Events in early life are associated with changes in the risk of disease in later life. There is increasing evidence that these associations are mediated by permanent transcriptional changes in metabolic pathways, in some cases linked to epigenetic alterations. We have proposed that this phenomenon of ‘developmental induction’ is not a manifestation of pathophysiological processes but rather represents the consequence of developmental decisions made during fetal and early postnatal life to maximize subsequent fitness. However, this fitness advantage is lost if the early and later environments are mismatched. Rats undernourished in utero by maternal underfeeding develop features of the metabolic syndrome, especially if fed on a high-fat diet, but transient neonatal treatment with leptin reverses induction of this adverse metabolic phenotype. This observation demonstrates that developmental programming is reversible and provides strong support for the match-mismatch or predictive model for the origins of developmental programming.

1.
Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Winter PD: Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991;303:1019–1022.
2.
Barker DJ, Osmond C: Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986;1:1077–1081.
3.
Eriksson J, Forsén T, Tuomilehto J, Osmond C, Barker D: Size at birth, childhood growth and obesity in adult life. Int J Obes 2001;25:735–740.
4.
Huxley R, Neil A, Collins R: Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? Lancet 2002;360:659–665.
5.
Barker DJP: In utero programming of chronic disease. Clin Sci 1998;95:115–128.
6.
Eriksson JG, Forsén T, Tuomilehto J, Osmond C, Barker DJ: Early adiposity rebound in childhood and risk of type 2 diabetes in adult life. Diabetologia 2003;46:190–194.
7.
Bhargava SK, Sachdev HS, Fall CHD, Osmond C, Lakshmy R, Barker DJP, Biswas SK, Ramji S, Prabhakaran D, Reddy KS: Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med 2004;350:865–875.
8.
Gluckman P, Hanson M, Morton S, Pinal C: Life-long echoes – a critical analysis of the developmental origins of adult disease model. Biol Neonate 2005;87:127–139.
9.
Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD: Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol 2000;279:E83–E87.
10.
Vickers MH, Reddy S, Ikenasio BA, Breier BH: Dysregulation of the adipoinsular axis – a mechanism for the pathogenesis of hyperleptinaemia and adipogenic diabetes induced by fetal programming. J Endocrinol 2001;170:323–332.
11.
Vickers M, Breier B, McCarthy D, Gluckman P: Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. Am J Physiol 2003;285:R271–R273.
12.
Brawley L, Itoh S, Torrens C, Barker A, Bertram C, Poston L, Hanson M: Dietary protein restriction in pregnancy induces hypertension and vascular defects in rat male offspring. Pediatr Res 2003;54:83–90.
13.
Bellinger L, Lilley C, Langley-Evans SC: Prenatal exposure to a maternal low-protein diet programmes a preference for high-fat foods in the young adult rat. Br J Nutr 2004;92:513–520.
14.
El-Haddad MA, Desai M, Gayle D, Ross MG: In utero development of fetal thirst and appetite: potential for programming. J Soc Gynecol Invest 2004;11:123–130.
15.
Burdge GC, Phillips ES, Dunn RL, Jackson AA, Lillycrop KA: Effect of reduced maternal protein consumption during pregnancy in the rat on plasma lipid concentrations and expression of peroxisomal proliferator-activated receptors in the liver and adipose tissue of the offspring. Nutr Res 2004;24:639–646.
16.
Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR: Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 1998;101:2174–2181.
17.
Ozanne SE, Olsen GS, Hansen LL, Tingey KJ, Nave BT, Wang CL, Hartil K, Petry CJ, Buckley AJ, Mosthaf-Seedorf L: Early growth restriction leads to down regulation of protein kinase C zeta and insulin resistance in skeletal muscle. J Endocrinol 2003;177:235–241.
18.
Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC: Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 2005;135:1382–1386.
19.
Neel JV: Diabetes mellitus: a ‘thrifty’ genotype rendered detrimental by ‘progress’? Bull World Health Organ 1999;77:694–703.
20.
Hattersley AT, Tooke JE: The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 1999;353:1789–1792.
21.
Hales CN, Barker DJ: The thrifty phenotype hypothesis. Br Med Bull 2001;60:5–20.
22.
Mericq V, Ong KK, Bazaes RA, Pena V, Avila A, Salazar T, Soto N, Iniguez G, Dunger DB: Longitudinal changes in insulin sensitivity and secretion from birth to age three years in small- and appropriate-for-gestational-age children. Diabetologia 2005;48:2609–2614.
23.
Wintour E, Moritz K, Johnson K, Ricardo S, Samuel CS, Dodic M: Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol 2003;549:929–935.
24.
Cutfield W: IVF children are taller with increased IGF-I, IGF-II and IGFBP-3 levels suggesting altered genetic imprinting. Proceedings of the 3rd International Congress on Developmental Origins of Health and Disease, 2005 Nov 16–19, Toronto, Canada.
25.
Gluckman PD, Hanson MA, Spencer HG, Bateson P: Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies. Proc Biol Sci 2005;272:671–677.
26.
West-Eberhard MJ: Developmental Plasticity and Evolution. New York, Oxford University Press, 2003.
27.
Gluckman PD, Hanson MA, Spencer HG: Predictive adaptive responses and human evolution. Trends Ecol Evol 2005;20:527–533.
28.
Singhal A, Fewtrel M, Cole TJ, Lucas A: Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Lancet 2003;361:1089–1097.
29.
Stettler N, Stallings VA, Troxel AB, Zhao J, Schinnar R, Nelson SE, Ziegler EE, Strom BL: Weight gain in the first week of life and overweight in adulthood: a cohort study of European American subjects fed infant formula. Circulation 2005;111:1897–1903.
30.
Singhal A, Lucas A: Early origins of cardiovascular disease: is there a unifying hypothesis? Lancet 2004;363:1642–1645.
31.
Jablonka E, Oborny B, Molnar I, Kisdi E, Hofbauer J, Czaran T: The adaptive advantage of phenotypic memory in changing environments. Philos Trans R Soc Lond B 1995;350:133–141.
32.
Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH, Brand-Miller J: Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr 2005;81:341–354.
33.
Gluckman PD, Hanson MA: Maternal constraint of fetal growth and its consequences. Semin Fetal Neonatal Med 2004;9:419–425.
34.
Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, Breier BH, Harris M: Neonatal leptin treatment reverses developmental programming. Endocrinology 2005;146:4211–4216.
35.
Bouret SG, Draper SJ, Simerly RB: Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004;304:108–110.
36.
Islam MS, Sjöholm Å, Emilsson V: Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells. Int J Obes Relat Metab Disord 2000;24:1246–1253.
37.
Gluckman P, Hanson M: Living with the past: evolution, development, and patterns of disease. Science 2004;305:1733–1736.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.