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Effect of intrauterine growth retardation on liver and long-term metabolic risk

Abstract

Intrauterine growth retardation predisposes toward long-term morbidity from type 2 diabetes and cardiovascular disease. To explain this association, the concept of programming was introduced to indicate a process whereby a stimulus or insult at a critical period of development has lasting or lifelong consequences on key endocrine and metabolic pathways. Subtle changes in cell composition of tissues, induced by suboptimal conditions in utero, can influence postnatal physiological functions. There is increasing evidence, suggesting that liver may represent one of the candidate organs targeted by programming, undergoing structural, functional and epigenetic changes following exposure to an unfavorable intrauterine environment. The aim of this review is to provide insights into the molecular mechanisms underlying liver programming that contribute to increase the cardiometabolic risk in subjects with intrauterine growth restriction.

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References

  1. Barker DJ, Osmond C . Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986; 1: 1077–1081.

    Article  CAS  PubMed  Google Scholar 

  2. Barker D, Winter P, Osmond C, Margetts B, Simmonds S . Weight in infancy and death from ischaemic heart disease. Lancet 1989; 2: 577–580.

    Article  CAS  PubMed  Google Scholar 

  3. Hales C, Barker D . Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595–601.

    Article  CAS  PubMed  Google Scholar 

  4. Hales C, Barker D . The thrifty phenotype hypothesis. Br Med Bull 2001; 60: 5–20.

    Article  CAS  PubMed  Google Scholar 

  5. Fowden A, Giussani D, Forhead A . Intrauterine programming of physiological systems: causes and consequences. Physiology (Bethesda) 2006; 21: 29–37.

    CAS  Google Scholar 

  6. Barker DJ . The fetal and infant origins of adult disease. BMJ 1990; 301: 1111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Godfrey K, Lillycrop K, Burdge G, Gluckman P, Hanson M . Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease. Pediatr Res 2007; 61: 5R–10R.

    Article  PubMed  Google Scholar 

  8. Cianfarani S, Germani D, Branca F . Low birthweight and adult insulin resistance: the "catch-up growth" hypothesis. Arch Dis Child Fetal Neonatal Ed 1999; 81: F71–F73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ozanne SE, Hales CN . Lifespan: catch-up growth and obesity in male mice. Nature 2004; 427: 411–412.

    Article  CAS  PubMed  Google Scholar 

  10. Gluckman P, Hanson M . Living with the past: evolution, development, and patterns of disease. Science 2004; 305: 1733–1736.

    Article  CAS  PubMed  Google Scholar 

  11. Canani RB, Di Costanzo M, Leone L, Bedogni G, Brambilla P, Cianfarani S et al. Epigenetic mechanisms elicited by nutrition in early life. Nutr Res Rev 2011; 1–8.

  12. Gluckman P, Hanson M, Bateson P, Beedle A, Law C, Bhutta Z et al. Towards a new developmental synthesis: adaptive developmental plasticity and human disease. Lancet 2009; 373: 1654–1657.

    Article  PubMed  Google Scholar 

  13. Morris TJ, Vickers M, Gluckman P, Gilmour S, Affara N . Transcriptional profiling of rats subjected to gestational undernourishment: implications for the developmental variations in metabolic traits. PLoS One 2009; 4: e7271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Puglianiello A, Germani D, Antignani S, Tomba GS, Cianfarani S . Changes in the expression of hypothalamic lipid sensing genes in rat model of intrauterine growth retardation (IUGR). Pediatr Res 2007; 61: 433–437.

    Article  CAS  PubMed  Google Scholar 

  15. Ritz E, Amann K, Koleganova N, Benz K . Prenatal programming-effects on blood pressure and renal function. Nat Rev Nephrol 2011; 7: 137–144.

    Article  PubMed  Google Scholar 

  16. Moritz KM, Singh RR, Probyn ME, Denton KM . Developmental programming of a reduced nephron endowment: more than just a baby's birth weight. Am J Physiol Renal Physiol 2009; 296: F1–F9.

    Article  CAS  PubMed  Google Scholar 

  17. Gingery A, Soldner EL, Heltemes A, Nelson A, Bozadjieva N . Developmental programming of the kidney: does sex matter? J Physiol 2009; 587: 5521–5522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Langley-Evans SC, Welham SJ, Jackson AA . Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat. Life Sci 1999; 64: 965–974.

    Article  CAS  PubMed  Google Scholar 

  19. Gluckman P, Hanson M, Buklijas T, Low F, Beedle A . Epigenetic mechanisms that underpin metabolic and cardiovascular diseases. Nat Rev Endocrinol 2009; 5: 401–408.

    Article  CAS  PubMed  Google Scholar 

  20. Pinney S, Simmons R . Epigenetic mechanisms in the development of type 2 diabetes. Trends Endocrinol Metab 2010; 21: 223–229.

    Article  CAS  PubMed  Google Scholar 

  21. Goldberg A, Allis C, Bernstein E . Epigenetics: a landscape takes shape. Cell 2007; 128: 635–638.

    Article  CAS  PubMed  Google Scholar 

  22. Fu Q, McKnight R, Yu X, Wang L, Callaway C, Lane R . Uteroplacental insufficiency induces site-specific changes in histone H3 covalent modifications and affects DNA-histone H3 positioning in day 0 IUGR rat liver. Physiol Genomics 2004; 20: 108–116.

    Article  CAS  PubMed  Google Scholar 

  23. Park J, Stoffers D, Nicholls R, Simmons R . Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest 2008; 118: 2316–2324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Raychaudhuri N, Raychaudhuri S, Thamotharan M, Devaskar S . Histone code modifications repress glucose transporter 4 expression in the intrauterine growth-restricted offspring. J Biol Chem 2008; 283: 13611–13626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Thompson R, Fazzari M, Niu H, Barzilai N, Simmons R, Greally J . Experimental intrauterine growth restriction induces alterations in DNA methylation and gene expression in pancreatic islets of rats. J Biol Chem 2010; 285: 15111–15118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. MacLennan N, James S, Melnyk S, Piroozi A, Jernigan S, Hsu J et al. Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats. Physiol Genomics 2004; 18: 43–50.

    Article  PubMed  Google Scholar 

  27. Lane R, Kelley D, Gruetzmacher E, Devaskar S . Uteroplacental insufficiency alters hepatic fatty acid-metabolizing enzymes in juvenile and adult rats. Am J Physiol Regul Integr Comp Physiol 2001; 280: R183–R190.

    Article  CAS  PubMed  Google Scholar 

  28. Lane R, MacLennan N, Hsu J, Janke S, Pham T . Increased hepatic peroxisome proliferator-activated receptor-gamma coactivator-1 gene expression in a rat model of intrauterine growth retardation and subsequent insulin resistance. Endocrinology 2002; 143: 2486–2490.

    Article  CAS  PubMed  Google Scholar 

  29. Yoon J, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 2001; 413: 131–138.

    Article  CAS  PubMed  Google Scholar 

  30. McGarry JD, Brown NF . The mitochondrial carnitine palmitoyltransferase system - from concept to molecular analysis. Eur J Biochem 1997; 244: 1–14.

    Article  CAS  PubMed  Google Scholar 

  31. Cianfarani S . Foetal origins of adult diseases: just a matter of stem cell number? Med Hypotheses 2003; 61: 401–404.

    Article  CAS  PubMed  Google Scholar 

  32. Fowden AL, Giussani DA, Forhead AJ . Endocrine and metabolic programming during intrauterine development. Early Hum Dev 2005; 81: 723–734.

    Article  CAS  PubMed  Google Scholar 

  33. McMillen IC, Robinson JS . Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 2005; 85: 571–633.

    Article  CAS  PubMed  Google Scholar 

  34. Lumey L, Stein A, Kahn H, van der Pal-de Bruin K, Blauw G, Zybert P et al. Cohort profile: the Dutch Hunger Winter families study. Int J Epidemiol 2007; 36: 1196–1204.

    Article  CAS  PubMed  Google Scholar 

  35. Heijmans B, Tobi E, Stein A, Putter H, Blauw G, Susser E et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 2008; 105: 17046–17049.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Steegers-Theunissen R, Obermann-Borst S, Kremer D, Lindemans J, Siebel C, Steegers E et al. Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One 2009; 4: e7845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Stein A, Lumey L . The relationship between maternal and offspring birth weights after maternal prenatal famine exposure: the Dutch Famine Birth Cohort Study. Hum Biol 2000; 72: 641–654.

    CAS  PubMed  Google Scholar 

  38. Skinner MK, Manikkam M, Guerrero-Bosagna C . Epigenetic transgenerational actions of environmental factors in disease etiology. Trends Endocrinol Metab 2010; 21: 214–222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Crews D, Gore AC, Hsu TS, Dangleben NL, Spinetta M, Schallert T et al. Transgenerational epigenetic imprints on mate preference. Proc Natl Acad Sci USA 2007; 104: 5942–5946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Seckl JR, Holmes MC . Mechanisms of disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology. Nat Clin Pract Endocrinol Metab 2007; 3: 479–488.

    Article  CAS  PubMed  Google Scholar 

  41. Doyle LW, Ford GW, Davis NM, Callanan C . Antenatal corticosteroid therapy and blood pressure at 14 years of age in preterm children. Clin Sci (Lond) 2000; 98: 137–142.

    Article  CAS  Google Scholar 

  42. Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 2005; 365: 1856–1862.

    Article  CAS  PubMed  Google Scholar 

  43. de Vries A, Holmes MC, Heijnis A, Seier JV, Heerden J, Louw J et al. Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function. J Clin Invest 2007; 117: 1058–1067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cianfarani S, Geremia C, Scott CD, Growth Germani D . IGF system, and cortisol in children with intrauterine growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-adrenal axis? Pediatr Res 2002; 51: 94–99.

    Article  CAS  PubMed  Google Scholar 

  45. Phillips DI, Barker DJ, Fall CH, Seckl JR, Whorwood CB, Wood PJ et al. Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 1998; 83: 757–760.

    CAS  PubMed  Google Scholar 

  46. Phillips DI, Walker BR, Reynolds RM, Flanagan DE, Wood PJ, Osmond C et al. Low birth weight predicts elevated plasma cortisol concentrations in adults from 3 populations. Hypertension 2000; 35: 1301–1306.

    Article  CAS  PubMed  Google Scholar 

  47. Reynolds RM, Walker BR, Syddall HE, Andrew R, Wood PJ, Whorwood CB et al. Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 2001; 86: 245–250.

    CAS  PubMed  Google Scholar 

  48. Buhl ES, Neschen S, Yonemitsu S, Rossbacher J, Zhang D, Morino K et al. Increased hypothalamic-pituitary-adrenal axis activity and hepatic insulin resistance in low-birth-weight rats. Am J Physiol Endocrinol Metab 2007; 293: E1451–E1458.

    Article  CAS  PubMed  Google Scholar 

  49. Berkowitz GS, Wolff MS, Janevic TM, Holzman IR, Yehuda R, Landrigan PJ . The World Trade Center disaster and intrauterine growth restriction. JAMA 2003; 290: 595–596.

    Article  PubMed  Google Scholar 

  50. Filiberto AC, Maccani MA, Koestler D, Wilhelm-Benartzi C, Avissar-Whiting M, Banister CE et al. Birthweight is associated with DNA promoter methylation of the glucocorticoid receptor in human placenta. Epigenetics 2011; 6: 566–572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lane RH, Flozak AS, Ogata ES, Bell GI, Simmons RA . Altered hepatic gene expression of enzymes involved in energy metabolism in the growth-retarded fetal rat. Pediatr Res 1996; 39: 390–394.

    Article  CAS  PubMed  Google Scholar 

  52. Ogata ES, Swanson SL, Collins JW, Finley SL . Intrauterine growth retardation: altered hepatic energy and redox states in the fetal rat. Pediatr Res 1990; 27: 56–63.

    Article  CAS  PubMed  Google Scholar 

  53. Lane RH, Crawford SE, Flozak AS, Simmons RA . Localization and quantification of glucose transporters in liver of growth-retarded fetal and neonatal rats. Am J Physiol 1999; 276: E135–E142.

    CAS  PubMed  Google Scholar 

  54. Germani D, Puglianiello A, Cianfarani S . Uteroplacental insufficiency down regulates insulin receptor and affects expression of key enzymes of long-chain fatty acid (LCFA) metabolism in skeletal muscle at birth. Cardiovasc Diabetol 2008; 7: 14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Puglianiello A, Germani D, Cianfarani S . Exposure to uteroplacental insufficiency reduces the expression of signal transducer and activator of transcription 3 and proopiomelanocortin in the hypothalamus of newborn rats. Pediatr Res 2009; 66: 208–211.

    Article  CAS  PubMed  Google Scholar 

  56. Moon S, Kim JH, Han JH, Ko SH, Ahn YB, Yang SH et al. Novel compound heterozygous mutations in the fructose-1,6-bisphosphatase gene cause hypoglycemia and lactic acidosis. Metabolism 2011; 60: 107–113.

    Article  CAS  PubMed  Google Scholar 

  57. Jiang MH, Fei J, Lan MS, Lu ZP, Liu M, Fan WW et al. Hypermethylation of hepatic Gck promoter in ageing rats contributes to diabetogenic potential. Diabetologia 2008; 51: 1525–1533.

    Article  CAS  PubMed  Google Scholar 

  58. Harding JW, Pyeritz EA, Copeland ES, White HB . Role of glycerol 3-phosphate dehydrogenase in glyceride metabolism. Effect of diet on enzyme activities in chicken liver. Biochem J 1975; 146: 223–229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Moreno F, Herrero P . The hexokinase 2-dependent glucose signal transduction pathway of Saccharomyces cerevisiae. FEMS Microbiol Rev 2002; 26: 83–90.

    Article  CAS  PubMed  Google Scholar 

  60. Manco L, Ribeiro ML . Novel human pathological mutations. Gene symbol: PKLR. Disease: pyruvate kinase deficiency. Hum Genet 2009; 125: 343.

    PubMed  Google Scholar 

  61. Olson AL, Pessin JE . Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu Rev Nutr 1996; 16: 235–256.

    Article  CAS  PubMed  Google Scholar 

  62. Huang J, Jia Y, Fu T, Viswakarma N, Bai L, Rao MS et al. Sustained activation of PPAR{alpha} by endogenous ligands increases hepatic fatty acid oxidation and prevents obesity in ob/ob mice. FASEB J 2011; 26: 628–638.

    Article  CAS  PubMed  Google Scholar 

  63. Simmons R, Templeton L, Gertz S . Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 2001; 50: 2279–2286.

    Article  CAS  PubMed  Google Scholar 

  64. Burns SP, Desai M, Cohen RD, Hales CN, Iles RA, Germain JP et al. Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation. J Clin Invest 1997; 100: 1768–1774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Desai M, Byrne CD, Zhang J, Petry CJ, Lucas A, Hales CN . Programming of hepatic insulin-sensitive enzymes in offspring of rat dams fed a protein-restricted diet. Am J Physiol 1997; 272: G1083–G1090.

    CAS  PubMed  Google Scholar 

  66. Desai M, Byrne CD, Meeran K, Martenz ND, Bloom SR, Hales CN . Regulation of hepatic enzymes and insulin levels in offspring of rat dams fed a reduced-protein diet. Am J Physiol 1997; 273: G899–G904.

    CAS  PubMed  Google Scholar 

  67. Vaiman D, Gascoin-Lachambre G, Boubred F, Mondon F, Feuerstein JM, Ligi I et al. The intensity of IUGR-induced transcriptome deregulations is inversely correlated with the onset of organ function in a rat model. PLoS One 2011; 6: e21222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Camm EJ, Martin-Gronert MS, Wright NL, Hansell JA, Ozanne SE, Giussani DA . Prenatal hypoxia independent of undernutrition promotes molecular markers of insulin resistance in adult offspring. FASEB J 2011; 25: 420–427.

    Article  CAS  PubMed  Google Scholar 

  69. Drake AJ, Reynolds RM . Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction 2010; 140: 387–398.

    Article  CAS  PubMed  Google Scholar 

  70. Gregorio BM, Souza-Mello V, Carvalho JJ, Mandarim-de-Lacerda CA, Aguila MB . Maternal high-fat intake predisposes nonalcoholic fatty liver disease in C57BL/6 offspring. Am J Obstet Gynecol 2010; 203: 495.e1–495.e8.

    Article  CAS  Google Scholar 

  71. Bruce KD, Cagampang FR, Argenton M, Zhang J, Ethirajan PL, Burdge GC et al. Maternal high-fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression. Hepatology 2009; 50: 1796–1808.

    Article  CAS  PubMed  Google Scholar 

  72. Strakovsky RS, Zhang X, Zhou D, Pan YX . Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase (Pck) expression and histone modification in neonatal offspring rats. J Physiol 2011; 589: 2707–2717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Oster M, Murani E, Metges CC, Ponsuksili S, Wimmers K . A high protein diet during pregnancy affects hepatic gene expression of energy sensing pathways along ontogenesis in a porcine model. PLoS One 2011; 6: e21691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Yamashita H, Shao J, Qiao L, Pagliassotti M, Friedman JE . Effect of spontaneous gestational diabetes on fetal and postnatal hepatic insulin resistance in Lepr(db/+) mice. Pediatr Res 2003; 53: 411–418.

    Article  CAS  PubMed  Google Scholar 

  75. Mulay S, Philip A, Solomon S . Influence of maternal diabetes on fetal rat development: alteration of insulin receptors in fetal liver and lung. J Endocrinol 1983; 98: 401–410.

    Article  CAS  PubMed  Google Scholar 

  76. Barker DJ, Meade TW, Fall CH, Lee A, Osmond C, Phipps K et al. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. BMJ 1992; 304: 148–152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Barker DJ, Martyn CN, Osmond C, Hales CN, Fall CH . Growth in utero and serum cholesterol concentrations in adult life. BMJ 1993; 307: 1524–1527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Barker DJ, Martyn CN, Osmond C, Wield GA . Abnormal liver growth in utero and death from coronary heart disease. BMJ 1995; 310: 703–704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Barker DJ, Hanson MA . Altered regional blood flow in the fetus: the origins of cardiovascular disease? Acta Paediatr 2004; 93: 1559–1560.

    Article  CAS  PubMed  Google Scholar 

  80. Latini G, De Mitri B, Del Vecchio A, Chitano G, De Felice C, Zetterström R . Foetal growth of kidneys, liver and spleen in intrauterine growth restriction: "programming" causing "metabolic syndrome" in adult age. Acta Paediatr 2004; 93: 1635–1639.

    Article  CAS  PubMed  Google Scholar 

  81. Cetin I, Giovannini N, Alvino G, Agostoni C, Riva E, Giovannini M et al. Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships. Pediatr Res 2002; 52: 750–755.

    Article  CAS  PubMed  Google Scholar 

  82. Mori TA, Bao DQ, Burke V, Puddey IB, Watts GF, Beilin LJ . Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects. Am J Clin Nutr 1999; 70: 817–825.

    Article  CAS  PubMed  Google Scholar 

  83. Couet C, Delarue J, Ritz P, Antoine JM, Lamisse F . Effect of dietary fish oil on body fat mass and basal fat oxidation in healthy adults. Int J Obes Relat Metab Disord 1997; 21: 637–643.

    Article  CAS  PubMed  Google Scholar 

  84. Jelenik T, Rossmeisl M, Kuda O, Jilkova ZM, Medrikova D, Kus V et al. AMP-activated protein kinase α2 subunit is required for the preservation of hepatic insulin sensitivity by n-3 polyunsaturated fatty acids. Diabetes 2010; 59: 2737–2746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kuda O, Jelenik T, Jilkova Z, Flachs P, Rossmeisl M, Hensler M et al. n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet. Diabetologia 2009; 52: 941–951.

    Article  CAS  PubMed  Google Scholar 

  86. Riediger ND, Othman RA, Suh M, Moghadasian MH . A systemic review of the roles of n-3 fatty acids in health and disease. J Am Diet Assoc 2009; 109: 668–679.

    Article  CAS  PubMed  Google Scholar 

  87. Simon JA, Hodgkins ML, Browner WS, Neuhaus JM, Bernert JT, Hulley SB . Serum fatty acids and the risk of coronary heart disease. Am J Epidemiol 1995; 142: 469–476.

    Article  CAS  PubMed  Google Scholar 

  88. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002; 346: 1113–1118.

    Article  CAS  PubMed  Google Scholar 

  89. Lindqvist HM, Sandberg AS, Fagerberg B, Hulthe J . Plasma phospholipid EPA and DHA in relation to atherosclerosis in 61-year-old men. Atherosclerosis 2009; 205: 574–578.

    Article  CAS  PubMed  Google Scholar 

  90. Labayen I, Moreno LA, Ruiz JR, Ortega FB, Sjostrom M, Huybrechts I et al. Associations of birth weight with serum long chain polyunsaturated fatty acids in adolescents; the HELENA study. Atherosclerosis 2011; 217: 286–291.

    Article  CAS  PubMed  Google Scholar 

  91. Agostoni C . Role of long-chain polyunsaturated fatty acids in the first year of life. J Pediatr Gastroenterol Nutr 2008; 47(Suppl 2): S41–S44.

    Article  CAS  Google Scholar 

  92. Das UN . A perinatal strategy to prevent coronary heart disease. Nutrition 2003; 19: 1022–1027.

    Article  PubMed  Google Scholar 

  93. Singhal A, Cole TJ, Lucas A . Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet 2001; 357: 413–419.

    Article  CAS  PubMed  Google Scholar 

  94. Singhal A, Cole TJ, Fewtrell M, Lucas A . Breastmilk feeding and lipoprotein profile in adolescents born preterm: follow-up of a prospective randomised study. Lancet 2004; 363: 1571–1578.

    Article  CAS  PubMed  Google Scholar 

  95. Martin RM, Davey Smith G . Does having been breastfed in infancy influence lipid profile in later life?: A review of the literature. Adv Exp Med Biol 2009; 646: 41–50.

    Article  PubMed  Google Scholar 

  96. Singhal A, Fewtrell M, Cole TJ, Lucas A . Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Lancet 2003; 361: 1089–1097.

    Article  CAS  PubMed  Google Scholar 

  97. Nobili V, Bedogni G, Alisi A, Pietrobattista A, Risé P, Galli C et al. Docosahexaenoic acid supplementation decreases liver fat content in children with non-alcoholic fatty liver disease: double-blind randomised controlled clinical trial. Arch Dis Child 2011; 96: 350–353.

    Article  PubMed  Google Scholar 

  98. Jensen CB, Storgaard H, Dela F, Holst JJ, Madsbad S, Vaag AA . Early differential defects of insulin secretion and action in 19-year-old caucasian men who had low birth weight. Diabetes 2002; 51: 1271–1280.

    Article  CAS  PubMed  Google Scholar 

  99. Arenz S, Rückerl R, Koletzko B, von Kries R . Breast-feeding and childhood obesity--a systematic review. Int J Obes Relat Metab Disord 2004; 28: 1247–1256.

    Article  CAS  PubMed  Google Scholar 

  100. Martin RM, Gunnell D, Smith GD . Breastfeeding in infancy and blood pressure in later life: systematic review and meta-analysis. Am J Epidemiol 2005; 161: 15–26.

    Article  PubMed  Google Scholar 

  101. Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG . Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin Nutr 2006; 84: 1043–1054.

    Article  CAS  PubMed  Google Scholar 

  102. Owen CG, Whincup PH, Kaye SJ, Martin RM, Davey Smith G, Cook DG et al. Does initial breastfeeding lead to lower blood cholesterol in adult life? A quantitative review of the evidence. Am J Clin Nutr 2008; 88: 305–314.

    Article  CAS  PubMed  Google Scholar 

  103. Nobili V, Bedogni G, Alisi A, Pietrobattista A, Alterio A, Tiribelli C et al. A protective effect of breastfeeding on the progression of non-alcoholic fatty liver disease. Arch Dis Child 2009; 94: 801–805.

    Article  CAS  PubMed  Google Scholar 

  104. Nolan CJ, Damm P, Prentki M . Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 2011; 378: 169–181.

    Article  PubMed  Google Scholar 

  105. Smith BW, Adams LA . Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nat Rev Endocrinol 2011; 7: 456–465.

    Article  CAS  PubMed  Google Scholar 

  106. Nobili V, Marcellini M, Marchesini G, Vanni E, Manco M, Villani A et al. Intrauterine growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes Care 2007; 30: 2638–2640.

    Article  PubMed  Google Scholar 

  107. Leunissen RW, Kerkhof GF, Stijnen T, Hokken-Koelega A . Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood. JAMA 2009; 301: 2234–2242.

    Article  CAS  PubMed  Google Scholar 

  108. Barker D, Osmond C, Forsén T, Kajantie E, Eriksson J . Trajectories of growth among children who have coronary events as adults. N Engl J Med 2005; 353: 1802–1809.

    Article  CAS  PubMed  Google Scholar 

  109. Widdowson EM, Crabb DE, Milner RD . Cellular development of some human organs before birth. Arch Dis Child 1972; 47: 652–655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel JC et al. Child health, developmental plasticity, and epigenetic programming. Endocr Rev 2011; 32: 159–224.

    Article  CAS  PubMed  Google Scholar 

  111. Vickers M, Gluckman P, Coveny A, Hofman P, Cutfield W, Gertler A et al. Neonatal leptin treatment reverses developmental programming. Endocrinology 2005; 146: 4211–4216.

    Article  CAS  PubMed  Google Scholar 

  112. Burdge GC, Lillycrop KA, Phillips ES, Slater-Jefferies JL, Jackson AA, Hanson MA . Folic acid supplementation during the juvenile-pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 2009; 139: 1054–1060.

    Article  CAS  PubMed  Google Scholar 

  113. Wiedmeier JE, Joss-Moore LA, Lane RH, Neu J . Early postnatal nutrition and programming of the preterm neonate. Nutr Rev 2011; 69: 76–82.

    Article  PubMed  Google Scholar 

  114. Choi SW, Friso S, Epigenetics A . New Bridge between nutrition and health. Adv Nutr (Bethesda) 2010; 1: 8–16.

    Article  CAS  Google Scholar 

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Correspondence to S Cianfarani.

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Cianfarani, S., Agostoni, C., Bedogni, G. et al. Effect of intrauterine growth retardation on liver and long-term metabolic risk. Int J Obes 36, 1270–1277 (2012). https://doi.org/10.1038/ijo.2012.54

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  • DOI: https://doi.org/10.1038/ijo.2012.54

Keywords

  • non-alcoholic fatty liver disease (NAFLD)
  • type 2 diabetes
  • cardiometabolic disease
  • programming
  • intrauterine growth retardation (IUGR)

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