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Fetal origins of insulin resistance and obesity

Published online by Cambridge University Press:  07 March 2007

Claire J. Stocker ,
Jonathan R. S. Arch  and
Michael A. Cawthorne
Claire J. Stocker*
Affiliation:
Clore Laboratory, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK
Jonathan R. S. Arch
Affiliation:
Clore Laboratory, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK
Michael A. Cawthorne
Affiliation:
Clore Laboratory, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK
*
*Corresponding author: Dr C. J. Stocker, fax +44 1280 820135, email claire.stocker@buckingham.ac.uk
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Abstract

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A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The ‘thrifty phenotype’ hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11β-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.

Keywords

Intrauterine growth restrictionLow birth weightObesityInsulin resistance
Type
Symposium on ‘Genes, behaviour and environment’
Information
Proceedings of the Nutrition Society , Volume 64 , Issue 2 , May 2005 , pp. 143 - 151
Copyright
Copyright © The Nutrition Society 2005

References

Agostoni, C, Grandi, F, Gianni, ML, Silano, M, Torcoletti, M, Giovannini, M & Riva, E (1999) Growth patterns of breast fed and formula fed infants in the first 12 months of life: an Italian study. Archives of Disease in Childhood 81, 395–399.CrossRefGoogle ScholarPubMed
Ahima, RS, Prabakaran, D & Flier, JS (1998) Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. Journal of Clinical Investigation 101, 1020–1027.CrossRefGoogle ScholarPubMed
Ahima, RS, Prabakaran, D, Mantzoros, C, Qu, D, Lowell, B, Maratos-Flier, E & Flier, JS (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252.CrossRefGoogle ScholarPubMed
Barker, DJ, Hales, CN, Fall, CH, Osmond, C, Phipps, K & Clark, PM (1993) Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36, 62–67.CrossRefGoogle ScholarPubMed
Benediktsson, R, Calder, AA, Edwards, CR & Seckl, JR (1997) Placental 11 beta-hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure. Clinical Endocrinology 46, 161–166.CrossRefGoogle ScholarPubMed
Bennis-Taleb, N, Remacle, C, Hoet, JJ & Reusens, B (1999) A low-protein isocaloric diet during gestation affects brain development and alters permanently cerebral cortex blood vessels in rat offspring. Journal of Nutrition 129, 1613–1619.CrossRefGoogle ScholarPubMed
Bispham, J, Gopalakrishnan, GS, Dandrea, J, Wilson, V, Budge, H, Keisler, DH, Broughton, F, Stephenson, T & Symonds, ME (2003) Maternal endocrine adaptation throughout pregnancy to nutritional manipulation: consequences for maternal plasma leptin and cortisol and the programming of fetal adipose tissue development. Endocrinology 144, 3575–3585.CrossRefGoogle ScholarPubMed
Bouret, SG, Draper, SJ & Simerly, RB (2004) Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 108–110.CrossRefGoogle ScholarPubMed
Brown, RW, Chapman, KE, Kotelevtsev, Y, Yau, JL, Lindsay, RS, Brett, L et al. (1996) Cloning and production of antisera to human placental 11 beta-hydroxysteroid dehydrogenase type 2. Biochemical Journal 313, 1007–1017.CrossRefGoogle ScholarPubMed
Cherif, H, Reusens, B, Ahn, MT, Hoet, JJ & Remacle, C (1998) Effects of taurine on the insulin secretion of rat fetal islets from dams fed a low-protein diet. Journal of Endocrinology 159, 341–348.CrossRefGoogle ScholarPubMed
Condon, J, Gosden, C, Gardener, D, Nickson, P, Hewison, M, Howie, AJ & Stewart, PM (1998) Expression of type 2 11beta-hydroxysteroid dehydrogenase and corticosteroid hormone receptors in early human fetal life. Journal of Clinical Endocrinology and Metabolism 83, 4490–4497.Google ScholarPubMed
Crescenzo, R, Samec, S, Antic, V, Rohner-Jeanrenaud, F, Seydoux, J, Montani, JP & Dulloo, AG (2003) A role for suppressed thermogenesis favoring catch-up fat in the pathophysiology of catch-up growth. Diabetes 52, 1090–1097.CrossRefGoogle ScholarPubMed
Dave-Sharma, S, Wilson, RC, Harbison, MD, Newfield, R, Azar, MR, Krozowski, ZS et al. (1998) Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess. Journal of Clinical Endocrinology and Metabolism 83, 2244–2254.Google ScholarPubMed
Desai, M, Byrne, CD, Zhang, J, Petry, CJ, Lucas, A & Hales, CN (1997) Programming of hepatic insulin-sensitive enzymes in offspring of rat dams fed a protein-restricted diet. American Journal of Physiology 272, G1083–G1090.Google ScholarPubMed
Desai, M, Crowther, NJ, Lucas, A & Hales, CN (1996) Organ-selective growth in the offspring of protein-restricted mothers. British Journal of Nutrition 76, 591–603.CrossRefGoogle ScholarPubMed
Dessolin, S, Schalling, M, Champigny, O, Lonnqvist, F, Ailhaud, G, Dani, C & Ricquier, D (1997) Leptin gene is expressed in rat brown adipose tissue at birth. FASEB Journal 11, 382–387.CrossRefGoogle ScholarPubMed
Dewey, KG, Heinig, MJ, Nommsen, LA, Peerson, JM & Lonnerdal, B (1993) Breast-fed infants are leaner than formula-fed infants at 1 y of age: the DARLING study. American Journal of Clinical Nutrition 57, 140–145.CrossRefGoogle ScholarPubMed
Ehrhardt, RA, Greenwood, PL, Bell, AW & Boisclair, YR (2003) Plasma leptin is regulated predominantly by nutrition in preruminant lambs. Journal of Nutrition 133, 4196–4201.CrossRefGoogle ScholarPubMed
Eriksson, JG, Forsen, T, Tuomilehto, J, Winter, PD, Osmond, C & Barker, DJ (1999) Catch-up growth in childhood and death from coronary heart disease: longitudinal study. British Medical Journal 318, 427–431.CrossRefGoogle ScholarPubMed
Fall, CH (2001) Non-industrialised countries and affluence. British Medical Bulletin 60, 33–50.CrossRefGoogle ScholarPubMed
Frayling, TM & Hattersley, AT (2001) The role of genetic susceptibility in the association of low birth weight with type 2 diabetes. British Medical Bulletin 60, 89–101.CrossRefGoogle ScholarPubMed
Gale, CR, Martyn, CN, Kellingray, S, Eastell, R & Cooper, C (2001) Intrauterine programming of adult body composition. Journal of Clinical Endocrinology and Metabolism 86, 267–272.Google ScholarPubMed
Glazier, JD, Cetin, I, Perugino, G, Ronzoni, S, Grey, AM, Mahendran, D, Marconi, AM, Pardi, G & Sibley, CP (1997) Association between the activity of the system A amino acid transporter in the microvillous plasma membrane of the human placenta and severity of fetal compromise in intrauterine growth restriction. Pediatric Research 42, 514–519.CrossRefGoogle ScholarPubMed
Goland, RS, Tropper, PJ, Warren, WB, Stark, RI, Jozak, SM & Conwell, IM (1995) Concentrations of corticotrophin-releasing hormone in the umbilical-cord blood of pregnancies complicated by pre-eclampsia. Reproduction, Fertility, and Development 7, 1227–1230.CrossRefGoogle ScholarPubMed
Hales, CN & Barker, DJ (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595–601.CrossRefGoogle ScholarPubMed
Hales, CN, Barker, DJ, Clark, PM, Cox, LJ, Fall, C, Osmond, C & Winter, PD (1991) Fetal and infant growth and impaired glucose tolerance at age 64. British Medical Journal 303, 1019–1022.CrossRefGoogle ScholarPubMed
Hales, CN, Desai, M, Ozanne, SE & Crowther, NJ (1996) Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesis. Biochemical Society Transactions 24, 341–350.CrossRefGoogle Scholar
Hales, CN & Ozanne, SE (2003) The dangerous road of catch-up growth. Journal of Physiology 547, 5–10.CrossRefGoogle ScholarPubMed
Hattersley, AT, Beards, F, Ballantyne, E, Appleton, M, Harvey, R & Ellard, S (1998) Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nature Genetics 19, 268–270.CrossRefGoogle ScholarPubMed
Hofmann, M, Pollow, K, Bahlmann, F, Casper, F, Steiner, E & Brockerhoff, P (2001) 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD-II) activity in human placenta: its relationship to placental weight and birth weight and its possible role in hypertension. Journal of Perinatal Medicine 29, 23–30.CrossRefGoogle ScholarPubMed
Holmes, MC, Yau, JL, Kotelevtsev, Y, Mullins, JJ & Seckl, JR (2003) 11 Beta-hydroxysteroid dehydrogenases in the brain: two enzymes two roles. Annals of the New York Academy of Sciences 1007, 357–366.CrossRefGoogle ScholarPubMed
Jansson, N, Greenwood, SL, Johansson, BR, Powell, TL & Jansson, T (2003) Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. Journal of Clinical Endocrinology and Metabolism 88, 1205–1211.CrossRefGoogle ScholarPubMed
Jaquet, D, Gaboriau, A, Czernichow, P, Levy-Marchal, C (2000) Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. Journal of Clinical Endocrinology and Metabolism 85, 1401–1406.Google ScholarPubMed
Langley, SC, Browne, RF & Jackson, AA (1994) Altered glucose tolerance in rats exposed to maternal low protein diets in utero. Comparative Biochemistry and Physiology 109, 223–229.CrossRefGoogle ScholarPubMed
Langley-Evans, SC (1997) Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. Journal of Hypertension 15, 537–544.CrossRefGoogle ScholarPubMed
Langley-Evans, SC, Phillips, GJ, Benediktsson, R, Gardner, DS, Edwards, CR, Jackson, AA & Seckl, JR (1996) Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta 17, 169–172.CrossRefGoogle ScholarPubMed
Leon, DA, Koupilova, I, Lithell, HO, Berglund, L, Mohsen, R, Vagero, D, Lithell, UB & McKeigue, PM (1996) Failure to realise growth potential in utero and adult obesity in relation to blood pressure in 50 year old Swedish men. British Medical Journal 312, 401–406.CrossRefGoogle ScholarPubMed
Léonhardt, M, Lesage, J, Croix, D, Dutriez-Casteloot, I, Beauvillain, JC & Dupouy, JP (2003) Effects of perinatal maternal food restriction on pituitary-gonadal axis and plasma leptin level in rat pup at birth and weaning and on timing of puberty. Biology of Reproduction 68, 390–400.CrossRefGoogle ScholarPubMed
Lesage, J, Blondeau, B, Grino, M, Breant, B & Dupouy, JP (2001) Maternal undernutrition during late gestation induces fetal overexposure to glucocorticoids and intrauterine growth retardation, and disturbs the hypothalamo-pituitary adrenal axis in the newborn rat. Endocrinology 142, 1692–1702.CrossRefGoogle ScholarPubMed
Lindsay, RS, Lindsay, RM, Waddell, BJ & Seckl, JR (1996) Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone. Diabetologia 39, 1299–1305.CrossRefGoogle ScholarPubMed
Locke, R (2002) Preventing obesity: the breast milk-leptin connection. Acta Paediatrica 91, 891–894.CrossRefGoogle ScholarPubMed
Maloney, CA, Gosby, AK, Phuyal, JL, Denyer, GS, Bryson, JM & Caterson, ID (2003) Site-specific changes in the expression of fat-partitioning genes in weanling rats exposed to a low-protein diet in utero. Obesity Research 11, 461–468.CrossRefGoogle ScholarPubMed
Matthews, SG (2002) Early programming of the hypothalamo-pituitary-adrenal axis. Trends in Endocrinology and Metabolism 13, 373–380.CrossRefGoogle ScholarPubMed
Montgomery, SM & Ekbom, A (2002) Smoking during pregnancy and diabetes mellitus in a British longitudinal birth cohort. British Medical Journal 324, 26–27.CrossRefGoogle Scholar
Newsome, CA, Shiell, AW, Fall, CH, Phillips, DI, Shier, R & Law, CM (2003) Is birth weight related to later glucose and insulin metabolism? – A systematic review. Diabetic Medicine 20, 339–348.CrossRefGoogle ScholarPubMed
Nilsson, C, Swolin-Eide, D, Ohlsson, C, Eriksson, E, Ho, HP, Bjorntorp, P & Holmang, A (2003) Reductions in adipose tissue and skeletal growth in rat adult offspring after prenatal leptin exposure. Journal of Endocrinology 176, 13–21.CrossRefGoogle ScholarPubMed
Njolstad, PR, Sagen, JV, Bjorkhaug, L, Odili, S, Shehadeh, N, Bakry, D et al. (2003) Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 52, 2854–2860.CrossRefGoogle ScholarPubMed
Nyirenda, MJ, Lindsay, RS, Kenyon, CJ, Burchell, A & Seckl, JR (1998) Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. Journal of Clinical Investigation 101, 2174–2181.CrossRefGoogle ScholarPubMed
Ong, KK, Ahmed, ML, Sherriff, A, Woods, KA, Watts, A, Golding, J & Dunger, DB (1999) Cord blood leptin is associated with size at birth and predicts infancy weight gain in humans. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Journal of Clinical Endocrinology and Metabolism 84, 1145–1148.CrossRefGoogle Scholar
Ong, KK, Preece, MA, Emmett, PM, Ahmed, ML & Dunger, DB (2002) Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast-feeding: longitudinal birth cohort study and analysis. Pediatric Research 52, 863–867.CrossRefGoogle ScholarPubMed
Ounsted, M & Sleigh, G (1975) The infant's self-regulation of food intake and weight gain. Difference in metabolic balance after growth constraint or acceleration in utero. Lancet i, 1393–1397.CrossRefGoogle Scholar
Ozanne, SE (2001) Metabolic programming in animals. British Medical Bulletin 60, 143–152.CrossRefGoogle ScholarPubMed
Ozanne, SE & Hales, CN (1999) The long-term consequences of intra-uterine protein malnutrition for glucose metabolism. Proceedings of the Nutrition Society 58, 615–619.CrossRefGoogle ScholarPubMed
Ozanne, SE & Hales, CN (2004) Lifespan: catch-up growth and obesity in male mice. Nature 427, 411–412.CrossRefGoogle ScholarPubMed
Ozanne, SE, Lewis, R, Jennings, BJ & Hales, CN (2004) Early programming of weight gain in mice prevents the induction of obesity by a highly palatable diet. Clinical Science 106, 141–145.CrossRefGoogle ScholarPubMed
Ozanne, SE, Nave, BT, Wang, CL, Shepherd, PR, Prins, J & Smith, GD (1997) Poor fetal nutrition causes long-term changes in expression of insulin signaling components in adipocytes. American Journal of Physiology 273, E46–E51.Google ScholarPubMed
Ozanne, SE, Olsen, GS, Hansen, LL, Tingey, KJ, Nave, BT, Wang, CL, Hartil, K, Petry, CJ, Buckley, AJ, Mosthaf-Seedorf, L (2003) Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. Journal of Endocrinology 177, 235–241.CrossRefGoogle ScholarPubMed
Ozanne, SE, Smith, GD, Tikerpae, J & Hales, CN (1996) Altered regulation of hepatic glucose output in the male offspring of protein-malnourished rat dams. American Journal of Physiology 270, E559–E564.Google ScholarPubMed
Park, KS, Kim, SK, Kim, MS, Cho, EY, Lee, JH, Lee, KU, Pak, YK & Lee, HK (2003) Fetal and early postnatal protein malnutrition cause long-term changes in rat liver and muscle mitochondria. Journal of Nutrition 133, 3085–3090.CrossRefGoogle ScholarPubMed
Perez-Escamilla, R, Cohen, RJ, Brown, KH, Rivera, LL, Canahuati, J & Dewey, KG (1995) Maternal anthropometric status and lactation performance in a low-income Honduran population: evidence for the role of infants. American Journal of Clinical Nutrition 61, 528–534.CrossRefGoogle Scholar
Petry, CJ, Dorling, MW, Wang, CL, Pawlak, DB & Ozanne, SE (2000) Catecholamine levels and receptor expression in low protein rat offspring. Diabetic Medicine 17, 848–853.CrossRefGoogle ScholarPubMed
Petry, CJ, Ozanne, SE, Wang, CL & Hales, CN (1997) Early protein restriction and obesity independently induce hypertension in 1-year-old rats. Clinical Science 93, 147–152.CrossRefGoogle ScholarPubMed
Phillips, DI, Walker, BR, Reynolds, RM, Flanagan, DE, Wood, PJ, Osmond, C, Barker, DJ & Whorwood, CB (2000) Low birth weight predicts elevated plasma cortisol concentrations in adults from 3 populations. Hypertension 35, 1301–1306.CrossRefGoogle ScholarPubMed
Poulsen, P, Vaag, AA, Kyvik, KO, Moller, D, Beck-Nielsen, H (1997) Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs. Diabetologia 40, 439–446.CrossRefGoogle ScholarPubMed
Proulx, K, Clavel, S, Nault, G, Richard, D & Walker, CD (2001) High neonatal leptin exposure enhances brain GR expression and feedback efficacy on the adrenocortical axis of developing rats. Endocrinology 142, 4607–4616.CrossRefGoogle ScholarPubMed
Proulx, K, Richard, D & Walker, CD (2002) Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. Endocrinology 143, 4683–4692.CrossRefGoogle ScholarPubMed
Ravelli, AC, van der Meulen, JH, Michels, RP, Osmond, C, Barker, DJ, Hales, CN & Bleker, OP (1998) Glucose tolerance in adults after prenatal exposure to famine. Lancet 351, 173–177.CrossRefGoogle ScholarPubMed
Sagawa, N, Yura, S, Itoh, H, Kakui, K, Takemura, M, Nuamah, MA, Ogawa, Y, Masuzaki, H, Nakao, K & Fujii, S (2002) Possible role of placental leptin in pregnancy: a review. Endocrine 19, 65–71.CrossRefGoogle ScholarPubMed
Savino, F, Costamagna, M, Prino, A, Oggero, R & Silvestro, L (2002) Leptin levels in breast-fed and formula-fed infants. Acta Paediatrica 91, 897–902.CrossRefGoogle ScholarPubMed
Seeber, RM, Smith, JT & Waddell, BJ (2002) Plasma leptin-binding activity and hypothalamic leptin receptor expression during pregnancy and lactation in the rat. Biology of Reproduction 66, 1762–1767.CrossRefGoogle ScholarPubMed
Smith, JT & Waddell, BJ (2003) Leptin distribution and metabolism in the pregnant rat: transplacental leptin passage increases in late gestation but is reduced by excess glucocorticoids. Endocrinology 144, 3024–3030.CrossRefGoogle ScholarPubMed
Snoeck, A, Remacle, C, Reusens, B & Hoet, JJ (1990) Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biology of the Neonate 57, 107–118.CrossRefGoogle ScholarPubMed
Soto, N, Bazaes, RA, Pena, V, Salazar, T, Avila, A, Iniguez, G, Ong, KK, Dunger, DB & Mericq, MV (2003) Insulin sensitivity and secretion are related to catch-up growth in small-for-gestational-age infants at age 1 year: results from a prospective cohort. Journal of Clinical Endocrinology and Metabolism 88, 3645–3650.CrossRefGoogle ScholarPubMed
Sparre, T, Reusens, B, Cherif, H, Larsen, MR, Roepstorff, P, Fey, SJ, Mose, P, Remacle, C & Nerup, J (2003) Intrauterine programming of fetal islet gene expression in rats – effects of maternal protein restriction during gestation revealed by proteome analysis. Diabetologia 46, 1497–1511.CrossRefGoogle ScholarPubMed
Stocker, C, O'Dowd, J, Morton, NM, Wargent, E, Sennitt, MV, Hislop, D, Glund, S, Seckl, JR, Arch, JR & Cawthorne, MA (2004) Modulation of susceptibility to weight gain and insulin resistance in low birthweight rats by treatment of their mothers with leptin during pregnancy and lactation. International Journal of Obesity and Related Metabolic Disorders 28, 129–136.CrossRefGoogle ScholarPubMed
Stocker, C, Wargent, E, Sennitt, M, Nolan, A, O'Dowd, J, Subramaniam, K, Wang, S & Cawthorne, MA (2001) Maternal leptin administration induces resistance to diet-induced obesity of early growth restricted rats. Diabetologia 44 Suppl.1, 641 Abstr.Google Scholar
Symonds, ME, Mostyn, A, Pearce, S, Budge, H & Stephenson, T (2003) Endocrine and nutritional regulation of fetal adipose tissue development. Journal of Endocrinology 179, 293–299.CrossRefGoogle ScholarPubMed
Toschke, AM, Koletzko, B, Slikker, W Jr, Hermann, M & von Kries, R (2002) Childhood obesity is associated with maternal smoking in pregnancy. European Journal of Pediatrics 161, 445–448.CrossRefGoogle ScholarPubMed
Vickers, MH, Breier, BH, Cutfield, WS, Hofman, PL & Gluckman, PD (2000) Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. American Journal of Physiology 279, E83–E87.Google ScholarPubMed
Waterland, RA & Jirtle, RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Molecular and Cellular Biology 23, 5293–5300.CrossRefGoogle ScholarPubMed
Wilson, MR & Hughes, SJ (1997) The effect of maternal protein deficiency during pregnancy and lactation on glucose tolerance and pancreatic islet function in adult rat offspring. Journal of Endocrinology 154, 177–185.CrossRefGoogle ScholarPubMed
Yuen, BS, Owens, PC, Muhlhausler, BS, Roberts, CT, Symonds, ME, Keisler, DH, McFarlane, JR, Kauter, KG, Evens, Y & McMillen, IC (2003) Leptin alters the structural and functional characteristics of adipose tissue before birth. FASEB Journal 17, 1102–1104.CrossRefGoogle ScholarPubMed