Fetal programming of adipose tissue function: an evolutionaryperspective

Myrte Merkestein • Felino R. Cagampang •

Dyan Sellayah

Received: 28 January 2014 / Accepted: 19 May 2014

� Springer Science+Business Media New York 2014

Abstract Obesity is an escalating threat of pandemic

proportions and has risen to such unrivaled prominence in

such a short period of time that it has come to define a

whole generation in many countries around the globe. The

burden of obesity, however, is not equally shared among

the population, with certain ethnicities being more prone to

obesity than others, while some appear to be resistant to

obesity altogether. The reasons behind this ethnic basis for

obesity resistance and susceptibility, however, have

remained largely elusive. In recent years, much evidence

has shown that the level of brown adipose tissue thermo-

genesis, which augments energy expenditure and is nega-

tively associated with obesity in both rodents and humans,

varies greatly between ethnicities. Interestingly, the inci-

dence of low birth weight, which is associated with an

increased propensity for obesity and cardiovascular disease

in later life, has also been shown to vary by ethnic back-

ground. This review serves to reconcile ethnic variations in

BAT development and function with ethnic differences in

birth weight outcomes to argue that the variation in obesity

susceptibility between ethnic groups may have its origins

in the in utero programming of BAT development and

function as a result of evolutionary adaptation to cold

environments.

Introduction

The concept of the developmental origins of health and

disease was first proposed by David Barker and colleagues

at the University of Southampton who published a series of

papers documenting the relationship between low birth

weight and subsequent cardiovascular and metabolic dis-

ease in adult life (Barker 1998, 1990, 1991). Ever since, a

wealth of epidemiological and experimental evidence

unequivocally support the claim that the in utero and early

postnatal periods are critical for establishing susceptibility

to metabolic disease in later life. Evidence suggests that in

utero malnutrition may predispose the offspring to obesity

and consequent cardiovascular disease and diabetes. It is

becoming increasingly clear that the rapid manifestation of

the modern obesity pandemic cannot be attributed to envi-

ronmental or genetic factors alone, but rather an interaction

between the two. Owing to a comparatively large degree of

developmental plasticity, likely due to a heightened sensi-

tivity to epigenetic mechanisms, the in utero and early

postnatal periods offer a unique opportunity for genetics to

more accurately align with the environment. Barker pro-

posed the thrifty phenotype hypothesis to explain how in

utero malnutrition may predispose to obesity through the

promotion of energy storage (Hales and Barker 2001).

Gluckman and Hanson subsequently proposed the predic-

tive adaptive response theory to explain how fetal pro-

gramming of obesity may be the result of an evolutionary

preserved mechanism that enhanced survival in the distant

past of human evolution during which the nutritional

environment was not as reliable as it is today (Gluckman

M. Merkestein � D. Sellayah (&)

MRC Harwell, Genetics of Type 2 Diabetes, Harwell Science

and Innovation Campus, Harwell, UK

e-mail: dyan.sellayah@dpag.ox.ac.uk

M. Merkestein � D. Sellayah

Department of Physiology, Anatomy & Genetics, University of

Oxford, Oxford, UK

F. R. Cagampang

Faculty of Medicine, Institute of Developmental Sciences,

University of Southampton, Southampton SO16 6YD, UK

123

Mamm Genome

DOI 10.1007/s00335-014-9528-9

and Hanson 2004a, 2004b, 2004c). The predictive adaptive

response theory suggests that the developing fetus makes

adaptations in utero based on a predicted postnatal envi-

ronment, sensed through maternal dietary and hormonal

cues. Such adaptations are advantageous for survival, but

only if the prediction is accurate, and become pathological

when the external environment diverges from that pre-

dicted. For instance, if a predicted nutrient-scarce envi-

ronment is met with a nutrient and calorie-rich postnatal

environment, the fetus, whose physiology was programed

for energy storage and thrift, is now programed for energy

storage and thus has a higher risk of developing obesity and

subsequent cardiovascular and metabolic disease.

Demographics of obesity

The burden of the obesity pandemic is not equally shared;

however, and certain ethnic groups have a greater sus-

ceptibility to it than others. The 20th and 21st centuries

have seen a large net increase of ethnic minorities (mainly

Africans, Indians, Pakistanis, Bangladeshi’s, Chinese des-

cent) in industrialized countries such as Britain, France,

Germany, Canada ,and the U.S. (Loue and Bunce 1999;

Castaneda 2012; Gagnon et al. 2009, 2011; Lassetter and

Callister 2009; Steffen et al. 2006). A report from the

United States Congressional Research Service articulated

the fast changing demographics in this country: ‘The U.S.

population—currently estimated at 308.7 million per-

sons—has more than doubled in size since its 1950 level of

152.3 million (Shrestha 2011). More than just being double

in size, the U.S. has become qualitatively different from

what it was in 1950’. The report attributed a large pro-

portion of the expanding population to immigration, par-

ticularly from Africa, Asia, and Central and South America

(Shrestha 2011). Studies assessing the ethnic and racial

susceptibility to metabolic dysfunction and obesity in the

U.S. have identified that African Americans, Hispanics,

and those of Native American ancestry are more prone to

obesity, cardiovascular disease, and diabetes than Cauca-

sians of European ancestry and people of East Asian

ancestry such as Chinese, Japanese, and Koreans (Caprio

et al. 2008; Taveras et al. 2013; Crawford et al. 2001;

Maskarinec et al. 2009). Similarly in United Kingdom,

whose population diversity is equal if not greater than that

of the U.S., Caucasians and East Asians are less prone to

obesity, diabetes ,and cardiovascular disease than those of

African and South East Asian origins such as Indians,

Pakistanis, and Bangladeshis. (Mary-Gatineau 2011).

While these ethnic variations in obesity susceptibility are

reasonably well recognized, very little is known about how

ethnicity may impact upon the pathophysiology of the

developmental programing of obesity.

Ethnic variation in birth weight outcomes

Interestingly, while birth weight is a strong predictor of

adulthood obesity and cardiovascular risk, it is stronger still

in African Americans than Caucasians, suggesting an eth-

nic bias in the importance of birth weight to obesity out-

comes in later life (Kuzawa and Sweet 2009). However,

such findings may simply reflect a bleaker picture in birth

weight outcomes in African Americans. Certainly, African

Americans have lower average birth weights and higher

frequencies of severely low birth weight, small for gesta-

tional age, and preterm births than their Caucasian coun-

terparts (Lu and Halfon 2003; Collins and David 2009).

This ethnic disparity in birth weight and subsequent health

outcomes has led to considerable focus in elucidating

underlying causal factors. In the debate regarding the eth-

nic variation in birth weight and its involvement in later

manifestation of disease, genetics has been cast aside in

favor of arguments for psycho-social and economic origins

of the ethnic disparity.

Studies comparing U.S.-born and foreign-born (those

born in Africa) African American pregnancies offer a

convincing argument against genetic causes for ethnic-

based disparities in birth outcomes and its impact on later

disease. Such studies are remarkably consistent in report-

ing a considerably reduced incidence of low birth weight

among infants born to foreign-born (first generation Afri-

can immigrants) rather than U.S.-born African American

mothers (Kurian and Cardarelli 2007). Interestingly, this

improved birth weight outcome is short lived as sub-

sequent generations born in the U.S. exhibit the reduced

average birth weight and increased risk of low and very

low birth weight that are characteristic of African Ameri-

can births (Acevedo-Garcia et al. 2005; Collins et al.

2002). Therefore it is postulated that environmental con-

siderations such as education level, social ,and health

status in country of origin as well as favorable familial and

economic factors may explain why foreign-born African

American immigrants have more positive birth outcomes

than their U.S.-born counterparts. Such explanations,

however, cannot account for why African mothers who

give birth in Africa are prone to deliver low birth weight

babies. Rather astonishingly, the same study identified an

opposite trend in European-born U.S. immigrants. Birth

weights were lower than average for infants born to

European-born U.S. Caucasian mothers, however, this

increased with each subsequent generation born in the U.S.

converging with the national average for Caucasian births

(the opposite trend for what was observed in African

American immigrants (Collins et al. 2002). Interestingly,

Chinese immigrants show the least difference in birth

weight outcomes between U.S. and foreign-born individ-

uals (Singh and Yu 1996), suggesting that nativity is less

M. Merkestein et al.: An evolutionary perspective

123

impactful for Chinese immigrants than for Africans and

Caucasians of European ancestry.

Several factors related to maternal stress and anxiety

have been shown to promote growth restriction in utero.

For instance, exposure to glucocorticoids of high enough

concentrations transmitted across the placenta to the fetal

blood supply, can lead to fetal growth restriction and pre-

term birth (Reynolds 2013). While exposure to stress hor-

mones is postulated to explain, at least in part, the high

incidence of low birth weight in African American infants

(Hobel and Culhane 2003), could the opposite explain the

more favorable birth weight outcomes in foreign-born

African Americans? This is unlikely, given that immigra-

tion itself is associated with great socio-economic upheaval

and emotional distress, which often involves familial iso-

lation, economic uncertainty and emotional insecurity

(Thomas 1995). Such acculturative stress can greatly

impact on the individual’s mental and physical wellbeing.

It is unlikely that reduced stress and anxiety in African

American immigrants is responsible for the improved birth

weight outcomes of foreign-born compared to U.S.-born

African American infants. Therefore, when attempting to

reconcile ethnic disparities in birth weight outcomes and

how it is impacted by one’s birthplace, it is important to

factor in other environmental considerations that may also

influence birth weight and influence future disease sus-

ceptibility. Such environmental factors include ambient

temperature and/or photoperiodic signals, which influence

brown adipose tissue (BAT) thermogenesis (Cannon and

Nedergaard 2004). Thermogenesis is the process by which

BAT (and potentially white adipose tissue (WAT) to a

lesser extent) produces heat through the uncoupling of

oxidative phosphorylation from ATP synthesis by uncou-

pling protein-1 (UCP1). UCP1 is found on the inner

mitochondrial membrane of BAT mitochondria and is

essential for BAT thermogenic function (Cannon and

Nedergaard 2004). BAT thermogenesis augments energy

expenditure at the basal level, but when activated, is

capable of further stimulating energy expenditure (Cannon

and Nedergaard 2004). BAT can be activated by cold,

reductions in photoperiodic length and high-fat, or high-

calorie feeding, a process termed diet-induced thermo-

genesis (Cannon and Nedergaard 2004). Interestingly,

studies reporting ethnic differences in BAT function have

been emerging in recent years (Symonds 2013a), and

indications that the regulation of BAT function is sensitive

to in utero events pose the intriguing question of whether it

is involved in ethnic variation in obesity susceptibility.

Reconciling ethnic discrepancies in birth weight outcomes

with environmental factors relevant to adipose tissue

development, is in our opinion, crucial in the deciphering

the mechanistic basis for the developmental programing of

obesity (Fig. 1)

Brown adipose tissue (BAT) function

In the U.S., African American infants have the highest

incidence of low birth weight at between 11 and 15 %,

while Caucasians and Chinese have the lowest, at 4–5.5 %

and 4–4.7 %, respectively (de Wilde et al. 2013). In fact

African babies (irrespective of birthplace) have, on aver-

age, the lowest birth weights, internationally (Airede 1995,

1996). Low birth weight in infants of African origin is

associated with decreased lean mass as well as fat mass,

compared to Caucasian infants (Lampl et al. 2012). Fat

mass plays a pivotal role in the regulation of body tem-

perature in infants. Unlike human adults, infants do not

shiver, owing to the immaturity of their skeletal muscles,

and thus need to maintain core body temperature by other

means (Dawkins and Scopes 1965). Subcutaneous fat is

believed to play a role in insulating the infant from the

large temperature gradient at birth, between the intra-

uterine environment and external ambient temperature

(Kuzawa 1998). Another vital means of preventing hypo-

thermia in early life is non-shivering thermogenesis which

occurs in BAT (Dawkins and Scopes 1965; Heim 1971).

BAT thermogenesis is a potent heat-generating mecha-

nism, and is the primary factor in body temperature

maintenance in infants (Cannon and Nedergaard 2004). In

fact, BAT paucity has been linked to increased infant

mortality due to hypothermia (Aherne and Hull 1966).

Histological analysis has revealed that following birth,

BAT triglycerides are utilized rapidly to fuel lipid oxida-

tion and mitochondrial uncoupling that drives thermogen-

esis (Smith et al. 2004). BAT lipids must be restored in

order for heat production to continue unabated (Sellayah

et al. 2011). While BAT is a highly effective thermogenic

organ, its energy demands are substantial. Hence high BAT

thermogenic function in adult rodents ,and humans is

associated with increased energy expenditure and protects

against obesity in adults, whereas impaired BAT thermo-

genesis leads to reduced energy expenditure and the pro-

motion of obesity. The energetic cost of maintaining BAT

thermogenesis at birth equates to the tripling of normal

daily energy requirements (van Marken-Lichtenbelt and

Schrauwen 2011). It is therefore plausible, that an energy

buffer in the form of WAT is required to supply BAT with

the fatty acids that fuel thermogenesis. Thus, the large

subcutaneous fat reserves in human infants are likely to

have three functions: (1) to act as an energy buffer during

periods of high energy demand, (2) to supply fatty acid fuel

to BAT for thermogenesis, and (3) to provide insulation

from the cold external environment. There is potentially a

fourth function in which WAT gives rise to thermogeni-

cally active brown adipocytes to augment heat production.

This process is termed ‘browning’ of WAT, and while its

contribution to thermogenesis is still unclear in adults, its

M. Merkestein et al.: An evolutionary perspective

123

role in infants is even more contentious. Nonetheless its

current prominence in obesity research is thoroughly jus-

tifiable given its clinical and therapeutic potential. Given

that both subcutaneous WAT reserves and BAT serve to

maintain core body temperature in response to environ-

mental cold in infants, it is not hard to imagine why human

infants possess such copious stores of both. A failure of

African American infants to deposit fat in the late stages of

gestation compared with Caucasians, however, has been

suggested to account for the low birth weights in this

population (Lampl et al. 2012). Thus, it is plausible that

African infants possess less BAT and subcutaneous fat (and

lower birth weight), not due to pathological but to evolu-

tionary reasons. It seems highly plausible that while Cau-

casians and East Asians, whose ancestors left Africa some

70,000 years ago and migrated to colder climates, had to

evolve traits for efficient cold tolerance, African Ameri-

cans, whose ancestors likely never evolved for cold adap-

tation, are not endowed with sufficient BAT function and

subcutaneous WAT reserves.

Evidence supports the notion that those populations who

evolved in colder regions have higher metabolic rates and

that at least part of these metabolic adaptations to cold are

mediated by BAT function. Research on indigenous

Siberians (whose ancestors were closely related to the first

humans to populate higher latitudes) revealed a consistent

elevation in their basal energy expenditure compared to

non-indigenous Siberians (Snodgrass et al. 2008, 2005).

This pattern of higher metabolic rates in indigenous peo-

ples living in cold climates has been observed in many

Arctic and sub-Arctic populations (Snodgrass et al. 2007;

Leonard et al. 2002; Milan and Evonuk 1967). For exam-

ple, indigenous Inuit inhabiting the Arctic regions of

Canada also have greatly elevated metabolic rates and are

thus protected from obesity (Rode 1995). Enhanced BAT

function has been suggested to account for the elevated

metabolic rate among populations inhabiting cold regions

of the globe (Sellayah et al. 2014a); however, whether this

reflects genetic alterations is yet to be confirmed. Clear

trends of elevated metabolic rates with increasing latitude

have been convincingly presented (Hancock et al. 2011a).

Such observations suggest that genetic factors relevant to

ancestral environmental exposures affect energy expendi-

ture even in peoples from non-homogeneous populations,

indicating a powerful selection advantage for genes

involved in facilitating adaptation to cold climatic envi-

ronment. Thus, basal metabolic rates are highest in people

inhibiting the Arctic region (Snodgrass et al. 2007),

Fig. 1 Schematic diagram depicting the impact of genetic, epigenetic, and physiological factors on birth weight, and consequent influence over

adulthood thermogenic capacity and obesity susceptibility

M. Merkestein et al.: An evolutionary perspective

123

intermediate in white Europeans inhibiting temperate

regions (Weyer et al. 1999), and lowest in people living in

tropical climes close to the equator, including Africans that

have migrated to the U.S (Wong et al. 1999). While lower

expression of thermogenic genes have been linked to lower

energy expenditures in African Americans (Kimm et al.

2002), more direct assessment of BAT function with regard

to ethnic differences in energy expenditure is needed to

confirm this relationship. One very recent study, however,

found that South Asians, i.e., those from India, Pakistan,

and Bangladesh, (Bakker et al. 2014) in whom obesity rates

are exceptionally high and rising rapidly, have lower levels

of BAT development and reduced BAT function compared

to Caucasians, and that these differences account for the

differences in energy expenditure observed between the

groups (Bakker et al. 2014). Given that BAT evolved to

function as a heat-producing organ in early mammals, its

evolution would have depended on the geographical loca-

tion and on the subsequent selection for genes equipped to

deal with the specific climate in question. This varied

hugely during the evolutionary migration of modern

humans out of Africa, which is today reflected in ethnicity.

Certainly, uncoupling protein expression in humans

resembles geographical latitudinal patterns, with high

expressions found in people living furthest from the

equator (Hancock et al. 2008, 2011b). This may possibly

explain why Africans and South East Asians have reduced

BAT function compared to Caucasians and East Asians

whose ancestors evolved in colder regions. Having evolved

in colder regions, Caucasians and East Asians would

therefore have efficient BAT thermogenic function, which,

in the modern environment, with central heating and effi-

cient clothing is more likely to be activated by over eating

or high-fat consumption (diet-induced thermogenesis). On

the other hand, however, those who evolved in hot cli-

mates, such as African Americans, would have impaired

thermogenic capacity in response to high-fat or high-cal-

orie feeding.

Evolutionary origins of BAT function

During early human evolution, before the advent of modern

medical care or even before modern humans were able to

manipulate the environment around them, the temperature

gradient experienced by the newborn between the intra-

uterine environment and external environment, would have

varied greatly depending on geographical location and

latitude. For instance, around 10,000 years ago, modern

humans were dispersed across a wide range of environ-

ments from Europe and North East Asia to Africa, Aus-

tralia, and the Americas. Thus the temperatures to which

infants were exposed at birth would have varied

accordingly. In Africa, where modern humans evolved

from archaic humans some 200,000 years ago, the climate

was predominantly tropical. Many early fossils suggested a

large presence of Homo sapiens in modern day Ethiopia,

where the climate was (and still is) exceedingly hot and

conferred an increased risk of heat stroke and dehydration.

It is not surprising therefore, that Africans, whose ancestors

evolved in the unforgiving heat and aridity of the African

Savannah, are anatomically and physiologically well-

equipped to survive and thrive in such a harsh environment

(Balaresque et al. 2007). Conversely, 10,000 years ago in

ice-age Europe, newborns would have been exposed to

extremely cold conditions, increasing the risk of hypo-

thermia. While possessing adequate and functional BAT

stores and subcutaneous fat may have provided European

and East Asian (i.e., Chinese, Japanese, and Korean)

infants with survival advantages, it would have increased

the risk of hyperthermia in infants born in Africa. In fact,

many incidents of sudden infant death syndrome have been

attributed to hyperactive BAT (Lean and Jennings 1989;

Kajimura et al. 2008). Moreover, possessing high levels of

BAT activity would have been energetically wasteful and

necessitated the need for extra fat to be laid down, at

additional energetic cost (Symonds et al. 2012). Thus it is

possible that the reduced fat mass and low birth weight of

infants of African origin reflects an evolutionary adaptation

to heat. The opposite may be true for Europeans and those

of East Asian origin, whose ancestors evolved in Siberia

and were adapted to cold climates (Lin et al. 2000; Beals

1972). This perhaps explains why, despite being small in

stature as adults, Chinese babies are the least likely to have

low birth weight and enjoy consistently good birth out-

comes (Xu and Rantakallio 1998). Similarly, European

babies have very low risk of being born underweight and

generally have high average birth weight, similar to that of

Chinese infants.

Despite being born lighter than Caucasian infants,

African American infants gain significantly more weight

than their Caucasian counterparts in the first 2–3 years of

life, and much of this is due to increased fat deposition

(Seed et al. 2000). This rebound elevation in adiposity that

commonly occurs following growth restriction, known as

‘catch-up growth’, has been depicted in numerous popu-

lations throughout the world and is associated with dele-

terious metabolic consequences and predisposition to

obesity and cardiovascular disease in later life (Ong et al.

2000). For example, data from Finland indicate that men

who were small at birth had increased risk of obesity in

childhood than men who were normal weight at birth

(Eriksson et al. 1999).

Much conjecture surrounds the mechanistic basis for

postnatal catch-up growth, however, several studies have

indicated that it involves increased energy efficiency and

M. Merkestein et al.: An evolutionary perspective

123

reduced oxygen consumption. Certainly, in response to

lower energy intake, BAT thermogenesis is reduced, in an

effort to minimize energy wastage. Conversely, BAT

thermogenesis and consequently energy expenditure are

greatly induced following high-fat feeding and caloric

excess to expend excess calories in an effort to maintain

body weight (Siyamak and Macdonald 1992; Lowell and

Bachman 2003). Additionally, reduced WAT stores have

been linked to suppression of thermogenesis in the early

postnatal period, indicating that catch-up growth in low

birth weight infants may be due to lack of BAT thermo-

genesis, reinforcing the notion of the requirement for the

deposition of sufficient WAT reserves to sustain effective

BAT function in newborns (Crescenzo et al. 2003).

The thrifty phenotype hypothesis suggests that the in

utero environment acts as a period of physiological plas-

ticity which aids in matching the developing fetus’ genes

with its environment. Gluckman and Hanson suggested that

in utero and early postnatal environmental cues are sensed

by the fetus and neonate, which responds appropriately to

aid survival (Gluckman and Hanson 2004c). However, if

the predicted environment is inaccurate, such as when a

growth restricted fetus is subsequently exposed to nutri-

tional abundance and caloric excess in adulthood, disease

manifests (Gluckman and Hanson 2004c). Thus the in utero

and early postnatal periods represent a window of oppor-

tunity for developmental plasticity. Epigenetic modifica-

tions during this window of exposure have been implicated

in the pathogenesis of the fetal programing of obesity

(Hanson and Gluckman 2011). The early postnatal period,

during which BAT is functional but is still in the process of

maturing, has been shown to be highly consequential to

increased risk of development of obesity and related met-

abolic disorders in adulthood through the phenomenon of

postnatal catch-up growth. Thus the evolution of BAT,

which develops in late gestation and matures in the early

postnatal period, may underlie the mechanistic basis for

‘postnatal catch-up growth’. Its relevance to ethnic varia-

tion in birth outcomes and associated prevalence of obesity

remains to be fully explored.

Impact of maternal environment and BAT development

BAT development occurs predominantly in the last tri-

mester of pregnancy in humans, and though it is fully

functional at birth, it expands to its maximum size during

the early postnatal period, after which it remains relatively

stable in size until adolescence and then begins to steadily

regress with age (Symonds 2013b). Studies in mice have

shown that, with advanced age, BAT morphology

increasingly takes on the appearance of WAT with uni-

locular lipid droplets, larger cell size ,and elevated

triglyceride content (Sellayah and Sikder 2013). Such

morphological changes are accompanied by reduced lipo-

lytic and thermogenic capacity and may be involved in the

increased risk of obesity associated with aging. Whether

the transformation of BAT to WAT is reversible remains

unknown. However, it is possible that while phenotypically

described as WAT, the transformed adipocytes may rep-

resent ‘beige’ cells that were induced to take on BAT

characteristics using certain chemicals and experimental

conditions (Giralt and Villarroya 2013). While the in utero

environment represents a critical window of opportunity

for BAT function to be enhanced, studies directly

addressing the effects (and side effects) of therapeutic

intervention to alter BAT function are needed to justify any

logical progression to the human scenario. While, thera-

peutic studies in humans are few and far between, studies

in rodents have offered some promise for intervening in

utero to promote BAT function. As a case in point,

maternal exposure to cold in sheep has been shown to

enhance BAT thermogenic function in their offspring

(Symonds et al. 1992). In mice, it has been reported that

maternal injections of the neuropeptide orexin, which has

BAT-stimulating capabilities, during the last trimester of

pregnancy enhances BAT morphology and development in

offspring who are genetically prone to lack BAT devel-

opment (Sellayah et al. 2011). On the other hand, warm

acclimation in the early postnatal period reduces BAT

UCP1 expression and depresses oxygen consumption

(Symonds et al. 1996). Moreover, maternal caloric

restriction (60 % of daily energy requirements) in late

gestation in sheep has been documented to reduce the

expression of thermogenic genes such as UCP1 in BAT of

offspring (Yakubu et al. 2007). Furthermore in rodents,

maternal caloric restriction during gestation and lactation

depressed the thermogenic capacity of BAT in the off-

spring (Felipe et al. 1988), as well as reducing sympathetic

innervation of adipose tissue and lowering circulating

catecholamines (Garcia et al. 2011). Our recent study has

also shown that feeding a high-fat diet causes an elevation

in energy expenditure due to diet-induced thermogenesis,

but this is abolished in mice whose mothers were protein-

restricted during pregnancy and lactation, most likely due

to an attenuation of the induction of UCP1 expression by

high-fat diet (Sellayah et al. 2014b). In sheep, maternal

caloric restriction has been shown to negatively affect

‘browning’ of WAT (Ojha et al. 2013). This study found

reduced expression of thermogenic genes UCP1 and beta-3

adrenergic receptor, while another study reported that

maternal caloric restriction during late gestation caused a

decrease in UCP1 mRNA in the perirenal adipose tissue

depot (Budge et al. 2004). In a further study, maternal

protein restriction during embryonic preimplantation

resulted in decreased UCP1 expression in retroperitoneal

M. Merkestein et al.: An evolutionary perspective

123

WAT in rats (Watkins et al. 2011), while a maternal diet

supplemented with olive oil during late gestation and lac-

tation (Priego et al. 2013) and a diet high in protein or fiber

led to an increase in UCP1 and PGC1a expression in BAT

of rat pups (Maurer and Reimer 2011). These studies

suggest the existence of developmental homeostatic

mechanisms that integrate BAT thermogenesis and WAT

reserves to regulate body weight and energy expenditure.

Mounting evidence suggests that the influence of maternal

factors affecting both BAT thermogenesis and WAT

browning are mediated via epigenetic modifications. The

genome is demethylated during preimplantation of the

embryo and undergoes remethylation following implanta-

tion (Saitou et al. 2012). Hence, during embryonic devel-

opment, the maternal environment plays a crucial role in

determining the epigenetic regulation of the fetal genome

(Burdge et al. 2007). Thus, the prenatal period represents a

critical time when the genetic makeup can be ‘adjusted’

through epigenetic modification to better align with the

predicted postnatal environment. Due to the sensitivity of

the in utero and early postnatal periods to epigenetic

modification, this period is also vulnerable to adverse

changes that can promote disease susceptibility in later life,

including obesity (Lillycrop and Burdge 2005).

Epigenetic regulation of BAT function

UCP1 expression is known to be regulated by methylation

status, with increased methylation leading to a reduction in

expression and vice versa (Shore et al. 2010). UCP1 is a

direct target of Jhdm2a, a H3K9 demethylase. H3K9

methylation is an epigenetic marker of heterochromatin

formation and transcriptional silencing. Jhmd2a catalyzes

the removal of mono- and di-methylation of H3K9 from

the UCP1 promoter, which causes transactivation of the

gene. Interestingly, Jhdm2a expression is induced by beta

adrenergic stimulation, which is upstream of UCP1 and

necessary for its activation and transcriptional upregula-

tion. Jhdm2a knockout mice display increased adiposity,

but normal food intake, and have a demonstrable failure to

upregulate UCP1 expression in response to exposure to a

cold environment (Tateishi et al. 2009; Inagaki et al. 2009;

Okada et al. 2010).

Another driver of methylation events in adipose tissue is

miR-196a, which has been shown to target Hoxc8, a

homeobox gene highly expressed in WAT. Increased

Hoxc8 activity leads to the downregulation in the expres-

sion of several BAT genes in WAT, including UCP1 and

C/EBPb. In response to cold exposure and adrenergic

stimulation, Hoxc8 activity is inhibited by increased

expression of miR-196a, which subsequently leads to the

induction of BAT genes and the occurrence of BAT-like

cells in WAT. Its physiological significance is illustrated

by the observation that miR196a overexpressing mice were

less susceptible to developing obesity, displayed an

increase in oxygen consumption, and exhibited greater cold

tolerance (Mori et al. 2012).

PGC1a, a mitochondrial gene that is essential for BAT

thermogenesis, has also been shown to be under epigenetic

control. In young men that had a low birth weight, PGC1aDNA methylation was found to increase under basal con-

ditions in comparison to young men with a normal birth

weight, but was attenuated in skeletal muscle in response to

a high-fat diet challenge (Brons et al. 2010). A similar

study observed an increase in PGC1a DNA methylation in

subcutaneous WAT in response to a high-fat diet (Gillberg

et al. 2013). These studies clearly indicate that epigenetic

events can influence thermogenic function and that devel-

opmental programing of BAT-associated genes might

affect the response to postnatal dietary challenges and

obesity susceptibility in adulthood. Whether differential

epigenetic influences during the in utero and early postnatal

periods may account for the ethnic variation in BAT

development and function and subsequent obesity remains

to be fully explored, but remains an intriguing probability.

Ethnic populations are certainly known to differ in

global DNA methylation. Non-Hispanic blacks for exam-

ple, exhibited reduced global DNA methylation levels

compared to Non-Hispanic whites (Zhang et al. 2011). In

addition, Europeans had lower methylation levels than

Indians at several loci associated with Type II Diabetes

(Elliott et al. 2013). In a multi-ethnic cohort in New York,

global DNA methylation levels varied significantly

between ethnicities, with black women having the lowest

levels of DNA methylation, followed by white women and

Hispanic women (Terry et al. 2008). Some of the differ-

ences in methylation levels between African Americans

and Caucasians are evident at birth (Adkins et al. 2011).

Interestingly, several studies have shown that ethnicity

influenced the association of polymorphisms in miR-196a

with cancer susceptibility. The C allele in SNP rs11614913

in miR-196a2 is associated with an increased risk for

cancer in Asians, but not Caucasians (Zhang et al. 2013;

Chen et al. 2013). Although decisive evidence for ethnic

variations in the effects of miR-196a in adipose tissue is

not currently forthcoming, these studies suggest that

polymorphisms in miR-196a have differential effects in

ethnic populations, which might affect the thermogenic

capacity of WAT.

Another key influence on thermogenic function is the

endogenous body clock system. The molecular components

of the endogenous mammalian body clock system have

been observed in many peripheral tissues, including BAT

and WAT (Zvonic et al. 2006; Otway et al. 2011). This

biological clock system coordinates the circadian, or

M. Merkestein et al.: An evolutionary perspective

123

24-hour, rhythm in body temperature that peaks during the

day and is at its lowest at night (Bass 2012). This mecha-

nism evolved in order to conserve energy while sleeping at

night, since maintaining body temperature above ambient

temperature required heat production from various meta-

bolic processes. While enabling the synchronization of

body temperature rhythms to the daily 24 h day-night

cycle, this clock system also has the ability to adapt to

changes in environmental temperature no matter what time

of the day or night it is. This was demonstrated in a recent

study where mice were able to withstand being exposed to

cold temperature better at the time when they are awake

compared to when they are normally asleep (Gerhart-Hines

et al. 2013). This adaptive response was controlled in

particular by a component of the endogenous clock system,

Rev-erb-alpha, and its effects were mainly produced by the

circadian regulation of UCP1 in BAT. Epigenetic modifi-

cations are also regulated by the body clock system. A

study has shown that chromatin modification is a contrib-

uting mechanism driving the co-ordinated expression of

various clock genes (Feng et al. 2011). This involves the

rhythmic binding of the histone deacetylase 3 (HDAC3) to

DNA in conjunction with Rev-erb-alpha. However, this

was shown in another tissue, the liver, and is implicated in

entrainment to food availability. Whether a similar mech-

anism occurs in BAT to regulate thermogenesis and

adaptation to changes in environmental temperature

remains to be examined. A number of studies have shown

association between clock gene polymorphisms and circa-

dian phenotypes in a variety of population blood and

buccal samples (Ciarleglio et al. 2008; Nadkarni et al.

2005); whether ethnic differences influence clock function

in the BAT remains to be investigated.

Conclusion

Obesity has risen to become one of the most important

health issues of current and future generations. Yet, not

every individual displays the same predisposition to its

pathogenesis. Certain ethnicities have higher predisposition

to fat accumulation, obesity ,and related metabolic distur-

bances. It is through understanding the pathogenesis of this

ethnic bias in obesity development that more effective and

potent treatments could be developed to combat obesity.

BAT is a specialized fat tissue that increases energy

expenditure through thermogenesis. BAT evolved in

eutherian mammals to provide heat for foraging at night

and in cold climates. Similarly, thermogenic capacity of

BAT in modern humans is likely to reflect their evolu-

tionary exposure to cold. Thus, modern humans who

evolved in Africa had to be well-equipped for heat, and

therefore BAT thermogenesis may not have been crucial

for survival. This might explain the low metabolic rate in

Africans. On the other hand, modern humans whose evo-

lutionary history necessitated adaptation to cold, such as

Caucasians and Chinese people have higher metabolic rates

and are relatively protected from obesity, which may be a

reflection of increased BAT function. Given that BAT

formation in humans begins during the later stages of

pregnancy and matures in early postnatal life, its devel-

opment appears to be sensitive to maternal cues during

these periods. This may be an adaptive mechanism to allow

for developmental plasticity in which environmental cues

are matched with genetics to better aid survival. Evidence

suggests that such developmental plasticity occurs through

epigenetic mechanisms, which in the case of BAT function,

presumably allows an individual to regulate its heat-gen-

erating capacity according to environmental cues that are

sensed by the mother. Thus, intervening through maternal

nutrition or other means to influence BAT development

and function during the in utero and early postnatal periods

potentially represent a crucial therapeutic window for

combatting obesity, though a considerable amount of

research effort needs to be invested before conclusions can

be drawn about the suitability of such an endeavor in

humans.

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