Skip to main content
SpringerLink
Log in

Fetal growth restriction, catch-up growth and the early origins of insulin resistance and visceral obesity

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

There is an association between growing slowly before birth, accelerated growth in early postnatal life and the emergence of insulin resistance, visceral obesity and glucose intolerance in adult life. In this review we consider the pathway through which intrauterine growth restriction (IUGR) leads to the initial increase in insulin sensitivity and to catch-up growth. We also discuss the importance of the early insulin environment in determining later visceral adiposity and the intrahepatic mechanisms that may result in the emergence of glucose intolerance in a subset of IUGR infants. We present evidence that a key fetal adaptation to poor fetal nutrition is an upregulation of the abundance of the insulin receptor in the absence of an upregulation of insulin signalling in fetal skeletal muscle. After birth, however, there is an upregulation in the abundance of the insulin receptor and the insulin signalling pathway in the IUGR offspring. Thus, the origins of the accelerated postnatal growth rate experienced by IUGR infants lie in the fetal adaptations to a poor nutrient supply. We also discuss how the intracellular availability of free fatty acids and glucose within the visceral adipocyte and hepatocyte in fetal and neonatal life are critical in determining the subsequent metabolic phenotype of the IUGR offspring. It is clear that a better understanding of the relative contributions of the fetal and neonatal nutrient environment to the regulation of key insulin signalling pathways in muscle, visceral adipose tissue and the liver is required to support the development of evidence-based intervention strategies and better outcomes for the IUGR infant.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Stocker CJ, Cawthorne MA (2008) The influence of leptin on early life programming of obesity. Trends Biotechnol 26:545–551

    Article  CAS  PubMed  Google Scholar 

  3. Briana DD, Malamitsi-Puchner A (2009) Intrauterine growth restriction and adult disease: the role of adipocytokines. Eur J Endocrinol 160:337–347

    Article  CAS  PubMed  Google Scholar 

  4. Evans SC (2009) Nutritional programming of disease: unravelling the mechanism. J Anat 215:36–51

    Article  Google Scholar 

  5. Yajnik CS (2009) Nutrient-mediated teratogenesis and fuel-mediated teratogenesis: two pathways of intrauterine programming of diabetes. Int J Gynaecol Obstet 104 [Suppl 1]:S27–S31

    Article  CAS  PubMed  Google Scholar 

  6. Hales C, Barker D (1992) Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 135:595–601

    Article  Google Scholar 

  7. Economides DL, Nicolaides KH, Campbell S (1991) Metabolic and endocrine findings in appropriate and small for gestational age fetuses. J Perinat Med 19:97–105

    Article  CAS  PubMed  Google Scholar 

  8. Enzi G, Zanardo V, Caretta F, Inelmen EM, Rubaltelli F (1981) Intrauterine growth and adipose tissue development. Am J Clin Nutr 34:1785–1790

    CAS  PubMed  Google Scholar 

  9. Fitzhardinge PM, Steven EM (1972) The small-for-date infant. I. Later growth patterns. Pediatrics 49:671–681

    CAS  PubMed  Google Scholar 

  10. Albertsson-Wikland K, Wennergren G, Wennergren M, Vilbergsson G, Rosberg S (1993) Longitudinal follow-up of growth in children born small for gestational age. Acta Paediatr 82:438–443

    Article  CAS  PubMed  Google Scholar 

  11. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ (1996) Birth weight and adult hypertension, diabetes mellitus and obesity in US men. Circulation 94:3246–3250

    CAS  PubMed  Google Scholar 

  12. Whincup PH, Cook DG, Adshead F, Taylor SJ, Walker M, Papacosta O, Alberti KG (1997) Childhood size is more strongly related than size at birth to glucose and insulin levels in 10–11-year-old children. Diabetologia 40:319–326

    Article  CAS  PubMed  Google Scholar 

  13. Bavdekar A, Yajnik C, Fall C, Bapat S, Pandit A, Deshpande V, Bhave S, Kellingray S, Joglekar C (1999) Insulin resistance syndrome in 8-year-old Indian children: small at birth, big at 8 years, or both? Diabetes 48:2422–2429

    Article  CAS  PubMed  Google Scholar 

  14. Eriksson J, Forsen T, Tuomilehto J, Osmond C, Barker D (2001) Size at birth, childhood growth and obesity in adult life. Int J Obes Relat Metab Disord 25:735–740

    Article  CAS  PubMed  Google Scholar 

  15. Levy-Marchal C, Jaquet D (2004) Long-term metabolic consequences of being born small for gestational age. Pediatr Diabetes 5:147–153

    Article  PubMed  Google Scholar 

  16. Hietakangas V, Cogen SM (2009) Regulation of tissue growth through nutrient sensing. Annu Rev Genet 43:389–410

    Article  CAS  PubMed  Google Scholar 

  17. Holemans K, Verhaeghe J, Dequeker J, Van Assche FA (1996) Insulin sensitivity in adult female rats subjected to malnutrition during the perinatal period. J Soc Gynecol Investig 3:71–77

    Article  CAS  PubMed  Google Scholar 

  18. Ozanne SE, Wang CL, Coleman N, Smith GD (1996) Altered muscle insulin sensitivity in the male offspring of protein-malnourished rats. Am J Physiol Endocrinol Metab 271:E1128–E1134

    CAS  Google Scholar 

  19. 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. J Endocrinol 177:235–241

    Article  CAS  PubMed  Google Scholar 

  20. Ozanne SE, Jensen CB, Tingey KJ, Storgaard H, Madsbad S, Vaag AA (2005) Low birthweight is associated with specific changes in muscle insulin-signaling protein expression. Diabetologia 48:547–552

    Article  CAS  PubMed  Google Scholar 

  21. Jensen CB, Martin-Gronert MS, Storgaard H, Madsbad S, Vaag A, Ozanne SE (2008) Altered PI3-Kinase/Akt signaling in skeletal muscle of young men with low birth weight. PLoS One 3:e3738

    Article  PubMed  CAS  Google Scholar 

  22. Edwards LJ, Simonetta G, Owens JA, Robinson JS, McMillen IC (1999) Restriction of placental and fetal growth in sheep alters fetal blood pressure responses to angiotensin II and captopril. J Physiol 515:897–904

    Article  CAS  PubMed  Google Scholar 

  23. Mc Millen IC, Adams MB, Ross JT, Coulter CL, Simonetta G, Owens JA, Robinson J, Edwards LJ (2001) Fetal growth restriction: adaptations and consequences. Reproduction 122:195–204

    Article  CAS  PubMed  Google Scholar 

  24. Morrison JL, Botting KJ, Dyer JL, Williams SJ, Thornburg KL, McMillen IC (2007) Restriction of placental function alters heart development in the sheep fetus. Am J Physiol Regul Integr Comp Physiol 293:R306–R313

    CAS  PubMed  Google Scholar 

  25. Morrison JL (2008) Sheep models of intrauterine growth restriction: fetal adaptations and consequences. Clin Exp Pharmacol Physiol 35:730–743

    Article  CAS  PubMed  Google Scholar 

  26. Muhlhausler BS, Duffield JA, Ozanne SE, Pilgrim C, Turner N, Morrison JL, McMillen IC (2009) The transition from fetal growth restriction to accelerated postnatal growth: a potential role for insulin signaling in skeletal muscle. J Physiol 587:4199–4211

    Article  CAS  PubMed  Google Scholar 

  27. De Blasio MJ, Gatford KL, McMillen IC, Robinson JS, Owens JA (2006) Placental restriction of fetal growth increases insulin action, growth and adiposity in the young lamb. Endocrinology 148:1350–1358

    Article  PubMed  CAS  Google Scholar 

  28. Beltrand J, Nicolescu R, Kaguelidou F, Verkauskiene R, Sibony O, Chevenne D, Claris O, Lévy-Marchal C (2009) Catch-up growth following fetal growth restriction promotes rapid restoration of fat mass but without metabolic consequences at one year of age. PLoS One 4:e5343

    Article  PubMed  CAS  Google Scholar 

  29. Hediger ML, Overpeck MD, Kuczmarski RJ, McGlynn A, Maurer KR, Davis WW (1998) Muscularity and fatness of infants and young children born small- or large-for-gestational-age. Pediatrics 102:e60

    Article  CAS  PubMed  Google Scholar 

  30. Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB (2000) Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 320:967–971

    Article  CAS  PubMed  Google Scholar 

  31. Law CM, Barker DJ, Osmond C, Fall CH, Simmonds SJ (1992) Early growth and abdominal fatness in adult life. J Epidemiol Community Health 46:184–186

    Article  CAS  PubMed  Google Scholar 

  32. Parsons TJ, Power C, Manor O (2001) Fetal and early life growth and body mass index from birth to early adulthood in 1958 British cohort: longitudinal study. BMJ 323:1331–1335

    Article  CAS  PubMed  Google Scholar 

  33. Yuen BS, McMillen IC, Symonds ME, Owens PC (1999) Abundance of leptin mRNA in fetal adipose tissue is related to fetal body weight. J Endocrinol 163:R11–R14

    Article  CAS  PubMed  Google Scholar 

  34. Yuen BS, Owens PC, McFarlane JR, Symonds ME, Edwards LJ, Kauter KG, McMillen IC (2002) Circulating leptin concentrations are positively related to leptin messenger RNA expression in the adipose tissue of fetal sheep in the pregnant ewe fed at or below maintenance energy requirements during late gestation. Biol Reprod 67:911–916

    Article  CAS  PubMed  Google Scholar 

  35. Yuen BSJ, 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 J 17:1102–1104

    CAS  PubMed  Google Scholar 

  36. Duffield JA, Vuocolo T, Tellam R, Yuen BS, Muhlhausler BS, McMillen IC (2008) Placental restriction of fetal growth decreases IGF1 and leptin mRNA expression in the perirenal adipose tissue of late gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 294:R1413–R1419

    CAS  PubMed  Google Scholar 

  37. Greenwood PL, Hunt AS, Hermanson JW, Bell AW (1998) Effects of birth weight and postnatal nutrition on neonatal sheep. I. Body growth and composition, and some aspects of energetic efficiency. J Anim Sci 76:2354–2367

    CAS  PubMed  Google Scholar 

  38. Poore KR, Fowden AL (2004) The effects of birth weight and postnatal growth patterns on fat depth and plasma leptin concentrations in juvenile and adult pigs. J Physiol 558:295–304

    Article  CAS  PubMed  Google Scholar 

  39. Louey S, Cock ML, Harding R (2005) Long term consequences of low birthweight on postnatal growth, adiposity and brain weight at maturity in sheep. J Reprod Dev 51:59–68

    Article  PubMed  Google Scholar 

  40. Holzenberger M, Hamard G, Zaoui R, Leneuve P, Ducos B, Beccavin C, Perin L, Le Bouc Y (2001) Experimental IGF-1 receptor deficiency generates a sexually dimorphic pattern of organ-specific growth deficits in mice, affecting fat tissue in particular. Endocrinology 142:4469–4478

    Article  CAS  PubMed  Google Scholar 

  41. Gregoire FM, Smas CM, Sul HS (1998) Understanding adipocyte differentiation. Physiol Rev 78:783–809

    CAS  PubMed  Google Scholar 

  42. Lefterova MI, Lazar MA (2009) New developments in adipogenesis. Trends Endocrinol Metab 20:107–114

    Article  CAS  PubMed  Google Scholar 

  43. Aouadi M, Laurent K, Prot M, Le Marchand-Brustel Y, Binetruy B, Bost F (2006) Inhibition of p38MAPK increases adipogenesis from embryonic to adult stages. Diabetes 55:281–289

    Article  CAS  PubMed  Google Scholar 

  44. Picard F, Auwerx J (2002) PPAR (gamma) and glucose homeostasis. Annu Rev Nutr 22:167–197

    Article  CAS  PubMed  Google Scholar 

  45. Jaquet D, Gaboriau A, Czernichow P, Levy-Marchal C (2001) Relatively low serum leptin levels in adults born with intra-uterine growth retardation. Int J Obes Relat Metab Disord 25:491–495

    Article  CAS  PubMed  Google Scholar 

  46. Leger J, Limoni C, Collin D, Czernichow P (1998) Prediction factors in the determination of final height in subjects born small for gestational age. Pediatr Res 43:808–812

    Article  CAS  PubMed  Google Scholar 

  47. Duffield JA, Vuocolo T, Tellam R, McFarlane JR, Kauter KG, Muhlhausler BS, McMillen IC (2009) Intrauterine growth restriction and the sex specific programming of leptin and peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA expression in visceral fat in the lamb. Pediatr Res 66:59–65

    Article  CAS  PubMed  Google Scholar 

  48. Sampath H, Ntambi JM (2005) Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu Rev Nutr 25:317–340

    Article  CAS  PubMed  Google Scholar 

  49. Ailhaud G, Amri EZ, Grimaldi PA (1995) Fatty acids and adipose cell differentiation. Prostaglandins Leukot Essent Fatty Acids 52:113–115

    Article  CAS  PubMed  Google Scholar 

  50. He W, Barak Y, Hevener A, Olson P, Liao D, Le J, Nelson M, Ong E, Olefsky JM, Evans RM (2003) Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA 100:15712–15717

    Article  CAS  PubMed  Google Scholar 

  51. Simmons RA, Templeton LJ, Gertz SJ (2001) Intrauterine growth retardation leads to the development of type 2 diabetes in the rat. Diabetes 50:2279–2286

    Article  CAS  PubMed  Google Scholar 

  52. Lane RH, MacLennan NK, Hsu JL, Janke SM, Pham TD (2002) Increased hepatic peroxisome proliferator-activated receptor-γ coactivator-1 gene expression in a rat model of intrauterine growth retardation and subsequent insulin resistance. Endocrinology 143:2486–2490

    Article  CAS  PubMed  Google Scholar 

  53. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138

    Article  CAS  PubMed  Google Scholar 

  54. 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. J Clin Invest 101:2174–2181

    Article  CAS  PubMed  Google Scholar 

  55. Gentili S, Morrison JL, McMillen IC (2009) Intrauterine growth restriction and differential patterns of hepatic growth and expression of IGF1, PCK2, and HSDL1 mRNA in the sheep fetus in late gestation. Biol Reprod 80:1121–1127

    Article  CAS  PubMed  Google Scholar 

  56. Postic C, Leturque A, Printz P, Maulard M, Loizeau M, Granner DK, Girard J (1994) Development and regulation of glucose transporter and hexokinase expression in rat. Am J Physiol 266:E548–E559

    CAS  PubMed  Google Scholar 

  57. Santalucia T, Camps M, Castello A, Munoz P, Nuel A, Testar X, Palacin M, Zorzano A (1992) Developmental regulation of GLUT-1 (erythroid/Hep G2) and GLUT-4 (muscle/fat) glucose transporter expression in rat heart, skeletal muscle, and brown adipose tissue. Endocrinology 130:837–846

    Article  CAS  PubMed  Google Scholar 

  58. Werner H, Adamo M, Lowe WLJ, Roberts CTJ, LeRoith D (1989) Developmental regulation of rat brain/Hep G2 glucose transporter gene expression. Mol Endocrinol 3:273–279

    Article  CAS  PubMed  Google Scholar 

  59. Leturque A, Postic C, Ferre P, Girard J (1991) Nutritional regulation of glucose transporter in muscle and adipose tissue of weaned rats. Am J Physiol 260:E588–E593

    CAS  PubMed  Google Scholar 

  60. Forhead AJ, Poore KR, Mapstone J, Fowden AL (2003) Developmental regulation of hepatic and renal gluconeogenic enzymes by thyroid hormones in fetal sheep during late gestation. J Physiol 548:941–947

    Article  CAS  PubMed  Google Scholar 

  61. Franko KL, Giussani DA, Forhead AJ, Fowden AL (2007) Effects of dexamethasone on the glucogenic capacity of fetal, pregnant, and non-pregnant adult sheep. J Endocrinol 192:67–73

    Article  CAS  PubMed  Google Scholar 

  62. Hales CN, Barker DJP (2001) The thrifty phenotype hypothesis. Br Med Bull 60:5–20

    Article  CAS  PubMed  Google Scholar 

  63. Neel JV (1962) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 14:353–362

    CAS  PubMed  Google Scholar 

  64. Neel JV (1999) The “thrifty genotype” in 1998. Nutr Rev 57:S2–S9

    Article  CAS  PubMed  Google Scholar 

  65. Bateson P, Barker D, Clutton-Brock T, Debal D, D'Udine B, Foley R, Gluckman P, Godfrey K, Kirkwood T, Lahr M, McNamara J, Metcalfe N, Monaghan P, Spencer H, Sultani S (2004) Developmental plasticity and human health. Nature 430:419–421

    Article  CAS  PubMed  Google Scholar 

  66. Gluckman PD, Hanson MA (2004) The developmental origins of the metabolic syndrome. Trends Endocrinol Metab 15:183–187

    Article  CAS  PubMed  Google Scholar 

  67. Waterland RA, Jirtle RL (2004) Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 20:63–68

    Article  CAS  PubMed  Google Scholar 

  68. Pandey AK, Agarwal P, Kaur K, Datta M (2009) MicroRNAs in diabetes: tiny players in big disease. Cell Physiol Biochem 23:221–232

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sansom Institute of Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5001, Australia

    Janna L. Morrison, Jaime A. Duffield, Beverly S. Muhlhausler, Sheridan Gentili & Isabella C. McMillen

Authors
  1. Janna L. Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaime A. Duffield
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beverly S. Muhlhausler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sheridan Gentili
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabella C. McMillen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isabella C. McMillen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morrison, J.L., Duffield, J.A., Muhlhausler, B.S. et al. Fetal growth restriction, catch-up growth and the early origins of insulin resistance and visceral obesity. Pediatr Nephrol 25, 669–677 (2010). https://doi.org/10.1007/s00467-009-1407-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-009-1407-3

Keywords

Search

Navigation