Biochimica et Biophysica Acta 1842 (2014) 495–506

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Review

Maternal nutrition and risk of obesity in offspring: The Trojan horse ofdevelopmental plasticity☆,☆☆,★

Sebastian D. Parlee, Ormond A. MacDougald ⁎Department of Molecular & Integrative Physiology, School of Medicine, University of Michigan, Ann Arbor, MI, USA

☆ This article is part of a Special Issue entitled: MoHealth and Disease.☆☆ Funding: This work was supported by grants from t(DK095705, DK062876, and DK092759 to O.A.M). S.D.P wfrom the University of Michigan Training Program in Org★ Disclosure statement: The authors have nothing to⁎ Corresponding author at: JohnA Faulkner Collegiate

ment of Molecular & Integrative Physiology, UniversityBrehm Center, 1000 Wall Street, Rm 6313, Ann Arbor, M4880; fax: +1 734 232 8175.

E-mail address: macdouga@umich.edu (O.A. MacDo

0925-4439/$ – see front matter. Published by Elsevier Bhttp://dx.doi.org/10.1016/j.bbadis.2013.07.007

a b s t r a c t

a r t i c l e i n f o

Article history:Received 17 February 2013Received in revised form 5 July 2013Accepted 8 July 2013Available online 16 July 2013

Keywords:Maternal healthObesityNutrition

Mammalian embryos have evolved to adjust their organ and tissue development in response to an atypical en-vironment. This adaptation, called phenotypic plasticity, allows the organism to thrive in the anticipated envi-ronment in which the fetus will emerge. Barker and colleagues proposed that if the environment in which thefetus emerges differs from that in which it develops, phenotypic plasticity may provide an underlying mecha-nism for disease. Epidemiological studies have shown that humans born small- or large-for-gestational-age,have a higher likelihood of developing obesity as adults. The amount and quality of food that the mother con-sumes during gestation influences birth weight, and therefore susceptibility of progeny to disease in later life.Studies in experimental animals support these observations, and find that obesity occurs as a result of maternalnutrient-restriction during gestation, followed by rapid compensatory growth associated with ad libitum foodconsumption. Therefore, obesity associated with maternal nutritional restriction has a developmental origin.Based on this phenomenon, one might predict that gestational exposure to a westernized diet would protectagainst future obesity in offspring. However, evidence fromexperimentalmodels indicates that, likematernal di-etary restriction, maternal consumption of a westernized diet during gestation and lactation interacts with anadult obesogenic diet to induce further obesity. Mechanistically, restriction of nutrients or consumption of ahigh fat diet during gestation may promote obesity in progeny by altering hypothalamic neuropeptide produc-tion and thereby increasing hyperphagia in offspring. In addition to changes in food intake these animals mayalso direct energy from muscle toward storage in adipose tissue. Surprisingly, generational inheritance studiesin rodents have further indicated that effects on body length, body weight, and glucose tolerance appear to bepropagated to subsequent generations. Together, the findings discussed herein highlight the concept thatmater-nal nutrition contributes to a legacy of obesity. Thus, ensuring adequate supplies of a complete and balanced dietduring and after pregnancy should be a priority for public health worldwide. This article is part of a Special Issueentitled: Modulation of Adipose Tissue in Health and Disease.

Published by Elsevier B.V.

1. Introduction

1.1. Plasticity during mammalian development helps optimize phenotypeto environment

In mammals, the complex process of fetal development occursthrough sequential events including morulation, gastrulation and

dulation of Adipose Tissue in

he National Institutes of Healthas supported by a training grantanogenesis (T32-HD007505).disclose.

Professor of Physiology, Depart-of Michigan Medical School,

I 48105, USA. Tel.: +1 734 647

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organogenesis. Each step is dependent uponmeticulous orchestrationof cell differentiation, migration, proliferation and apoptosis, whichare regulated by signaling pathways including Notch, TGFβ and Wnt[1,2]. Interactions between intrinsic fetal factors (e.g. genetics) andextrinsic environmental factors (e.g. maternal pre-pregnancy weightand nutrition, placental insufficiency) influence these developmentalsignaling pathways and may culminate in abnormal organ develop-ment [3,4]. However, aberrant fetal environments do not necessarilycause a deleterious developmental program. Specifically, mammalianembryos have evolved with the capacity to adjust their pattern of de-velopment in response to atypical fetal environments, in a processcalled developmental (or phenotypic) plasticity. As an example, neo-natal rats exposed to a low (10%), medium (18%) or high (36%) pro-tein diet during gestation and lactation have a greater survival ratewhen their post-weaning diet matches the diet consumed by their re-spective dam during gestation and lactation [5]. Thus, developmentalplasticity allows the organism to thrive in the anticipated environ-ment in which the fetus will emerge [6–8].

496 S.D. Parlee, O.A. MacDougald / Biochimica et Biophysica Acta 1842 (2014) 495–506

1.2. Disease occurs when there is a mismatch between pre- andpost-natal environments

Barker and colleagues proposed that phenotypic plasticity may be-come maladaptive and cause disease in the long term if there is amismatch between the environment in which the organism developsand that in which it emerges [9–12]. Accordingly, mice exposed to alow (10%), medium (18%) or high (36%) protein diet in utero andthrough lactation have lower survival rates at two years if weanedonto a diet that differed from that of their mother [5]. Barker termedthis concept the “developmental origins of health and disease” [9–12].

1.3. Phenotypic plasticity and the development of obesity

Although not currently a pervasive problem in industrialized na-tions, food shortages have been very common for the larger part ofhuman history. Consequently, nutritional restriction is believed tohave been a powerful force on human evolution, favoring individualswho effectively stored calories in times of surplus. The plasticity of de-veloping organs, especially in times of nutritional restriction, is there-fore thought to have favored a thrifty metabolic phenotype [13,14].The developmental origin of disease predicts that a fetal environmentpromoting metabolic thriftiness, coupled to an adult environment ofnutrient surplus, causes dysfunction in themetabolic systems control-ling food intake and storage, and results in obesity. In recent years,epidemiological, clinical and basic research has established the inter-relationships between fetal nutrition, adipose tissue development,central control of energy balance and the propensity for obesity inadult life.

Obesity is a disorder characterized by excess white adipose tissueand is the result of chronic positive energy imbalance [15]. As obesitydevelops, excess energy is stored in adipocytes as triacylglycerol,resulting in increased adipocyte size (hypertrophy) [16]. When de-mand for lipid storage exceeds the capacity of existing adipocytes,the pool of adipocytes increases through hyperplasia, with new adipo-cytes arising from differentiation of preadipocytes [16]. Impairedadipogenesis is hypothesized to contribute to the development oftype 2 diabetes, because engorgement of adipocytes with excess lipidstriggers pathological changes to adipose tissue. These include adiposetissue inflammation, which is characterized by increased macrophageinfiltration into the adipose tissue and altered adipokine (e.g. TNFα)secretion [17]. Surplus lipids that cannot be stored in adipocytes areectopically deposited in the liver, muscle and pancreas, and also circu-late at higher levels [18–20]. Together these metabolic abnormalitiestrigger systemic insulin resistance, which alongwith insufficient insu-lin production, results in type 2 diabetes. It is important to note thatwhile an increase in total body weight often occurs in parallel withan increase in fat mass and associated metabolic derangements, it isnot a necessary precondition. Metabolic derangements can occur asa result of a shift in body composition without a change in bodyweight. In humans, studies have indicated that individuals with simi-lar body mass index but with increased visceral adipose tissue (e.g.TOFI patients: thin outside, fat inside) have increased prevalence ofmetabolic comorbidities [21]. Accordingly within this review, theterm obesity will be used to indicate both an increase in body weightand fat mass, or a shift toward elevated fat mass alone.

Using developmental plasticity and the developmental origin ofdisease as a conceptual framework, we explore in this review how ex-posing progeny to nutrient-restriction or excess in utero and/orthrough lactation influences development of obesity in later life. Obe-sity due to developmental plasticity appears to be propagated to sub-sequent generations, which is worrisome given the rising rates ofobesity worldwide [22,23]. While the current review will discussthe effects of maternal nutrition in terms of white adipose tissueand metabolic derangements exclusively, Symonds et al. [24] providean elegant review of fetal programming of brown adipose tissue.

2. Epidemiological evidence for the developmental origin ofhuman obesity

2.1. The Dutch famine: maternal malnutrition during gestation influenceslikelihood of developing obesity in adulthood

From October 1944 until May 1945 cities in the western Nether-lands, including Amsterdam, suffered extreme famine resulting froman embargo of food supplies imposed by the Nazi régime and an in-ability to transport food through the frozen waterways. Rationswere reduced from 1800 calories per capita per day in December1943 to below 800 calories at the height of the famine from December1944 to April 1945 [25]. While initially pregnant and lactating womenwere given supplemental food, at the heart of the famine this couldnot be provided. Thus at 800 calories, women were receiving approx-imately ~40% of the recommended calories during pregnancy [26].The homogenous and sharply defined famine, in addition to the trace-ability of those afflicted, provided a unique circumstance for studyingthe long-term effects of extreme nutritional deprivation [27]. Basedon relative conception and birth dates, analysis of the Dutch cohortidentified two groups of males whose obesity rates at 19 years ofage were significant deviations from the norm. Males exclusively ex-posed to famine prenatally during the first two trimesters of gestationhad about 2-fold higher prevalence of obesity (2.77%) than controlcounterparts (1.45%). Of note, the likelihood of developing obesityin either group is far below the national average for overweight andobese individuals in westernized countries today [28]. In contrast,males exposed to famine prenatally during the third trimester, andpost-natally during the first three to five months of life, were foundto be approximately half as likely to develop obesity (0.82%) thanthe controls (1.32%) at age 19 [29], although these thin men weremore likely to be glucose intolerant at 50 years of age [30]. Followingadjustment for known obesogenic conditions e.g. socioeconomic sta-tus at birth, present level of education, and smoking, women at age 50who were similarly exposed to prenatal famine in early gestation hadelevated body weight, body mass index (BMI) and waist circumfer-ence [31]. Men at 50 years of age did not show this trend even thoughtheir reported weight was elevated at 20 years of age. These resultssuggest that developmental plasticity resulting from neonatal expo-sure to global maternal nutrient-restriction has a time dependent,profound and opposing effect on the propensity to develop obesity.Furthermore, the absence of sustained elevated body weight fromage 19–20 to age 50 in men, but not women, suggests a distinct sexualdimorphic effect of maternal nutrition on obesity. Finally, the devel-opment of glucose intolerance but not obesity in males exposed tofamine during the third trimester suggests differential mechanismsfor these pathologies.

2.2. Fetal birth weight and adult obesity follow a J- or U-shapedrelationship

Using birth weights relative to parental size as an indicator of fetalrestricted or excess nutrition, Parsons et al. [32] identified a linear rela-tionship between birth weight and BMI at age seven, eleven, sixteenand twenty-three years of age. By age thirty-three, however, the rela-tionship shifts toward a J-shape curve in which both low and highbirth weights are weakly correlated with subsequent obesity [32]. A J-or U-shaped relationship between birth weight and later BMI,waist-to-hip ratio and percent body fat was also identified in numerousindependent studies (Fig. 1) [33–40]. Nevertheless, this connection isnot without controversy: a meta-analysis of fifteen epidemiologicaland clinical studies involving a total of ~22,000 individuals found thathigher, but not lower, birth weight is associated with an increased riskof being overweight or obese [41]. Considering that nutritional deficien-cy has opposing effects on adult obesity, depending on its timingwithingestation [29], discrepancies in the epidemiological literature may be

Birth Weight

Pro

pens

ityfo

r O

besi

ty

Fig. 1. Epidemiological studies have described a J- or U-shaped relationship betweenbirth weight (a marker of fetal nutritional exposure) and the propensity to developobesity in adulthood.

497S.D. Parlee, O.A. MacDougald / Biochimica et Biophysica Acta 1842 (2014) 495–506

associated with differences in onset, duration and type of nutrient-deprivation, rather than the deficiency itself.

2.3. Post-natal compensatory growth influences adult human obesity

Expanding on their findings associated with low birth weight andobesity, Parsons and colleagues [32] observed that, for men with lowfetal birth weights and a greater percentage of their adult height byage seven, the risk of developing obesity at age 33 is elevated comparedtomenwith lowbirthweight alone [32]. These results suggest that fetalgrowth when combined with rapid compensatory childhood growthpredisposes children to obesity as adults [32]. Accordingly, childrenwith low birth weights and rapid compensatory growth between zeroand two years have more centralized adipose tissue at age five com-pared with other children [42]. Similar results associated with rapidcompensatory growth and heightened susceptibility for type 2 diabeteshave been independently documented [43,44]. Perhaps the discrepan-cies identified in the literature [41] associated with low birth weightand adult obesity may be associated with variation in compensatory‘catch-up’ growth or biological, socioeconomic, and demographic fac-tors not accounted for in the study methods.

Nevertheless, epidemiological and clinical data jointly support adevelopmental origin for obesity when humans are exposed to globalnutrient-restriction in utero and a higher calorie diet in adulthood[33–40]. The relationship between high birth weight, which is corre-lated to in utero exposure to surplus energy, and adult obesity goescontrary to the protective effects on obesity that developmental plas-ticity would predict. Rather, it suggests that in addition tomismatchedfetal and post-natal environments, aberrant high calorie fetal environ-ments can combinewith a similar high calorie post-natal environmentto cause obesity.

3. Developmental origin of obesity in animal models

3.1. Maternal global nutrient-restriction and low-protein diets duringgestation cause intrauterine growth restriction by impairing placentalamino acid transfer

Maternal malnutrition, including chronic energy and micronutrientdeficiencies, remains prevalent in the non-westernized world (e.g.Sub-Saharan Africa), where more than 20% of women have a BMIbelow 18.5 [45]. Low maternal BMI is associated with intrauterinegrowth restriction, and neonates are thus often born smaller-for-gestational age [46]. To ascertain the long-term effects of maternalnutrient-restriction on obesity of progeny, intrauterine growth restric-tion can be modeled in rodents by restricting consumption during ges-tation of a balanced diet, or by feeding a complete diet low in protein.Although these experimental approaches will not be included within

the current review, intrauterine growth restriction can also be modeledthrough pharmacological (e.g. elevated glucocorticoids), or surgical(uterine artery ligation) means (see [47] for a review of the differentmodels).

The placenta serves as the nutritional interface between the ma-ternal and fetal circulations via a wide array of nutrient transport sys-tems including placental glucose transporter (GLUT3) and neutralamino acid transporters (system A). Alterations in the placental bio-logical barrier can therefore act to modify nutritional transport andthus fetal development. In particular, fetal growth is strongly depen-dent on the maternal nutrient supply for amino acids necessary tosynthesize proteins during development [48–52]. Accordingly, rodentpups born to mothers on a low-protein diet have restricted growth inutero due to decreased amino acid transport across the placentawhich appears prior to the restriction itself [53–55]. System A is sim-ilarly decreased in growth-restricted humans [48–52]. In contrast, thetransport of glucose, a major energy source for the growing fetus, isnot altered in low-protein [53] or global nutrient-restricted rodentmodels [56], or in humans [52]. Accordingly, the impaired growth fol-lowing maternal nutrient-restriction is mainly due to altered aminoacid transfer [48–52].

3.2. Intrauterine growth restriction due to maternal global nutrient- orprotein-deficiency causes obesity in adult animals

As discussed above, human growth restriction early in gestation in-creases the probability of developing obesity in later life, particularly ifcombined with rapid compensatory growth after birth [29,33–40].Studies in experimental animals such as rodents and sheep reproducethese findings [57–62]. For example, when placed on an isoenergeticdiet containing 40% less protein per kg, female rats gave birth to pupswith 35% lower body weights and proportionally smaller organ sys-tems, including the pancreas, liver, muscle and spleen [63]. However,certain organs, including the brain, remain relatively unaffected [63].Adipose tissues are also largely spared from the effects of fetalmalnutri-tion, consistent with the thrifty phenotype hypothesis that energystores are preserved for survival under conditions of food scarcity fol-lowing birth [64,65]. It is this preservation of adipose tissue mass thatalso supports the developmental origin of obesity hypothesis.When de-veloping rats are exposed to maternal nutrient-restriction through thefirst 14 days of gestation, they gain significantly more body weightand epididymal adipose tissue on a chow diet than rats that were notexposed to nutrient-restriction [66]. If these rats are switched fromchow to a high-fat diet, males, but not females, continue to increasetheir weight gain [66]. The increase in male body weight reflects an in-crease in epididymal and retroperitoneal adipose tissue, due to adipo-cyte hypertrophy. Although females do not gain significantly morebody weight following transfer onto a high-fat diet, there is a trendtoward larger adipose depots and adipocyte size (Table 1). However,female rats do gain body weight and adiposity on either chow or highfat diet if food restriction is initiated at the beginning [67] or even atday 10 of gestation [68–70]. Similar results are found with pups borntomothers fed a low-protein diet throughout gestation [71–74]. Specif-ic gestational timing of maternal nutrient-deprivation also appears tobe important in other models. For example, lambs exposed to maternalnutrient-restriction between gestational day 28–80, the maximum pe-riod of placental growth, have elevated levels of adipose depositionlate in gestation [75], whereas if the deprivation occurs after 110 daysof gestation, adipose tissue mass is decreased [29,75–77]. It should benoted, however, that increased adiposity of rodent offspring exposedto maternal food restriction has not been uniformly observed when an-imals were weaned onto a regular chow diet [66,70,73,74,78], and dif-ferences in results might be accounted for by the extent of protein-(30% [73] vs 40% [74]), or nutrient-restriction (50% [70] vs 70% [78]),or animal model used (C57BL/6J mice [73,78] versus Sprague Dawleyrats [70,74]).

Table 1Overview of nutritional exposure on adipose phenotype of adult offspring.

Period of Maternal Nutritional Exposure Adult adipose phenotype compared to respective sex control

Animal Model

Pregravid Gestation Lactation

Offspring Post-

Weaning Male Females

Lean LeanMice, Rats,

Ewes, Monkeys

AT and

adipocyte hypertrophy

[109−111, 113, 132]

AT and

adipocyte hypertrophy

[109, 112, 113, 132]

Rats AT and

adipocyte hypertrophy

[114, 115]

AT and

adipocyte hypertrophy

[114, 115, 133]

Mice, Rats

AT and

adipocyte hypertrophy

[116−118, 139]

AT

[117, 118]

Rats Lean [113, 118] Lean [113, 118]

Rats AT [118, 137] AT [118, 137]

Rats, Ewes, Mice

AT [62, 68-70] AT [68-70]

Mice

Mice

Mice

AT and

adipocyte hypertrophy

[57, 58, 66, 68, 69, 73, 78]

Trend/ AT and

adipocyte hypertrophy

[58, 66, 68-70, 73]

Lean [57, 68, 69] Lean[68, 69]

Lean[57, 68, 69] Lean[68, 69]

Control Diet: Black; Obesogenic Diet: Red; Global-Nutrient or Protein-Restricted diet: Green; AT, adipose tissue

498 S.D. Parlee, O.A. MacDougald / Biochimica et Biophysica Acta 1842 (2014) 495–506

3.3. Growth rate to weaning influences development of adiposity andmetabolic abnormalities

The postnatal nutritional environment also contributes to thecompensatory growth and phenotype of the offspring. Pups born toglobal-nutrient or protein-restricted females that are fostered by con-trol rats have hyperphagia and compensatory growth by weaning, andhave increased adipose tissue as adults [67,70,79]. Increased bodyweights and adipose tissue are further elevated if these rats are weanedonto western diets [68]. Consistent with an obese phenotype, maleand female rats have metabolic abnormalities including insulin resis-tance, glucose intolerance, hyperleptinemia and elevated blood lipids[67,68,71,79], although not all differences were uniformly observed be-tween studies.

In contrast, however, growth-restricted newborn rats subjected tocontinued nutrient-restriction throughout suckling have slowed com-pensatory growth and normalized or reduced adipose tissue weights(Table 1; [57,67,70,79]). Similar delayed growth occurs in pups bornto control mothers that are then reared by nutrient-restricted mothers.In both cases, animal body weights are smaller at weaning but reboundslowly to weights that are equal or slightly lower than controls. Thisdecreased growth is attributable to lower production of milk [80–84]and reduced lactose [82,85]. In addition, reduced milk protein is deliv-ered from lactating females on the protein-deficient diet [83,86]. Inline with a leaner phenotype, male and female rodents exposed tonutrient-restriction in utero and during lactation have improved or sim-ilar glucose homeostasis compared to nutrient-restriction in utero, orcontrols, respectively [57,79].

3.4. Gestational nutrient-deprivation increases hyperphagia as a result ofleptin resistance in offspring

Fetal exposure to maternal nutrient-restriction during gestation canincrease hyperphagia post-natally through dysregulation of central

pathways controlling food intake [58,59,68,70]. At birth, pups exposedto maternal global nutrient-deficiency have reduced hypothalamicphosphorylation of STAT3 in response to leptin. Following compensatorygrowth to three weeks of age, phosphorylation of STAT3 and reductionin food intake in response to leptin are both impaired [58]. Duringpostnatal development, a surge in circulating leptin is associated withhypothalamic growth; however, in pups exposed tomaternal dietary re-striction, the leptin surge occurs six days earlier. The premature spike inleptin is proposed to cause leptin resistance by impairing transport ofleptin across the blood–brain barrier [78]. Reduced central leptin in-creases density of the hypothalamic neurotransmitters neuropeptide Y,and cocaine and amphetamine regulated transcript, and causes hyper-phagia [60,78]. An independent study observed that mice exposed inutero to maternal nutrient-restriction had a smaller amplitude of leptinconcentration during the spike, but the timing was not premature.Lower peripheral circulating leptinwas associatedwith decreased levelsof hypothalamic anorexigenic POMC expression [87]. The discrepancybetween possible mechanisms driving hyperphagia may result fromthe different timing of nutritional restriction (e.g. E10.5 to P1 vs E14 toweaning; Fig. 2). Regardless, both studies support a model in whichnutrient-deprivation during gestation causes leptin resistance, whichmodifies the development of central neural pathways that regulatefood intake, and results in hyperphagia and obesity.

3.5. Maternal nutrient-restriction impairs early development and functionof β-cells

The predominant role of the endocrine pancreas is to monitor andregulate glucose homeostasis. In the absorptive state,β-cells of the pan-creas secrete insulin to promote uptake of glucose into tissues includingmuscle and adipose tissue. The ability of the endocrine pancreas to pro-duce insulin is determined by a combination of β-cell differentiation,replication, and apoptosis, islet size, and vascularization [88]. Maternalnutrient-restriction during gestation (either global or low protein)

Early or BluntedDevelopmental Leptin Surge

LeptinResistance

IncreasedOrexigenic

Neuropeptides

Hyperphagia

Global/Protein Restricted Diet Exposure

CompensatoryGrowth

Obesity

HypertrophicAdipocyte

(Post-Natal Day10 in Mice)

Decreased Amino Acid Transferthrough the Placenta

Intrauterine GrowthRestriction

Glucose

Insulin Resistant

Insulin Sensitive

Muscle

Adipose Tissue

?

Energy Redistribution ?

Pancreas

Decreased Beta-Cell MassIn

Ute

roF

rom

Birt

h un

til W

eani

ngF

ollo

win

g W

eani

ng

Fig. 2. Fetal exposure to maternal global- or protein-restriction during gestation decreases amino acid transfer through the placenta leading to intrauterine growth restriction(IUGR). IUGR leads to decreased β-cell mass and altered timing (IUGR indicated in red, control in black) or amplitude of the developmental leptin surge. The decrease surge con-tributes to leptin resistance, increased orexigenic neuropeptide production and hyperphagia. Compensatory growth may favor deposition of adipose tissue with energyredistributed from insulin-resistant skeletal muscle toward insulin-sensitive adipocytes.

499S.D. Parlee, O.A. MacDougald / Biochimica et Biophysica Acta 1842 (2014) 495–506

causes a decrease in pancreatic β-cell mass and dysfunction, whichmaycontribute to the glucose intolerance identified in the adult animals[89–93]. Themechanisms driving this decrease inβ-cells are dependentupon the model of nutritional deficiency.With in utero global nutrient-restriction, the decrease in fetal and early postnatal β-cell mass is asso-ciated with an elevation in plasma glucocorticoids, which in turnincreases PGC-1α and impairs β-cell differentiation [90,94,95]. How-ever, with protein-restricted models, reduced islet mass results from adecrease in vascularization [90,91], β-cell proliferation [90,91] andincreased susceptibility to β-cell apoptosis [96]. With both models ofgestational nutrient-restriction [89,96], decreased islet mass and dys-functional β-cells result in lower insulin secretion. Although a severedecrease in β-cell mass can obviously cause diabetes, β-cells have a re-markable ability to compensate by increasing insulin production [97].Accordingly while fetal nutrient-deficiency impairs early developmentand function of β-cells, the islets appear to readily compensate forinsulin-resistance that occurs with later obesity. Indeed, in adult

rodents exposed to maternal nutrient-deficiency, hyperinsulinemia isobserved, although not enough to combat glucose intolerance.

3.6. Decreased energy expenditure in the semistarvation–refeedingmodelcauses adipose tissue deposition and associated metabolic complications

To control for the effects of hyperphagia on adipose tissue devel-opment following a period of nutrient-restriction, Dulloo and col-leagues have used a rat model of semistarvation–refeeding. In thismodel, male Sprague–Dawley rats ranging in age from 21 days to7 weeks are food restricted to 50% of their spontaneous food intakefor two weeks, and then refed with the diet at a level equal to the me-tabolizable energy content of control rats matched for weight at theonset of refeeding [98–100]. Rats under the semistarvation–refeedingconditions have reduced energy expenditure and while they gainequal amounts of lean mass as their controls, their fat mass is in-creased more than two-fold [98]. One week following refeeding,

500 S.D. Parlee, O.A. MacDougald / Biochimica et Biophysica Acta 1842 (2014) 495–506

when body fat is similar between refed and weight matched groups,refed animals had elevated basal (postabsorptive) plasma glucoseand insulin without alterations in whole body glucose homeostasis.However, under hyperinsulinemic conditions, glucose uptake was in-creased to white adipose tissues (e.g. epididymal, retroperitoneal andinguinal tissue depots) and decreased to skeletal muscles (e.g. tibialisanterior, white and red quadriceps) [101]. The hyperresponsivenessof the adipose tissue, and redistribution of glucose from the relativeinsulin resistant skeletal muscle result in de novo lipogenesis. The in-crease in weight of epididymal WAT is due to both adipocyte hyper-plasia and hypertrophy [102,103].

While the model of semistarvation–refeeding differs from that ofgestational nutrient-restriction, a compensatory elevation in fat massis a common thread in situations accompanied by a period of starvationand rebound weight gain. These states include both newborns bornsmall-for-gestational-age or young and elderly adults duringweight re-bound [104]. Thus, the mechanisms described in the rodent model ofsemistarvation–refeeding may be applicable to the obesity associatedwith maternal nutrient-restriction during gestation, although this re-mains conjecture until these mechanisms are explored directly.

3.7. Maternal obesity combined with westernized or high-fat diet duringpregnancy increases the risk of offspring developing obesity in adulthood

In contrast to nutrient deficiency, global nutrient excess and obesityis emerging as one of the greatest health problems in the industrializedworld [28]. In the United States alone, the incidence of obesity amongpregnant women ranges from 18.5% to 38.3% [105]. Pre-pregnancyBMI is a strong predictor of birth weight and obese mothers deliverlarge-for-gestational-age infants 1.4- to 18-times more frequently,which predisposes to obesity in later life [105]. Pregravid obesity inhumans is associated with a poor quality, high-fat diet, suggesting arole for maternal nutrition in predisposing neonates to high birthweight and obesity [106]. Maternal nutrition remains an important reg-ulator of offspring obesity evenwhen genetic contribution is controlled.Children of mothers who have undergone weight loss surgery arethree-times less likely to be severely obesewhen compared to their sib-lings whowere born prior to surgery [107]. They are alsomore likely tohave improved insulin sensitivity, improved lipid variables (e.g. HDL,total cholesterol, triacylglycerols), and are less likely to be born large-for-gestational age. Similar results have been repeated in an indepen-dent study [108]. Thus, the effects of maternal obesity on the intrauter-ine environment appear to be particularly important for determininghealth of progeny.

A variety of animalmodels have been developed to explore the rela-tionship betweenmaternal nutrition and progeny obesity. For example,obesemice fed awesternized diet rich in fats, sugar and salt during ges-tation and lactation give birth to pups that gain significantly more bodyweight afterweaning than pups born to chow-fed controls (see Table 1)[109]. Here, weight gain is accounted for by an increase in adipose tissuemass due to adipocyte hypertrophy. Pups born to obese mothers alsoshow indications of metabolic disease, including elevated circulatingglucose, triacylglycerols and cholesterol [109]. Similar results havebeen found in rats placed on a high-fat diet [110,111] and in ewes,which are a more comparable model of human gestation [112].

3.8. Maternal obesity is not required for effects of a western diet onobesity of progeny

Elevated maternal body weight prior to conception is not arequirement for effects of westernized/high-fat diets in utero on subse-quent obesity in rodents. Maternal consumption of a westernized (i.e.“junk-food”) diet at the commencement of gestation and through lacta-tion,without pregravid obesity, produces offspringwith increasedmea-sures of adiposity after weaning, including greater body weight,perirenal adipose tissue, and adipocyte hypertrophy (see Table 1)

[113–115]. This increased adiposity is amplified if animals are placedon a high-fat diet at weaning [116,117]. Indeed, cross-fostering be-tween dietary treatments has established that, in rodents, maternalconsumption of western diet during the suckling period is particularlycritical for the ability of amaternal western diet to cause obesity and as-sociated metabolic consequences in offspring [113,118]. Diets high inlipids increase dailymilk volume and lipid concentration [119]. Further-more a high fat diet also changes the fatty acid composition of rat milkby increasing long-chain fatty acids to the detriment of medium-chainfatty acids [120]. Long-chain fatty acids are not as readily utilized for en-ergy and are thereforemore likely stored in adipocyteswhen comparedto medium-chain fatty acids, thus providing one potential mechanismfor how a maternal western diet affects adiposity of progeny.

3.9. Maternal obesity or high fat diets induce placental inflammation andalter nutritional transfer to the offspring

Although maternal diet during lactation contributes to obesity ofprogeny, maternal obesity is associated with changes in the placentathat also play roles in development of adiposity. Obesity during preg-nancy of non-humanprimates causes placental inflammation, includingmacrophage accumulation [121,122] and enhanced expression of thepro-inflammatory cytokines MCP-1, IL-1 and TNFα [122,123]. Similarresults are found in humans [121,124]. Inflammatorymediators includ-ing IL-6 and TNFα stimulate system A amino acid transporter activity oftrophoblast cells of the placenta in vitro [125]. Adipose-derived signal-ing proteins such as leptin, which are elevated in maternal obesity,also up-regulate systemA [126]. A proposed cause for the obesity in off-spring may be that the maternal high-fat diet or obesity increases pla-cental inflammation and thus increases nutrient transport and fetalgrowth. Accordingly, a high-fat diet before and during pregnancy inmice leads to an up-regulation of system A and glucose transport, andpups that are heavier at birth [127]. Placental system A activity [128]and inflammation [129] have also been reported to be increased inhumanmothers with diabetes, an independent risk factor for deliveringbabies that are large-for-gestational age. In ewes, pregravid maternalobesity also increases the expression of placental CD36, FATP1 andFATP4, resulting in elevated circulating lipids in fetal lambs [130]. An in-crease in expression of CD36 has also been observed in placenta ofobese humans [131].

In contrast to the above findings, Japanese macaques [132] and ba-boons [122] fed a high fat diet during gestation have reduced systemA transport across the placenta. Inmacaques this decrease in fetal nutri-tional transport resulted in fetuses with less leanmass and bodyweightin the early third trimester. However, by postnatal day 30, theweight offetuses had rebounded to that of controls with increased percent bodyfat by 90 days, thusmimicking the responses described above for nutri-ent deprivation during gestation, but running counter to effects of ro-dents, sheep and humans described above [52,127,129,130].

3.10. Maternal obesogenic diets during gestation and lactation increasefood intake and high-fat food preference in offspring

Pups born to mothers fed a westernized diet during gestation andlactation have higher daily energy intake than controls [113,133]. Fur-thermore, given the choice between chow and westernized chow,these mice preferentially select the westernized food rich in fat, sugarand salt, and are less motivated to perform a task if rewarded by achow pellet, which otherwise would be motivating. Thus, weight gainand adiposity as a result of fetal exposure to a maternal obesogenicdiet can be attributed to hyperphagia and change in food preference.Children from obese/overweight families also have a higher preferencefor fatty foods [134,135]. However, whether this choice is as a result ofenvironmental learning or directly caused by fetal reprogramming isnot clear.

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3.11. Hyperphagia in offspring exposed in utero to maternal obesogenicdiet is associated with leptin resistance and increased orexigenicneuropeptide production

The adipokine leptin decreases food intake by altering the activityof anorexigenic and orexigenic neuropeptides in the hypothalamusand other brain nuclei [136]. Pups exposed to maternal high-fat dietin utero have elevated leptin concentrations in peripheral circulation,as well as blunted leptin-associated pSTAT3 activation in the hypo-thalamus [118]. Thus, central leptin insensitivity may be the basisfor the documented hyperphagia and increased weight gain in pupsexposed to maternal obesogenic diets through gestation and lacta-tion. Similar results are reported in two independent models of fetalover-nutrition, including non-human primates [137,138]. Elevatedcirculating lipids in the developing pups have been proposed to stim-ulate the proliferation and differentiation of neuroepithelial cells inthe third ventricle. Once differentiated, these cells migrate into thehypothalamus where they stimulate production of orexigenic neuro-peptides, which then may cause hyperphagia, weight gain, and fur-ther exacerbation of this process by leptin resistance (Fig. 3) [139].Although mechanisms such as repression of adipocyte lipolysis can-not be excluded as influencing adiposity [109], findings from humansand experimental animal models generally suggest that fetal expo-sure to maternal obesogenic diet in utero and through lactation pro-motes plasticity in neural processes controlling food intake and foodpreference, which leads to subsequent obesity.

3.12. Maternal high fat or westernized diet during gestation decreasespancreatic β-cell mass in progeny

Similar to nutrient-restriction, maternal high fat diet during gesta-tion significantly reduces β-cell mass in rats by reducing β-cell numberand volume leading to impaired insulin release [140–144]. In contrast,the volume of α-cells, which are responsible for glucagon secretion, isexpanded due to increased cell number and size. Thus at birth these ne-onates show signs of hyperglycemia [141]. However, by three weeks ofage, the volume, number and size of both α- and β-cells are similar tocontrols, although these animals still have decreased fasting insulinconcentrations and relative glucose intolerance [142,144]. Similar re-sults occur if rats are exposed to a high fat diet during both gestationand lactation [143,144]. At three months of age, males exposed to ma-ternal high fat diet during gestation had fasting blood glucose and insu-lin concentrations similar to controls, consistentwith their findings thatβ- and α-cell number and mass were normalized. When exposed tohigh fat diet during both gestation and lactation, elevated bodyweights,hyperleptinemia, hyperglycemia and hyperinsulinemia occurred with-out changes in β-cell or α-cell size or number [145]. Thus it appearsthat high fat diet during early development modifies pancreatic devel-opment leading to decreased insulin production and hyperglycemiaduring early post-natal growth. However, as the animal continues toage, the pancreas largely compensates, although in animals exposedto high fat diet during both gestation and lactation, it still remains un-able to completely control blood glucose levels thus contributing to ametabolic phenotype.

3.13. Developmental plasticity does not protect against effects ofmaternal obesogenic diet

One might predict that developmental reprogramming in responseto a maternal high-fat diet allows mammals to better thrive in anobesogenic environment; however, these variables surprisingly com-bine to exacerbate the obese state [109–111]. One can speculate that areason in uteromaternal obesogenic diets donot protect against obesityin progenymay be that nutritional surplus rarely existed inmammalianevolutionary history. Therefore, evolution has not influenced the devel-opment of organ or tissue plasticity in response to an obesogenic diet.

Mammals are also believed to have evolved tomaximize ametabolicallythrifty phenotype [14]. Thus, another possibility for the lack of protec-tive effect of in utero exposure to a high-fat or westernized diet maybe that the thrifty phenotype is dominant over protective developmen-tal plasticity. One other consideration is that the primate studies indi-cate that maternal obesogenic diets cause a relative state of fetalnutrient-restriction [132]. If this mechanism is also true in humans,then the restricted fetal nutrition caused by placental inflammation inthe high fat fed mother would prepare the fetus to emerge into anutrient-restricted environment. In this case, obesity in the progenywould fulfill the developmental origin of disease.

4. Inheritance of metabolic phenotypes

4.1. Maternal nutrient-deprivation during gestation increases weightgain and fat mass for two generations

As described above, pups born to females on a restricted dietthrough gestation have significantly lower birth weights [146,147],and when fostered by controls, rapid compensatory growth resultsin elevated total body weight, adipose tissue and serum glucose atweaning and as adults [146,147] (Fig. 2). Mating of female progenyproduces second-generation pups that are large-for-gestational-ageand maintain the elevated body weight, blood glucose and insulin re-sistance observed in their mothers. As with maternal malnutritionduring gestation, nutrient-deprivation in lactating mothers also re-sults in pups that subsequently transmit obesity to the next genera-tion [146]. Mechanistic studies suggest that the heritability ofadipose tissue accumulation cannot be explained by maternal hyper-phagia or expression of adipose genes encoding proteins such asPPARγ, C/EBPα, FABP4 and GLUT4 [147]. Changes in glucocorticoid re-ceptor and isoforms of 11β-hydroxysteroid dehydrogenase1 and 2may, however, contribute to these phenotypes. Rats born to mothersrestricted of protein during gestation have elevated expressionof the glucocorticoid receptor and decreased expression of 11β-hydroxysteroid dehydrogenase 2, which catalyzes the inactivation ofcorticosterone to 11-dehydrocorticosterone in neonatal and adult tis-sues including the kidney, liver and lung [148]. These pups show de-creased CpG methylation in the predominant hepatic promoters ofthe glucocorticoid receptor and PPARα, resulting in greater GR andPPARα expression in the liver [149]. These methylation patterns aresubsequently passed to F1 and F2 generations of males [150]. Giventhe role glucocorticoids and PPARα ligands play in the regulation ofdevelopment andmetabolism, these epigenetic marks may contributeto the inheritance of metabolic disease. However, mechanisms of in-heritance will be complex and tissue-specific as glucose intolerancecan be passed to the second and third generations through maternaland paternal lines and may be secondary to impaired expression ofSur1, and altered function of pancreatic islet potassium channels[147,151]. It should be noted that while a number of studies haveshown other epigenetic changes in animals exposed to maternalnutrient-restriction in utero (e.g. [152,153]), they have not tracedthese changes in lineage studies. Accordingly it is difficult to assesswhether or not these epigenetic changes are directly contributing tothe transmitted phenotypes described above.

4.2. Maternal high-fat diet during gestation increases body length in thesubsequent two generations

Mice exposed in utero to maternal high-fat diet have increased bodylength and bodyweight, alongwith glucose intolerance and insulin resis-tance [154–157]. Second-generation mice, however, were found tomimic their parents in increased body length and insulin resistance butwithout effects on body weight [154–157]. By the third generation,male and female progeny had elevated body length and normal glucosetolerance, while females alone inherited increased body weight [155].

HypertrophicAdipocyte

Lipid storage

NeuroepithelialDifferentation

and Translocation

Mito

sis

Differentiation

IncreasedOrexigenic

Neuropeptides

SerumTriglyceride

LeptinResistance

High-Fat/ Western Diet Exposure

Hyperphagia

Obesity

Post-Natal Day 8

Placental Inflammation

Mammary Gland

Increased Milk Volume and Lipid Concentration

Pancreas

Decreased Beta-Cell Mass

In U

tero

Fro

m B

irth

until

Wea

ning

Fol

low

ing

Wea

ning

Fig. 3. Exposure to maternal obesogenic diet through gestation and lactation increases placental inflammation resulting in modified amino acid transport and fetal growth includingdecreased β-cell mass. Following birth, maternal high fat diet consumption through lactation increases milk volume and lipid concentration, increasing circulating blood lipids, andcausing neonatal neuroepithelial cells to undergo mitosis, differentiation and translocation into the hypothalamus where they elevate levels of orexigenic neuropeptides. Whencombined with accompanying leptin resistance, this increase in orexigenic neuropeptide production stimulates offspring hyperphagia and obesity.

502 S.D. Parlee, O.A. MacDougald / Biochimica et Biophysica Acta 1842 (2014) 495–506

Longer body lengths are passed onto the second generation through ei-ther the maternal or paternal lineages, and into the third generation tofemales via the paternal lineage alone. The inheritance of body length ap-pears to be due to increased IGF-1/IGFBP-3 mediated growth [154,155].A potential mechanism is that reduced promoter methylation of thegrowth hormone secretagogue receptor gene increases expression of

its mRNA. Elevated release of growth hormone from the anterior pitui-tary then induces IGF-I production from the liver [154]. In addition, thepaternal passage of elevated body length to third-generation femalessuggests a stable alteration in the paternal germ line governing bodygrowth, although the mark has yet to be identified. It is conceivablethat common epigenetic mechanisms, such as DNA methylation and

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modification, restructuring of histone and nonhistone DNA-bindingproteins and RNA regulatory systems [158], are responsible for thisinheritance.

4.3. Maternal nutrition: a legacy of obesity

For much of mammalian history, ultimate reproductive success hasbeen dependent upon the capacity to modify development toward athrifty phenotype [14,65]. For areas of the world where starvation stillremains an obstacle [45], this evolutionary system continues to be ad-vantageous. Unfortunately, with the increase in globalization, underde-veloped countries have seen a dramatic shift toward the populationover consuming inexpensive foods that are high in fat, sugar and salt[159]. In these situations, developmental plasticity may act as a Trojanhorse, with maternal nutrient-deficiency interacting with a high-fatdiet to increase susceptibility to obesity. One could envision that thismay, in part, explain the rise in numbers of obese individuals in devel-oping nations [160,161].

For the western world, obesity, rather than starvation, remains agrowing threat [28]. Nearly one in every two women of childbearingage in the United States is considered overweight or obese [162]. Un-fortunately, evidence suggests that mammals have not evolved devel-opmental plasticity toward maternal obesogenic diets. Given thatpregravid obesity is associated with poor nutrition during pregnancy,including a high-fat diet, obese women, as well as women consumingwesternized diets, may be endangering the future health of their chil-dren by predisposing them to a lifetime of obesity.

If the animal research described within this review truly reflectsthe human condition then what remains most concerning is the lega-cy of obesity that each generation will bestow upon the next. If we areto interrupt this transferance of disease we must make it a global pri-ority to provide pregnant mothers and their offspring access to ade-quate and balanced nutrition throughout their lifetimes. Such effortscan only benefit from improved understanding of how maternal nu-trition impacts metabolic disease risk in offspring; hence, researchseeking to further elucidate the biological mechanisms driving suchadverse developmental plasticity should be a priority.

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