Maternal micronutrient restriction programs the bodyadiposity, adipocyte function and lipid metabolismin offspring: A review

K. Rajender Rao & I. J. N. Padmavathi & M. Raghunath

Published online: 20 March 2012# Springer Science+Business Media, LLC 2012

Abstract Fetal growth is a complex process which dependsboth on the genetic makeup and intrauterine environment.Maternal nutrition during pregnancy is an important deter-minant of fetal growth. Adequate nutrient supply is requiredduring pregnancy and lactation for the support of fetal/infantgrowth and development. Macro- and micronutrients areboth important to sustain pregnancy and for appropriategrowth of the fetus. While macronutrients provide energyand proteins for fetal growth, micronutrients play a majorrole in the metabolism of macronutrients, structural andcellular metabolism of the fetus. Discrepancies in maternaldiet at different stages of foetal growth / offspring develop-ment can have pronounced influences on the health andwell-being of the offspring. Indeed intrauterine growth re-striction induced by nutrient insult can irreversibly modulatethe endocrine/metabolic status of the fetus that leads to thedevelopment of adiposity and insulin resistance in its laterlife. Understanding the role of micronutrients during thedevelopment of fetus will provide insights into the probable

underlying / associated mechanisms in the metabolic path-ways of endocrine related complications. Keeping in viewthe modernized lifestyle and food habits that lead to thedevelopment of adiposity and world burden of obesity, thisreview focuses mainly on the role of maternal micronu-trients in the foetal origins of adiposity.

Keywords Fetal programming . Adiposity . Micronutrients .

Maternal undernutrition . Body fat% . Adiposity index

1 Introduction

Fetal growth restriction is a leading cause of infant morbid-ity and mortality [1, 2], whose incidence is estimated to beapproximately 5% in the general obstetric population [3]. Infetuses with intra-uterine growth retardation (IUGR), only athird of birth weight variations are determined by geneticfactors, while two-thirds are determined by environmentalones [4]. The risk of adverse pregnancy outcome has beenvariously attributed to poor socio-economic and nutritionalstatus of the mother at the time of conception [5]. Humanfetuses with severe IUGR have lesser endocrine pancreatictissue and exhibit β-cell dysfunction [6, 7]. Such defects, ifpermanent, might limit β-cell function in later life andcontribute to the increased incidence of non-insulin-dependent diabetes mellitus. Indeed, consequences of IUGRand the resultant low birth weight (LBW) such as hyperten-sion [8], increased cardiovascular mortality, insulin resis-tance, impaired glucose tolerance and type 2 diabetesmellitus [9, 10] have been reported in several studies.LBW is a major determinant of mortality, morbidity anddisability in infancy and childhood and it has a long-termimpact on health outcomes in adult life. Around 30 millionLBW babies born annually worldwide [11] (23.8% of all

All the authors contributed equally.

K. R. Rao : I. J. N. Padmavathi :M. Raghunath (*)Division of Endocrinology and Metabolism,National Institute of Nutrition,Jamai Osmania P O,Hyderabad 500 007, Indiae-mail: mraghunath55@yahoo.com

K. R. Raoe-mail: rkrajender@yahoo.com

I. J. N. Padmavathie-mail: padmaijn@yahoo.co.in

K. R. RaoNational Center for Laboratory Animal Sciences,National Institute of Nutrition,Hyderabad 500 007, India

Rev Endocr Metab Disord (2012) 13:103–108DOI 10.1007/s11154-012-9211-y

births) often face severe short- and long-term health con-sequences. In the developed world 6–8% of babies weighless than 2500 g at birth and as many as 15% of them willdie at or around birth [12]. Adolescent girls have a high riskof delivering LBW and premature babies that have highmortality rates within the first year of life [13–15].Although the global prevalence of such births is slowlydropping, it is as high as 30% in many developingcountries. India alone accounts for 40% of the incidenceof LBW babies in the developing world [16]. Prematureinfants weighing <1500 g at birth are at greater risk ofsignificant micronutrient deficiencies [17]. Prevalence ofmicronutrient deficiency is reported to be in around 2billion people worldwide [18] which probably results inlong lasting effects such as metabolic syndrome and theassociated diseases.

The dietary requirement for micronutrients (vitamins andminerals) during development is small; however, adequateamounts are essential for both the immediate and long-termwell-being of the embryo, fetus and neonate. They have amajor function during pre and post implantation of theembryo. They regulate the expression of many developmen-tal genes and commitment of stem cells to specific lineagesof different tissues or organs. They have varied biochemicalroles. B complex vitamins act as enzyme cofactors in manycellular metabolisms. Folate helps in increasing red cellmass, enlargement of uterus and growth of placenta andfetus during pregnancy [19]. Vitamin B6 regulates DNAsynthesis, cerebroside formation and its deficiency mayresult in mental retardation [20]. Retinoic acid is an impor-tant regulator of cell division and differentiation in embry-onic tissues. Vitamin C and E act as antioxidants, protect thefetus from insults resulting from oxygen free radicals byscavenging hydroxyl radicals and reduce the rates of con-genital malformations and late resorptions [21, 22]. Lowmaternal calcium intakes may be a risk for lower bone massin neonates [23, 24]. That concentration of maternal serumiron and copper throughout pregnancy are twice that of anon pregnant woman, [25, 26] suggests their critical roleduring pregnancy [27]. Zinc plays an important role ingrowth, development and reproduction and its deficiencyduring pregnancy and lactation has adverse effects in labo-ratory animals, including congenital malformations, embry-onic and fetal death and intrauterine growth retardation [28].Magnesium, manganese and chromium play vital role inthe synthesis, storage and secretion of insulin. Thusvarious minerals and vitamins play a critical role atdifferent stages of gestation and lactation for the devel-opment of a healthy fetus. Deficiency in maternal foodintake during pregnancy could result either in globaldeficiency of nutrients or of individual micronutrients,which may show negative effect on the postnatal physiolog-ical functions.

2 Fetal programming of adiposity in the offspring

The concept of the developmental origins of adult diseasesis now well accepted. Suboptimal environments in thewomb and during early neonatal life alter development andpredispose the individual to lifelong health problems [29,30]. During the adverse environmental conditions, the fetus‘programmes’ to altered physiological processes which maybe beneficial for short term survival in utero, but maladap-tive in postnatal life, contributing to poor health outcomes.This phenotype is more at risk when exposed to catch upgrowth leading to diet-induced obesity. The ‘thrifty’ pheno-type hypothesis proposed by Hales and Barker suggests thatexposure of thrifty phenotype to a postnatal environmentconsisting of an excessive nutrition overloads the reducedmetabolic capacity of the thrifty phenotype resulting in thestorage of surplus energy as fat. This increased fat is theearliest programmed physiology in the progeny and a fore-known diagnostic marker for various adult onset diseases.Studies showed that increased body fat% (visceral fat) inAsian Indians is associated with dyslipidemia and insulinresistance which may further contribute to the developmentof diabetes mellitus and cardiovascular disease [31, 32].Yajnik et al also reported that Indian babies were lighter,shorter and thinner but had preserved body fat and higherleptin levels compared with the British babies (“thin-fat”babies) [33]. These studies indicate that intrauterine regula-tion of adipogenesis may be an important mechanism of thefetal origins of adult diseases. Thus the present reviewfocuses on the role of pre-/peri and postnatal maternalmicronutrient deficiency in manipulating adiposity and theprobable associated and / or underlying mechanisms whichmay eventually result in the increased risk of chronic met-abolic diseases later in the life of the offspring.

2.1 Micronutrient restriction and body fat%development / adiposity index

Substantial evidence suggests that accumulation of fat in thebody accelerates during neonatal life which is a predictor ofinsulin resistance. This is evident from studies both inhuman subjects and rodents on global or individual micro-nutrient deficiency per se or maternal micronutrient defi-ciency. A study in school-aged children showed that vitaminD sero-status was inversely correlated with adiposity [34]and low vitamin D status was prevalent among adolescentswho showed adiposity [35]. Krishnaveni et al suggested thatmaternal vitamin B 12 deficiency was associated with in-creased adiposity, insulin resistance and GDM in AsianIndians and implicated that vitamin B 12 deficiency maybe an important factor underlying the high risk of obesityand type 2 diabetes mellitus [36]. Adiposity in young womenpredicts low iron absorption and pediatric adiposity predicts

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iron deficiency along with a reduced response to iron fortifi-cation [37]. These studies suggest that rapid increase in over-weight seen in countries in transition may impair efforts tocontrol micronutrient deficiency in these target groups. Inter-actions of the 'double burden' of malnutrition (under and overnutrition) during the nutrition transition may have adverseconsequences.

Our initial studies in rat models showed that chronic 50%restriction of multiple vitamins / minerals from the mothers’diet significantly increased body fat % in the offspring [38,39] and almost similar observations were made in the off-spring of rat dams on dietary restriction of individual micro-nutrients : Mg, Mn, Cr, Zn, folic acid and / or vitamin B12[40–46]. Increased body fat % in these offspring was usuallyassociated with significantly higher central adiposity. It wasof interest that the effects of maternal Cr or Mn restrictionwere corrected by different rehabilitation regimens whilethose of Mg and Zn restriction appeared to be irreversible.Similar changes were reported earlier in the offspring ofvitamin A restricted mothers [47]. Therefore micronutrientsappear to play an important role in regulating body fat in theoffspring.

2.2 Micronutrient restriction and adipogenesis: expressionof genes involved in adipogenesis

Adipogenesis is a highly regulated process that is modulatedby peroxisome proliferator-activated receptors (PPARs),CCAAT enhancer binding proteins (C/EBPs), sterol regula-tory element-binding proteins (SREBPs) and glucocorticoidmediated 11β hydroxysteroid dehydrogenase 1 (11βHSD1). Expression of PPARγ in adipose tissue promotesdifferentiation of pre-adipocytes and regulates the expres-sion of fat cell-specific genes [48]. SREBPs modulate lipo-genesis and cholesterol homeostasis and SREBP-2 over-expression results in increased FAS gene expression [49].Abundant literature also links the expression of PPARγ,SREBP2 and 11β HSD1 in adipose tissue to the develop-ment of visceral adiposity, obesity, dyslipidemia, insulinresistance, diabetes and its associated complications [50,51]. In addition to their classical nutritional roles, micro-nutrients modify gene expression and function in target cellswhich affect basic metabolic processes. This is evident fromour study conducted in rat model which showed elevatedexpression of 11β-HSD1 and leptin in maternal dietary Crrestricted offspring [44]. Sandrine et al also reported thatover expression of 11β HSD1 in rats through high fat dietinduced programming resulted in adipose tissue dysregula-tion [52]. These observations suggest that increase in theexpression of 11β HSD1 and leptin could be the contribut-ing factors for enhanced body adiposity (fat % & visceraladiposity) in the offspring of Cr restricted rat dams. In-creased expression of 11β-HSD1 in the offspring of Mg

restricted rat dams and high cortisol levels in the offspringof folate and / or vitamin 12 restricted rat dams (our unpub-lished observations) appear to lend further support thisinference.

2.3 Micronutrient restriction and adipocyte function(Adipocytokine levels)

Adipose tissue secretes adipocytokines like adiponectin,leptin, PAI, IL-6, TNFα etc [53] which regulate energymetabolism, insulin sensitivity and play a vital role in thepathogenesis of obesity, atherosclerotic vascular disease,hypertension and diabetes mellitus [54].

Maternal micronutrient restriction (multivitamin, multi-mineral, Cr, Mg, Mn, vitamin B12 and /or folate) signifi-cantly altered leptin, TNFα and adiponectin, in plasma and/or adipose tissue in the offspring of the respective micronu-trient restricted rat dams [41, 42, 44, 45, Anand et al (un-published results)]. It is evident from these studies thatmaternal micronutrient restriction alters not only body fat %and central adiposity but also is associated with altered adi-pose tissue function suggesting a programming effect in adi-pose tissue metabolism. Although both maternal vitamin andmineral (trace element) restrictions increased body adiposityin the offspring, considering that the changes induced byvitamin but not mineral restriction were mitigatable, even ifpartially, it appears that the probable mechanism(s) leading toadiposity and the associated functional changes may differbetween these two conditions at least to some extent.

2.4 Micronutrient restriction and lipid metabolism(plasma lipid levels)

Impaired lipid metabolism as represented by fasting hyper-triglyceridemia and / or low HDL cholesterol levels areassociated with insulin resistance [55, 56]. Further thesechanges can be associated with altered activities and/orvaried expression of enzymes of lipid metabolism such asfatty acid synthase (FAS), fatty acid transport proteins(FATPs) and acetyl CoA carboxylase (ACC). Maternal Crrestriction in WNIN rats increased plasma triglycerides andfree fatty acids albeit in female chromium restricted off-spring. Expression of FAS and FATPs, was significantlyincreased in the liver and adipose tissue of magnesiumrestricted offspring. Offspring of Mn restricted rat damshad higher (than control) susceptibility to high fat dietinduced adiposity, dyslipidaemia and a pro-inflammatorystate [45]. In contrast, maternal 50% multiple mineral orMg restriction resulted in low cholesterol levels in theoffspring [38, 41] whereas maternal zinc restriction de-creased the cholesterol and triglycerides in rat offspring[43]. Indeed some studies showed that the intestinal absorp-tion of lipids in general is impaired in zinc-deficient rats [57,

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58]. Moderate iron deficiency during gestation and lactationis reported to alter brain fatty acid and eicosanoid metabo-lism in adult guinea pig offspring [59]. Numerous studieshave demonstrated that maternal dietary Fe restriction dur-ing gestation retards fetal growth [60], decreases birthweight [61], and alters lipid metabolism [62] in offspring.In another study maternal dietary Fe restriction during preg-nancy was reported to increase hepatic cholesterol andreduce triglyceride concentrations which were coordinated inthe fetuses through down regulation of genes in bileacid and fatty acid synthesis pathways [63]. Further,Fe deficiency in early life caused changes in brainbiochemistry and development and the changes persistedeven after Fe supplementation, suggesting the irrevers-ible consequences of developmental Fe restriction [64].It appears from these observations that maternal micro-nutrient restriction not only affects adipose tissue contentand function but also alters lipid metabolism in differenttissues / organs such as liver and brain in addition to theadipose tissue.

3 Probable role of epigenetics

Environmental, particularly, nutritional factors operate fromthe earliest stages of development of the fetus [65, 66].However the mechanisms through which specific tissuescould be affected permanently by nutritional perturbationsin early life is still a matter of debate. The molecular mech-anisms underlying the fetal programming may in part berelated to epigenetic regulation (the developmental process-es by which genotype gives rise to phenotype) of the ex-pression of key developmental genes [67].

Alterations in nutrition during development can alterepigenetic markers, including DNA methylation [68] andhistone modifications [69] in rodents. Methylation of CpGrich clusters termed CpG islands, which often span thepromoter regions of genes, is associated with transcriptionalrepression, whereas hypomethylation of CpGs is associatedwith transcriptional activity [70]. In rats, protein restricted(PR) diet during pregnancy, induced the expression of theglucocorticoid receptor (GR) and PPARα in the liver whichwas observed to be due to hypomethylation of the PPARαand GR [71]. Hypomethylation of the hepatic GR andPPARα promoters was inhibited by supplementation of 5-fold more folic acid to the protein-restricted diet [71]. Inanother study offspring of rats fed protein restricted dietduring pregnancy induced hypertension and endothelialfunction which was prevented by supplementation of theprotein-restricted diet with glycine or folic acid [72, 73].This suggests that 1- carbon metabolism plays a central rolein the induction of imprinting genes by maternal dietaryrestriction [67].

Thus converging data are now available to support thehypothesis that, in addition to “thrifty genotype” inheri-tance, individuals with metabolic syndrome undergo incor-rect “epigenetic programming” during fetal/postnataldevelopment because of inadequate nutrition and metabolicdisturbances in the mother [74]. These individuals may alsodisplay “trans-generational effects” because of the inheri-tance of epigenetic changes first experienced by theirparents and/or grandparents.

4 Summary

Restriction of all micronutrients (studied so far) in experi-mental animals (rats) resulted in similar changes in theoffspring, such as, increased body fat %, specially thevisceral/central adiposity, elevated expression of adiposityrelated genes, altered adipose tissue function and lipidmetabolism. Although there is some insight into theepigenetic regulation of adiposity by maternal macronu-trient deficiencies, the role of epigenetics in maternalmicronutrient restriction induced adiposity has not beeninvestigated so far. Hence future studies should focus onepigenetic regulation of adipogenesis and lipid metabolism inmaternal micronutrient restriction induced adiposity andtheir transgenerational transfer. This would help formulateappropriate nutrition intervention strategies to curb theglobal epidemic of obesity.

References

1. Bernstein I, Gabbe SG. Intrauterine growth restriction. In: Gabbe SG,Niebyl JR, Simpson JL, eds. Obstetrics: normal & problem pregnan-cies. 3rd ed. New York: Churchill Livingstone; 1996. p. 863–886.

2. Eleftheriades M, Creatsas G, Nicolaides K. Fetal growth restrictionand postnatal development. Ann N YAcad Sci. 2006;1092:319–30.

3. Neerhof MG. Causes of intrauterine growth restriction. Clin Peri-natol. 1995;22:375–85.

4. Bryan SM, Hindmarsh PC. Normal and abnormal fetal growth.Horm Res. 2006;65 Suppl 3:19–27.

5. Fraser AM, Brockert JE, Ward RH. Association of young maternalage with adverse reproductive outcomes. N Engl J Med.1995;332:1113–7.

6. Van Assche FA, De Prins F, Aerts L, Verjans M. The endocrinepancreas in small-for-dates infants. Br J Obstet Gynaecol.1977;84:751–3.

7. Nicolini U, Hubinont C, Santolaya J, Fisk NM, Rodeck CH.Effects of fetal intravenous glucose challenge in normal andgrowth retarded fetuses. Horm Metab Res. 1990;22:426–30.

8. Barker DJ. In utero programming of chronic disease. Clin Sci(Lond). 1998;95:115–28.

9. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C,Winter PD. Fetal and infant growth and impaired glucose toleranceat age 64. BMJ. 1991;303:1019–22.

10. Jaquet D, Gaboriau A, Czernichow P, Levy-Marchal C. Insulinresistance early in adulthood in subjects born with intrauterinegrowth retardation. J Clin Endocrinol Metab. 2000;85:1401–6.

106 Rev Endocr Metab Disord (2012) 13:103–108

11. de Onis M, Blossner M, Villar J. Levels and patterns of intrauterinegrowth retardation in developing countries. Eur J Clin Nutr.1998;52 Suppl 1:S5–S15.

12. Pollack RN, Divon MY. Intrauterine growth retardation: definition,classification, and etiology. Clin Obstet Gynecol. 1992;35:99–107.

13. McAnarney ER. Young maternal age and adverse neonatal out-come. Am J Dis Child. 1987;141:1053–9.

14. Adelson PL, Frommer MS, Pym MA, Rubin GL. Teenage preg-nancy and fertility in New South Wales: an examination of fertilitytrends, abortion and birth outcomes. Aust J Public Health.1992;16:238–44.

15. Cooper LG, Leland NL, Alexander G. Effect of maternal age onbirth outcomes among young adolescents. Soc Biol. 1995;42:22–35.

16. WHO/UNICEF. Low birthweight: country, regional and globalestimates. New York, United Nations Children’s Fund and WorldHealth Organization, 2004

17. Abrams SA. In utero physiology: role in nutrient delivery and fetaldevelopment for calcium, phosphorus, and vitamin D. Am J ClinNutr. 2007;85:604S–7S.

18. UNICEF: Vitamin and mineral deficiencies: a global progressreport. The Micronutrient Initiative and UNICEF, 2004 by PeterAdamson, P&LA, Oxfordshire, UK.

19. Scholl TO, Johnson WG. Folic acid: influence on the outcome ofpregnancy. Am J Clin Nutr. 2000;71:1295S–303S.

20. Coursin DB. Vitamin B6 metabolism in infants and children.Vitam Horm. 1964;22:755–86.

21. Cederberg J, Siman CM, Eriksson UJ. Combined treatment withvitamin E and vitamin C decreases oxidative stress and improvesfetal outcome in experimental diabetic pregnancy. Pediatr Res.2001;49:755–62.

22. Siman CM, Eriksson UJ. Vitamin C supplementation of the ma-ternal diet reduces the rate of malformation in the offspring ofdiabetic rats. Diabetologia. 1997;40:1416–24.

23. Raman L, Rajalakshmi K, Krishnamachari KA, Sastry JG. Effectof calcium supplementation to undernourished mothers duringpregnancy on the bone density of the bone density of the neonates.Am J Clin Nutr. 1978;31:466–9.

24. Koo WW, Walters JC, Esterlitz J, Levine RJ, Bush AJ, Sibai B.Maternal calcium supplementation and fetal bone mineralization.Obstet Gynecol. 1999;94:577–82.

25. Linder MC. The biochemistry of copper. New York: Plenum Press;1991.

26. Bothwell TH. Iron requirements in pregnancy and strategies tomeet them. Am J Clin Nutr. 2000;72:257S–64S.

27. Krachler M, Rossipal E, Micetic-Turk D. Trace element transferfrom the mother to the newborn–investigations on triplets of co-lostrum, maternal and umbilical cord sera. Eur J Clin Nutr.1999;53:486–94.

28. Hurley LS. Developmental nutrition. Englewood Cliffs: Prentice-Hall; 1980.

29. Barker DJ. The fetal and infant origins of disease. Eur J ClinInvest. 1995;25:457–63.

30. Barker DJ. Intrauterine programming of adult disease. Mol MedToday. 1995;1:418–23.

31. Banerji MA, Faridi N, Atluri R, Chaiken RL, Lebovitz HE. Bodycomposition, visceral fat, leptin, and insulin resistance in AsianIndian men. J Clin Endocrinol Metab. 1999;84:137–44.

32. Deurenberg P, Deurenberg-Yap M, Guricci S. Asians are differentfrom Caucasians and from each other in their body mass index/body fat per cent relationship. Obes Rev. 2002;3:141–6.

33. Yajnik CS. Early life origins of insulin resistance and type 2diabetes in India and other Asian countries. J Nutr. 2004;134:205–10.

34. Gilbert-Diamond D, Baylin A, Mora-Plazas M, Marin C, ArsenaultJE, Hughes MD, Willett WC, Villamor E. Vitamin D deficiency

and anthropometric indicators of adiposity in school-age children:a prospective study. Am J Clin Nutr. 2010;92:1446–51.

35. Dong Y, Pollock N, Stallmann-Jorgensen IS, Gutin B, Lan L,Chen TC, Keeton D, Petty K, Holick MF, Zhu H. Low 25-hydroxyvitamin D levels in adolescents: race, season, adipos-ity, physical activity, and fitness. Pediatrics. 2010;125:1104–11.

36. Krishnaveni GV, Hill JC, Veena SR, Bhat DS, Wills AK, Karat CL,Yajnik CS, Fall CH. Low plasma vitamin B12 in pregnancy isassociated with gestational 'diabesity' and later diabetes. Diabeto-logia. 2009;52:2350–8.

37. Zimmermann MB, Zeder C, Muthayya S, Winichagoon P, ChaoukiN, Aeberli I, Hurrell RF. Adiposity in women and children fromtransition countries predicts decreased iron absorption, iron defi-ciency and a reduced response to iron fortification. Int J Obes(Lond). 2008;32:1098–104.

38. Venu L, Harishankar N, Krishna TP, Raghunath M. Does maternaldietary mineral restriction per se predispose the offspring to insulinresistance? Eur J Endocrinol. 2004;151:287–94.

39. Venu L, Harishankar N, Prasanna Krishna T, RaghunathM.Maternaldietary vitamin restriction increases body fat content but not insulinresistance inWNIN rat offspring up to 6months of age. Diabetologia.2004;47:1493–501.

40. Venu L, Kishore YD, Raghunath M. Maternal and perinatal mag-nesium restriction predisposes rat pups to insulin resistance andglucose intolerance. J Nutr. 2005;135:1353–8.

41. Venu L, Padmavathi IJ, Kishore YD, Bhanu NV, Rao KR, SainathPB, Ganeshan M, Raghunath M. Long-term effects of maternalmagnesium restriction on adiposity and insulin resistance in ratpups. Obesity (Silver Spring). 2008;16:1270–6.

42. Raghunath M, Venu L, Padmavathi I, Kishore YD, Ganeshan M,Anand Kumar K, Sainath PB, Rao KR. Modulation of mac-ronutrient metabolism in the offspring by maternal micronu-trient deficiency in experimental animals. Indian J Med Res.2009;130:655–65.

43. Padmavathi IJ, Kishore YD, Venu L, Ganeshan M, Harishankar N,Giridharan NV, Raghunath M. Prenatal and perinatal zinc restric-tion: effects on body composition, glucose tolerance and insulinresponse in rat offspring. Exp Physiol. 2009;94:761–9.

44. Padmavathi IJN, Rao KR, Venu L, Ganeshan M, Kumar KA,Rao Ch N, Harishankar N, Ismail A, Raghunath M: Chronicmaternal dietary chromium restriction modulates visceral adi-posity: probable underlying mechanisms. Diabetes. 2010;59:98–104.

45. Manisha Ganeshan SP, Padmavathi IJN, Venu L, Kishore YD,Anand K, Harishanker N, Srinivasa Rao J, Raghunath M (2011)Maternal manganese restriction increases susceptibility to high fatdiet induced dyslipidemia and altered adipose function in WNINmale rat offspring. Exp Diabetes Res (In press)

46. Anand Kumar K, Padmavathi IJN, Lalitha A, Manisha G, Rao KR,Mahesh Kumar J, Chandak GR, Raghunath M: Chronic maternalvitamin B12 restriction induced changes in the wistar rat off-spring are partly correctable by rehabilitation (Abstract). CMRe-journal 2010

47. Ribot J, Felipe F, Bonet ML, Palou A. Changes of adiposity inresponse to vitamin A status correlate with changes of PPARgamma 2 expression. Obes Res. 2001;9:500–9.

48. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS,Spiegelman BM, Mortensen RM. PPAR gamma is required for thedifferentiation of adipose tissue in vivo and in vitro. Mol Cell.1999;4:611–7.

49. Horton JD, Shimomura I, Brown MS, Hammer RE, Goldstein JL,Shimano H. Activation of cholesterol synthesis in preference tofatty acid synthesis in liver and adipose tissue of transgenic miceoverproducing sterol regulatory element-binding protein-2. J ClinInvest. 1998;101:2331–9.

Rev Endocr Metab Disord (2012) 13:103–108 107

50. Joss-Moore LA, Wang Y, Campbell MS, Moore B, Yu X, CallawayCW, McKnight RA, Desai M, Moyer-Mileur LJ, Lane RH. Utero-placental insufficiency increases visceral adiposity and visceral adi-pose PPARgamma2 expression inmale rat offspring prior to the onsetof obesity. Early Hum Dev. 2010;86:179–85.

51. Desbriere R, Vuaroqueaux V, Achard V, Boullu-Ciocca S, LabuhnM, Dutour A, GrinoM. 11beta-hydroxysteroid dehydrogenase type 1mRNA is increased in both visceral and subcutaneous adipose tissueof obese patients. Obesity (Silver Spring). 2006;14:794–8.

52. Boullu-Ciocca S, Achard V, Tassistro V, Dutour A, Grino M.Postnatal programming of glucocorticoid metabolism in rats mod-ulates high-fat diet-induced regulation of visceral adipose tissueglucocorticoid exposure and sensitivity and adiponectin and proin-flammatory adipokines gene expression in adulthood. Diabetes.2008;57:669–77.

53. Jazet IM, Pijl H,Meinders AE. Adipose tissue as an endocrine organ:impact on insulin resistance. Neth J Med. 2003;61:194–212.

54. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J ClinEndocrinol Metab. 2004;89:2548–56.

55. Fontbonne A, Eschwege E, Cambien F, Richard JL, Ducimetiere P,Thibult N, Warnet JM, Claude JR, Rosselin GE. Hypertriglycer-idaemia as a risk factor of coronary heart disease mortality insubjects with impaired glucose tolerance or diabetes. Results fromthe 11-year follow-up of the Paris Prospective Study. Diabetologia.1989;32:300–4.

56. Smith U. Impaired ('diabetic') insulin signaling and action occur infat cells long before glucose intolerance–is insulin resistance initi-ated in the adipose tissue? Int J Obes Relat Metab Disord.2002;26:897–904.

57. Koo SI, Norvell JE, Algilani K, Chow J. Effect of marginal zincdeficiency on the lymphatic absorption of [14C]cholesterol. J Nutr.1986;116:2363–71.

58. Kim ES, Noh SK, Koo SI. Marginal zinc deficiency lowers the lym-phatic absorption of alpha-tocopherol in rats. J Nutr. 1998;128:265–70.

59. LeBlanc CP, Fiset S, Surette ME, Turgeon O'Brien H, Rioux FM.Maternal iron deficiency alters essential fatty acid and eicosanoidmetabolism and increases locomotion in adult guinea pig off-spring. J Nutr. 2009;139:1653–9.

60. Crowe C, Dandekar P, Fox M, Dhingra K, Bennet L, Hanson MA.The effects of anaemia on heart, placenta and body weight, and bloodpressure in fetal and neonatal rats. J Physiol. 1995;488(Pt 2):515–9.

61. Lewis RM, Petry CJ, Ozanne SE, Hales CN. Effects of maternaliron restriction in the rat on blood pressure, glucose tolerance,and serum lipids in the 3-month-old offspring. Metabolism.2001;50:562–7.

62. Singla PN, Tyagi M, Kumar A, Dash D, Shankar R. Fetal growthin maternal anaemia. J Trop Pediatr. 1997;43:89–92.

63. Zhang J, Lewis RM, Wang C, Hales N, Byrne CD. Maternaldietary iron restriction modulates hepatic lipid metabolism in thefetuses. Am J Physiol Regul Integr Comp Physiol. 2005;288:R104–11.

64. Kwik-Uribe CL, Gietzen D, German JB, Golub MS, Keen CL.Chronic marginal iron intakes during early development in miceresult in persistent changes in dopamine metabolism and myelincomposition. J Nutr. 2000;130:2821–30.

65. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternalundernutrition during the preimplantation period of rat develop-ment causes blastocyst abnormalities and programming of postna-tal hypertension. Development. 2000;127:4195–202.

66. Brawley L, Itoh S, Torrens C, Barker A, Bertram C, Poston L,Hanson M. Dietary protein restriction in pregnancy induces hyper-tension and vascular defects in rat male offspring. Pediatr Res.2003;54:83–90.

67. Waterland RA, Jirtle RL. Early nutrition, epigenetic changes attransposons and imprinted genes, and enhanced susceptibility toadult chronic diseases. Nutrition. 2004;20:63–8.

68. Waterland RA, Dolinoy DC, Lin JR, Smith CA, Shi X, TahilianiKG. Maternal methyl supplements increase offspring DNA meth-ylation at Axin Fused. Genesis. 2006;44:401–6.

69. Fu Q, McKnight RA, Yu X, Wang L, Callaway CW, Lane RH.Uteroplacental insufficiency induces site-specific changes in his-tone H3 covalent modifications and affects DNA-histone H3 po-sitioning in day 0 IUGR rat liver. Physiol Genomics. 2004;20:108–16.

70. Razin A. CpG methylation, chromatin structure and genesilencing-a three-way connection. EMBO J. 1998;17:4905–8.

71. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC.Dietary protein restriction of pregnant rats induces and folic acidsupplementation prevents epigenetic modification of hepatic geneexpression in the offspring. J Nutr. 2005;135:1382–6.

72. Jackson AA, Dunn RL, Marchand MC, Langley-Evans SC. In-creased systolic blood pressure in rats induced by a maternal low-protein diet is reversed by dietary supplementation with glycine.Clin Sci (Lond). 2002;103:633–9.

73. Brawley L, Torrens C, Anthony FW, Itoh S, Wheeler T, JacksonAA, Clough GF, Poston L, Hanson MA. Glycine rectifies vasculardysfunction induced by dietary protein imbalance during pregnan-cy. J Physiol. 2004;554:497–504.

74. Gallou-Kabani C, Junien C. Nutritional epigenomics of metabolicsyndrome: new perspective against the epidemic. Diabetes.2005;54:1899–906.

108 Rev Endocr Metab Disord (2012) 13:103–108