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YALE JOURNAL OF BIOLOGY AND MEDICINE 87 (2014), pp.99-112.Copyright © 2014.

FOCUS: 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 theircauses are not fully understood. Research into the etiology of the obesity epidemic is highlyinfluenced by our understanding of the evolutionary roots of metabolic control. For half a cen-tury, the thrifty gene hypothesis, which argues that obesity is an evolutionary adaptation forsurviving periods of famine, has dominated the thinking on this topic. Obesity researchersare often not aware that there is, in fact, limited evidence to support the thrifty gene hy-pothesis and that alternative hypotheses have been suggested. This review presents evi-dence for and against the thrifty gene hypothesis and introduces readers to additionalhypotheses for the evolutionary origins of the obesity epidemic. Because these alternatehypotheses imply significantly different strategies for research and clinical management ofobesity, their consideration is critical to halting the spread of this epidemic.

INTRODUCTION

The incidence of obesity worldwidehas risen dramatically in the past century,enough to be formally declared a globalepidemic by the World Health Organizationin 1997 [1]. Obesity (defined by a bodymass index exceeding 30 kg/m), togetherwith insulin resistance, dyslipidemia, andrelated conditions, defines “metabolic syn-

drome,” which strongly predisposes suffersto type 2 diabetes, cardiovascular disease,and early mortality [2]. Metabolic syn-drome affects 34 percent of Americans, 53percent of whom are obese [3]. Obesity is agrowing concern in developing nations[4,5] and is now one of the leading causesof preventable death worldwide [6].

Logically, a rapid increase in any med-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 hypothe-sis

Author’s note: Funding provided through the National Science Foundation Graduate Re-search Fellowship Program.

ronmental changes, yet obesity has beenshown in numerous studies to have a stronggenetic component [7,8], indicating a po-tential gene-environment interaction [9].Curiously, certain populations appear par-ticularly susceptible to obesity and meta-bolic syndrome [1,10], while others appearresistant [10,11]. The high prevalence of thisseemingly detrimental condition, combinedwith its uneven distribution among both in-dividuals and populations, has led to specu-lation about potential evolutionary origins ofobesity and metabolic syndrome [12-15].

Here I will review several hypotheses(both competing and complementary) forthe evolutionary origins of the obesity epi-demic and discuss their implications. I arguethat a better understanding of the evolution-ary forces that have shaped human meta-bolic control is critical to fighting themodern day obesity epidemic. Understand-ing the evolutionary origins of obesity canlead to novel approaches for research intothe pathophysiology of obesity as well as itsclinical management.

WHY CONTROL BODY WEIGHT?To understand the modern pathophysi-

ology of obesity, it is useful to examine thepart that body weight regulation plays in theevolutionary fitness of animals. What forcesdrive an organism to maintain a minimumor maximum weight limit? It is important tofirst note that “body weight regulation” is anextremely complex process involving muchmore than simple metabolic efficiency. Itcomprises both peripheral and central sati-ety/hunger signals [16,17] as well as cogni-tive control [18], all of which are influencedby both genetic and environmental factors.

There are many forces acting to controlbody weight and adiposity of mammals. Thethreat of starvation drives the need to main-tain a lower limit on body fat. Energy storesare needed to avoid starving to death at anyminor disruption in food access. Fertility isalso profoundly affected by body fat [19].Ovarian cycles are very sensitive to energybalance signals [20], and a certain percent-age of body fat is needed for female mam-

mals to retain fertility and successfully ges-tate offspring [19]. Additionally, body fathelps to maintain temperature homeostasis.White adipose tissue acts as an insulator[21], while brown adipose actively con-tributes to thermogenesis [22].

Several forces maintain the upperboundary of body fat in animals. The timeneeded to devote to foraging is one. Main-taining high adiposity is energetically costlyand requires large caloric input [23]. Formost wild animals, far too much time wouldneed to be devoted to foraging at the ex-pense of other important activities such asmating, sleeping, or avoiding predators [23].Prey animals must remain lean enough toavoid predation. An obese animal cannotmove as quickly nor hide as efficiently as alean animal [24]. It has been demonstratedin laboratory studies that many small preyanimals are resistant to diet-induced obesity,even with unlimited access to highly caloricfood [25]. In addition, some prey animalshave been shown experimentally to reducebody weight when predators are present intheir habitat [26,27], presumably to avoidpredation.

Modern humans are largely bufferedfrom these factors. Global economies safe-guard developed nations from starvation andallow for easy access to highly caloric food.Shelter and clothing protect us from thecold. We are seldom forced to hunt prey, andneither do we worry about becoming preyourselves [24]. Though modern humans mayno longer be subject to these forces, they arestill highly relevant to our health. Under-standing how these forces contributed tohuman evolution gives us insight into howhuman body weight is regulated and whatchanges need to be made to our societies andhealth care strategies to better protectagainst metabolic disease.

ADAPTATIONS FOR THRIFTINESS

The Thrifty Gene HypothesisIn 1962, geneticist James Neel intro-

duced the first major evolution-based expla-nation for the modern obesity epidemic [12].

100 Genné-Bacon: Thinking evolutionarily about obesity

His original hypothesis centered on explain-ing the unusually high prevalence of dia-betes in certain human populations, but hasbeen revised to include both obesity andother components of the metabolic syn-drome [28].

Neel argued that the tendency to de-velop diabetes (or become obese) is an adap-tive trait that has become incompatible withmodern lifestyles. His “thrifty gene hypoth-esis (TGH†)” rests on the assumption thatduring the course of human evolution, hu-mans were constantly subjected to periodsof feast and famine. During famines, indi-viduals who had more energy stores weremore likely to survive and produce more off-spring. Therefore, evolution acted to selectfor genes that made those who possessedthem highly efficient at storing fat duringtimes of plenty. In modern industrialized so-cieties where feasts are common andfamines rare, this evolutionary adaptationbecomes maladaptive. Thus, there is a mis-match between the environment in whichhumans live and the environment in whichwe evolved. Thrifty genes act to efficientlystore energy to prepare for a famine thatnever comes [12].

The TGH provides a simple and elegantexplanation for the modern obesity epidemicand was quickly embraced by scientists andlay people alike. Some evidence supportsthis hypothesis. An important implication ofthe TGH is that identifiable genetic poly-morphisms that confer a “thrifty” phenotypeshould exist. Both obesity and diabetes areknown to have a strong genetic component[7,8,29,30], and several genetic polymor-phisms have been found that predispose in-dividuals to obesity [31,32], suggestingpotential components of the “thrifty geno-type.” Many single nucleotide polymor-phisms (SNPs) associated with increasedrisk of obesity have now been identifiedthrough genome-wide association (GWA)studies, though each has relatively small ef-fect [13].

One main criticism to the thrifty genehypothesis is that it is unable to explain theheterogeneity of diabetes and obesity be-tween and within populations [33]. If the

cycle of feast and famine was an importantdriving force throughout all of human evo-lution, why are not all humans obese?Human populations show great differencesin their susceptibility to obesity and diabetes[1,10]. Further, even within populations liv-ing in the same environments there are manyindividuals who appear to be resistant toobesity [34]. To address this shortcoming,Andrew Prentice later proposed that ratherthan famine being an “ever present” selec-tive pressure throughout human evolution, itis only much more recently, in the approxi-mately 10,000 years since the advent of agri-culture, that famine has become a majorselective pressure, and as such it’s possiblethat there hasn’t been sufficient time forthrifty genes to reach fixation [35]. Hunter-gatherer societies, the main lifestyle of ar-chaic humans, do not often experiencefamine because their mobility and flexibil-ity allows them to move or utilize alterna-tive food sources when they encounterenvironmental hardship [36]. In contrast,agriculturalists exploit relatively few staplecrops and have less flexibility to handledroughts and other calamities. Thus, thefeast/famine cycle may have selected forthrifty genes only in agricultural societies[36]. This could explain why not all humansbecome obese and why there is variation be-tween populations. Some populations mayhave experienced more famine or periods offood scarcity throughout their history andthus had more pressure to develop a thriftygenotype.

The TGH provides several testable pre-dictions. One such prediction, if the post-agricultural model is assumed, is thatgenetic loci associated with obesity and di-abetes should show characteristic signs ofrecent positive selection. However, a studyby Southam et al. (2007) testing 13 obesity-and 17 type 2 diabetes-associated geneticvariants (comprising a comprehensive list ofthe most well-established obesity- and dia-betes-associated loci at the time of publica-tion) found little evidence for recent positiveselection [37]. This study found only onerisk loci, a mutation in the obesity-associ-ated FTO gene, showing evidence for recent

101Genné-Bacon: Thinking evolutionarily about obesity

positive selection. This would appear tomainly be evidence against the TGH; how-ever, it relied on SNP data, and so these locimay only be associative rather than func-tional. Refinement of the genetics of obesityand diabetes risk should result in more in-formative tests for selection.

Another prediction of the post-agricul-tural TGH is that populations that have his-torically encountered more famine and foodscarcity should be more prone to obesity anddiabetes once exposed to an obesogenic en-vironment. So far, there is mixed evidencefor this prediction. Some hunter-gathererpopulations, for whom famine would havebeen historically uncommon, seem to showsome resistance to diet-induced obesity [35]compared to populations with a history ofagriculture, which is consistent with theTGH’s predictions. However, this modelalso predicts that agricultural societies, par-ticularly those from colder climates, wouldhave experienced the strongest selectivepressures for genetic thriftiness and thus beparticularly prone to obesity and type 2 dia-betes. Europe is a prime example of this typeof environment: Its peoples have long beenpracticing agriculture, and the historicalrecord for war and famine in this region islong and extensive [38]. Yet Europeans havea lower rate of obesity than many popula-tions and seem partially resistant to type 2diabetes [10,11]. Pacific Islanders, in con-trast, have some of the highest rates of obe-sity and type 2 diabetes in the world [10],despite living in a tropical climate with verylittle history of famine [15,38].

Some researchers explain these dis-crepancies by taking a flipped view of theTGH, arguing that instead of recent selec-tion for thrifty genes, it is actually genesconferring resistance to obesity and othermetabolic disorders that are a modern adap-tation. This modified TGH posits that adap-tations for thriftiness are ancient, butpopulations that have switched to richerfood sources since the advent of agriculturehave gained some adaptations to preventmetabolic disorders. Riccardo Baschetti’sgenetically unknown foods hypothesis ar-gues that Europeans have become partially

adapted to a diabetogenic diet [38]. Intro-duction of a European-style diet to popula-tions that are not used to it, such as NativeAmericans and Pacific Islanders, creates amismatch between their modern diet and thediet they have evolved with, leading tometabolic dysfunction. This potentially ex-plains the recent dramatic increase in dia-betes and obesity in these populations.Others suggest that loss of thriftiness is a re-cent adaptation, causing differences in theprevalence of metabolic disease betweenpopulations [39]. Instead of searching fordisease-risk genes conferring susceptibilityto metabolic disease, we should insteadfocus efforts on finding genetic variants con-ferring resistance to these disorders [39].The study by Southam et al. found evidenceof recent positive selection on one allele thatis protective against diabetes [37]. A large-scale study searching for signs of recent pos-itive selection on diabetes and obesityresistance alleles could be fruitful to testthese hypotheses.

In terms of clinical management of obe-sity and other metabolic disorders, the TGHimplies that a return to the traditionallifestyle of a population would be beneficialfor treating the metabolic syndrome. If obe-sity is caused by a mismatch between ourgenes and the environment we currently livein, changing the environment to match howour genomes have adapted should reversethe obesity epidemic. Obviously, returningto the traditional hunter-gather lifestyles ofour ancestors is not practical. However, it ispossible to restrict calories and increase ex-ercise to more closely mimic various tradi-tional lifestyles [40]. Current medicalguidelines for the management of obesityand diabetes are based on this strategy[41,42]. Though this strategy seems to workfor some patients, there is much variabilityin its efficacy, especially in managing obe-sity and diabetes long-term [43,44].

The Thrifty Phenotype Hypothesis

Not all researchers were convinced thatthe TGH satisfactorily explained the etiol-ogy of obesity and metabolic syndrome. In1992, Charles Hales and David Barker pro-


posed his “thrifty phenotype hypothesis”(also sometimes called the Barker Hypothe-sis), partly to address the inadequacies ofgene-based obesity hypotheses such as TGHand also to explain an observed phenome-non: that babies with low birth weight seemparticularly prone to diabetes, obesity, heartdisease, and other metabolic disorders laterin life [45].

Barker’s hypothesis centers on the con-cept of “thriftiness,” but in a much differentway than Neel’s hypothesis. In Barker’s hy-pothesis, it is the developing fetus that mustbe thrifty. An undernourished fetus must al-locate resources carefully if it is to survive tobirth and adulthood. Barker argues that thedeveloping fetus, when faced with an energyshortage, will allocate energy away from thepancreas in favor of other tissues such as thebrain. This is a reasonable tradeoff, since ifthe same nutritional environment in whichthe fetus develops persists into its childhoodand adult life, there will be little need forwell-developed glucose-response systems.However, if nutrition improves later in life,the individual who once had a thrifty fetuswill possess a pancreas ill-equipped to dealwith the glucose energy it now has access toand will be prone to developing diabetes andother metabolic diseases. This could explainwhy babies with low birth weight seem par-ticularly prone to adulthood metabolic dis-orders [45].

Barker’s original hypothesis does notspecifically address evolutionary history, butit does have evolutionary implications. Inthis hypothesis, it is genes allowing com-pletion of prenatal development and survivalof the fetus that are selected for, rather thanadaptive capability in adult life. It is only be-cause in the past prenatal nutrition matchedadulthood nutrition that this process wasadaptive. Now that this is often not the case,this allocation of resources away from thepancreas becomes maladaptive.

Since its proposal, the thrifty phenotypehypothesis has inspired much further workconnecting the hypothesis to evolutionarytheory. Jonathan Wells reviewed severalcompeting or complementary models for theevolutionary uses of the thrifty phenotype

hypotheses in 2007 [14]. These models gen-erally fall into two categories: weather fore-cast models and maternal fitness models.

Weather forecast models argue that thefetus uses signals from the in utero environ-ment ― particularly nutritional signals — to“predict” what kind of environment it islikely to encounter during childhood and/oradult life. It can be argued that it is evolu-tionarily advantageous to “prime” metabolicsystems for thriftiness if poor nutrition issensed early in life, in order to better dealwith a lifetime of poor nutrition. Metabolicdisorders then occur if the adult or childhoodenvironment and fetal environment are mis-matched. An individual whose fetal envi-ronment “predicted” a lifetime of starvationwill readily develop diabetes and obesitywhen he or she encounters a high caloric diet[14,46,47]. Although this family of modelscan explain the rapid onset of the obesityepidemic in cultures suddenly introduced toWestern diets, it does not adequately explainwhy obesity and diabetes persist after sub-sequent generations.

Maternal fitness models argue that thesignals a fetus receives about nutrition in thewomb allow it to align its energy needs withits mother’s ability to supply during child-hood. Humans have an unusually long pe-riod of childhood growth, during which timechildren are nearly completely dependent ontheir mother for resources, even beyondweaning. It is therefore adaptive to bothmother and child if the child’s metabolic de-mand is synchronized with the mother’sown phenotype, so that the child will not re-quire more (or less) than she can provide.Aligning infant and maternal metabolismeases parent-offspring conflict and is impor-tant for the successful rearing of the child[14,48], and thus this adaptation enhancesinclusive fitness. This thrifty phenotypemodel could explain why obesity is possibleeven when a fetus is not malnourished.

The implications of the thrifty pheno-type hypotheses for clinical management ofthe metabolic syndrome are clear: Propermaternal and gestational nutrition are muchmore important than interventions in adultlife. If the thrifty phenotype hypothesis is


correct, focusing preventive public healthresources on pregnant woman will do muchmore to combat the obesity epidemic thanfocusing on treating disease in adults or evenchildren.

The Thrifty Epigenome Hypothesis

One of the main criticisms of the TGH isthat if famine were such a strong drivingforce throughout human evolution, why donot all humans become obese? As mentionedearlier, proponents of the TGH often arguethat perhaps famine only became a strong se-lective pressure since the rise of agricultureand, therefore, only certain populations havebeen subject to this kind of selective pressure[49]. Richard Stöger’s “thrifty epigenome”hypothesis takes the opposite view and ar-gues that all humans harbor a thrifty genome.In fact, he argues that food scarcity has likelybeen one of the key evolutionary forcesthroughout all the history of life, and meta-bolic thrift is likely a feature of all organisms.Stöger’s hypothesis sets out to reconcilesome of the holes in the thrifty genotype hy-pothesis while integrating it with the thriftyphenotype hypotheses [50].

Stöger’s hypothesis relies on the con-cept of genetic canalization. Genetic canal-ization is a process through which apolygenic phenotype becomes “buffered”against genetic polymorphism and environ-mental variation. This process is adaptivebecause fluctuating environmental pressurescan leave subsequent generations unfit fortheir new environment. Thus, the long-termevolutionary history of the species selectsfor a multigenetic system in which smallmutations make little difference in overallphenotypic expression [51]. One potentialway that species are able to maintain thiskind of phenotypic robustness is throughepigenetic regulation [50].

Stöger argues that metabolic thrift hasbeen subject to genetic canalization and is aphenotypic trait that is able to adjust to dif-fering environmental pressures through epi-genetic modification. All humans have athrifty genome, but phenotypic expressioncan vary based on environmental input dueto epigenetic modifications inherited across

generations. Thus, a generation born duringa time of famine may have epigeneticgenome modifications that allow for moreefficient energy storage, and these modifi-cations can be passed down through thegerm line. Evidence from the “DutchHunger Winter” study supports this. Thisstudy tracked the health of a cohort of malesborn before, after, and during a severefamine that occurred in the Netherlands dur-ing World War II [52]. The study found thatmales whose mothers had experiencedfamine during the first two trimesters ofpregnancy had a much higher rate of obe-sity and diabetes than males born before orafter the famine [53]. Importantly, many ofthe traits of the Dutch famine cohort havepassed down to subsequent generations,leading to the hypothesis that this cohortwas subject to some kind of epigeneticmodification affecting body weight and canthus be said to have a “thrifty epigenotype”[50]. To test this hypothesis, Tobi et al.(2009) examined methylation patterns in in-dividuals conceived during or shortly beforethe 1944 famine and compared them to theirun-exposed same-sex siblings [54]. Theyfound changes in the pattern of DNAmethylation of several growth and metabo-lism-associated loci in famine-exposed in-dividuals, providing support for thehypothesis that in utero nutritional environ-ment can induce epigenetic modifications[54].

Likewise, a generation born duringtimes of great food excess should be pro-grammed for this environmental conditionand thus less prone to obesity. Stöger arguesthat this is exactly what is beginning to hap-pen among the Nauru people of the SouthPacific. This population is believed to haveencountered repeated bouts of food scarcitythroughout history and currently has one ofthe highest obesity and diabetes rates in theworld, indicating that they have a “thriftygenotype.” However, in recent years, thistrend has begun to reverse, with the rate oftype 2 diabetes falling, despite little changein diet or lifestyle. Stöger argues that theNauruans are beginning to transition to a“feast epigenotype” [50].


An important implication of this hy-pothesis is that genetic polymorphismslikely have very little effect on the patho-physiology of obesity. This could be an ex-planation for why, despite decades ofresearch and countless GWA studies of ge-netic polymorphism, relatively few geneticvariants have been found that are associatedwith development of obesity or type 2 dia-betes. Instead, the thrifty epigenome hy-pothesis implies that GWA studies ofepigenetic markers for obesity would bemore fruitful.

Additionally, implicit in this hypothesisis the idea that the obesity epidemic willeventually solve itself, if Western diets re-main constant. Populations currently expe-riencing an obesity problem will eventuallytransition from a thrifty epigenome to a feastepigenome. Recent evidence shows that thistransition has already begun. The U.S. obe-sity rate seems to have leveled off in recentyears [34], and worldwide data shows thatthe rate of childhood obesity has alsoplateaued [55].

A BEHAVIORAL ADAPTATIONWhile obesity and metabolic syndrome

are often only considered in terms of purelyphysiological processes and basic survivalmechanisms, many others have framed thesedisorders in a more social context. Mankar(2008) showed that humans associate differ-ent adiposity levels with social status [56].Others argue that during human history, obe-sity has been a signal for wealth or fertility,allowing those who easily became obese toattract more mates and successfully produceand rear more offspring [57]. Indeed, someof the oldest examples of human art ― Pa-leolithic Venus figurines — depict womenwith obese bodies and are thought to be fer-tility symbols [58]. Humans are a highly so-cial species, and thus, social interactionshave played a major part in shaping humanevolution.

Watve and Yajnik’s (2007) “behavioralswitch hypothesis” integrates both socialand physiological mechanisms into a unifiedtheory for the evolutionary origins of insulin

resistance and obesity. It argues that meta-bolic diseases are byproducts of a socio-eco-logical adaptation that allows humans toswitch between both reproductive and socio-behavioral strategies. The strategies theyswitch between are r- and K-selected repro-duction and “stronger and smarter” lifestylestrategies (which they describe as the “sol-dier to diplomat” transition). r/K selectiontheory deals with the concept of parental in-vestment in offspring and the trade-off be-tween quality and quantity. Organisms thatpractice “r” selection invest more energyinto producing many offspring, with less in-vestment into the care of each [59]. It is fa-vored when a species is well below thecarrying capacity of their environment [59].Organisms that practice K-selection investmuch time and energy into their offspring,but produce relatively few [59]. It is favoredin species close to the carrying capacity oftheir environment [59]. The authors arguethat the environmental and social conditionsthat favor a “K-selected” reproductive strat-egy (such as high population density) are thesame as those that favor a “diplomat” be-havioral strategy (such as food abundanceand social competition stress), and insulinhas evolved to be a common switch for boththese transitions.

In this hypothesis, environmental stim-uli such as food abundance, population den-sity, social stressors, and others serve as asingle for the body to alter its use of insulin.Their hypothesis hinges on the idea that dif-ferent tissues have different levels of de-pendence on insulin for glucose uptake, withskeletal muscle tissue being among the mostinsulin-dependent and brain and placentaltissue being among the most insulin-inde-pendent [15]. By decreasing the use of in-sulin by muscle and other insulin-dependenttissues, insulin resistance frees up energy foruse in the brain and/or placenta, facilitatinga switch in both behavioral and reproductivestrategies. More glucose diverted to the pla-centa could result in larger infant birthweights and mediate a switch to a K-selectedreproductive strategy. Additionally, insulinresistance reduces ovulation, thus resultingin fewer offspring and allowing greater in-


vestment in each. Diverting glucose frommuscle tissue to the brain could mediate aswitch from a “soldier” to “diplomat”lifestyles. When food is scarce, energy is di-verted to the skeletal muscle to enhance for-aging ability, so insulin sensitivity would beincreased. When food is plentiful, the brainis more important than the muscles to the fit-ness of a social animal, so insulin sensitivitywould decrease in order to allocate more re-sources to brain development. Insulin sig-naling in the brain is involved in manycognitive processes. The authors proposethat when intense brain activity is needed,plasma levels of insulin increase, allowingfor more insulin signaling in the brain. Be-cause high plasma insulin levels can resultin hypoglycemia, the body develops periph-eral insulin resistance to compensate [15].

The hypothesis suggests an explanationfor the association between insulin resist-ance and morbidity. The authors note that el-evated testosterone increases maleaggression and is associated with a “soldier”lifestyle, redistributing immune systemfunction to emphasize the sub-cutaneous tis-sues in anticipation of increased need forwound healing [60]. They posit that the ab-dominal obesity associated with a transitionfrom a soldier to diplomat lifestyles does theopposite: It redistributes immune functionaway from the periphery and focuses it onmore central tissues. In the exaggerated“diplomat” lifestyles of modern civilization,this redistribution becomes pathological,leading to slowed wound healing and the in-creased inflammatory response that has beenshown to be associated with many disordersof the metabolic syndrome [15]. Impor-tantly, this implies the morbidity of insulinresistance is driven by changes in inflam-matory response that are by-products of be-havioral transition, not because of insulinitself. If this is true, it has profound implica-tions for the clinical management of insulinresistance and obesity. A focus on control-ling the immunological changes that comewith the metabolic syndrome could do moreto mitigate disease and mortality than at-tempting to treat obesity or insulin resistancethemselves [15].

The behavioral switch hypothesis ex-plains the modern pandemic of metabolicdiseases as caused by extreme environmen-tal stimuli: population density, urbanization,social competition, caloric access, andsedentary lifestyles exaggerated to an extentnever before seen in human history [15]. Aswith the “thrifty” family of hypotheses,physiological responses that were adaptivein the past have become maladaptive inmodern environments. This implies a clini-cal and epidemiological management strat-egy much different from the standard careguidelines. The hypothesis strongly suggeststhat social reforms will be critical to com-batting obesity and metabolic syndrome asa pandemic. The hypothesis predicts thatobesity and diabetes should be more preva-lent in areas with higher population densi-ties and with greater socioeconomiccompetition [15]. Reducing overcrowding inurban areas and alleviating social competi-tion by reducing wealth gaps and making so-cieties more egalitarian might affect thisout-of-control insulin response.

NON-ADAPTIVE ORIGINS OF OBESITY

While all other explanations so far of-fered in this review have relied on the as-sumption that obesity was once an adaptivemechanism of our evolutionary past, biolo-gist John Speakman argues in his “driftygene hypothesis” just the opposite: that obe-sity is non-adaptive and has risen to high fre-quency through neutral (i.e., random,non-selective) evolutionary processes[9,24,33].

Speakman’s hypothesis is offered as adirect alternative to Neel’s hypothesis.Through statistical models, he argues that ifthe feast/famine cycle was an “ever-present”driving force of human evolution, as theoriginal TGH argued, even small selectiveadvantages for increased adiposity wouldhave resulted in near fixation in all humansover 2 million years of human evolution[13]. If this version of the TGH is accurate,Speakman argues, all humans would beobese. However, even in the highly obeso-


geneic environments of modern industrial-ized nations, only a fraction of the popula-tion is obese, while others seem resistant toobesity [33]. Indeed, as mentioned previ-ously, the obesity rate in the United Stateshas stalled recently [34]. A possible expla-nation is that all people who are prone toobesity have already become obese, leavingno room for further growth. Alternatively,Speakman argues that if thriftiness is a post-agricultural adaptation, as Prentice and oth-ers argue [49], not enough time has passedto explain the extent of the modern obesityepidemic, given the small contribution to ad-iposity conferred by the obesity-associatedgenes identified thus far.

Speakman also argues that the TGH’sfeast/famine cycle is not historically accu-rate. He notes that while periods of minorfood scarcity are relatively common, theseperiods do not result in increased mortality.True famines that result in high mortalityhave been relatively rare throughout humanhistory, and during these periods the greatestmortality is among the very old and veryyoung and thus unlikely to be a strong evo-lutionary force [9].

Speakman argues that freedom from se-lective constraint over high adiposity, notadaptation, is a better model to explain thecurrent prevalence of obesity in modern so-ciety. To explain what could have allowedthis freedom from selective constraint,Speakman offers a “predation-release” hy-pothesis. It has been shown that predation-threat impacts weight regulation in preyanimals. Prey mammals reduce body sizeand foraging time when predators are pres-ent [26,27]. When predators are experimen-tally excluded from an area, bank and prairievoles increase their body weight comparedto controls [27]. In the laboratory, thesesame animals decrease their body masswhen exposed to feces from a predator, butnot feces from a non-predator [24,27]. Thisis thought to protect against predation, sincesmaller animals are able to move faster, fitinto a greater number of hideaways, andmake for less appealing prey targets [24].

In the past, archaic humans were alsosubject to strong predation pressure [61].

However, beginning approximately 2 mil-lion years ago with the rise of the Homogenus, archaic humans developed largerbody size, increased intelligence, tool use,and were largely no longer subject to preda-tion pressure [24]. Speakman argues that be-cause predation was no longer important,there was no more strong selective pressureto remain lean. Thus, genes controlling theupper limit of body weight in humans werefreed from selective constraint and subjectto genetic drift. This allowed mutations tooccur freely in these genes, resulting in theirfunction being lost or reduced in some indi-viduals and populations [33]. Speakman ar-gues that genetic drift is a better explanationfor the variability seen in human bodyweight than adaptation-based models.

Speakman’s hypothesis has been criti-cized on a few points, most notably in fail-ing to take into account the profound impactthat famine has on fertility. In direct rebuttalto Speakman’s hypothesis, Prentice et al.(2008) [35] agreed with Speakman that mor-tality during famine was not great enough todrive evolution of a thrifty genotype, but ar-gued instead that the profound effect thatstarvation has on female fertility drove se-lection for metabolic thriftiness. They pointout that near-complete suppression of fertil-ity has been observed in historical severefamines and that fertility can be reduced by30 to 50 percent during normal hungry sea-sons in modern day Gambia and Bangladesh[35]. Thus, the TGH could still be viable, be-cause metabolic thriftiness increases inclu-sive fitness. Speakman has countered thesearguments by noting that after periods offamine, there is often a “bounce-back” infertility, with an increase in conceptions oc-curring to make up for the period of low fer-tility during the famine [13,33].

Despite the controversy, this hypothesishas intriguing implications for the study ofhuman obesity. If mechanisms once existedin humans who suppressed weight gain inresponse to predators, finding similar mech-anisms in animals may lead to identificationof human genes and metabolic mechanismsresponsible for the control of body weightand the variation we see in populations. True



Table 1. Summary of evolutionary hypotheses for the metabolic syndrome.

Thrifty phenotype hypotheses

Barker hypothesis

Weather Forecast model

Maternal Fitnessmodel

Intergenerationalphenotypic inertiamodel

Predictive adaptiveresponse model

Proposed by

James Neel

Charles Halesand DavidBarker

Patrick Bateson

JonathanWells

ChristopherKuzawa

Peter Gluckman and Mark Hanson

ReinhardStöger

Milind Watveand ChittaranjanYajnik

Prakakta Belsare et al.

John Speakman

John Speakman

RiccardoBaschetti

Stephen Corbett et al.

Description

Repeated exposure to famine led topositive selection for genes promot-ing efficient energy storage.

An undernourished fetus must be“thrifty” with its resources, and sac-rifices pancreas development infavor of other tissues.

Fetal environment predicts the qual-ity of the childhood environment.Mismatches between fetal and child-hood environments lead to disease.

Fetal environment uses nutritionalsignals to align its metabolism withits mothers.

Intrauterine nutritional signals pro-vide information about long-termnutritional history of the mother andher recent ancestors through epige-netic mechanisms.

Fetal environment predicts adult en-vironment and primes metabolismfor adult life.

All humans have a thrifty genotype.Phenotypic expression of this is al-tered by epigenetic modificationsthat respond to environmental con-ditions.

Insulin resistance is a mechanismfor both a switch between r/K repro-ductive strategies and a switch be-tween soldier/diplomat behavioralstrategies.

Insulin and satiety mediate aggres-sive and non-aggressive lifestylestrategies.

Genes controlling the upper limit ofbody weight have been freed fromselective constrain and subject togenetic drift.

Obesity is a byproduct of variationin positive selection for thermogen-esis.

Obesity and diabetes occurs whenpopulations are introduced to newfoods that they haven’t adapted to.

Fertility, rather than starvation, isthe main driver of selection forthrifty phenotypes.

Sources

[12,28]

[45]

[14,46]

[14,48]

[14,62]

[14,47]

[50]

[15]

[63]

[9,24,33]

[13]

[38]

[64]

Name

Thrifty gene hypothesis

Thrifty epigenome hypothesis

Behavioral switch hypothesis

Aggression control hypothesis

Drifty gene/predation release

Maladaptation to brown adipose tissue requirement

Genetically unknown foods hypothesis

Fertility first hypothesis

or not, Speakman’s hypothesis highlights theneed for a better understanding of bodyweight regulation in other animals with arange of evolutionary histories in order totruly understand the origins of human obe-sity.

In terms of clinical implications, if obe-sity is the result of deleterious mutations andgenetic drift, rather than an ingrained adap-tive mechanism, it can be treated like a het-erogenic disease. Insights from studyinghow lean people (and other animals) regu-late their body weight can help identifywhich genes have been mutated in obese in-dividuals. Speakman’s hypothesis wouldpredict that many different systems inweight regulation might have suffered loss-of-function mutations due to genetic drift,and different systems may be affected in dif-ferent individuals. Modern science is rapidlyapproaching the era of personal genetics. Ifthe genetics of the control of body weightlimit were well understood, weight manage-ment interventions could be tailored to an in-dividual based on his or her individualgenetic profile. For example, weight man-agement strategies would be very differentfor someone whose obesity was caused byan underlying genetic problem with controlof food intake versus someone who had agenetic defect in metabolic rate.

CONCLUSIONSIn this review, I have discussed several

prominent competing hypotheses for theevolutionary origins of the obesity epidemic.They are summarized in Table 1, with addi-tional hypotheses listed for reader interest.These hypotheses appear disparate, but arenot necessarily incompatible. The thriftyepigenome hypothesis is a bridge betweenthe thrifty gene and thrifty phenotype hy-potheses. It offers a mechanism by whichthrifty phenotypes work to shape metabo-lism in utero, while making the same as-sumptions about evolutionary forces on thegenome that the TGH posits. The behavioralswitch hypothesis is also not incompatiblewith the thrifty family of hypotheses. Foodscarcity pressures (or lack thereof) are an

important factor in mediating the switch be-tween reproductive and lifestyle strategies.Food scarcity favors a “soldier” lifestyle,while food abundance favors a “diplomat”lifestyle. Metabolic thriftiness is still an im-portant evolutionary force in the behavioralswitch hypothesis. Finally, despite the factthat the drifty gene hypothesis was formedto directly challenge the TGH, it is possiblefor elements of both hypotheses to be accu-rate. Selection for thrifty genes could havebeen accelerated in a predation-release/free-dom from selective constraint scenario. Inthe distant past, a balance may have existedbetween metabolic thriftiness and weight-control to avoid predation, which may havelimited selection for thrifty genes. Oncepredator threat was eliminated and there wasno more selection for leanness, it would bepossible for selection for thriftiness to takeoff.

Though there is room for more than onehypothesis to be correct, it is still importantto determine the accurate evolutionary ori-gins of obesity. Despite very little rigorousresearch to back it up, both researchers andthe general public have largely accepted theTGH. As a result, many assumptions havebeen made about the causes of obesity basedon the TGH, which have highly influencedresearch and clinical management of obesityand diabetes. Substantial research fundshave been poured into finding the elusive“thrifty” genes that would explain the extentof the obesity epidemic, yet those that havebeen found either explain obesity in only avery small fraction of the population or in-crease risk of obesity by extremely smallmeasures. A more rigorous examination ofthe validity of the TGH could lead to a moredirected and efficient approach to the etiol-ogy of obesity. Each hypothesis I have dis-cussed suggests very different researchstrategies.

Finally, the evolutionary mechanismsthat allow for obesity are highly relevant toclinical and public health management of theepidemic. The TGH suggests that simplechanges in diet and exercise should preventobesity, and while this intuitively makessense, we know that this strategy is easier


said than done. Although correction of the“mismatch” between the environment inwhich humans evolved and our modern en-vironment could conceivably combat theobesity epidemic according to most of thehypotheses discussed, other hypotheses pro-vide much different and more specific strate-gies into the treatment and prevention ofobesity then does the TGH. The drifty genehypothesis implies that a more disease-based strategy focusing on individual ge-netic history is needed to treat obesity. Boththe thrifty phenotype and thrifty epigenomehypotheses put emphasis on in utero nutri-tion and imply that lifestyle changes madeduring adulthood are largely futile. Thesehypotheses have particular importance tofighting the rise of obesity in the developingworld. Finally, the behavioral switch hy-pothesis suggests a radically different treat-ment strategy for type 2 diabetes andobesity, with emphasis largely on fightinginflammatory response, rather than thesedisorders themselves. Additionally, the be-havioral switch hypothesis suggests thatsweeping social and economic reforms willreduce the underlying causes of the obesityepidemic and halt its growth.

While all of these strategies for clinicmanagement are not incompatible and couldcertainly be applied in parallel, given thelimited resources of global health care facil-ities, it is clear that further research isneeded to tailor treatments and find thosethat will prove most effective. Far frombeing a simple academic pursuit, the studyof human evolution is critically important tothe health of modern humans.

REFERENCES1. Caballero B. The Global Epidemic of Obesity:

An Overview. Epidemiol Rev. 2007;29:1-5. 2. Beltrán-Sánchez H, Harhay MO, Harhay

MM, McElligott S. Prevalence and Trends ofMetabolic Syndrome in the Adult U.S. Pop-ulation, 1999-2010. J Am Coll Cardiol.2013;62(8):697-703.

3. Ervin RB. Prevalence of metabolic syndromeamong adults 20 years of age and over, bysex, age, race and ethnicity, and body massindex: United States, 2003-2006. Natl HealthStat Report. 2009;(13):1-7.

4. Popkin BM, Adair LS, Ng SW. Global nutri-tion transition and the pandemic of obesity in

developing countries. Nutr Rev.2012;70(1):3-21.

5. Prentice AM. The emerging epidemic of obe-sity in developing countries. Int J Epidemiol.2006;35(1):93-9.

6. Barness LA, Opitz JM, Gilbert-Barness E.Obesity: genetic, molecular, and environ-mental aspects. Am J Med Genet A.2007;143A(24):3016-34.

7. Stunkard AJ, Sørensen TIA, Hanis C, Teas-dale TW, Chakraborty R, Schull WJ, et al. AnAdoption Study of Human Obesity. N Engl JMed. 1986;314(4):193-8.

8. Sørensen TI, Price RA, Stunkard AJ,Schulsinger F. Genetics of obesity in adultadoptees and their biological siblings. BMJ.1989;298(6666):87-90.

9. Speakman JR. Thrifty genes for obesity andthe metabolic syndrome—time to call off thesearch? Diab Vasc Dis Res. 2006;3(1):7-11.

10. Diamond J. The double puzzle of diabetes.Nature. 2003;423(6940):599-602.

11. Beck-Nielsen HH. General characteristics ofthe insulin resistance syndrome: prevalenceand heritability. European Group for thestudy of Insulin Resistance (EGIR). Drugs.1999;58(Suppl 1):75-82.

12. Neel JV. Diabetes Mellitus: A “Thrifty”Genotype Rendered Detrimental by“Progress”? Am J Hum Genet. 1962;14:353-62.

13. Speakman JR. Evolutionary perspectives onthe obesity epidemic: adaptive, maladaptive,and neutral viewpoints. Annu Rev Nutr.2013;33:289-317.

14. Wells JCK. Environmental quality, develop-mental plasticity and the thrifty phenotype: areview of evolutionary models. Evol Bioin-form Online. 2007;3:109-20.

15. Watve MG, Yajnik CS. Evolutionary originsof insulin resistance: a behavioral switch hy-pothesis. BMC Evol Biol. 2007;7:61.

16. Simpson K, Parker J, Plumer J, Bloom S.CCK, PYY and PP: The Control of EnergyBalance. Handbook of Experimental Phar-macology. Berlin, Heidelberg: SpringerBerlin Heidelberg; 2011. pp. 209-30.

17. Karatsoreos IN, Thaler JP, Borgland SL,Champagne FA, Hurd YL, Hill MN. Food forthought: hormonal, experiential, and neuralinfluences on feeding and obesity. J Neurosci.2013;33(45):17610-6.

18. Vainik U, Dagher A, Dubé L, Fellows LK.Neurobehavioural correlates of body massindex and eating behaviours in adults: A sys-tematic review. Neurosci Biobehav Rev.2013;37(3):279-99.

19. Frisch RE. Female Fertility and the Body FatConnection. Chicago: University of ChicagoPress; 2002.

20. The ESHRE Capri Workshop Group. Nutri-tion and reproduction in women. Hum Re-prod Update. 2006;12(3):193-207.

21. Daniels F, Baker PT. Relationship betweenbody fat and shivering in air at 15 C. J ApplPhysiol. 1961;16:421-5.


22. Cannon B, Nedergaard J. Brown AdiposeTissue: Function and Physiological Signifi-cance. Physiol Rev. 2004; 84(1):277-359.

23. Rowland N, Vaughan C, Mathes C, Mitra A.Feeding behavior, obesity, and neuroeco-nomics. Physiol Behav. 2008;93(1-2):97-109.

24. Speakman JR. A nonadaptive scenario ex-plaining the genetic predisposition to obesity:the “predation release” hypothesis. CellMetab. 2007;6(1):5-12.

25. Peacock WL, Speakman JR. Effect of high-fat diet on body mass and energy balance inthe bank vole. Physiol Behav. 2001;74(1-2):65-70.

26. Liesenjohann T, Eccard JA. Foraging underuniform risk from different types of preda-tors. BMC Ecol. 2008;8:19.

27. Carlsen M, Lodal J, Leirs H, Secher JensenT. The effect of predation risk on body weightin the field vole, Microtus agrestis. Oikos.1999;(87):277-85.

28. Neel JV. The “thrifty genotype” in 1998. NutrRev. 1999;57(5 Pt 2):S2-9.

29. Newman B, Selby JV, King MC, Slemenda C,Fabsitz R, Friedman GD. Concordance for Type2 (non-insulin-dependent) diabetes mellitus inmale twins. Diabetologia. 1987;30(10):763-8.

30. Poulsen PP, Kyvik KOK, Vaag AA, Beck-Nielsen HH. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormalglucose tolerance--a population-based twinstudy. Diabetologia. 1999;42(2):139-45.

31. Razquin CC, Marti AA, Martinez JAJ. Evi-dences on three relevant obesogenes: MC4R,FTO and PPARγ. Approaches for personal-ized nutrition. Mol Nutr Food Res.2011;55(1):136-49.

32. Loos RJF. Recent progress in the genetics ofcommon obesity. Br J Clin Pharmacol.2009;68(6):811-29.

33. Speakman JR. Thrifty genes for obesity, anattractive but flawed idea, and an alternativeperspective: the “drifty gene” hypothesis. IntJ Obes (London). 2008;32(11):1611-7.

34. Flegal KMK, Carroll MDM, Kit BKB, OgdenCLC. Prevalence of obesity and trends in thedistribution of body mass index among USadults, 1999-2010. JAMA. 2012;307(5):491-7.

35. Prentice AM, Hennig BJ, Fulford AJ. Evolu-tionary origins of the obesity epidemic: natu-ral selection of thrifty genes or genetic driftfollowing predation release? Int J Obes(Lond). 2008;32(11):1607-10.

36. Prentice AM. Early influences on human en-ergy regulation: thrifty genotypes and thriftyphenotypes. Physiol Behav. 2005;86(5):640-5.

37. Southam L, Soranzo N, Montgomery SB,Frayling TM, Mccarthy MI, Barroso I, et al.Is the thrifty genotype hypothesis supportedby evidence based on confirmed type 2 dia-betes- and obesity-susceptibility variants? Di-abetologia. 2009;52(9):1846-51.

38. Baschetti R. Diabetes epidemic in newlywesternized populations: is it due to thriftygenes or to genetically unknown foods? Jour-nal of the Royal Society of Medicine.1998;91(12):622-5.

39. Sharma AM. The thrifty-genotype hypothe-sis and its implications for the study of com-plex genetic disorders in man. J Mol Med(Berl). 1998;76(8):568-71.

40. Kagawa Y, Yanagisawa Y, Hasegawa K,Suzuki H, Yasuda K, Kudo H, et al. Singlenucleotide polymorphisms of thrifty genesfor energy metabolism: evolutionary originsand prospects for intervention to prevent obe-sity-related diseases. Biochem Biophys ResCommun. 2002;295(2):207-22.

41. Lau DCW, Douketis JD, Morrison KM,Hramiak IM, Sharma AM, Ur E. 2006 Cana-dian clinical practice guidelines on the man-agement and prevention of obesity in adults andchildren [summary]. CMAJ. 2007;176(8):S1-13.

42. Grundy SM, Hansen B, Smith SC, CleemanJI, Kahn RA. Clinical Management of Meta-bolic Syndrome: Report of the AmericanHeart Association/National Heart, Lung, andBlood Institute/American Diabetes Associa-tion Conference on Scientific Issues Relatedto Management. Circulation. 2004;109(4):551-6.

43. Rolls BJ, Bell EA. Dietary Approaches to theTreatment of Obesity. Med Clin North Am.2000;84(2):401-18.

44. King NA, Horner K, Hills AP, Byrne NM,Wood RE, Bryant E, et al. Exercise, appetiteand weight management: understanding thecompensatory responses in eating behaviourand how they contribute to variability in ex-ercise-induced weight loss. Br J Sports Med.2012;46(5):315-22.

45. Hales CN, Barker DJ. Type 2 (non-insulin-de-pendent) diabetes mellitus: the thrifty phenotypehypothesis. Diabetologia. 1992;35(7):595-601.

46. Bateson P. Fetal experience and good adultdesign. Int J Epidemiol. 2001;30(5):928-34.

47. Gluckman P, Hanson M. The Fetal Matrix:Evolution, Development and Disease. NewYork: Cambridge University Press; 2005.

48. Wells JCK. The thrifty phenotype hypothe-sis: thrifty offspring or thrifty mother? JTheor Biol. 2003;221(1):143-61.

49. Prentice AM. Starvation in humans: evolution-ary background and contemporary implica-tions. Mech Ageing Dev. 2005;126(9):976-81.

50. Stöger R. The thrifty epigenotype: An ac-quired and heritable predisposition for obesityand diabetes? Bioessays. 2008;30(2):156-66.

51. Kawecki TJ. The evolution of genetic canal-ization under fluctuating selection. Evolution.2000;54(1):1-12.

52. Stein Z, Susser M, Saenger G, Marolla F.Famine and human development: The Dutchhunger winter of 1944-1945. Oxford Univer-sity Press; 1975.


53. Ravelli GP, Stein ZA, Susser MW. Obesity inyoung men after famine exposure in uteroand early infancy. N Engl J Med.1976;295(7):349-53.

54. Tobi EW, Lumey LH, Talens RP, Kremer D,Putter H, Stein AD, et al. DNA methylationdifferences after exposure to prenatal famineare common and timing- and sex-specific.Hum Mol Genet. 2009;18(21):4046-53.

55. Olds TT, Maher CC, Zumin SS, Péneau SS,Lioret SS, Castetbon KK, et al. Evidence thatthe prevalence of childhood overweight isplateauing: data from nine countries. Int J Pe-diatr Obes. 2011;6(5-6):342-60.

56. Mankar M, Joshi RS, Belsare PV, Jog MM,Watve MG. Obesity as a Perceived SocialSignal. PLoS ONE. 2008;3(9):e3187.

57. Wells JCK. The evolution of human fatnessand susceptibility to obesity: an ethologicalapproach. Biol Rev Camb Philos Soc.2006;81(2):183-205.

58. Seshadri KG. Obesity: A Venusian story ofPaleolithic proportions. Indian J EndocrinolMetab. 2012;16(1):134-5.

59. Pianka ER. On r-and K-selection. AmericanNaturalist. 1970:592-97.

60. Braude S. Stress, testosterone, and the im-munoredistribution hypothesis. BehavioralEcology. 1999;10(3):345-50.

61. Berger LR. Brief communication: Predatorybird damage to the Taung type-skull of Aus-tralopithecus africanus Dart 1925. Am J PhysAnthropol. 2006;131(2):166-8.

62. Kuzawa C. The developmental origins ofadult health: intergenerational inertia in adap-tation and disease. Evolution and Health.2008:325-49.

63. Belsare PV, Watve MG, Ghaskadbi SS, BhatDS, Yajnik CS, Jog M. Metabolic syndrome:Aggression control mechanisms gone out ofcontrol. Med Hypotheses. 2010;74(3):578-89.

64. Corbett SJ, McMichael AJ, Prentice AM.Type 2 diabetes, cardiovascular disease, andthe evolutionary paradox of the polycysticovary syndrome: A fertility first hypothesis.Am J Hum Biol. 2009;21(5):587-98.


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