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Maternal Nutritional Programming of Fetal Adipose Tissue Development: Long-Term Consequences for Later Obesity Helen Budge, Mo G. Gnanalingham, David S. Gardner, Alison Mostyn, Terence Stephenson, and Michael E. Symonds* INTRODUCTION Obesity is of immense significance in the health and the premature mortality of the population. It af- fects almost all organ systems (Must and Strauss, 1999), and is a risk factor for hypertension (Hall, 2003), type 2 diabetes (Laaksonen et al., 2002), cardiovascular mor- tality (Peters et al., 1995), and de- mentia (Whitmer et al., 2005). The latest data from the U.S. National Center for Health Statistics show that 30% of adults above 20 years of age and older are now obese, i.e., over 60 million people. This dramatic rise in obesity is strongly reflected among young people, the number of whom are overweight more than tripling since 1980. Cur- rently, 9 million children or teenag- ers, i.e., 16% of those aged be- tween 6 19 years, are now considered overweight in the United States. This transition in body size is now being followed in Europe where, in the United King- dom for example, nearly 1 million children are now obese (Reilly et al., 2005). The prevalence of obe- sity is accelerating, and in the United States and Europe is now rising by at least 1% of children per annum (Lobstein et al., 2004). Obesity in childhood not only leads to increased morbidity, but also to adult obesity and its related ad- verse metabolic and cardiovascular sequelae. For example, being over- weight in adolescence leads to dys- lipidemia, which tracks from child- hood into adulthood (Bao et al., 1996) and contributes to at least a five times increased risk of hyper- tension (Field et al., 2005). In ad- dition, not only is the incidence of adult diabetes associated with in- creased body mass index (BMI) in childhood (Eriksson et al., 2003), but so is adult death from cardio- vascular disease (Eriksson et al., 1999). CAUSES OF ADULT OBESITY Epidemiological studies have fo- cused attention on contemporary lifestyles with a much greater avail- ability of excess, palatable, energy rich foods (Putman et al., 2002) and increased prevalence of seden- tary behavior (Sturm, 2004). Al- though it is generally accepted that the rise in obesity stems from an increase in energy intake, evidence from human longitudinal studies is sparse. Some studies have even suggested that energy intakes have fallen (Cavadini et al., 2000), while As obesity reaches epidemic levels in the United States there is an urgent need to understand the developmental pathways leading to this condition. Obesity increases the risk of hypertension and diabetes, symptoms of which are being seen with increased incidence in children. Adipocyte development begins in the fetus and, in contrast to all other tissues whose growth ceases in late juvenile life, it has the capacity for unlimitedgrowth. In normal healthy individuals, the increase in fat mass with age is accompanied by a parallel increase in cortisol sensitivity, i.e., increased glucocorticoid receptor abundance and increased activity of the enzyme 11 hydroxysteroid dehydrogenase type 1. Enhanced adipocyte sensitivity to cortisol is promoted in offspring born to mothers that were nutrient-restricted in utero in conjunction with increased peroxisome proliferator activated receptor . This adaptation only appears to be associated with greater fat mass in the offspring when maternal nutrient restriction is confined to late gestation, coincident with the period of maximal fetal growth. In these offspring, increased fat mass is accompanied by glucose intolerance and insulin resistance, in conjunction with an adipose tissue specific reduction in glucose transporter 4 abundance. In conclusion, changes in maternal and, therefore, fetal nutrient supply at specific stages of gestation have the potential to substantially increase the risk of those offspring becoming obese in later life. The extent to which changes in dietary habits, both during pregnancy and in later life, may act to contribute to the current explosion in childhood and adult obesity remains a scientific and public health challenge to us all. Birth Defects Research (Part C) 75:193199, 2005. © 2005 Wiley-Liss, Inc. Helen Budge, Mo G. Gnanalingham, David S. Gardner, Alison Mostyn, Terence Stephenson, and Michael E. Symonds are from the Centre for Reproduction and Early Life, Institute of Clinical Research, University of Nottingham, United Kingdom. *Correspondence address: Michael E. Symonds, Professor, Academic Division of Child Health, School of Human Development, Queens Medical Centre, University Hospital, Nottingham, NG7 2UH, United Kingdom. E-mail: [email protected] Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdrc.20044 REVIEW Birth Defects Research (Part C) 75:193199 (2005) © 2005 Wiley-Liss, Inc.

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Page 1: Maternal nutritional programming of fetal adipose tissue development: Long-term consequences for later obesity

Maternal Nutritional Programming of FetalAdipose Tissue Development: Long-TermConsequences for Later Obesity

Helen Budge, Mo G. Gnanalingham, David S. Gardner, Alison Mostyn,Terence Stephenson, and Michael E. Symonds*

INTRODUCTIONObesity is of immense significancein the health and the prematuremortality of the population. It af-fects almost all organ systems(Must and Strauss, 1999), and is arisk factor for hypertension (Hall,2003), type 2 diabetes (Laaksonenet al., 2002), cardiovascular mor-tality (Peters et al., 1995), and de-mentia (Whitmer et al., 2005). Thelatest data from the U.S. NationalCenter for Health Statistics showthat 30% of adults above 20 yearsof age and older are now obese,

i.e., over 60 million people. Thisdramatic rise in obesity is stronglyreflected among young people, thenumber of whom are overweightmore than tripling since 1980. Cur-rently, 9 million children or teenag-ers, i.e., 16% of those aged be-tween 6–19 years, are nowconsidered overweight in theUnited States. This transition inbody size is now being followed inEurope where, in the United King-dom for example, nearly 1 millionchildren are now obese (Reilly etal., 2005). The prevalence of obe-

sity is accelerating, and in theUnited States and Europe is nowrising by at least 1% of children perannum (Lobstein et al., 2004).Obesity in childhood not only leadsto increased morbidity, but also toadult obesity and its related ad-verse metabolic and cardiovascularsequelae. For example, being over-weight in adolescence leads to dys-lipidemia, which tracks from child-hood into adulthood (Bao et al.,1996) and contributes to at least afive times increased risk of hyper-tension (Field et al., 2005). In ad-dition, not only is the incidence ofadult diabetes associated with in-creased body mass index (BMI) inchildhood (Eriksson et al., 2003),but so is adult death from cardio-vascular disease (Eriksson et al.,1999).

CAUSES OF ADULTOBESITYEpidemiological studies have fo-cused attention on contemporarylifestyles with a much greater avail-ability of excess, palatable, energyrich foods (Putman et al., 2002)and increased prevalence of seden-tary behavior (Sturm, 2004). Al-though it is generally accepted thatthe rise in obesity stems from anincrease in energy intake, evidencefrom human longitudinal studies issparse. Some studies have evensuggested that energy intakes havefallen (Cavadini et al., 2000), while

As obesity reaches epidemic levels in the United States there is an urgentneed to understand the developmental pathways leading to this condition.Obesity increases the risk of hypertension and diabetes, symptoms ofwhich are being seen with increased incidence in children. Adipocytedevelopment begins in the fetus and, in contrast to all other tissues whosegrowth ceases in late juvenile life, it has the capacity for “unlimited”growth. In normal healthy individuals, the increase in fat mass with age isaccompanied by a parallel increase in cortisol sensitivity, i.e., increasedglucocorticoid receptor abundance and increased activity of the enzyme11� hydroxysteroid dehydrogenase type 1. Enhanced adipocytesensitivity to cortisol is promoted in offspring born to mothers that werenutrient-restricted in utero in conjunction with increased peroxisomeproliferator activated receptor �. This adaptation only appears to beassociated with greater fat mass in the offspring when maternal nutrientrestriction is confined to late gestation, coincident with the period ofmaximal fetal growth. In these offspring, increased fat mass isaccompanied by glucose intolerance and insulin resistance, in conjunctionwith an adipose tissue specific reduction in glucose transporter 4abundance. In conclusion, changes in maternal and, therefore, fetalnutrient supply at specific stages of gestation have the potential tosubstantially increase the risk of those offspring becoming obese in laterlife. The extent to which changes in dietary habits, both during pregnancyand in later life, may act to contribute to the current explosion in childhoodand adult obesity remains a scientific and public health challenge to us all.Birth Defects Research (Part C) 75:193–199, 2005.© 2005 Wiley-Liss, Inc.

Helen Budge, Mo G. Gnanalingham, David S. Gardner, Alison Mostyn, Terence Stephenson, and Michael E. Symonds are fromthe Centre for Reproduction and Early Life, Institute of Clinical Research, University of Nottingham, United Kingdom.

*Correspondence address: Michael E. Symonds, Professor, Academic Division of Child Health, School of Human Development, Queen’sMedical Centre, University Hospital, Nottingham, NG7 2UH, United Kingdom. E-mail: [email protected]

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdrc.20044

REVIE

WBirth Defects Research (Part C) 75:193–199 (2005)

© 2005 Wiley-Liss, Inc.

Page 2: Maternal nutritional programming of fetal adipose tissue development: Long-term consequences for later obesity

others have shown the expected in-crease. This may reflect inherentdifficulties with self-reported di-etary data (Harnack et al., 2000).Furthermore, while the increase inportion sizes in Western societies(Young and Nestle, 2002) has beenheld responsible, there is little in-formation on the overall effect ofthis trend on daily energy intake.Nevertheless, excess intake of en-ergy rich foods does appear to beone factor in obesity. This is impor-tant because disinhibition of thecontrol of food intake is associatedwith the presence of obesity in hu-mans (Bellisle et al., 2004), andrats fed “cafeteria” (Petry et al.,1997) or high-fat (Khan et al.,2004) diets become obese.

Although the energy balanceequation between food intake andenergy expenditure may appeardeceptively simple, it appears thatthese variables have a much morecomplex relationship. For example,rats fed a palatable and caloriedense diet during phases of physi-cal activity (i.e., at night) moderatetheir energy intake for body weightmaintenance and do not becomeobese, whereas they have acceler-ated body weight gain when fedsuch a diet in resting phases, duringthe day (Kretschmer et al., 2005).Rat studies of this type may, how-ever, be confounded, as obese ratsfed such a high-calorie “cafeteria”diet maintain energy loss throughuncoupling of the mitochondrialproton conductance pathway throughuncoupling proteins, especially un-coupling protein 1 (UCP1) (Rodri-guez et al., 2001), which is able togenerate 300 W of heat/gm of tissuecompared with �1 W/gm by all othertissues (Power, 1989). Importantly,UCP1 is not present in humans orlarge mammals such as sheep out-side the newborn period (Lean,1989; Clarke et al., 1997a) and, notsurprisingly, is under very tight nu-tritional control in utero (Budge etal., 2000; Budge et al., 2004).

In humans, paradoxically, appe-tite appears to increase with inac-tivity (Mayer and Thomas, 1967;Tsofliou et al., 2003) and, surpris-ingly, the relative contributions ofthese etiologies to obesity and itssequelae are unknown. Physical ac-

tivity is associated with a lower BMIin childhood (Eisenmann et al.,2002). However, although lack ofphysical activity is associated withthe metabolic syndrome in adults(Gustat et al., 2002; Rennie et al.,2003a, 2003b), the exact timing ofsedentary behavior in relation tothe onset of obesity is unclear. Fur-thermore, lack of physical activityand excess energy intake may actindependently in the etiology ofchildhood obesity (Reilly et al.,2005).

PROGRAMMING OBESITYBY MATERNAL NUTRITIONAND MODULATION BYSUBSEQUENT ENERGYINTAKE AND SEDENTARYBEHAVIOR

Whereas being overweight in child-hood is a good predictor of being anoverweight adult (Field et al.,2005), many obese adults were notobese as children (Viner and Cole,2005). While cross-sectional andshort-term cohort studies cannotdeduce whether these adultsadopted lifestyles leading to posi-tive energy balance later than theirobese childhood peers, program-ming effects of the fetal environ-ment on metabolism are stronglyimplicated. There is a U-shaped re-lationship between birth weight andadult BMI, i.e., with the smaller andlarger birth weights tending to havehigher adult BMIs (Curhan et al.,1996; Martorell et al., 2001; Par-sons et al., 2001). Excess fetal glu-cose supply, such as in maternal di-abetes during pregnancy, results ininfants of greater birth weight andrisk of later obesity (Whitaker andDietz, 1998), while rat offspring ofmothers fed a high fat diet duringpregnancy have greater adiposity(Buckley et al., 2005). Conversely,severe maternal nutrient depriva-tion during late fetal developmentresults in reduction of offspringbirth weight (Roseboom et al.,1999), adult glucose intolerance,and insulin resistance (Ravelli etal., 1998). Although these studieshave used birth weight as a proxyfor the fetal environment, famine inearly gestation results in adult obe-

sity without a preceding alterationin birth weight (Ravelli et al.,1999). Similarly, in sheep, modestmaternal nutrient restriction, whilenot reducing birth weight (Sy-monds et al., 1998; Budge et al.,2000), results in increased adipos-ity (Gardner et al., 2005b) and hy-pertension by adulthood (Go-palakrishnan et al., 2004). Thisfinding supports multiple humanand animal studies that have dem-onstrated that birth weight is justone parameter reflecting the intra-uterine environment. Indeed, re-duced maternal energy intake inpregnancy has significant cardio-vascular and metabolic effectswithout altering birth weight in hu-mans (Eriksson et al., 1999; Rose-boom et al., 2000) and in animalssuch as sheep (Edwards and Mc-Millen, 2002; Gardner et al.,2005b). In addition to these effectsof maternal nutrition, the risk oflater obesity (Reilly et al., 2005),glucose intolerance (Eriksson et al.,2003), and adult death from cardio-vascular disease in humans (Eriks-son et al., 1999) and mice (Halesand Ozanne, 2003; Ozanne andHales, 2004) appears to be ampli-fied when a suboptimal fetal envi-ronment is followed by acceleratedpostnatal weight gain.

In summary, the fetal nutrientenvironment, as well as postnatalenergy intake and physical activity,is implicated in the etiology of obe-sity and its later sequelae. The rel-ative contributions of these factorsand their effects on metabolism,especially before the onset of dis-ease, are largely unknown. As obe-sity, once established, may be lessamenable to population-based life-style interventions than might bepredicted (Swinburn and Egger,2004), it is clearly not only impor-tant to dissect these etiologies, butalso to deduce the physiologicalmechanisms which act to produceobesity sequelae before they occur.A precise understanding of themain factors regulating adipose tis-sue development (see Fig. 1) may,therefore, greatly aid our under-standing of the potential impor-tance of a compromised in uteroenvironment on the risk of laterobesity.

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FETAL AND POSTNATALADIPOSE TISSUEDEVELOPMENT

Adipose tissue development beginsin utero, with the adipocyte lineagebeing derived from stem cell pre-cursors, which have the potential tobecome brown or white adipose tis-sue (Smas and Sul, 1995). Both ofthese forms of adipose tissue havecritical functions, which are depen-dent on the stage of the life cycle.While brown adipose tissue canrapidly generate large amounts ofheat (Cannon and Nedergaard,1985), white adipose tissue repre-sents an endogenous energy storethat secretes a range of hormonesthat regulate appetite regulationand energy homeostasis (Friedmanand Halaas, 1998; Ahima and Flier,2000; Trayhurn, 2005). In largemammals, such as sheep, fat dep-osition in the fetus occurs primarilyduring late gestation (Symonds andStephenson, 1999), with 20–30 gmof adipose tissue being present atbirth around the perirenal-abdomi-

nal region, constituting at least80% of total fat stores in the new-born. Fetal adipose tissue has themorphological and biochemicalproperties of brown adipose tissue,with a large number of mitochon-dria and multilocular fat droplets(Gemmel et al., 1972; Vernon,1986), and can be distinguishedfrom white adipose tissue by thepresence of the brown adipose tis-sue specific-UCP1 (Casteilla et al.,1989). Messenger RNA for UCP1 isthen lost rapidly soon after birth,followed by a gradual loss of theprotein which has a half-life ofseven days (Clarke et al., 1997a).

In the fetus, adipose tissue devel-opment is geared towards maxi-mizing the abundance of UCP1 atbirth. This is critical in precocialthermoregulators, such as humansand sheep, in enabling heat pro-duction to be maximal followingcold exposure to the extrauterineenvironment (Symonds, 1995). In-creases in the plasma concentra-tions of the endocrine stimulatory

factors, including cortisol, triiodo-thyronine, noradrenaline, prolac-tin, and insulin-like growth factors,in parallel with upregulation of therespective receptor populationsand the development of the sympa-thetic nervous system (Symonds etal., 2003), are all essential in pro-moting peripartum adipose tissuedeposition and ensuring maximalUCP1 abundance at birth (Clarke etal., 1997b). Then, following the pe-ripartum period, and in contrast toall other organs or tissues, adiposetissue is capable of seemingly “un-limited” growth in postnatal life(Clarke et al., 1997a; Gardner etal., 2005a).

The increase in fat mass duringlater life appears to be dependent onan increase in local glucocorticoidaction during the postnatal period(Gnanalingham et al., 2005). Adi-pose tissue sensitivity to glucocorti-coids is regulated predominantly byintracellular expression of the gluco-corticoid receptor (GR) and 11 �-hy-droxysteroid dehydrogenase type 1

Figure 1. Summary of the main regulators of local glucocorticoid action and UCP2 within perirenal adipose tissue. AT, adipose tissue;GR, glucocorticoid receptor; IR, insulin receptor; NEFA, nonesterified fatty acids; PPAR, peroxisome proliferator activated receptor;UCP2, uncoupling protein-2; 11�-hydroxysteroid dehydrogenase type 1 (11�HSD1) and (11�HSD2).

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(11�HSD1) and type 2 (11�HSD2) atthe level of gene transcription.11�HSD1 behaves predominantly asan 11-oxoreductase, utilizing nico-tinamide adenine dinucleotide phos-phate as a cofactor to catalyze theconversion of inactive cortisone tobioactive cortisol, and as an intracel-lular amplifier of glucocorticoidexcess to the GR (Bamberger etal., 1996; Stewart and Krozowski,1999). Conversely, 11�HSD2 be-haves as a nicotinamide adeninedinucleotide - dependent dehydro-genase, catalyzing the inactivation ofcortisol to cortisone and, thereby,maintains the specificity of the min-eralocorticoid receptor for aldoste-rone (Stewart and Krozowski, 1999).Both GR and 11�HSD1 mRNA in-crease with fat mass, while 11�HSD2mRNA demonstrates a converse de-

cline (Gnanalingham et al., 2005).Furthermore, GR and 11�HSD1mRNA are strongly positively corre-lated with total and relative perirenaladipose tissue weight and with eachother (Fig. 2). In addition, data areemerging of roles for the differentisoforms of the peroxisome prolifera-tor activated receptor (PPAR). Theabundance of PPAR �, but not �, isupregulated in fetal adipose tissuefollowing maternal nutrient restric-tion between early to mid gestation,an adaptation that is accompaniedby increased fat mass (Bispham etal., 2005). PPAR �, however, in-creases in adipose tissue with over-feeding in juveniles (Redonnet et al.,2001) and, through disruption of itsrole in the regulation of triglyceridehomeostasis, is implicated in ad-verse lipid metabolism in diabetes

(Tenenbaum et al., 2004), and thedysregulation of adipocyte differenti-ation that occurs in obesity.

Inappropriate regulation of localglucocorticoid action and PPARs inadipose tissue may well predisposeto the development of visceral obe-sity in adulthood by acting as patho-physiological mediators. Indeed, in-creased GR (Boullu-Ciocca et al.,2003) and 11�HSD1 (Bujalska et al.,1997; Paulmyer-Lacroix et al., 2002;Rask et al., 2002; Engeli et al., 2004)and decreased 11�HSD2 (Engeli etal., 2004) expression have all beenobserved in patients with visceralobesity. Furthermore, transgenicmice that over express 11�HSD1 se-lectively in adipose tissue have in-creased adipose tissue levels ofcorticosterone, develop visceral obe-sity, and are glucose intolerant (Ma-

Figure 2. Positive relationships between (A) glucocorticoid receptor (GR) mRNA and relative (total perirenal adipose tissue weight perkilogram body weight) perirenal adipose tissue weight (R2 � 0.64, p � 0.0001, where y � 0.09x � 0.68), (B) 11�-hydroxysteroiddehydrogenase type 1 (11�HSD1) mRNA and relative perirenal adipose tissue weight (R2 � 0.66, p � 0.0001, where y � 0.07x � 1.58),(C) GR and 11�HSD1 mRNA abundance (R2 � 0.89, p � 0.0001, where y � 0.74x � 14.09), and (D) UCP2 and GR mRNA abundance(R2 � 0.58, p � 0.0001, where y � 0.56x � 12.40), in perirenal adipose tissue sampled from control sheep (total n � 42). Adapted fromGnanalingham et al., (2005).

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suzaki et al., 2001). Conversely, ho-mozygous 11�HSD1 knockout miceare protected from features of themetabolic syndrome and obesity(Kotelevtsev et al., 1997). Changesin GR response could also be impor-tant, either at the level of the centralnervous system, by modulating thenegative glucocorticoid feedback (DeKloet et al., 1998), or peripherally byregulating preadipocyte differentia-tion and adipocyte metabolism in asite-specific fashion (Kissebah andKrakower, 1994). There is also a sig-nificant interaction between the vari-ation in the GR gene and body fatgain in female subjects experiencingthe transition between adolescenceand adulthood (Tremblay et al.,2003).

An increase in adipocyte GR sen-sitivity following maternal nutrientrestriction (Gnanalingham et al.,2005) could be a pivotal adaptationleading to later obesity and would,thus, fit in well with current theoriesof fetal programming of adult dis-ease. For example, in the thriftyphenotype hypothesis (Hales andBarker, 1992) it is postulated thatdiabetes and the metabolic syn-drome result from the challengethat postnatal exposure to excessnutrition places on a glucose-insu-lin system programmed for a thriftypostnatal lifestyle by in utero ma-ternal nutrient restriction. In con-trast, however, the hypothesis ofpredictive adaptive responses(Gluckman and Hanson, 2004), bywhich environmental interactions inearly development lead to pheno-typical changes in expectation of afuture adult environment, mightlead to a better or worse outcomefor the offspring who subsequentlyexperience a very different level ofpostnatal nutrition.

TIMING OF MATERNALNUTRIENT RESTRICTIONIN UTERO ANDMAGNITUDE OFPOTENTIALLY ADVERSELONG-TERM OUTCOMES

The primary adverse physiologicaloutcome in offspring born to moth-ers that were nutrient restricted inutero is an increase in blood pres-

sure (Armitage et al., 2005). Thisappears to be related to a resettingof the central relationship betweenblood pressure and heart ratewhich, combined with limited bra-dycardia during hypertensive chal-lenges (Gardner et al., 2004), indi-cates that these individuals are atincreased risk of developing laterhypertension and coronary heartdisease (Eckberg, 1979; Ookuwa etal., 1987). Indeed, the develop-mental outcome of this adaptationis that blood pressure in nutrientrestricted offspring is actually lowerin juvenile life (Gopalakrishnan etal., 2005) and, subsequently, grad-ually increases with advancing ageto eventually become greater thanoffspring of well fed mothers (Go-palakrishnan et al., 2004). Thesepotentially adverse blood pressureoutcomes appear to be confined toperiods of nutrient restriction thatencompass the periods of early de-velopment, i.e., during the embry-onic and placental phases of gesta-tion.

With regard to the long term ef-fects on excess fat deposition in nu-trient restricted offspring, althoughmore fat is present at term in fe-tuses whose mothers were nutrientrestricted over the period of maxi-mal placental growth (Bispham etal., 2003), it is those offspring thatwere nutrient restricted in late ges-tation that have more fat as youngadults (Gardner et al., 2005b). Thisincreased fat mass is accompaniedby glucose intolerance and insulinresistance, in conjunction with po-tentially altered glucose uptake inadipose tissue but not skeletalmuscle (Gardner et al., 2005b). In-deed, as in human diabetes, themolecular basis of this insulin resis-tance appears to lie downstream ofthe insulin receptor (Krook et al.,2000), given there is also an in-crease in expression of the adiposeinsulin receptor in nutrient re-stricted offspring (Gardner et al.,2005b). Our finding that glucosetransporter 4, the major insulin re-sponsive glucose transporter, wasspecifically reduced in adipose tis-sue strongly suggests that impairedglucose tolerance was related tothe ability of adipose tissue to takeup glucose in an insulin responsive

manner. Indeed, expression of ad-ipose specific glucose transporter 4is essential for whole body glucosedisposal (Wallberg-Henriksson andZierath, 2001), and a reduction inits abundance is closely associatedwith insulin resistance.

It therefore appears that findingsin large animal studies directly sup-port retrospective data from the“Dutch Hunger Winter Famine” thathas clearly shown that specific pe-riods of famine exposure may im-pact upon specific physiologicalcontrol systems in adult life. Expo-sure to the famine during early ges-tation influenced the cardiovascularsystem, clinically reflected as an in-creased risk of coronary heart dis-ease (Roseboom et al., 2000);whereas exposure during late ges-tation tended to affect intermediarymetabolism, in particular, glucose-insulin homeostasis, leading to anincreased risk of type 2 diabetes(Ravelli et al., 1998).

PERSPECTIVES

Although the later effects on adi-pose tissue in obesity in adults arealso just being explored, current in-vestigations using animal modelssuch as sheep are now beginning todetermine the effects of obesityduring juvenile life on adiposetissue and adipocyte function(Bispham et al., 2005; Gnanaling-ham et al., 2005). Importantly,these studies can be conducted at astage of development before thecrucial and severe deleterious ef-fects of increased adiposity are es-tablished. They provide an opportu-nity to study obesity in recognizedanimal models in which much is al-ready known about adipocyte func-tion, and in whom the endocrineenvironment both before and afterbirth is similar to that of human in-fants (Symonds et al., 2003).Clearly, randomized trials to eluci-date the relative contribution ofsedentary behavior and maternalnutrition and their modulation bypostnatal diet are not feasible inhuman populations and obser-vational studies are significantlyhandicapped by confounders. Theuse of animal models is thereforeessential if the relative contribu-

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tions of maternal nutrition duringfetal development and postwean-ing nutrition and sedentary behav-ior are to be explored, and the cel-lular changes that occur during theevolution of obesity during postna-tal development fully elucidated.

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