, cross-laboratory comparisons, and meta-analyses; and 3) the ability to identify many different hormones and neuropeptides that influence energy intake, storage, and expenditure. The benefits, however, can turn into liabilities if standardized, artificial conditions obscure the reality of hormone– behavior relations as they exist in nature. Furthermore, mice and rats housed in standard laboratory conditions with ad libitum access to laboratory chow are overweight, insulin resistant, hypertensive, hyperglycemic, hyperinsulinemic, and hyperleptinemic (reviewed by (Martin et al., 2010)). The question then is not “Why should we study other species in a more relevant context?” but rather, “Why are we still studying male
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Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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mice and rats living 24-7 at the all-you-can-eat buffet and calling them ‘the control group?’”. Regular readers of Hormones and Behavior are likely familiar with the limitations of studying animals confined to small enclosures. We need only remember the erroneous assumptions that were reinforced when female sex behavior was studied in rats or monkeys in small testing arenas with a single male conspecific, and the way that the dogma was shattered when females were housed in larger arenas with multiple conspecifics, and when female motivation was examined separately from that of the male (reviewed by Erskine, 1989; Wallen, 1990, 2001). A similar situation exists in the field of energy homeostasis, but we have not broken out of the traditional mode, and we are suffering the consequences. Despite enormous progress in identifying new neuropeptides and peripheral hormones that influence energy homeostasis (reviewed by (Schneider et al., 2013; Sohn et al., 2013), the global prevalence of obesity is still at its highest level in recent history (Ogden et al., 2013, 2014). It has been almost two decades since the watershed discovery of leptin, the adipocyte protein encoded by the ob gene (Zhang et al., 1994), and yet we still lack successful therapeutic treatments that ameliorate or prevent obesity. One obstacle to progress might be the erroneous picture that is painted by studying homeostatic variables in isolation from the selection pressures that molded them. The mechanisms and function of the traits involved in energy homeostasis appear in a new light when animals of both sexes are considered within the context of development, opposite-sex conspecifics, fluctuations in food availability, ambient temperature, and day length. Readers of this special issue are in for an upgrade if not a total transformation of their understanding of energy homeostasis. In these articles, energy intake, storage, and expenditure are viewed within the context of reproduction, seasonality, migration, and development, and in some cases the articles consider the interactions among these factors. Within these articles, there are representative species of mammals, birds, reptiles, amphibians, and fish. Mice and rats are not excluded, but where they are included, they are studied in relation to reproduction or sexual differentiation. The penultimate review article is concerned with sex differences in energy homeostasis, primarily white adipose tissue (WAT) distribution, in our own species. Each of these articles contains surprising conclusions about the mechanisms that underlie energy homeostasis. When viewed as a group, these articles compel us to face the true meaning of energy “homeostasis” and to more closely define the words “regulate” and “control.” The word homeostasis stems from the Latin words for staying “similar to,” not “the same as,” and thus it implies some degree of fluctuation as well as maintenance within a range of values (reviewed by (Friedman, 2008). These central points of equilibrium might change somewhat over the lifespan, during periods of growth, during different reproductive stages, and in response to changes in the environment. Examples of variables that must be maintained in relatively tight homeostasis include body temperature (in homeotherms), blood pH, and the intracellular availability of oxidizable metabolic fuels. Thermotaxis is controlled (not regulated) in service of regulating body temperature, i.e., maintaining body temperature homeostasis. If your body temperature were to rise above 107 °C (or your blood pH rises above 8.0) you would be in trouble. For you, the only alternative to tight regulation of these variables is death. By contrast, excess levels of food intake or a high percentage of WAT can be tolerated for months or years prior to any major effect. In fact, survival often depends on the ability to increase food intake and accumulate WAT stores. This is because all cellular processes require a continuous supply of metabolic fuels, but energy is not continuously available in the environment. Most animals evolved in habitats where energy was not continuously available (Bronson, 1989), and survival in such environments often required anticipatory overeating and WAT accumulation as a buffer against future energy shortages. Periods of food scarcity coupled with high-energy demands are accompanied by
hydrolysis and mobilization of fuels from lipids stored in WAT and loss of body weight and overall levels of body fat. To defend a particular level of body fat content in the face of low food availability and high energetic demand would be a fatal mistake. Survival requires that we allow the level of body fat to fall as we use the fatty acids derived from those fat stores to fuel essential cellular processes. Another fatal mistake would be to defend a particular level of body fat content instead of accumulating body fat in preparation for future food shortages or impending periods of high energy demand when feeding is not continuously possible; e.g., migration. This concern for future food scarcity might be hard for first-world academics to imagine, but it would not be an unusual scenario for most wild animals or for the early hominids from which we evolved (Brown and Konner, 1987; Pennington, 2001). This explains why this special issue concerns energy homeostasis, not body weight homeostasis. A common feature in vertebrates is that body fat content and food intake are controlled (not regulated) in service of the regulated homeostatic variable: the availability of oxidizable fuels (Friedman, 2008). In response to such realities, it has been suggested that we replace the term “homeostasis” with “rheostasis” or “allostasis” (McEwen and Wingfield, 2003; Mrosovsky, 1990). Perhaps the best example is the control of energy intake, storage, and expenditure in service of reproductive success. Review articles Energy homeostasis in the reproductive context In the first group of articles, we learn that energy intake, storage, and expenditure are controlled so the high energetic cost of female reproduction can be paid from the females' bank account or insurance policy. The bank account is often filled in advance of the metabolic challenge by increased food intake and the accumulation of body fat and/or external food caches. Instead of defending a low-medium body weight, females of many species will overeat or hoard food weeks or months in advance of mating. Furthermore, instead of maintaining some sort of homeostasis in food intake, females of many species increase their food intake, sometime three or more fold, during lactation (reviewed by (Schneider et al., 2013)) or posthatching (e.g., Koch et al., 2002, 2004; Ramakrishnan et al., 2007; Strader and Buntin, 2003). In times of food shortage or high energy demand, energy can be conserved for those processes necessary for survival, and thus, metabolic challenges can inhibit every aspect of the hypothalamic-pituitary-gonadal (HPG) system. The primary effect, however, is on the gonadotropinreleasing hormone (GnRH) pulse generator (reviewed by Wade and Schneider (1992)). In this way, the systems controlling energy homeostasis and reproduction are reciprocally linked. Virtually every hormone or neuropeptide that controls ingestive behavior also controls reproduction, and it is difficult to understand energy homeostasis except in the context of reproduction (reviewed by Schneider et al. (2013)). 1. Nicole Bellefontaine and Carol Elias review an excellent example of this link between energy homeostasis and female reproduction. Mice with mutations in the gene that encodes the adipocyte protein, leptin are both obese and infertile, and the obesity and infertility are ameliorated by treatment with leptin. In strains of mice that lack the functional leptin receptor, obesity and infertility are ameliorated with genetic restoration of leptin receptors restricted to neurons (reviewed by Donato et al. (2011)). This leads to an interesting question. Is the infertility secondary to the obesity? Members of the Elias laboratory answered this question using viral vector delivery and the Cre/loxP system. Whereas large body of data using traditional neuroanatomical methodologies has implicated kisspeptin cells in the arcuate as targets of leptin-induced effects on GnRH cells, the Elias laboratory refutes this idea. Rather, they demonstrate that leptin can reverse the effects of fasting on the HPG system via action in the ventral premammillary
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
Editorial
nucleus (PMv). This is fascinating because this brain area is responsive to olfactory cues, and contains both estrogen and leptin receptor, and projects to GnRH cells. These and other findings reviewed by Bellefontaine and Elias open the door to unexplored possibilities. For example, future work might combine genetic manipulations with manipulations of metabolic fuel availability and/or energy expenditure. This work is so far restricted to the role of leptin control of the HPG system, but does not rule out direct control by the availability of fuels or by other hormones such as ghrelin. Given the importance of the PMv, it will be interesting to include observations of sex and courtship behavior, appetitive aspects of ingestion, and other olfactory mediated behaviors in ovariectomized females brought into estrous with exogenous hormone treatment. 2. Iain Clarke provides a heroic review of energy homeostasis and reproduction in ruminants with particular attention to sheep. His clear description of the ruminant HPG system illustrates the need to elucidate the basic biology of the estrous cycle in order to fully understand metabolic control of female reproduction. For example, we lack a clear understanding of the molecular and neurophysiological mechanisms that generate pulsatile GnRH secretion and mediate negative and positive steroid feedback on the brain and pituitary. Understanding these processes, particularly the role of kisspeptins (Kp) and gonadotropin-inhibiting hormone (GnIH), will be critical because changes in the availability of metabolic fuels influence GnRH sensitivity to steroid feedback , and Kp and GnIH, but not GnRH cells contain steroid receptors . It should be noted here, that whereas Bellefontaine and Elias restricted their review to leptin control of the HPG system, there is still reason to examine environmental control of the HPG system by metabolic fuel availability and other hormones using other model systems. One principle that arises from the Clarke review is that the so-called “appetite regulatory peptides” are not just for ingestive behavior any more. They are major players in control of reproduction. In this way, the metabolic control of reproduction in ruminants shares much in common with that of rodents and primates, but these large animals allow the experimenter to take the research a step further, to observe acute changes in pulsatile gonadotropin and GnRH secretion in response to environmental manipulations. For example, using these methodologies, the Clarke and Schneider laboratories discovered that in sheep food-resticted to the point of hypogonadotropism, restoration of the HPG system by re-feeding or infusion of metabolic fuels does not require an increase in circulating levels of leptin. 3. Scott Davies and Pierre Deviche review the metabolic control of reproduction in birds. Most of this work comes from an ecological perspective that highlights the allocation of energy toward reproductive success and survival in environments where energy supply and demand fluctuate. As in sheep and rodents, the HPG system in birds is dependent upon food availability, and body weight is not defended at low levels prior to the breeding season. To the contrary, a period of massive hyperphagia and body weight gain anticipate or accompanies the breeding season, such as during the well-known period of parental hyperphagia (Koch et al., 2002, 2004; Ramakrishnan et al., 2007; Strader and Buntin, 2001, 2003) . When wild populations are compared across years or within a year across habitats that differ with respect to environmental food availability, we find that this variable is significantly correlated with reproductive success. Davies and Deviche bring us up to date on the role of hormones and neuropeptides in mediating the effects of energy availability on reproduction in birds. This field of research is in its early stages, and there is room for more research on male and female reproductive physiology and behavior in response to manipulations of energy availability, photoperiod, and ambient temperature. In some of the above-mentioned review articles, both homeostasis and reproduction are placed in the seasonal context. In seasonal species,
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the day length often provides a reliable predictor of the coming increase in food availability in the environment, allowing these species to time their matings so that the offspring are born in an environment of energy abundance. This is currently of enormous importance because the data show that some populations have become increasingly out of synch with the availability of food for their young due to climate change. Energy homeostasis in the seasonal context Just as females must anticipate potential food shortages by overeating and storing body fat or food in their homes, caches, or burrows, so also must temperate zone animals of both sexes anticipate harsh seasons when food availability is low and energy demands for thermogenesis are high. Thus, the next two articles explore energy homeostasis in seasonal animals. 1. Fran Ebling, with exceptional clarity, reviews energy homeostasis in mammalian species that undergo natural seasonal cycles of over and under-eating and fat deposition and catabolism. We find that the Ebling and Barrett laboratory groups have made great strides toward understanding the central mechanisms that underlie these seasonal changes in physiology and behavior. Readers may be surprised to find that these mechanisms are distinct from the hypothalamic neuropeptide systems purported to control body weight and fat content in laboratory mice and rats. The Ebling and Barrett groups find no support for the idea that seasonal cycles of body weight and food intake are controlled by leptin receptors acting on orexigenic and anorectic neuropeptide systems in the arcuate nucleus of the hypothalamus. Not only are the key neuropeptides systems not in the arcuate nuclues, they are not even in neurons. In this unique and insightful review, Ebling predicts that when we gain an understanding of how altered thyroid milieu controls neurogenesis and plasticity, we will be able to envision new avenues of translational research aimed at preventing and reversing obesity. 2. Craig Willis and Alana Wilcox study energy homeostasis in the context of hibernation, periods of reduced body temperature and metabolic rate that can last from days to weeks. In the bat species that they study, mating occurs in the fall and early winter prior to hibernation, and females store the sperm or delay implantation of embryos until spring when they might become officially pregnant, an event that is stamped for approval by high levels of body fat. Entry and exit from hibernation or torpor are controlled by neuroendocrine mechanisms acting on many traits, including ingestive behavior, metabolic rate, and general activity. The hormones and neuropeptides involved in control of hibernation in bats include the usual suspects (e.g., leptin, melatonin, glucocorticoids). The surprises in this fascinating and well-written article include the fact that plasma leptin levels are not always positively correlated with body fat deposition; high levels of leptin and leptin sensitivity are not compatible with hibernation; and leptin may also be necessary for arousal from hibernation. Again, we see that when behavior and physiology cannot be explained by the expected relations among body fat levels, leptin concentrations, and food intake, the same old questions raise their heads: How are metabolic fuels measured? Where are they measured, and how do they change leptin sensitivity? How do changes in fuel availability uncouple plasma leptin and body weight gain? In addition, Willis and Wilcox discuss hibernation in bats from a conservation physiology perspective, specifically with regard to whitenose syndrome, an emerging infectious disease causing catastrophic mortality among hibernating bats in eastern North America. Energy homeostasis in a developmental and social context When should organisms “regulate” their food intake or body weight? If newly conceived animals chose to defend a “set point” of
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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body weight by decreasing their energy intake intake, they might never progress from embryo to infant. The same might be said about the transition from infant to juvenile or from juvenile to adult. Just as females must anticipate potential food shortages by overeating and storing body fat or food in their homes, caches, or burrows, so also must developing animals of both sexes anticipate the energetic consequences of pubertal and psychosocial development by accumulating body mass, neuroendocrine maturity, and body fat. Thus, the next articles explore energy homeostasis in the context of development and adult social behaviors. 1. Erica Crespi and Margaret Unkefer take a comparative approach to energy homeostasis in a developmental context. This unique review article compares and contrasts energy homeostasis during early life history stages in fish, amphibians, birds, and mammals. Amphibians, for example, pass through discrete stages of development in which physiological systems differ between early and late stage tadpoles and post-metamorphic adults. Although the morphological transitions between early and later life history stages are not as dramatic, all vertebrates experience similar transitions in energy balance homeostasis between early and later life history stages. For example, within each vertebrate group there are early life history stages in which eating is largely unrestricted to meet the energetic requirements of rapid growth and development. Thus, in neonates and larval forms, food intake is emancipated from effects of so-called “satiety” factors (e.g., leptin, melanocortins, corticotropin-releasing factor), and environmental effects. Recent studies of fish and amphibians demonstrate that many different hormones and their receptors have been conserved during vertebrate evolution. Crespi and Unkefer shows that there is much developmental plasticity in controls of food and stress responsiveness, and adult characteristics are highly dependent on early experience and the organizational effects of gonadal hormones. 2. Mark Wilson, Carla Moore; Kelly Ethun, and Zachary Johnson discuss energy homeostasis, especially food intake, in nonhuman primates. They illustrate that many of the hormones and neuropeptides that play a role in laboratory rodents have similar effects in adult nonhuman primates, and the effects of hormones and neuropeptides in nonhuman primates are programmed during early development. In primates, however, effects of hormones and diet on ingestive behavior differ according to social dominance status. These insights would not have been possible without Wilson's techniques used to measure food intake and foraging in free-ranging populations of nonhuman primates (usually monkeys) housed in social groups. Wilson's group finds that access to food and other resources is delayed in socially subordinate monkeys. Among other fascinating facts, Wilson's group reports that the inhibitory effects of estradiol on appetite can be reversed with a calorically-dense diet, and only socially subordinate females gain weight on calorically-dense diets. They have begun to examine whether these differences are due to differences in sensitivity to orexigenic or stress-related peptides. These results might applied to understanding the increased incidence of binge eating and body weight accumulation in some women in certain phases of the menstrual cycle or post menopause, and alert us to the possibility that the effects of hormones on ingestive behavior can vary with caloric density of the diet. 3. Michael Symonds discusses energy homeostasis in the context of the development of sex differences in Homo sapiens. He notes that women tend to develop a greater abundance subcutaneous WAT located mainly on the gluteofemoral region whereas men accumulate more WAT in the visceral abdominal area. The masculine pattern of adipocyte distribution is associated with negative health consequences, whereas the feminine pattern is associated with successful lactation. This review notes the link between adipocyte differentiation, sex differences in body fat distribution and inflammation, and the possible role of brown adipose tissue in these sex differences.
Readers of Hormones and Behavior might recall that a role for brown adipose tissue in the effects of ovarian steroids on body weight and adiposity has been ruled out in rats and hamsters (McElroy and Wade, 1987; Richard, 1986; Schneider et al., 1986), but Symonds introduces a new kind of adipose tissue, beige adipose tissue, which might be more prevalent in a wider range of species. Beige adipose tissue might be more closely linked to energy homeostasis in some species, particularly in our own. 4. Jill Schneider, Jeremy Brozek, and Erin Keen-Rhinehart review energy homeostasis in the context of maternal programming and the effects of environmental obesogens, in particular endocrine disruptors. We provide several lines of evidence suggesting that the sharp increase in global obesity that occurred since the end of World War II might be at least partially related to the increase in endocrine disrupting compounds in the environment. Obesity, for example, is not limited to human beings, but occurs in domestic and feral animals. As we learned from the Symonds review, aspects of energy intake, storage, and expenditure are sexually dimorphic, with the masculine phenotype most closely associated with negative health consequences. The most profound effects of endocrine disruptors are to disrupt the process of sexual differentiation, which in turn alters many physiological systems, including the system that control energy homeostasis. Thus, there is a potential for endocrine disruptors to have profound influence on early development and inheritance of obesity and metabolic disease. One of the most useful aspects of this review might be the exposition of how the mechanisms that control peripheral changes in lipogenesis, lipolysis, and fuel oxidation can bring about changes in the neural circuits that control ingestive behavior.
Data articles The importance of context is best illustrated in the data articles of the special issue of Hormones and Behavior. The first two articles examine energy homeostasis in a reproductive context. Using red-sided garter snakes, Deborah Lutterschmidt and Ashley Maine studied the role of glucocorticoids in mediating the preference for food odors vs. pheromones from opposite-sex conspecifics. Here the Lutterschmidt lab members show that the preference for food over sex is stimulated in response to a fall in endogenous glucocorticoids and also in response to treatments that decrease glucocorticoid synthesis and increase the number of NPY immunoreactive cells in brain areas homologous with the mammalian hippocampus and amygdala. Their clever experiments show that these effects of lower glucocorticoids (and possibly lower availability of metabolic fuels) appear to act on hunger motivation and are independent of the effects on sexual motivation. In a similar vein, Amir Abdulhay, Noah Benton (co-first authors), Candice Klingerman, Kaila Krishnamoorthy, Jeremy Brozek, and Jill Schneider examine the preference for food or potential mating partners in Syrian hamsters. We see that there is an interaction between energy availability and ovarian hormones such that when females live in an environment where energy is abundant, estrous cycle fluctuations in appetitive behavior are masked. By contrast, when energy demands are high (such as in the cold) or where energy availability is low (food restriction), appetitive sex behaviors are restricted to the periovulatory period when fertilization is most likely to result from mating, and the rest of the estrous cycle dominated by vigilant appetitive ingestive behavior (food hoarding). Both of the above-mentioned papers agree that energy availability interacts with steroid hormones to orchestrate the appetites for food and sex. After reading both of these papers, I can't help but wonder whether garter snakes in lower body condition would switch more rapidly from sexual to food preference, and whether Syrian hamsters preference for sex would be altered by treatment with glucocorticoid synthesis inhibitors.
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
Editorial
The next three data articles are concerned with energy homeostasis in a seasonal context. Migratory species optimize reproductive success by first restricting their reproductive behaviors to the season and location where food is abundant, and then leaving for more hospitable habitats after the breeding season. Breeding and migration are both energetically costly and require anticipatory overeating and body fat deposition concomitant with reproductive recrudescence. Marilyn Ramenofsky and Zoltán Németh ask whether a short pulse of testosterone is both necessary and sufficient to regulate development and expression of the vernal traits. I won't give away the punch line, but these results begin to parse the organizational and activational effects of gonadal steroids in relation to annual change in photoperiod on the sequential steps of preparation for spring migration that involve prenuptial molt, fattening, mass gain, flight muscle hypertrophy, and expression of migratory flight or migratory restlessnessness . In the next data article, Sean Bradley and Brian Prendergast ask whether there is an interaction between photic cues (day length) and food cues to entrain circadian timed behavior in Siberian hamsters. They wonder whether the food entrainable oscillator is more sensitive when animals are housed in short day lengths that mimic winter conditions. The answer is interesting because it suggests one way that Siberian hamsters limit their exposure to cold for more efficient foraging during harsh winter conditions. Paul Heideman's laboratory might be the only group dedicated to determining which aspects of variation in the reproductive and energy balancing systems are heritable, and how these heritable differences determine the reproductive response to the environment. A large team of students led by Jordan White uses selectively bred lines of white-footed mice (Peromyscus leucopus) derived from a wild population. The selected lines therefore display phenotypes spanning the full range of variation observed in nature, and the variability between the selected lines raised in a common environment represents genetic variation. In this article, they tested for heritable variation in circulating levels of hormones involved in energy homeostasis. They compared mice selected for high and low photoresponsiveness provided with either high or low energy diets. Readers might be surprised to find which aspects of the HPG and energy balancing systems are heritable and which are not. Huidi Yang, Qian Wang, and Dehua Wang show that food deprivation increases the appetitive behavior, food hoarding, but not the consummatory behavior, food intake, in female gerbils. They explore the effects GABAA in the mesolimbic dopamine system and specific hippocampal areas. This represents a unique perspective on the plasticity and development of brain areas involved in appetitive behaviors, behaviors that provide a window into motivation. Finally, Kathryn Davis, Elizabeth Carstens, Boman Irani, Lana Gent, Lisa Hahner and Deborah Clegg tested whether G protein-coupled estrogen receptor 1 (GPER) is necessary to prevent hyperphagia and the premature development of obesity. Using a very thorough experimental design and attention to many different aspects of energy balance, they discovered interesting sexual dimorphisms in the role of GPER in control of body weight, energy expenditure, and adiposity. These results are yet another example of the link between energy homeostasis and the reproductive system, and also of the fact that nonclassical steroid hormone receptor action can alter the organization and activation of mechanisms involved in energy homeostasis. Summary and conclusions Together these articles illustrate that the function of energy balancing traits is revealed when those traits are viewed in contexts closer to those in which they evolved. From our day-to-day human perspective, it might seem that a large part of our lifespan is concerned with the maintenance of a stable body weight and body fat content. From the perspective of natural selection, however, energy balance must be in flux for most of the lifespan because energy
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demands are always increasing during periods of growth, and body fat content must be increased in anticipation of reproduction, migration, hibernation, and possible future food shortages. Females of most species are likely to spend their lives first in a period of rapid growth and development, then in a series of pregnancies, or fluctuating between reproductive inhibition when energy is scarce and reproductive activity when energy is abundant. The importance of body weight “regulation” is not obvious when females are viewed from this perspective. Environmental factors have molded an energy homeostasis system that requires a dynamic and responsive, not a static, stubborn mechanism for control of food intake and adiposity, particularly in females (McEwan and Wingfield, 2003; Mrosovsky, 1990). There may be specific cases in some species in which the primary function of energy homeostasis is to tightly regulate body weight and adiposity. It cannot be denied, however, that in most species, one very critical function of energy balancing traits is to optimize reproductive success in environments where energy supply and demand fluctuate (reviewed by Schneider et al., 2013). The vast information yielded from the studying animals housed alone with ad libitum food intake represents a major contribution, but it might be rendered even more useful when it is integrated with information generated by studying energy balancing traits in other contexts, i.e., in many different species representing the different vertebrate taxa, in different stages of life history, and in environmental conditions that are more closely related to the selection pressures that molded those species during their evolution. I encourage readers to enjoy all of these articles, so that they might glean for themselves the common themes that emerge and the new questions that arise from these different experimental designs and these different model systems. Just to illustrate one example: A thread that runs through many of these articles is that inhibition of the HPG system or stimulation of food intake can occur even when plasma leptin concentrations are very high or even at their peak (e.g., Willis and Wilcox, 2014; Crespi and Unkefer, 2014) , suggesting that the energetic state must affect leptin sensitivity or transport. In other cases, the HPG system is stimulated food intake is inhibited in the face of low circulating levels of leptin (e.g.,Clarke, 2014; Ebling, 2014) . This suggests that leptin is not providing information about body fat content, but rather, leptin is functioning in other capacities (reviewed by Londraville et al., 2014). One possibility is that alterations in the availability of oxidizable metabolic fuels are somehow detected and sent to the mechanisms that control leptin transport or leptin sensitivity. Future work might examine the nature of the detectors of fuel availability and how these alter leptin transport or sensitivity. This is just one of the many common threads running through the data from many of these different model systems and different experimental methodologies. Serving as guest editor for this special issue has been an exhausting pleasure. I extend my heartfelt thanks to all of the authors for their excellent contributions, their courageous scientific forays into the unknown, and their resistance to doing what everyone else is doing. I also thank the authors and the many unsung, anonymous reviewers for their dedication to clear communication and scholarship. Acknowledgments This introduction has been a collaborative enterprise. I am very grateful to all of the authors of the special issue for their feedback, and in particular, Jeremy Brozek, Noah Benton, Paul Heideman, Marilyn Ramenofsky, Erica Crespi, Pierre Deviche, Scott Davies, Carol Elias, and Craig Willis. I thank Melynda Dalzon for expert proof reading. A special “thank you” goes to Fran Ebling for critical insights, inspiration, information, and references. I sincerely appreciate the opportunity to serve as guest editor for this issue of Hormones and Behavior, and thank Kim Wallen, the associate editors, and the editorial board for the invitation, and Shamus O'Reilly, and Nithya Sathishkumar from Elsevier for their
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
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Editorial
assistance. I also send my warm appreciation to Denise Blake, journal manager, for tireless efforts, efficient management, and endless patience. The scholarship and research involved in this introduction and the special issue on Homeostasis in Context was supported by a grant from the National Science Foundation IOS 1257876. References Beery, A.K., Zucker, I., 2011. Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 35, 565–572. Bronson, F.H., 1989. Mammalian Reproductive Biology, 1st ed. The University of Chicago Press, Chicago and London. Brown, P.J., Konner, M., 1987. An anthropological perspective on obesity. Ann. N. Y. Acad. Sci. 499, 29–46. Donato Jr., J., Cravo, R.M., Frazao, R., Elias, C.F., 2011. Hypothalamic sites of leptin action linking metabolism and reproduction. Neuroendocrinology 93, 9–18. Ebling, F.J., 2014. On the value of seasonal mammals for identifying mechanisms underlying the control of food intake and body weight. Horm. Behav. (this issue). Erskine, M.S., 1989. Solicitation behavior in the estrous female rat: a review. Horm Behav 23, 473–502. Friedman, M.I., 2008. Food intake: control, regulation and the illusion of dysregulation. In: Harris, R.B., Mattes, R. (Eds.), Appetite and Food Intake: Behavioral and Physiological Considerations. CRC Press, Boca Raton, Florida, USA, pp. 1–19. Koch, K.A., Wingfield, J.C., Buntin, J.D., 2002. Glucocorticoids and parental hyperphagia in ring doves (Streptopelia risoria). Hormones and Behavior 41, 9–21. Koch, K.A., Wingfield, J.C., Buntin, J.D., 2004. Prolactin−induced parental hyperphagia in ring doves: are glucocorticoids involved? Hormones and Behavior 46, 498–505. Londraville, R.L., Macotela, Y., Duff, R.J., Easterling, M.R., Liu, Q., Crespi, E.J., 2014. Comparative endocrinology of leptin: Assessing function in a phylogenetic context. General and Comparative Endocrinology. Martin, B., Ji, S., Maudsley, S., Mattson, M.P., 2010. “Control” laboratory rodents are metabolically morbid: why it matters. Proc. Natl. Acad. Sci. U. S. A. 107, 6127–6133. McElroy, J.F., Wade, G.N., 1987. Short- and long-term effects of ovariectomy on food intake, body weight, carcass composition, and brown adipose tissue in rats. Physiol. Behav. 39, 361–365. McEwen, B.S., Wingfield, J.C., 2003. The concept of allostasis in biology and biomedicine. Hormones and Behavior 43, 2–15.
Mrosovsky, N., 1990. Rheostasis: the physiology of change. Oxford University Press. Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M., 2013. Prevalence of obesity among adults: United States, 2011–2012. NCHS Data Brief 1–8. Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M., 2014. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 311, 806–814. Pennington, R., 2001. Hunter–gatherer Demography. University of Cambridge Press, Cambridge, UK. Ramakrishnan, S., Strader, A.D., Wimpee, B., Chen, P., Smith, M.S., Buntin, J.D., 2007. Evidence for increased neuropeptide Y synthesis in mediobasal hypothalamus in relation to parental hyperphagia and gonadal activation in breeding ring doves. Journal of Neuroendocrinology 19, 163–171. Richard, D., 1986. Effects of ovarian hormones on energy balance and brown adipose tissue thermogenesis. Am. J. Physiol. 250, R245–R249. Schneider, J.E., Palmer, L.A., Wade, G.N., 1986. Effects of estrous cycles and ovarian steroids on body weight and energy expenditure in Syrian hamsters. Physiol. Behav. 38, 119–126. Schneider, J.E., Wise, J.D., Benton, N.A., Brozek, J.M., Keen-Rhinehart, E., 2013. When do we eat? Ingestive behavior, survival, and reproductive success. Horm. Behav. 64, 702–728. Sohn, J.W., Elmquist, J.K., Williams, K.W., 2013. Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 36, 504–512. Strader, A.D., Buntin, J.D., 2001. Neuropeptide−Y: a possible mediator of prolactin −induced feeding and regulator of energy balance in the ring dove (Streptopelia risoria). Journal of Neuroendocrinology 13, 386–392. Strader, A.D., Buntin, J.D., 2003. Changes in agouti−related peptide during the ring dove breeding cycle in relation to prolactin and parental hyperphagia. Journal of Neuroendocrinology 15, 1046–1053. Wade, G.N., Schneider, J.E., 1992. Metabolic fuels and reproduction in female mammals. Neurosci. Biobehav. Rev. 16, 235–272. Wallen, K., 1990. Desire and ability: hormones and the regulation of female sexual behavior. Neurosci Biobehav Rev 14, 233–241. Wallen, K., 2001. Sex and context: hormones and primate sexual motivation. Horm Behav 40, 339–357. Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., Friedman, J.M., 1994. Positional cloning of the mouse Obese gene and its human homologue. Nature 372, 425–431.
Please cite this article as: Schneider, J.E., Guest editor's introduction: Energy homeostasis in context, Horm. Behav. (2014), http://dx.doi.org/ 10.1016/j.yhbeh.2014.05.001
