The Developmental Mechanisms of Obesity by Maternal Obesity

  • Long T. NguyenEmail author
  • Carol A. Pollock
  • Sonia Saad
Part of the Advances in Biochemistry in Health and Disease book series (ABHD, volume 19)


Obesity is a major global concern due to its alarming prevalence and associated risks for multiple diseases. The rate of obesity has nearly tripled in the last four decades and amounting evidence is implying a critical role of developmental factors before, during and after pregnancy in promoting this global pandemic. Maternal obesity in particular has been associated with large-for-gestational age babies and increased risk of obesity in adulthood, thus generating a vicious cycle. Studies in animal models demonstrated that such effects of maternal obesity can be detected in the offspring across up to three generations, suggesting a profound transgenerational impact. This chapter will discuss critical windows for developmental programming of obesity and possible mechanisms involved such as oxidative stress, mitochondrial dysfunction, placental insults, intrauterine overnutrition, appetite dysregulation and microbiome. A special focus will be put on epigenetic regulation and the role of sirtuins, which have been suggested to play a central role in the metabolic programming process. Finally, the prospective of intervention therapies for maternal obesity-induced developmental programming will be briefly discussed.


Obesity Metabolic disorders Pregnancy Developmental programming Epigenetic Sirtuin 


  1. 1.
    Barker DJ, Osmond C (1986) Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1(8489):1077–1081PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Barker DJ et al (1989) Weight in infancy and death from ischaemic heart disease. Lancet 2(8663):577–580PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Lucas A (1991) Programming by early nutrition in man. Child Environ Adult Dis 1991:38–55Google Scholar
  4. 4.
    Black RE et al (2013) Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet 382(9890):9427–9451Google Scholar
  5. 5.
    Padmanabhan V, Cardoso RC, Puttabyatappa M (2016) Developmental programming, a pathway to disease. Endocrinology 157(4):1328–1340PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Fullston T et al (2013) Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J 27(10):4226–4243PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Linabery AM et al (2013) Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the F els L ongitudinal S tudy. Pediatric obesity 8(3):159–169PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Shankar K et al (2011) Maternal obesity promotes a proinflammatory signature in rat uterus and blastocyst. Endocrinology 152(11):4158–4170PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Jungheim ES et al (2010) Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring. Endocrinology 151(8):4039–4046PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Shah DK et al (2010) Oocyte and embryo quality in obese patients undergoing in vitro fertilization (IVF). Fertil Steril 94(4):S51CrossRefGoogle Scholar
  11. 11.
    Zhang L et al (2015) Sirt3 prevents maternal obesity-associated oxidative stress and meiotic defects in mouse oocytes. Cell Cycle 14(18):2959–2968PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Wang H et al (2018) Loss of TIGAR induces oxidative stress and meiotic defects in oocytes from obese mice. Mol Cell Proteomics 17(7):1354–1364PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Han L et al (2018) Embryonic defects induced by maternal obesity in mice derive from Stella insufficiency in oocytes. Nat Genet 50(3):432–442PubMedCrossRefGoogle Scholar
  14. 14.
    Igosheva N et al (2010) Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS ONE 5(4):e10074PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Dokras A et al (2006) Obstetric outcomes after in vitro fertilization in obese and morbidly obese women. Obstet Gynecol 108(1):61–69PubMedCrossRefGoogle Scholar
  16. 16.
    Leary C, Leese HJ, Sturmey RG (2014) Human embryos from overweight and obese women display phenotypic and metabolic abnormalities. Hum Reprod 30(1):122–132PubMedCrossRefGoogle Scholar
  17. 17.
    Taylor PD et al (2005) Impaired glucose homeostasis and mitochondrial abnormalities in offspring of rats fed a fat-rich diet in pregnancy. Am J Physiol-Regul Integr Comp Physiol 288(1):R134–R139PubMedCrossRefGoogle Scholar
  18. 18.
    Zhang L et al (2015) Sirt3 prevents maternal obesity-associated oxidative stress and meiotic defects in mouse oocytes. Cell Cycle 14:2959–2968PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Wu LL et al (2015) Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors. Development 142(4):681–691PubMedCrossRefGoogle Scholar
  20. 20.
    Saben JL et al (2016) Maternal metabolic syndrome programs mitochondrial dysfunction via germline changes across three generations. Cell Reports 16(1):1–8PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Liang C, DeCourcy K, Prater MR (2010) High–saturated-fat diet induces gestational diabetes and placental vasculopathy in C57BL/6 mice. Metabolism 59(7):943–950PubMedCrossRefGoogle Scholar
  22. 22.
    Li H-P, Chen X, Li M-Q (2013) Gestational diabetes induces chronic hypoxia stress and excessive inflammatory response in murine placenta. Int J Clin Exp Pathol 6(4):650PubMedPubMedCentralGoogle Scholar
  23. 23.
    Zhu MJ et al (2010) Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe. Am J Physiol-Regul Integr Comp Physiol 299(5):R1224–R1231PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Saben J et al (2014) Maternal obesity is associated with a lipotoxic placental environment. Placenta 35(3):171–177PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Jones HN et al (2009) High-fat diet before and during pregnancy causes marked up-regulation of placental nutrient transport and fetal overgrowth in C57/BL6 mice. FASEB J 23(1):271–278PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Magnusson-Olsson A et al (2006) Gestational and hormonal regulation of human placental lipoprotein lipase. J Lipid Res 47(11):2551–2561PubMedCrossRefGoogle Scholar
  27. 27.
    Qiao L et al (2015) Maternal high fat feeding increases placenta lipoprotein lipase activity by reducing Sirt1 expression in mice. Diabetes 64(9):3111–3120PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Heerwagen MJ et al (2010) Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am J Physiol-Regul Integr Comp Physiol 299(3):R711–R722PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Vega CC et al (2015) Exercise in obese female rats has beneficial effects on maternal and male and female offspring metabolism. Int J Obes (Lond) 39(4):712–719CrossRefGoogle Scholar
  30. 30.
    Catalano P (2015) Maternal obesity and metabolic risk to the offspring: why lifestyle interventions may have not achieved the desired outcomes. Int J Obes 39(4):642CrossRefGoogle Scholar
  31. 31.
    Shankar K et al (2008) Maternal obesity at conception programs obesity in the offspring. Am J Physiol-Regul Integr Comp Physiol 294(2):R528–R538PubMedCrossRefGoogle Scholar
  32. 32.
    Oben JA et al (2010) Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. J Hepatol 52(6):913–920PubMedCrossRefGoogle Scholar
  33. 33.
    Sun B et al (2012) Maternal high-fat diet during gestation or suckling differentially affects offspring leptin sensitivity and obesity. Diabetes 61(11):2833–2841PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Desai M et al (2014) Maternal obesity and high-fat diet program offspring metabolic syndrome. Am J Obstet Gynecol 211(3):237. e1–237. e13PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Rasmussen KM (2007) Association of maternal obesity before conception with poor lactation performance. Annu Rev Nutr 27:103–121PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Leonard SA et al (2011) Associations between high prepregnancy body mass index, breast-milk expression, and breast-milk production and feeding–. Am J Clin Nutr 93(3):556–563PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Saben JL et al (2014) Maternal obesity reduces milk lipid production in lactating mice by inhibiting acetyl-CoA carboxylase and impairing fatty acid synthesis. PLoS ONE 9(5):e98066PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Chen H, Morris MJ (2009) Differential responses of orexigenic neuropeptides to fasting in offspring of obese mothers. Obesity 17(7):1356–1362PubMedGoogle Scholar
  39. 39.
    Nguyen LT et al (2019) SIRT1 overexpression attenuates offspring metabolic and liver disorders as a result of maternal high-fat feeding. J Physiol 597(2):467–480PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Purcell RH et al (2011) Maternal stress and high-fat diet effect on maternal behavior, milk composition, and pup ingestive behavior. Physiol Behav 104(3):474–479PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Bautista CJ et al (2016) Changes in milk composition in obese rats consuming a high-fat diet. Br J Nutr 115(3):538–546PubMedCrossRefGoogle Scholar
  42. 42.
    Fields DA, Demerath EW (2012) Relationship of insulin, glucose, leptin, IL-6 and TNF-α in human breast milk with infant growth and body composition. Pediatric Obesity 7(4):304–312PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Isganaitis E et al (2019) Maternal obesity and the human milk metabolome: associations with infant body composition and postnatal weight gain. Am J Clin NutrGoogle Scholar
  44. 44.
    Brion MJ et al (2010) Maternal macronutrient and energy intakes in pregnancy and offspring intake at 10 y: exploring parental comparisons and prenatal effects. Am J Clin Nutr 91(3):748–756PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Morris MJ, Chen H (2009) Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth. Int J Obes 33(1):115CrossRefGoogle Scholar
  46. 46.
    Chang G-Q et al (2008) Maternal high-fat diet and fetal programming: increased proliferation of hypothalamic peptide-producing neurons that increase risk for overeating and obesity. J Neurosci 28(46):12107–12119PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Férézou-Viala J et al (2007) Long-term consequences of maternal high-fat feeding on hypothalamic leptin sensitivity and diet-induced obesity in the offspring. Am J Physiol-Regul Integr Comp Physiol 293(3):R1056–R1062PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Page KC et al (2009) Maternal and postweaning diet interaction alters hypothalamic gene expression and modulates response to a high-fat diet in male offspring. Am J Physiol-Regul Integr Comp Physiol 297(4):R1049–R1057PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Chen H et al (2008) Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism. Endocrinology 149(11):5348–5356PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Schuster S et al (2011) Leptin in maternal serum and breast milk: association with infants’ body weight gain in a longitudinal Study over 6 months of lactation. Pediatr Res 70:633PubMedCrossRefGoogle Scholar
  51. 51.
    Suter MA et al (2012) A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J 26(12):5106–5114PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Borengasser SJ et al (2014) High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring. PLoS ONE 9(1):e84209PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Suter MA et al (2014) In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model. Am J Obstet Gynecol 210(5):463. e1–463. e11PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Osorio JS et al (2013) Effect of the level of maternal energy intake prepartum on immunometabolic markers, polymorphonuclear leukocyte function, and neutrophil gene network expression in neonatal Holstein heifer calves1. J Dairy Sci 96(6):3573–3587PubMedCrossRefGoogle Scholar
  55. 55.
    Friedman JE (2018) Developmental programming of obesity and diabetes in mouse, monkey, and man in 2018: where are we headed? Diabetes 67(11):2137–2151PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Yu H-L et al (2015) Global DNA methylation was changed by a maternal high-lipid, high-energy diet during gestation and lactation in male adult mice liver. Br J Nutr 113(7):1032–1039PubMedCrossRefGoogle Scholar
  57. 57.
    Seki Y et al (2017) In utero exposure to a high-fat diet programs hepatic hypermethylation and gene dysregulation and development of metabolic syndrome in male mice. Endocrinology 158(9):2860–2872PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Michels KB, Harris HR, Barault L (2011) Birthweight, maternal weight trajectories and global DNA methylation of LINE-1 repetitive elements. PLoS ONE 6(9):e25254PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Benatti R et al (2014) Maternal high-fat diet consumption modulates hepatic lipid metabolism and microRNA-122 (miR-122) and microRNA-370 (miR-370) expression in offspring. Br J Nutr 111(12):2112–2122PubMedCrossRefGoogle Scholar
  60. 60.
    Yan X et al (2013) Maternal obesity downregulates microRNA let-7g expression, a possible mechanism for enhanced adipogenesis during ovine fetal skeletal muscle development. Int J Obes 37(4):568CrossRefGoogle Scholar
  61. 61.
    Fernandez-Twinn DS et al (2014) Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms. Mol Metab 3(3):325–333PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Laker RC et al (2014) Exercise prevents maternal high-fat diet–induced hypermethylation of the Pgc-1α gene and age-dependent metabolic dysfunction in the offspring. Diabetes 63(5):1605–1611PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lesseur C et al (2013) Tissue-specific Leptin promoter DNA methylation is associated with maternal and infant perinatal factors. Mol Cell Endocrinol 381(1–2):160–167PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Sharp GC et al (2015) Maternal pre-pregnancy BMI and gestational weight gain, offspring DNA methylation and later offspring adiposity: findings from the Avon Longitudinal Study of Parents and Children. Int J Epidemiol 44(4):1288–1304PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Miller C et al (2011) The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion. Biochimica et Biophysica Acta (BBA)-Mol Basis Dis 1812(5):625–629CrossRefGoogle Scholar
  66. 66.
    Obermann-Borst SA et al (2013) Duration of breastfeeding and gender are associated with methylation of the LEPTIN gene in very young children. Pediatr Res 74(3):344PubMedCrossRefGoogle Scholar
  67. 67.
    Skinner MK (2008) What is an epigenetic transgenerational phenotype?: F3 or F2. Reprod Toxicol 25(1):2–6PubMedCrossRefGoogle Scholar
  68. 68.
    Tsoulis MW et al (2016) Maternal high-fat diet-induced loss of fetal oocytes is associated with compromised follicle growth in adult rat offspring. Biol Reprod 94(4):94, 1–11Google Scholar
  69. 69.
    Cheong Y et al (2014) Diet-induced maternal obesity alters ovarian morphology and gene expression in the adult mouse offspring. Fertil Steril 102(3):899–907PubMedCrossRefGoogle Scholar
  70. 70.
    Masuyama H et al (2015) The effects of high-fat diet exposure in utero on the obesogenic and diabetogenic traits through epigenetic changes in adiponectin and leptin gene expression for multiple generations in female mice. Endocrinology 156(7):2482–2491PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Chang H-C, Guarente L (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab 25(3):138–145PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Gao Z et al (2011) Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. J Biol Chem 286(25):22227–22234PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    dos Santos Costa C et al (2010) SIRT1 transcription is decreased in visceral adipose tissue of morbidly obese patients with severe hepatic steatosis. Obes Surg 20(5):633–639CrossRefGoogle Scholar
  74. 74.
    Çakir I et al (2009) Hypothalamic Sirt1 regulates food intake in a rodent model system. PLoS ONE 4(12):e8322PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Hasegawa K et al (2013) Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat Med 19(11):1496–1504PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lappas M et al (2011) SIRT1 is a novel regulator of key pathways of human labor. Biol Reprod 84(1):167–178PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Kawamura Y et al (2010) Sirt3 protects in vitro–fertilized mouse preimplantation embryos against oxidative stress–induced p53-mediated developmental arrest. J Clin Investig 120(8):2817PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Borengasser SJ et al (2011) Maternal obesity during gestation impairs fatty acid oxidation and mitochondrial SIRT3 expression in rat offspring at weaning. PLoS ONE 6(8):e24068PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Di Emidio G et al (2014) SIRT1 signalling protects mouse oocytes against oxidative stress and is deregulated during aging. Hum Reprod 29(9):2006–2017PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Nguyen LT et al (2018) SRT1720 attenuates obesity and insulin resistance but not liver damage in the offspring due to maternal and postnatal high-fat diet consumption. Am J Physiol-Endocrinol Metab 315(2):E196–E203PubMedCrossRefGoogle Scholar
  81. 81.
    Uddin GM et al (2017) Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Sci Rep 7(1):15063PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Nguyen LT et al (2017) SIRT1 reduction is associated with sex-specific dysregulation of renal lipid metabolism and stress responses in offspring by maternal high-fat diet. Sci Rep 7(1):8982PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Nguyen LT et al (2019) SIRT1 attenuates kidney disorders in male offspring due to maternal high-fat diet. Nutrients 11(1):146PubMedCentralCrossRefGoogle Scholar
  84. 84.
    Jain AP et al (2013) The impact of interpregnancy weight change on birthweight in obese women. Am J Obstet Gynecol 208(3):205. e1–205. e7CrossRefGoogle Scholar
  85. 85.
    Oteng-Ntim E et al (2018) Interpregnancy weight change and adverse pregnancy outcomes: a systematic review and meta-analysis. BMJ Open 8(6):e018778PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Zambrano E et al (2010) RAPID REPORT: dietary intervention prior to pregnancy reverses metabolic programming in male offspring of obese rats. J Physiol 588(10):1791–1799PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Willmer M et al (2013) Surgically induced interpregnancy weight loss and prevalence of overweight and obesity in offspring. PLoS ONE 8(12):e82247PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Berglind D et al (2014) Differences in gestational weight gain between pregnancies before and after maternal bariatric surgery correlate with differences in birth weight but not with scores on the body mass index in early childhood. Pediatr Obes 9(6):427–434PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Long T. Nguyen
    • 1
    Email author
  • Carol A. Pollock
    • 1
  • Sonia Saad
    • 1
  1. 1.Renal Medicine, Kolling Institute Level 9Royal North Shore Hospital, The University of SydneySt. LeonardAustralia

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