Maternal Obesity and Developmental Programming of Metabolic Disorders in Offspring: Evidence from Animal Models

The incidence of obesity and overweight has reached epidemic proportions in the developed world as well as in those countries transitioning to first world economies, and this represents a major global health problem. Concern is rising over the rapid increases in childhood obesity and metabolic disease that will translate into later adult obesity. Although an obesogenic nutritional environment and increasingly sedentary lifestyle contribute to our risk of developing obesity, a growing body of evidence links early life nutritional adversity to the development of long-term metabolic disorders. In particular, the increasing prevalence of maternal obesity and excess maternal weight gain has been associated with a heightened risk of obesity development in offspring in addition to an increased risk of pregnancy-related complications. The mechanisms that link maternal obesity to obesity in offspring and the level of gene-environment interactions are not well understood, but the early life environment may represent a critical window for which intervention strategies could be developed to curb the current obesity epidemic. This paper will discuss the various animal models of maternal overnutrition and their importance in our understanding of the mechanisms underlying altered obesity risk in offspring.

[1]  L. Gregerson.  Environmental , 2020, Modern Pathology.

[2]  M. Morris,et al.  Interaction between maternal obesity and post-natal over-nutrition on skeletal muscle metabolism. , 2012, Nutrition, metabolism, and cardiovascular diseases : NMCD.

[3]  T. Moran,et al.  Maternal stress and high-fat diet effect on maternal behavior, milk composition, and pup ingestive behavior , 2011, Physiology & Behavior.

[4]  D. Stoffers,et al.  Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat , 2011, Diabetologia.

[5]  Xu Yan,et al.  Maternal Obesity-Impaired Insulin Signaling in Sheep and Induced Lipid Accumulation and Fibrosis in Skeletal Muscle of Offspring1 , 2011, Biology of reproduction.

[6]  B. Muhlhausler,et al.  Maternal “junk‐food” feeding of rat dams alters food choices and development of the mesolimbic reward pathway in the offspring , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  K. Rooney,et al.  Maternal over-nutrition and offspring obesity predisposition: targets for preventative interventions , 2011, International Journal of Obesity.

[8]  Keith M. Godfrey,et al.  Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity , 2011, Diabetes.

[9]  R. Godschalk,et al.  Effects of Maternal Exposure to Cow's Milk High or Low in Isoflavones on Carcinogen-Induced Mammary Tumorigenesis among Rat Offspring , 2011, Cancer Prevention Research.

[10]  T. Bale,et al.  Maternal high-fat diet effects on third-generation female body size via the paternal lineage. , 2011, Endocrinology.

[11]  K. Thornburg,et al.  Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition. , 2011, Endocrinology.

[12]  K. Rooney,et al.  A systematic review on animal models of maternal high fat feeding and offspring glycaemic control , 2011, International Journal of Obesity.

[13]  P. Nathanielsz,et al.  Maternal obesity eliminates the neonatal lamb plasma leptin peak , 2011, The Journal of physiology.

[14]  C. Newgard,et al.  Cafeteria Diet Is a Robust Model of Human Metabolic Syndrome With Liver and Adipose Inflammation: Comparison to High-Fat Diet , 2011, Obesity.

[15]  L. Poston,et al.  Obesity in Pregnancy: Implications for the Mother and Lifelong Health of the Child. A Consensus Statement , 2011, Pediatric Research.

[16]  D. Sloboda,et al.  A maternal high-fat diet in rat pregnancy reduces growth of the fetus and the placental junctional zone, but not placental labyrinth zone growth , 2011, Journal of Developmental Origins of Health and Disease.

[17]  C. Tessier,et al.  Hepatic and very low-density lipoprotein fatty acids in obese offspring of overfed dams. , 2010, Metabolism: clinical and experimental.

[18]  R. Simmons.  Epigenetics and maternal nutrition: nature v. nurture , 2010, Proceedings of the Nutrition Society.

[19]  J. Nadeau,et al.  Ancestral paternal genotype controls body weight and food intake for multiple generations. , 2010, Human molecular genetics.

[20]  C. Mandarim-de-Lacerda,et al.  Maternal high-fat intake predisposes nonalcoholic fatty liver disease in C57BL/6 offspring. , 2010, American journal of obstetrics and gynecology.

[21]  Mei J. Zhu,et al.  Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe. , 2010, American journal of physiology. Regulatory, integrative and comparative physiology.

[22]  Margaret J. Morris,et al.  Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring , 2010, Nature.

[23]  Luigi Bouchard,et al.  Leptin Gene Epigenetic Adaptation to Impaired Glucose Metabolism During Pregnancy , 2010, Diabetes Care.

[24]  M. Morris,et al.  Maternal Overnutrition Impacts Offspring Adiposity and Brain Appetite Markers‐Modulation by Postweaning Diet , 2010, Journal of neuroendocrinology.

[25]  A. B. Uthlaut,et al.  Different levels of overnutrition and weight gain during pregnancy have differential effects on fetal growth and organ development , 2010, Reproductive biology and endocrinology : RB&E.

[26]  P. Taylor,et al.  Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. , 2010, Journal of hepatology.

[27]  P. Nathanielsz,et al.  RAPID REPORT: Dietary intervention prior to pregnancy reverses metabolic programming in male offspring of obese rats , 2010, The Journal of physiology.

[28]  Sarah M. Williams,et al.  Changes in melanocortin expression and inflammatory pathways in fetal offspring of nonhuman primates fed a high-fat diet. , 2010, Endocrinology.

[29]  P. Taylor,et al.  Maternal obesity programmes offspring development of non-alcoholic fatty pancreas disease , 2010, Biochemical and biophysical research communications.

[30]  A. Nobre,et al.  Chronic Consumption of a High-Fat Diet during Pregnancy Causes Perturbations in the Serotonergic System and Increased Anxiety-Like Behavior in Nonhuman Primate Offspring , 2010, The Journal of Neuroscience.

[31]  P. Taylor,et al.  Evidence for Sympathetic Origins of Hypertension in Juvenile Offspring of Obese Rats , 2010, HYPERTENSION.

[32]  L. Poston,et al.  Maternal high‐fat feeding primes steatohepatitis in adult mice offspring, involving mitochondrial dysfunction and altered lipogenesis gene expression , 2009, Hepatology.

[33]  M. Oest,et al.  Intrauterine exposure to high saturated fat diet elevates risk of adult-onset chronic diseases in C57BL/6 mice. , 2009, Birth defects research. Part B, Developmental and reproductive toxicology.

[34]  P. Higgins,et al.  Feto-placental adaptations to maternal obesity in the baboon. , 2009, Placenta.

[35]  P. Taylor,et al.  Maternal Obesity Induced by Diet in Rats Permanently Influences Central Processes Regulating Food Intake in Offspring , 2009, PloS one.

[36]  C. Morrison,et al.  Maternal obesity is necessary for programming effect of high-fat diet on offspring. , 2009, American journal of physiology. Regulatory, integrative and comparative physiology.

[37]  M. Szyf.  Epigenetics, DNA methylation, and chromatin modifying drugs. , 2009, Annual review of pharmacology and toxicology.

[38]  L. Poston,et al.  Established diet-induced obesity in female rats leads to offspring hyperphagia, adiposity and insulin resistance , 2009, Diabetologia.

[39]  M. Hanson,et al.  Long-term maternal high-fat feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids and fatty liver in mice , 2009, British Journal of Nutrition.

[40]  Sarah M. Williams,et al.  Maternal high-fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. , 2009, The Journal of clinical investigation.

[41]  N. Stickland,et al.  Evidence that a maternal “junk food” diet during pregnancy and lactation can reduce muscle force in offspring , 2009, European journal of nutrition.

[42]  G. Howie,et al.  Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet , 2009, The Journal of physiology.

[43]  Christian U. Krägeloh,et al.  Prenatally undernourished rats show increased preference for wheel running v. lever pressing for food in a choice task , 2008, British Journal of Nutrition.

[44]  P. Gluckman,et al.  Predictive adaptive responses in perspective , 2008, Trends in Endocrinology & Metabolism.

[45]  T. Ørntoft,et al.  The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation , 2008, Diabetologia.

[46]  P. Taylor,et al.  Diet-Induced Obesity in Female Mice Leads to Offspring Hyperphagia, Adiposity, Hypertension, and Insulin Resistance: A Novel Murine Model of Developmental Programming , 2008, Hypertension.

[47]  A. El-Osta,et al.  Epigenetic regulation and fetal programming. , 2008, Best practice & research. Clinical endocrinology & metabolism.

[48]  J. Craigon,et al.  DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status , 2007, Proceedings of the National Academy of Sciences.

[49]  P. Taylor,et al.  In utero exposure to maternal obesity and diabetes: animal models that identify and characterize implications for future health. , 2007, Obstetrics and gynecology clinics of North America.

[50]  N. Stickland,et al.  A maternal 'junk food' diet in pregnancy and lactation promotes an exacerbated taste for 'junk food' and a greater propensity for obesity in rat offspring. , 2007, The British journal of nutrition.

[51]  Hong Zhou,et al.  Effect of milk on the 7,12-dimethylbenz[a]-anthracene-induced mammary tumor model in rat. , 2007, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[52]  S. Ho,et al.  Epigenetic reprogramming and imprinting in origins of disease , 2007, Reviews in Endocrine and Metabolic Disorders.

[53]  K. Godfrey,et al.  Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications , 2007, British Journal of Nutrition.

[54]  D. Iliopoulos,et al.  Epigenetic regulation of leptin affects MMP-13 expression in osteoarthritic chondrocytes: possible molecular target for osteoarthritis therapeutic intervention , 2007, Annals of the rheumatic diseases.

[55]  D. J. Barker.  The origins of the developmental origins theory , 2007, Journal of internal medicine.

[56]  S. Ho,et al.  Techniques used in studies of epigenome dysregulation due to aberrant DNA methylation: an emphasis on fetal-based adult diseases. , 2007, Reproductive toxicology.

[57]  R. Jirtle,et al.  Environmental epigenomics and disease susceptibility , 2007, Nature Reviews Genetics.

[58]  D. Barker.  Obesity and early life , 2007, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[59]  L. Poston,et al.  Developmental programming of obesity in mammals , 2007, Experimental physiology.

[60]  R. Stöger.  In Vivo Methylation Patterns of the Leptin Promoter in Human and Mouse , 2006, Epigenetics.

[61]  Karine Clément,et al.  Genetics of human obesity. , 2006, The Proceedings of the Nutrition Society.

[62]  I. Weaver,et al.  Maternal Care Associated with Methylation of the Estrogen Receptor-α1b Promoter and Estrogen Receptor-α Expression in the Medial Preoptic Area of Female Offspring , 2006 .

[63]  S. Langley-Evans,et al.  Exposure to undernutrition in fetal life determines fat distribution, locomotor activity and food intake in ageing rats , 2006, International Journal of Obesity.

[64]  P. Gluckman,et al.  Neonatal leptin treatment reverses developmental programming. , 2005, Endocrinology.

[65]  N. Stickland,et al.  A maternal cafeteria diet during gestation and lactation promotes adiposity and impairs skeletal muscle development and metabolism in rat offspring at weaning , 2005, The Journal of physiology.

[66]  D. Flint,et al.  Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland. , 2005, American journal of physiology. Endocrinology and metabolism.

[67]  M. Hanson,et al.  Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. , 2005, The Journal of nutrition.

[68]  P. Taylor,et al.  Developmental programming of aortic and renal structure in offspring of rats fed fat‐rich diets in pregnancy , 2005, The Journal of physiology.

[69]  P. Gluckman,et al.  Living with the Past: Evolution, Development, and Patterns of Disease , 2004, Science.

[70]  Imran Y. Khan,et al.  Predictive Adaptive Responses to Maternal High-Fat Diet Prevent Endothelial Dysfunction but Not Hypertension in Adult Rat Offspring , 2004, Circulation.

[71]  ImranKhan,et al.  Predictive Adaptive Responses to Maternal High-Fat Diet Prevent Endothelial Dysfunction but Not Hypertension in Adult Rat Offspring , 2004 .

[72]  Michael J Meaney,et al.  Epigenetic programming by maternal behavior , 2004, Nature Neuroscience.

[73]  P. Gluckman,et al.  Developmental Origins of Disease Paradigm: A Mechanistic and Evolutionary Perspective , 2004, Pediatric Research.

[74]  Y. S. Diniz,et al.  Toxicity of hypercaloric diet and monosodium glutamate: oxidative stress and metabolic shifting in hepatic tissue. , 2004, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[75]  P. Gluckman,et al.  Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[76]  Imran Y. Khan,et al.  Uterine Artery Function in Pregnant Rats Fed a Diet Supplemented with Animal Lard , 2003, Experimental physiology.

[77]  D. Stoffers,et al.  Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat. , 2003, Diabetes.

[78]  M. Wabitsch,et al.  Leptin Gene Expression in Human Preadipocytes Is Switched on by Maturation-induced Demethylation of Distinct CpGs in Its Proximal Promoter* , 2002, The Journal of Biological Chemistry.

[79]  K. Hofbauer.  Molecular pathways to obesity , 2002, International Journal of Obesity.

[80]  B. Breier,et al.  Fetal programming of appetite and obesity , 2001, Molecular and Cellular Endocrinology.

[81]  A. Parent,et al.  Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites , 2001, Molecular and Cellular Endocrinology.

[82]  M. Bartolomei,et al.  Differential Effects of Culture on Imprinted H19 Expression in the Preimplantation Mouse Embryo1 , 2000, Biology of reproduction.

[83]  D J Barker,et al.  Fetal nutrition and adult disease. , 2000, The American journal of clinical nutrition.

[84]  C Osmond,et al.  Obesity at the age of 50 y in men and women exposed to famine prenatally. , 1999, The American journal of clinical nutrition.

[85]  T. Onaya,et al.  DNA demethylation during the differentiation of 3T3-L1 cells affects the expression of the mouse GLUT4 gene. , 1999, Diabetes.

[86]  J. Prieto,et al.  Transformed but not normal hepatocytes express UCP2 , 1998, FEBS letters.

[87]  J. Flier,et al.  Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. , 1998, The Journal of clinical investigation.

[88]  K. Jen,et al.  High-fat feeding during pregnancy and lactation affects offspring metabolism in rats , 1995, Physiology & Behavior.

[89]  H. Mcgill,et al.  Preweaning food intake influences the adiposity of young adult baboons. , 1986, The Journal of clinical investigation.

[90]  Y. Ma,et al.  Maternal obesity in ewes results in reduced fetal pancreatic β-cell numbers in late gestation and decreased circulating insulin concentration at term. , 2011, Domestic animal endocrinology.

[91]  J. Ordovás,et al.  Nutrition, metabolism and cardiovascular disease , 2011 .

[92]  Vuk Vrhovac.  THE METABOLIC SYNDROME – AN ONGOING STORY , 2010 .

[93]  M. Davison,et al.  Moderate daily exercise activates metabolic flexibility to prevent prenatally induced obesity. , 2009, Endocrinology.

[94]  M. Morris,et al.  Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth , 2009, International Journal of Obesity.

[95]  I. Weaver,et al.  Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. , 2006, Endocrinology.

[96]  T. Onaya,et al.  DNA demethylation modulates mouse leptin promoter activity during the differentiation of 3T3-L1 cells , 2002, Diabetologia.