Prenatal Programming and Epigenetics of Obesity Metabolic Phenotype: Pre- and Postnatal Metabolic Phenotypes and Molecular Mechanisms

  • Antonio Gonzalez-BulnesEmail author
  • Susana Astiz
Reference work entry


The incidence of obesity and comorbidities has increased to epidemic levels in recent years, with important changes in the sociodemographic profile of the disease. At present, a high prevalence of the disease is not only found in developed countries but also in developing areas like India, Brazil, China, and Middle East countries. Concomitantly, the highest prevalence has moved from mature individuals to infant, young, and middle-aged populations. There is currently strong evidence supporting that these changes are related to modifications in nutritional patterns and lifestyle of women in childbearing age that affects prenatal and early postnatal environment, and therefore, modifies the developmental programming of their offspring. The present chapter outlines, based on the results of translational animal research and epidemiological human studies, the processes of developmental programming involved in the onset of obesity at infancy and adulthood.


Animal models Developmental programming Epigenetics Fetus Intrauterine-growth-restriction Lifestyle Metabolism Metabolic syndrome Nutrition Obesity Obesogenics Pregnancy Transgenerational programming 

List of Abbreviations


Agouti related protein


Deoxyribonucleic acid


Developmental Origins of Health and Disease


Intrauterine Growth Restriction or Retardation




Leptin receptor




Melanocortin 3 receptor


Melanocortin 4 receptor


Neuropeptide Y




Ribonucleic acid




Alpha-melanocyte stimulating hormone


  1. Barker JP, Clark PM (1997) Fetal undernutrition and disease in later life. Rev Reprod 2:105–112CrossRefGoogle Scholar
  2. Barker DJ, Osmond C, Law CM (1989) The intrauterine and early postnatal origins of cardiovascular disease and chronic bronchitis. J Epidemiol Community Health 43:237–240CrossRefGoogle Scholar
  3. 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 36:62–67CrossRefGoogle Scholar
  4. Baschat AA (2004) Fetal responses to placental insufficiency: an update. BJOG 111:1031–1041CrossRefGoogle Scholar
  5. Bavdekar A, Yajnik CS, Fall CH, Bapat S, Pandit AN, Deshpande V, Bhave S, Kellingray SD, Joglekar C (1999) Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both? Diabetes 48:2422–2429CrossRefGoogle Scholar
  6. Bellinger L, Lilley C, Langley-Evans SC (2004) Prenatal exposure to a maternal low-protein diet programmes a preference for high-fat foods in the young adult rat. Br J Nutr 92:513–520CrossRefGoogle Scholar
  7. Bird IM, Zhang LB, Magness RR (2003) Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function. Am J Phys 284:245–258Google Scholar
  8. Breier BH, Vickers MH, Ikenasio BA, Chan KY, Wong WPS (2001) Fetal programming of appetite and obesity. Mol Cell Endocrinol 185:73–79CrossRefGoogle Scholar
  9. Burdge GC, Hanson MA, Slater-Jefferies JL, Lillycrop KA (2007) Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? Br J Nutr 97:1036–1046CrossRefGoogle Scholar
  10. Cochrane WA (1965) Overnutrition in prenatal and neonatal life: a problem? Can Med Assoc J 93:893–899PubMedPubMedCentralGoogle Scholar
  11. Eaton SB, Konner M, Shostak M (1988) Stone agers in the fast lane: chronic degenerative diseases in evolutionary perspective. Am J Med 84:739–749CrossRefGoogle Scholar
  12. Eriksson JG (2006) Early growth, and coronary heart disease and type 2 diabetes: experiences from the Helsinki birth cohort studies. Int J Obes 30:S18–S22CrossRefGoogle Scholar
  13. Fisher DA (1973) Diabetes, pregnancy and obesity. Calif Med 119:35–37PubMedPubMedCentralGoogle Scholar
  14. Ghidini A (1996) Idiopathic fetal growth restriction: a pathophysiologic approach. Obstet Gynecol Surv 51:376–382CrossRefGoogle Scholar
  15. Giussani DA, Niu Y, Herrera EA, Richter HG, Camm EJ, Thakor AS, Kane AD, Hansell JA, Brain KL, Skeffington KL, Itani N, Wooding FB, Cross CM, Allison BJ (2014) Heart disease link to fetal hypoxia and oxidative stress. Adv Exp Med Biol 814:77–87CrossRefGoogle Scholar
  16. Gluckman PD, Hanson MA (2004) Living with the past: evolution, development, and patterns of disease. Science 305:1733–1736CrossRefGoogle Scholar
  17. Gluckman PD, Hanson MA, Spencer HG (2005a) Predictive adaptive responses and human evolution. Trends Ecol Evol 20:527–533CrossRefGoogle Scholar
  18. Gluckman PD, Hanson MA, Spencer HG, Bateson P (2005b) Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies. Proc R Soc Biol 272:671–677CrossRefGoogle Scholar
  19. Gluckman PD, Hanson MA, Beedle AS (2007) Early life events and their consequences for later disease: a life history and evolutionary perspective. Am J Hum Biol 19:1–19CrossRefGoogle Scholar
  20. Gluckman PD, Hanson MA, Beedle AS, Spencer HG (2008) Predictive adaptive responses in perspective. Trends Endocrinol Metabol 19:109–110CrossRefGoogle Scholar
  21. Hales CN, Ozanne SE (2003) The dangerous road of catch-up growth. J Physiol Lond 547:5–10CrossRefGoogle Scholar
  22. Herrera BM, Lindgren CM (2010) The genetics of obesity. Curr Diab Rep 10:498–505CrossRefGoogle Scholar
  23. Hofman PL, Cutfield WS, Robinson EM et al (1997) Insulin resistance in short children with intrauterine growth retardation. J Clin Endocrinol Metab 82:402–406PubMedGoogle Scholar
  24. Ibañez L, Ong K, Dunger DB, de Zegher F (2006) Early development of adiposity and insulin resistance after catch-up weight gain in small-for-gestational-age children. J Clin Endocrinol Metab 91:2153–2158CrossRefGoogle Scholar
  25. Ismail-Beigi F, Catalano PM, Hanson RW (2006) Metabolic programming: fetal origins of obesity and metabolic syndrome in the adult. Am J Phys Endocrinol Metab 291:439–440CrossRefGoogle Scholar
  26. Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33:245–254CrossRefGoogle Scholar
  27. Jensen GM, Moore LG (1997) The effect of high altitude and other risk factors on birthweight: independent or interactive effects? Am J Public Health 87:1003–1007CrossRefGoogle Scholar
  28. Kahn HS, Graff M, Stein AD, Lumey LH (2009) A fingerprint marker from early gestation associated with diabetes in middle age: the Dutch Hunger Winter Families Study. Int J Epidemiol 38: 101–109CrossRefGoogle Scholar
  29. Keyes LE, Armaza JF, Niermeyer S, Vargas E, Young DA, Moore LG (2003) Intrauterine growth restriction, preeclampsia, and intrauterine mortality at high altitude in Bolivia. Pediatr Res 54: 20–25CrossRefGoogle Scholar
  30. Kong AP, Xu G, Brown N, So WY, Ma RC, Chan JC (2013) Diabetes and its comorbidities-where East meets West. Nature Rev Endocrinol 9:537–547CrossRefGoogle Scholar
  31. Krebs C, Macara LM, Leiser R, Bowman AW, Greer IA, Kingdom JC (1996) Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstetr Gynecol 175:1534–1542CrossRefGoogle Scholar
  32. Lecklin A, Dube MG, Torto RN, Kalra PS, Kalra SP (2005) Perigestational suppression of weight gain with central leptin gene therapy results in lower weight F1 generation. Peptides 26: 1176–1187CrossRefGoogle Scholar
  33. Lindstrom P (2007) The physiology of obese-Hyperglycaemic mice [ob/ob Mice]. Sci World J 7: 666–685CrossRefGoogle Scholar
  34. Lucas A (1998) Programming by early nutrition: an experimental approach. J Nutr 128:401–406CrossRefGoogle Scholar
  35. Lumey LH, Stein AD, Kahn HS, Romijn JA (2009) Lipid profiles in middle-aged men and women after famine exposure during gestation: the Dutch hunger winter families study. Am J Clin Nutr 89:1737–1743CrossRefGoogle Scholar
  36. Marliss EB, Chevalier S, Gougeon R et al (2006) Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover. Diabetologia 49: 351–359CrossRefGoogle Scholar
  37. McMillen IC, Robinson JS (2005) Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85:571–633CrossRefGoogle Scholar
  38. Moore LG, Niermeyer S, Zamudio S (1998) Human adaptation to high altitude: regional and life-cycle perspectives. Am J Phys Anthropol Suppl 27:25–64CrossRefGoogle Scholar
  39. Mortola JP, Frappell PB, Aguero L, Armstrong K (2000) Birth weight and altitude: a study in Peruvian communities. J Pediatr 136:324–329CrossRefGoogle Scholar
  40. Mühlhäusler BS, Adam CL, McMillen IC (2008) Maternal nutrition and the programming of obesity: the brain. Organogenesis 4:144–152CrossRefGoogle Scholar
  41. Nohr EA, Bech BH, Davies MJ, Frydenberg M, Henriksen TB, Olsen J (2005) Pre-pregnancy obesity and fetal death: a study within the Danish National Birth Cohort. Obstet Gynecol 106:250–259CrossRefGoogle Scholar
  42. Nohr EA, Bech BH, Vaeth M, Rasmussen KM, Henriksen TB, Olsen J (2007a) Obesity, gestational weight gain and preterm birth: a study within the Danish National Birth Cohort. Paediatr Perinat Epidemiol 21:5–14CrossRefGoogle Scholar
  43. Nohr EA, Vaeth M, Bech BH, Henriksen TB, Cnattingius S, Olsen J (2007b) Maternal obesity and neonatal mortality according to subtypes of preterm birth. Obstet Gynecol 110:1083–1090CrossRefGoogle Scholar
  44. Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB (2000) Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. Br Med J 320:967–971CrossRefGoogle Scholar
  45. Painter RC, Roseboom TJ, Bleker OP (2005) Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 20:345–352CrossRefGoogle Scholar
  46. Patterson AJ, Zhang L (2010) Hypoxia and fetal heart development. Curr Mol Med 10:653–666CrossRefGoogle Scholar
  47. Ravelli GP, Stein ZA, Susser MW (1976) Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 295:349–353CrossRefGoogle Scholar
  48. Ravelli AC, van der Meulen JH, Michels RP et al (1998) Glucose tolerance in adults after prenatal exposure to famine. Lancet 351:173–177CrossRefGoogle Scholar
  49. Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP (1999) Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 70:811–816CrossRefGoogle Scholar
  50. Roseboom T, de Rooij S, Painter R (2006) The Dutch famine and its long-term consequences for adult health. Early Hum Dev 82:485–491CrossRefGoogle Scholar
  51. Savvidou MD, Hingorani AD, Tsikas D, Frolich JC, Vallance P, Nicolaides KH (2003) Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet 361:1511–1517CrossRefGoogle Scholar
  52. Schulz LC (2010) The Dutch Hunger Winter and the developmental origins of health and disease. Proc Natl Acad Sci USA 107:16757–16758CrossRefGoogle Scholar
  53. Scully T (2012) Diabetes in numbers. Nature 485:S2–S3CrossRefGoogle Scholar
  54. Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87:4–14CrossRefGoogle Scholar
  55. Simmons RA (2007) Developmental origins of diabetes: the role of epigenetic mechanisms. Curr Opin Endocrinol Diabetes Obes 14:13–16CrossRefGoogle Scholar
  56. Stanner SA, Yudkin JS (2001) Fetal programming and the Leningrad Siege study. Twin Res 4: 287–292CrossRefGoogle Scholar
  57. Stein Z, Susser M (1975a) The Dutch famine, 1944–1945, and the reproductive process. I. Effects on six indices at birth. Pediatr Res 9:70–76PubMedGoogle Scholar
  58. Stein Z, Susser M (1975b) The Dutch famine, 1944–1945, and the reproductive process. II. Interrelations of caloric rations and six indices at birth. Pediatr Res 9:76–83PubMedGoogle Scholar
  59. Teramo KA (2010) Obstetric problems in diabetic pregnancy – the role of fetal hypoxia. Best Pract Res Clin Endocrinol Metab 24:663–671CrossRefGoogle Scholar
  60. Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD (2000) Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab 279:83–87CrossRefGoogle Scholar
  61. Vickers MH, Reddy S, Ikenasio BA, Breier BH (2001) Dysregulation of the adipoinsular axis–a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming. J Endocrinol 170:323–332CrossRefGoogle Scholar
  62. Vickers MH, Breier BH, McCarthy D, Gluckman PD (2003) Sedentary behaviour during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. Am J Physiol Regul Integr Comp Physiol 285:271–273CrossRefGoogle Scholar
  63. Watkins AJ, Ursell E, Panton R et al (2008) Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease. Biol Reprod 78:299–306CrossRefGoogle Scholar
  64. Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE (2004) Maternal nutrition and fetal development. J Nutr 134:2169–2172CrossRefGoogle Scholar
  65. Wu G, Bazer FW, Wallace JM, Spencer TE (2006) Intrauterine growth retardation: implications for the animal sciences. J Anim Sci 84:2316–2337CrossRefGoogle Scholar
  66. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Comparative Physiology Group. SGIT-INIAAvda. Puerta de Hierro s/nMadridSpain

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