Genne-Bacon Thinking Evolutionarily About Obesity

Thinking Evolutionarily About Obesity

Elizabeth A. Genné-Bacon

Department of Genetics, Yale University, Connecticut Mental Health Center, New Haven, Connecticut

Obesity, diabetes, and metabolic syndrome are growing worldwide health concerns, yet their causes are not fully understood. Research into the etiology of the obesity epidemic is highly influenced by our understanding of the evolutionary roots of metabolic control. For half a century, the thrifty gene hypothesis, which argues that obesity is an evolutionary adaptation for surviving periods of famine, has dominated the thinking on this topic. Obesity researchers are often not aware that there is, in fact, limited evidence to support the thrifty gene hypothesis and that alternative hypotheses have been suggested. This review presents evidence for and against the thrifty gene hypothesis and introduces readers to additional hypotheses for the evolutionary origins of the obesity epidemic. Because these alternate hypotheses imply significantly different strategies for research and clinical management of obesity, their consideration is critical to halting the spread of this epidemic.

INTRODUCTION drome,” which strongly predisposes suffers to type 2 diabetes, cardiovascular disease, The incidence of obesity worldwide and early mortality [2]. Metabolic syn- has risen dramatically in the past century, drome affects 34 percent of Americans, 53 enough to be formally declared a global percent of whom are obese [3]. Obesity is a epidemic by the World Health Organization growing concern in developing nations in 1997 [1]. Obesity (defined by a body [4,5] and is now one of the leading causes mass index exceeding 30 kg/m), together of preventable death worldwide [6]. with insulin resistance, dyslipidemia, and Logically, a rapid increase in any med- related conditions, defines “metabolic syn- ical condition should be attributed to envi-

To whom all correspondence should be addressed: Elizabeth A. Genné-Bacon, Depart- ment of Genetics, Yale University, Connecticut Mental Health Center, 34 Park St., DiLeone Lab, Room 306, New Haven, CT 06519; Tele: 203-974-7784; Fax: 203-974- 7686.

†Abbreviations: TGH, thrifty gene hypothesis; SNP, single nucleotide polymorphism; GWA, genome-wide association.

Keywords: review, obesity, diabetes, metabolic syndrome, evolution, thrifty gene hypothesis

Author’s note: Funding provided through the National Science Foundation Graduate Re- search Fellowship Program. 99 100 Genné-Bacon: Thinking evolutionarily about obesity

ronmental changes, yet obesity has been mals to retain fertility and successfully ges- shown in numerous studies to have a strong tate offspring [19]. Additionally, body fat genetic component [7,8], indicating a po- helps to maintain temperature homeostasis. tential gene-environment interaction [9]. White adipose tissue acts as an insulator Curiously, certain populations appear par- [21], while brown adipose actively con- ticularly susceptible to obesity and meta- tributes to thermogenesis [22]. bolic syndrome [1,10], while others appear Several forces maintain the upper resistant [10,11]. The high prevalence of this boundary of body fat in animals. The time seemingly detrimental condition, combined needed to devote to foraging is one. Main- with its uneven distribution among both in- taining high adiposity is energetically costly dividuals and populations, has led to specu- and requires large caloric input [23]. For lation about potential evolutionary origins of most wild animals, far too much time would obesity and metabolic syndrome [12-15]. need to be devoted to foraging at the ex- Here I will review several hypotheses pense of other important activities such as (both competing and complementary) for mating, sleeping, or avoiding predators [23]. the evolutionary origins of the obesity epi- Prey animals must remain lean enough to demic and discuss their implications. I argue avoid predation. An obese animal cannot that a better understanding of the evolution- move as quickly nor hide as efficiently as a ary forces that have shaped human meta- lean animal [24]. It has been demonstrated bolic control is critical to fighting the in laboratory studies that many small prey modern day obesity epidemic. Understand- animals are resistant to diet-induced obesity, ing the evolutionary origins of obesity can even with unlimited access to highly caloric lead to novel approaches for research into food [25]. In addition, some prey animals the pathophysiology of obesity as well as its have been shown experimentally to reduce clinical management. body weight when predators are present in their habitat [26,27], presumably to avoid predation. WHY CONTROL BODY WEIGHT? Modern humans are largely buffered To understand the modern pathophysi- from these factors. Global economies safe- ology of obesity, it is useful to examine the guard developed nations from starvation and part that body weight regulation plays in the allow for easy access to highly caloric food. evolutionary fitness of animals. What forces Shelter and clothing protect us from the drive an organism to maintain a minimum cold. We are seldom forced to hunt prey, and or maximum weight limit? It is important to neither do we worry about becoming prey first note that “body weight regulation” is an ourselves [24]. Though modern humans may extremely complex process involving much no longer be subject to these forces, they are more than simple metabolic efficiency. It still highly relevant to our health. Under- comprises both peripheral and central sati- standing how these forces contributed to ety/hunger signals [16,17] as well as cogni- human evolution gives us insight into how tive control [18], all of which are influenced human body weight is regulated and what by both genetic and environmental factors. changes need to be made to our societies and There are many forces acting to control health care strategies to better protect body weight and adiposity of mammals. The against metabolic disease. threat of starvation drives the need to maintain a lower limit on body fat. Energy stores ADAPTATIONS FOR THRIFTINESS are needed to avoid starving to death at any minor disruption in food access. Fertility is also profoundly affected by body fat [19]. The Thrifty Gene Hypothesis Ovarian cycles are very sensitive to energy In 1962, geneticist James Neel intro- balance signals [20], and a certain percent- duced the first major evolution-based expla- age of body fat is needed for female mam- nation for the modern obesity epidemic [12]. Genné-Bacon: Thinking evolutionarily about obesity 101

His original hypothesis centered on explain- cycle of feast and famine was an important ing the unusually high prevalence of dia- driving force throughout all of human evo- betes in certain human populations, but has lution, why are not all humans obese? been revised to include both obesity and Human populations show great differences other components of the metabolic syn- in their susceptibility to obesity and diabetes drome [28]. [1,10]. Further, even within populations liv- Neel argued that the tendency to de- ing in the same environments there are many velop diabetes (or become obese) is an adap- individuals who appear to be resistant to tive trait that has become incompatible with obesity [34]. To address this shortcoming, modern lifestyles. His “thrifty gene hypoth- Andrew Prentice later proposed that rather esis (TGH†)” rests on the assumption that than famine being an “ever present” selec- during the course of human evolution, hu- tive pressure throughout human evolution, it mans were constantly subjected to periods is only much more recently, in the approxi- of feast and famine. During famines, indi- mately 10,000 years since the advent of agri- viduals who had more energy stores were culture, that famine has become a major more likely to survive and produce more off- selective pressure, and as such it’s possible spring. Therefore, evolution acted to select that there hasn’t been sufficient time for for genes that made those who possessed thrifty genes to reach fixation [35]. Hunter- them highly efficient at storing fat during gatherer societies, the main lifestyle of ar- times of plenty. In modern industrialized so- chaic humans, do not often experience cieties where feasts are common and famine because their mobility and flexibil- famines rare, this evolutionary adaptation ity allows them to move or utilize alterna- becomes maladaptive. Thus, there is a mis- tive food sources when they encounter match between the environment in which environmental hardship [36]. In contrast, humans live and the environment in which agriculturalists exploit relatively few staple we evolved. Thrifty genes act to efficiently crops and have less flexibility to handle store energy to prepare for a famine that droughts and other calamities. Thus, the never comes [12]. feast/famine cycle may have selected for The TGH provides a simple and elegant thrifty genes only in agricultural societies explanation for the modern obesity epidemic [36]. This could explain why not all humans and was quickly embraced by scientists and become obese and why there is variation be- lay people alike. Some evidence supports tween populations. Some populations may this hypothesis. An important implication of have experienced more famine or periods of the TGH is that identifiable genetic poly- food scarcity throughout their history and morphisms that confer a “thrifty” phenotype thus had more pressure to develop a thrifty should exist. Both obesity and diabetes are genotype. known to have a strong genetic component The TGH provides several testable pre- [7,8,29,30], and several genetic polymor- dictions. One such prediction, if the post- phisms have been found that predispose in- agricultural model is assumed, is that dividuals to obesity [31,32], suggesting genetic loci associated with obesity and di- potential components of the “thrifty geno- abetes should show characteristic signs of type.” Many single nucleotide polymor- recent positive selection. However, a study phisms (SNPs) associated with increased by Southam et al. (2007) testing 13 obesity- risk of obesity have now been identified and 17 type 2 diabetes-associated genetic through genome-wide association (GWA) variants (comprising a comprehensive list of studies, though each has relatively small ef- the most well-established obesity- and dia- fect [13]. betes-associated loci at the time of publica- One main criticism to the thrifty gene tion) found little evidence for recent positive hypothesis is that it is unable to explain the selection [37]. This study found only one heterogeneity of diabetes and obesity be- risk loci, a mutation in the obesity-associ- tween and within populations [33]. If the ated FTO gene, showing evidence for recent 102 Genné-Bacon: Thinking evolutionarily about obesity

positive selection. This would appear to adapted to a diabetogenic diet [38]. Intro- mainly be evidence against the TGH; how- duction of a European-style diet to popula- ever, it relied on SNP data, and so these loci tions that are not used to it, such as Native may only be associative rather than func- Americans and Pacific Islanders, creates a tional. Refinement of the genetics of obesity mismatch between their modern diet and the and diabetes risk should result in more in- diet they have evolved with, leading to formative tests for selection. metabolic dysfunction. This potentially ex- Another prediction of the post-agricul- plains the recent dramatic increase in dia- tural TGH is that populations that have his- betes and obesity in these populations. torically encountered more famine and food Others suggest that loss of thriftiness is a re- scarcity should be more prone to obesity and cent adaptation, causing differences in the diabetes once exposed to an obesogenic en- prevalence of metabolic disease between vironment. So far, there is mixed evidence populations [39]. Instead of searching for for this prediction. Some hunter-gatherer disease-risk genes conferring susceptibility populations, for whom famine would have to metabolic disease, we should instead been historically uncommon, seem to show focus efforts on finding genetic variants con- some resistance to diet-induced obesity [35] ferring resistance to these disorders [39]. compared to populations with a history of The study by Southam et al. found evidence agriculture, which is consistent with the of recent positive selection on one allele that TGH’s predictions. However, this model is protective against diabetes [37]. A large- also predicts that agricultural societies, par- scale study searching for signs of recent pos- ticularly those from colder climates, would itive selection on diabetes and obesity have experienced the strongest selective resistance alleles could be fruitful to test pressures for genetic thriftiness and thus be these hypotheses. particularly prone to obesity and type 2 dia- In terms of clinical management of obe- betes. Europe is a prime example of this type sity and other metabolic disorders, the TGH of environment: Its peoples have long been implies that a return to the traditional practicing agriculture, and the historical lifestyle of a population would be beneficial record for war and famine in this region is for treating the metabolic syndrome. If obe- long and extensive [38]. Yet Europeans have sity is caused by a mismatch between our a lower rate of obesity than many popula- genes and the environment we currently live tions and seem partially resistant to type 2 in, changing the environment to match how diabetes [10,11]. Pacific Islanders, in con- our genomes have adapted should reverse trast, have some of the highest rates of obe- the obesity epidemic. Obviously, returning sity and type 2 diabetes in the world [10], to the traditional hunter-gather lifestyles of despite living in a tropical climate with very our ancestors is not practical. However, it is little history of famine [15,38]. possible to restrict calories and increase ex- Some researchers explain these dis- ercise to more closely mimic various tradi- crepancies by taking a flipped view of the tional lifestyles [40]. Current medical TGH, arguing that instead of recent selec- guidelines for the management of obesity tion for thrifty genes, it is actually genes and diabetes are based on this strategy conferring resistance to obesity and other [41,42]. Though this strategy seems to work metabolic disorders that are a modern adap- for some patients, there is much variability tation. This modified TGH posits that adap- in its efficacy, especially in managing obe- tations for thriftiness are ancient, but sity and diabetes long-term [43,44]. populations that have switched to richer The Thrifty Phenotype Hypothesis food sources since the advent of agriculture have gained some adaptations to prevent Not all researchers were convinced that metabolic disorders. Riccardo Baschetti’s the TGH satisfactorily explained the etiol- genetically unknown foods hypothesis ar- ogy of obesity and metabolic syndrome. In gues that Europeans have become partially 1992, Charles Hales and David Barker pro- Genné-Bacon: Thinking evolutionarily about obesity 103

posed his “thrifty phenotype hypothesis” hypotheses in 2007 [14]. These models gen- (also sometimes called the Barker Hypothe- erally fall into two categories: weather fore- sis), partly to address the inadequacies of cast models and maternal fitness models. gene-based obesity hypotheses such as TGH Weather forecast models argue that the and also to explain an observed phenome- fetus uses signals from the in utero environ- non: that babies with low birth weight seem ment ― particularly nutritional signals — to particularly prone to diabetes, obesity, heart “predict” what kind of environment it is disease, and other metabolic disorders later likely to encounter during childhood and/or in life [45]. adult life. It can be argued that it is evolu- Barker’s hypothesis centers on the con- tionarily advantageous to “prime” metabolic cept of “thriftiness,” but in a much different systems for thriftiness if poor nutrition is way than Neel’s hypothesis. In Barker’s hy- sensed early in life, in order to better deal pothesis, it is the developing fetus that must with a lifetime of poor nutrition. Metabolic be thrifty. An undernourished fetus must al- disorders then occur if the adult or childhood locate resources carefully if it is to survive to environment and fetal environment are mis- birth and adulthood. Barker argues that the matched. An individual whose fetal envi- developing fetus, when faced with an energy ronment “predicted” a lifetime of starvation shortage, will allocate energy away from the will readily develop diabetes and obesity pancreas in favor of other tissues such as the when he or she encounters a high caloric diet brain. This is a reasonable tradeoff, since if [14,46,47]. Although this family of models the same nutritional environment in which can explain the rapid onset of the obesity the fetus develops persists into its childhood epidemic in cultures suddenly introduced to and adult life, there will be little need for Western diets, it does not adequately explain well-developed glucose-response systems. why obesity and diabetes persist after sub- However, if nutrition improves later in life, sequent generations. the individual who once had a thrifty fetus Maternal fitness models argue that the will possess a pancreas ill-equipped to deal signals a fetus receives about nutrition in the with the glucose energy it now has access to womb allow it to align its energy needs with and will be prone to developing diabetes and its mother’s ability to supply during child- other metabolic diseases. This could explain hood. Humans have an unusually long pe- why babies with low birth weight seem par- riod of childhood growth, during which time ticularly prone to adulthood metabolic dis- children are nearly completely dependent on orders [45]. their mother for resources, even beyond Barker’s original hypothesis does not weaning. It is therefore adaptive to both specifically address evolutionary history, but mother and child if the child’s metabolic de- it does have evolutionary implications. In mand is synchronized with the mother’s this hypothesis, it is genes allowing com- own phenotype, so that the child will not re- pletion of prenatal development and survival quire more (or less) than she can provide. of the fetus that are selected for, rather than Aligning infant and maternal metabolism adaptive capability in adult life. It is only be- eases parent-offspring conflict and is impor- cause in the past prenatal nutrition matched tant for the successful rearing of the child adulthood nutrition that this process was [14,48], and thus this adaptation enhances adaptive. Now that this is often not the case, inclusive fitness. This thrifty phenotype this allocation of resources away from the model could explain why obesity is possible pancreas becomes maladaptive. even when a fetus is not malnourished. Since its proposal, the thrifty phenotype The implications of the thrifty pheno- hypothesis has inspired much further work type hypotheses for clinical management of connecting the hypothesis to evolutionary the metabolic syndrome are clear: Proper theory. Jonathan Wells reviewed several maternal and gestational nutrition are much competing or complementary models for the more important than interventions in adult evolutionary uses of the thrifty phenotype life. If the thrifty phenotype hypothesis is 104 Genné-Bacon: Thinking evolutionarily about obesity

correct, focusing preventive public health generations. Thus, a generation born during resources on pregnant woman will do much a time of famine may have epigenetic more to combat the obesity epidemic than genome modifications that allow for more focusing on treating disease in adults or even efficient energy storage, and these modifi- children. cations can be passed down through the germ line. Evidence from the “Dutch The Thrifty Epigenome Hypothesis Hunger Winter” study supports this. This One of the main criticisms of the TGH is study tracked the health of a cohort of males that if famine were such a strong driving born before, after, and during a severe force throughout human evolution, why do famine that occurred in the Netherlands dur- not all humans become obese? As mentioned ing World War II [52]. The study found that earlier, proponents of the TGH often argue males whose mothers had experienced that perhaps famine only became a strong se- famine during the first two trimesters of lective pressure since the rise of agriculture pregnancy had a much higher rate of obe- and, therefore, only certain populations have sity and diabetes than males born before or been subject to this kind of selective pressure after the famine [53]. Importantly, many of [49]. Richard Stöger’s “thrifty epigenome” the traits of the Dutch famine cohort have hypothesis takes the opposite view and ar- passed down to subsequent generations, gues that all humans harbor a thrifty genome. leading to the hypothesis that this cohort In fact, he argues that food scarcity has likely was subject to some kind of epigenetic been one of the key evolutionary forces modification affecting body weight and can throughout all the history of life, and meta- thus be said to have a “thrifty epigenotype” bolic thrift is likely a feature of all organisms. [50]. To test this hypothesis, Tobi et al. Stöger’s hypothesis sets out to reconcile (2009) examined methylation patterns in in- some of the holes in the thrifty genotype hy- dividuals conceived during or shortly before pothesis while integrating it with the thrifty the 1944 famine and compared them to their phenotype hypotheses [50]. un-exposed same-sex siblings [54]. They Stöger’s hypothesis relies on the con- found changes in the pattern of DNA cept of genetic canalization. Genetic canal- methylation of several growth and metabo- ization is a process through which a lism-associated loci in famine-exposed in- polygenic phenotype becomes “buffered” dividuals, providing support for the against genetic polymorphism and environ- hypothesis that in utero nutritional environmental variation. This process is adaptive ment can induce epigenetic modifications because fluctuating environmental pressures [54]. can leave subsequent generations unfit for Likewise, a generation born during their new environment. Thus, the long-term times of great food excess should be pro- evolutionary history of the species selects grammed for this environmental condition for a multigenetic system in which small and thus less prone to obesity. Stöger argues mutations make little difference in overall that this is exactly what is beginning to hap- phenotypic expression [51]. One potential pen among the Nauru people of the South way that species are able to maintain this Pacific. This population is believed to have kind of phenotypic robustness is through encountered repeated bouts of food scarcity epigenetic regulation [50]. throughout history and currently has one of Stöger argues that metabolic thrift has the highest obesity and diabetes rates in the been subject to genetic canalization and is a world, indicating that they have a “thrifty phenotypic trait that is able to adjust to dif- genotype.” However, in recent years, this fering environmental pressures through epi- trend has begun to reverse, with the rate of genetic modification. All humans have a type 2 diabetes falling, despite little change thrifty genome, but phenotypic expression in diet or lifestyle. Stöger argues that the can vary based on environmental input due Nauruans are beginning to transition to a to epigenetic modifications inherited across “feast epigenotype” [50]. Genné-Bacon: Thinking evolutionarily about obesity 105

An important implication of this hy- resistance and obesity. It argues that meta- pothesis is that genetic polymorphisms bolic diseases are byproducts of a socio-eco- likely have very little effect on the pathological adaptation that allows humans to physiology of obesity. This could be an ex- switch between both reproductive and socio- planation for why, despite decades of behavioral strategies. The strategies they research and countless GWA studies of ge- switch between are r- and K-selected repro- netic polymorphism, relatively few genetic duction and “stronger and smarter” lifestyle variants have been found that are associated strategies (which they describe as the “sol- with development of obesity or type 2 dia- dier to diplomat” transition). r/K selection betes. Instead, the thrifty epigenome hy- theory deals with the concept of parental in- pothesis implies that GWA studies of vestment in offspring and the trade-off be- epigenetic markers for obesity would be tween quality and quantity. Organisms that more fruitful. practice “r” selection invest more energy Additionally, implicit in this hypothesis into producing many offspring, with less in- is the idea that the obesity epidemic will vestment into the care of each [59]. It is fa- eventually solve itself, if Western diets re- vored when a species is well below the main constant. Populations currently expe- carrying capacity of their environment [59]. riencing an obesity problem will eventually Organisms that practice K-selection invest transition from a thrifty epigenome to a feast much time and energy into their offspring, epigenome. Recent evidence shows that this but produce relatively few [59]. It is favored transition has already begun. The U.S. obe- in species close to the carrying capacity of sity rate seems to have leveled off in recent their environment [59]. The authors argue years [34], and worldwide data shows that that the environmental and social conditions the rate of childhood obesity has also that favor a “K-selected” reproductive strat- plateaued [55]. egy (such as high population density) are the same as those that favor a “diplomat” behavioral strategy (such as food abundance A BEHAVIORAL ADAPTATION and social competition stress), and insulin While obesity and metabolic syndrome has evolved to be a common switch for both are often only considered in terms of purely these transitions. physiological processes and basic survival In this hypothesis, environmental stim- mechanisms, many others have framed these uli such as food abundance, population den- disorders in a more social context. Mankar sity, social stressors, and others serve as a (2008) showed that humans associate differ- single for the body to alter its use of insulin. ent adiposity levels with social status [56]. Their hypothesis hinges on the idea that dif- Others argue that during human history, obe- ferent tissues have different levels of de- sity has been a signal for wealth or fertility, pendence on insulin for glucose uptake, with allowing those who easily became obese to skeletal muscle tissue being among the most attract more mates and successfully produce insulin-dependent and brain and placental and rear more offspring [57]. Indeed, some tissue being among the most insulin-inde- of the oldest examples of human art ― Pa- pendent [15]. By decreasing the use of in- leolithic Venus figurines — depict women sulin by muscle and other insulin-dependent with obese bodies and are thought to be fer- tissues, insulin resistance frees up energy for tility symbols [58]. Humans are a highly so- use in the brain and/or placenta, facilitating cial species, and thus, social interactions a switch in both behavioral and reproductive have played a major part in shaping human strategies. More glucose diverted to the pla- evolution. centa could result in larger infant birth Watve and Yajnik’s (2007) “behavioral weights and mediate a switch to a K-selected switch hypothesis” integrates both social reproductive strategy. Additionally, insulin and physiological mechanisms into a unified resistance reduces ovulation, thus resulting theory for the evolutionary origins of insulin in fewer offspring and allowing greater in- 106 Genné-Bacon: Thinking evolutionarily about obesity

vestment in each. Diverting glucose from The behavioral switch hypothesis ex- muscle tissue to the brain could mediate a plains the modern pandemic of metabolic switch from a “soldier” to “diplomat” diseases as caused by extreme environmen- lifestyles. When food is scarce, energy is di- tal stimuli: population density, urbanization, verted to the skeletal muscle to enhance for- social competition, caloric access, and aging ability, so insulin sensitivity would be sedentary lifestyles exaggerated to an extent increased. When food is plentiful, the brain never before seen in human history [15]. As is more important than the muscles to the fit- with the “thrifty” family of hypotheses, ness of a social animal, so insulin sensitivity physiological responses that were adaptive would decrease in order to allocate more re- in the past have become maladaptive in sources to brain development. Insulin sig- modern environments. This implies a clini- naling in the brain is involved in many cal and epidemiological management strat- cognitive processes. The authors propose egy much different from the standard care that when intense brain activity is needed, guidelines. The hypothesis strongly suggests plasma levels of insulin increase, allowing that social reforms will be critical to com- for more insulin signaling in the brain. Be- batting obesity and metabolic syndrome as cause high plasma insulin levels can result a pandemic. The hypothesis predicts that in hypoglycemia, the body develops periph- obesity and diabetes should be more preva- eral insulin resistance to compensate [15]. lent in areas with higher population densi- The hypothesis suggests an explanation ties and with greater socioeconomic for the association between insulin resist- competition [15]. Reducing overcrowding in ance and morbidity. The authors note that el- urban areas and alleviating social competi- evated testosterone increases male tion by reducing wealth gaps and making so- aggression and is associated with a “soldier” cieties more egalitarian might affect this lifestyle, redistributing immune system out-of-control insulin response. function to emphasize the sub-cutaneous tissues in anticipation of increased need for NON-ADAPTIVE ORIGINS OF wound healing [60]. They posit that the ab- OBESITY dominal obesity associated with a transition from a soldier to diplomat lifestyles does the While all other explanations so far of- opposite: It redistributes immune function fered in this review have relied on the as- away from the periphery and focuses it on sumption that obesity was once an adaptive more central tissues. In the exaggerated mechanism of our evolutionary past, biolo- “diplomat” lifestyles of modern civilization, gist John Speakman argues in his “drifty this redistribution becomes pathological, gene hypothesis” just the opposite: that obe- leading to slowed wound healing and the in- sity is non-adaptive and has risen to high fre- creased inflammatory response that has been quency through neutral (i.e., random, shown to be associated with many disorders non-selective) evolutionary processes of the metabolic syndrome [15]. Impor- [9,24,33]. tantly, this implies the morbidity of insulin Speakman’s hypothesis is offered as a resistance is driven by changes in inflam- direct alternative to Neel’s hypothesis. matory response that are by-products of be- Through statistical models, he argues that if havioral transition, not because of insulin the feast/famine cycle was an “ever-present” itself. If this is true, it has profound implica- driving force of human evolution, as the tions for the clinical management of insulin original TGH argued, even small selective resistance and obesity. A focus on control- advantages for increased adiposity would ling the immunological changes that come have resulted in near fixation in all humans with the metabolic syndrome could do more over 2 million years of human evolution to mitigate disease and mortality than at- [13]. If this version of the TGH is accurate, tempting to treat obesity or insulin resistance Speakman argues, all humans would be themselves [15]. obese. However, even in the highly obeso- Genné-Bacon: Thinking evolutionarily about obesity 107

geneic environments of modern industrial- However, beginning approximately 2 mil- ized nations, only a fraction of the popula- lion years ago with the rise of the Homo tion is obese, while others seem resistant to genus, archaic humans developed larger obesity [33]. Indeed, as mentioned previ- body size, increased intelligence, tool use, ously, the obesity rate in the United States and were largely no longer subject to preda- has stalled recently [34]. A possible expla- tion pressure [24]. Speakman argues that be- nation is that all people who are prone to cause predation was no longer important, obesity have already become obese, leaving there was no more strong selective pressure no room for further growth. Alternatively, to remain lean. Thus, genes controlling the Speakman argues that if thriftiness is a post- upper limit of body weight in humans were agricultural adaptation, as Prentice and oth- freed from selective constraint and subject ers argue [49], not enough time has passed to genetic drift. This allowed mutations to to explain the extent of the modern obesity occur freely in these genes, resulting in their epidemic, given the small contribution to ad- function being lost or reduced in some indi- iposity conferred by the obesity-associated viduals and populations [33]. Speakman ar- genes identified thus far. gues that genetic drift is a better explanation Speakman also argues that the TGH’s for the variability seen in human body feast/famine cycle is not historically accu- weight than adaptation-based models. rate. He notes that while periods of minor Speakman’s hypothesis has been criti- food scarcity are relatively common, these cized on a few points, most notably in fail- periods do not result in increased mortality. ing to take into account the profound impact True famines that result in high mortality that famine has on fertility. In direct rebuttal have been relatively rare throughout human to Speakman’s hypothesis, Prentice et al. history, and during these periods the greatest (2008) [35] agreed with Speakman that mor- mortality is among the very old and very tality during famine was not great enough to young and thus unlikely to be a strong evo- drive evolution of a thrifty genotype, but ar- lutionary force [9]. gued instead that the profound effect that Speakman argues that freedom from se- starvation has on female fertility drove selective constraint over high adiposity, not lection for metabolic thriftiness. They point adaptation, is a better model to explain the out that near-complete suppression of fertil- current prevalence of obesity in modern so- ity has been observed in historical severe ciety. To explain what could have allowed famines and that fertility can be reduced by this freedom from selective constraint, 30 to 50 percent during normal hungry sea- Speakman offers a “predation-release” hy- sons in modern day Gambia and Bangladesh pothesis. It has been shown that predation- [35]. Thus, the TGH could still be viable, be- threat impacts weight regulation in prey cause metabolic thriftiness increases inclu- animals. Prey mammals reduce body size sive fitness. Speakman has countered these and foraging time when predators are pres- arguments by noting that after periods of ent [26,27]. When predators are experimen- famine, there is often a “bounce-back” in tally excluded from an area, bank and prairie fertility, with an increase in conceptions oc- voles increase their body weight compared curring to make up for the period of low fer- to controls [27]. In the laboratory, these tility during the famine [13,33]. same animals decrease their body mass Despite the controversy, this hypothesis when exposed to feces from a predator, but has intriguing implications for the study of not feces from a non-predator [24,27]. This human obesity. If mechanisms once existed is thought to protect against predation, since in humans who suppressed weight gain in smaller animals are able to move faster, fit response to predators, finding similar mech- into a greater number of hideaways, and anisms in animals may lead to identification make for less appealing prey targets [24]. of human genes and metabolic mechanisms In the past, archaic humans were also responsible for the control of body weight subject to strong predation pressure [61]. and the variation we see in populations. True 108 Genné-Bacon: Thinking evolutionarily about obesity

Table 1. Summary of evolutionary hypotheses for the metabolic syndrome. Name Proposed by Description Sources

Thrifty gene hypothesis James Neel Repeated exposure to famine led to [12,28] positive selection for genes promot- ing efficient energy storage.

Thrifty Barker Charles Hales An undernourished fetus must be [45] phenotype hypothesis and David “thrifty” with its resources, and sac- hypotheses Barker rifices pancreas development in favor of other tissues.

Weather Patrick Bateson Fetal environment predicts the qual- [14,46] Forecast model ity of the childhood environment. Mismatches between fetal and childhood environments lead to disease.

Maternal Fitness Jonathan Fetal environment uses nutritional [14,48] model Wells signals to align its metabolism with its mothers.

Intergenerational Christopher Intrauterine nutritional signals pro- [14,62] phenotypic inertia Kuzawa vide information about long-term model nutritional history of the mother and her recent ancestors through epigenetic mechanisms.

Predictive adaptive Peter Fetal environment predicts adult en- [14,47] response model Gluckman and vironment and primes metabolism Mark Hanson for adult life.

Thrifty epigenome hypothesis Reinhard All humans have a thrifty genotype. [50] Stöger Phenotypic expression of this is al- tered by epigenetic modifications that respond to environmental conditions.

Behavioral switch hypothesis Milind Watve Insulin resistance is a mechanism [15] and for both a switch between r/K repro- Chittaranjan ductive strategies and a switch be- Yajnik tween soldier/diplomat behavioral strategies.

Aggression control hypothesis Prakakta Insulin and satiety mediate aggres- [63] Belsare et al. sive and non-aggressive lifestyle strategies.

Drifty gene/predation release John Genes controlling the upper limit of [9,24,33] Speakman body weight have been freed from selective constrain and subject to genetic drift.

Maladaptation to brown adipose John Obesity is a byproduct of variation [13] tissue requirement Speakman in positive selection for thermogenesis.

Genetically unknown foods Riccardo Obesity and diabetes occurs when [38] hypothesis Baschetti populations are introduced to new foods that they haven’t adapted to.

Fertility first hypothesis Stephen Fertility, rather than starvation, is [64] Corbett et al. the main driver of selection for thrifty phenotypes. Genné-Bacon: Thinking evolutionarily about obesity 109

or not, Speakman’s hypothesis highlights the important factor in mediating the switch be- need for a better understanding of body tween reproductive and lifestyle strategies. weight regulation in other animals with a Food scarcity favors a “soldier” lifestyle, range of evolutionary histories in order to while food abundance favors a “diplomat” truly understand the origins of human obe- lifestyle. Metabolic thriftiness is still an im- sity. portant evolutionary force in the behavioral In terms of clinical implications, if obe- switch hypothesis. Finally, despite the fact sity is the result of deleterious mutations and that the drifty gene hypothesis was formed genetic drift, rather than an ingrained adap- to directly challenge the TGH, it is possible tive mechanism, it can be treated like a het- for elements of both hypotheses to be accu- erogenic disease. Insights from studying rate. Selection for thrifty genes could have how lean people (and other animals) regu- been accelerated in a predation-release/free- late their body weight can help identify dom from selective constraint scenario. In which genes have been mutated in obese in- the distant past, a balance may have existed dividuals. Speakman’s hypothesis would between metabolic thriftiness and weight- predict that many different systems in control to avoid predation, which may have weight regulation might have suffered loss- limited selection for thrifty genes. Once of-function mutations due to genetic drift, predator threat was eliminated and there was and different systems may be affected in dif- no more selection for leanness, it would be ferent individuals. Modern science is rapidly possible for selection for thriftiness to take approaching the era of personal genetics. If off. the genetics of the control of body weight Though there is room for more than one limit were well understood, weight manage- hypothesis to be correct, it is still important ment interventions could be tailored to an in- to determine the accurate evolutionary ori- dividual based on his or her individual gins of obesity. Despite very little rigorous genetic profile. For example, weight man- research to back it up, both researchers and agement strategies would be very different the general public have largely accepted the for someone whose obesity was caused by TGH. As a result, many assumptions have an underlying genetic problem with control been made about the causes of obesity based of food intake versus someone who had a on the TGH, which have highly influenced genetic defect in metabolic rate. research and clinical management of obesity and diabetes. Substantial research funds have been poured into finding the elusive CONCLUSIONS “thrifty” genes that would explain the extent In this review, I have discussed several of the obesity epidemic, yet those that have prominent competing hypotheses for the been found either explain obesity in only a evolutionary origins of the obesity epidemic. very small fraction of the population or in- They are summarized in Table 1, with addi- crease risk of obesity by extremely small tional hypotheses listed for reader interest. measures. A more rigorous examination of These hypotheses appear disparate, but are the validity of the TGH could lead to a more not necessarily incompatible. The thrifty directed and efficient approach to the etiol- epigenome hypothesis is a bridge between ogy of obesity. Each hypothesis I have dis- the thrifty gene and thrifty phenotype hy- cussed suggests very different research potheses. It offers a mechanism by which strategies. thrifty phenotypes work to shape metabo- Finally, the evolutionary mechanisms lism in utero, while making the same as- that allow for obesity are highly relevant to sumptions about evolutionary forces on the clinical and public health management of the genome that the TGH posits. The behavioral epidemic. The TGH suggests that simple switch hypothesis is also not incompatible changes in diet and exercise should prevent with the thrifty family of hypotheses. Food obesity, and while this intuitively makes scarcity pressures (or lack thereof) are an sense, we know that this strategy is easier 110 Genné-Bacon: Thinking evolutionarily about obesity

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