Maternal hyperinsulinemia predisposes rat fetuses for hyperinsulinemia, and adult-onset obesity and maternal mild food restriction reverses this phenotype

Srinivasan, Malathi; Aalinkeel, Ravikumar; Song, Fei; Mitrani, Paul; Pandya, Jignesh D.; Strutt, Brenda; Hill, David J.; Patel, Mulchand S.

doi:10.1152/ajpendo.00248.2005

Cited by 71 publications

(43 citation statements)

References 35 publications

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“…By 6 months the males showed frank diabetes with fasting hyperglycemia, reduced fasting plasma insulin, and reduced pancreatic insulin content, indicative of beta cell exhaustion, as reported previously in offspring of rats fed a lard-rich diet. 38 It remains to be determined whether fetal and neonatal pancreatic development is compromised, as shown by others, in neonates of dams fed a fat-rich diet 39 or whether this occurs as a result of offspring adiposity.…”

Section: Discussionmentioning

confidence: 99%

Diet-Induced Obesity in Female Mice Leads to Offspring Hyperphagia, Adiposity, Hypertension, and Insulin Resistance

et al. 2008

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Abstract-Maternal obesity is increasingly prevalent and may affect the long-term health of the child. We investigated the effects of maternal diet-induced obesity in mice on offspring metabolic and cardiovascular function. Female C57BL/6J mice were fed either a standard chow (3% fat, 7% sugar) or a palatable obesogenic diet (16% fat, 33% sugar) for 6 weeks before mating and throughout pregnancy and lactation. Offspring of control (OC) and obese dams (OO) were weaned onto standard chow and studied at 3 and 6 months of age. OO were hyperphagic from 4 to 6 weeks of age compared with OC and at 3 months locomotor activity was reduced and adiposity increased (abdominal fat pad mass; PϽ0.01). OO were heavier than OC at 6 months (body weight, PϽ0.05). OO abdominal obesity was associated with adipocyte hypertrophy and altered mRNA expression of ␤-adrenoceptor 2 and 3, 11␤HSD-1, and PPAR-␥ 2. OO showed resistance artery endothelial dysfunction at 3 months, and were hypertensive, as assessed by radiotelemetry (nighttime systolic blood pressure at 6 months [ Key Words: obesity Ⅲ pregnancy Ⅲ developmental programming Ⅲ metabolic syndrome Ⅲ appetite Ⅲ blood pressure Ⅲ mouse O besity among women of reproductive age is presenting a critical challenge to health care. 29% of USA women aged 20 to 39 years are reported to be clinically obese 1 and there is serious concern in many European countries over the increasing obesity among young women. 2 While obesity is associated with increased risk of almost every common complication of pregnancy, obesity in the mother may play a direct role in transmission of an obesogenic and diabetogenic trait from generation to generation. Increasing evidence suggests that children born of pregnancies complicated by either obesity or related gestational diabetes mellitus (GDM) are at increased risk of obesity, impaired glucose tolerance, and other facets of the metabolic syndrome. 3 Animal models have proven invaluable in interrogation of associations between maternal diet and body composition and offspring phenotype. 4 Those studies which have addressed effects of maternal calorific excess, including several from our laboratory, have generally fed rats diets rich in animal fat. 4 -7 Because young women of reproductive age often consume excessive amounts of sugars as well as fats, 8 the relevance of a diet rich in fat alone is limited. In this study, we induced obesity by feeding mice a highly palatable diet rich in sugars and animal fat, and addressed the hypothesis that diet-induced obesity during pregnancy can transmit a propensity for adiposity, glucose intolerance, and cardiovascular dysfunction to the offspring. Obesity was induced in female mice and offspring cardiovascular and metabolic function

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Section: Discussionmentioning

confidence: 99%

Diet-Induced Obesity in Female Mice Leads to Offspring Hyperphagia, Adiposity, Hypertension, and Insulin Resistance

et al. 2008

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“…A mild dietary restriction reversed their HC phenotype and also prevented the development of the HC phenotype in their offspring [98].…”

Section: Alleviating Malprogramming By Diet or Drug?mentioning

confidence: 98%

Sexual dimorphism in environmental epigenetic programming

Gabory

Attig

Junien

2009

Molecular and Cellular Endocrinology

249

196

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The phenotype of an individual is the result of complex interactions between genotype and current, past and ancestral environment leading to a lifelong remodelling of our epigenomes. The vast majority of common diseases, including atherosclerosis, diabetes, osteoporosis, asthma, neuropsychological and autoimmune diseases, which often take root in early development, display some degree of sex bias, very marked in some cases. This bias could be explained by the role of sex chromosomes, the different regulatory pathways underlying sexual development of most organs and finally, lifelong fluctuating impact of sex hormones. A substantial proportion of dimorphic genes expression might be under the control of sex-specific epigenetic marks. Environmental factors such as social behaviour, nutrition or chemical compounds can influence, in a gender-related manner, these flexible epigenetic marks during particular spatiotemporal windows of life. Thus, finely tuned developmental program aspects, for each sex, may be more sensitive to specific environmental challenges, particularly during developmental programming and gametogenesis, but also throughout the individual's life under the influence of sex steroid hormones and/or sex chromosomes. An unfavourable programming could thus lead to various defects and different susceptibility to diseases between males and females. Recent studies suggest that this epigenetic programming could be sometimes transmitted to subsequent generations in a sex specific manner and lead to transgenerational effects (TGEs).This review summarizes the current understanding in the field of epigenetic programming and highlights the importance of studying both sexes in epidemiological protocols or dietary interventions both in humans and in experimental animal models.

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“…Early life is considered to be a critical ontogenic window when significant maturation of different organs occurs (Plagemann et al 1999, Waterland & Garza 1999. Therefore, nutritional disturbances occurring during this period can lead to the development of persistent effects lasting into adulthood (Bassett & Craig 1988, Plagemann et al 1999, Waterland & Garza 1999, Srinivasan et al 2006. Furthermore, results from previous studies supported the idea that fetal and/or neonatal nutrition, including nutritional alterations during the lactation period, could modulate the risks of developing adult obesity, diabetes, and cardiovascular diseases (Waterland & Garza 1999, Srinivasan et al 2006.…”

Section: Discussionmentioning

confidence: 88%

Early overnutrition impairs insulin signaling in the heart of adult Swiss mice

Renovato-Martins¹,

Vieira²,

Souza³

et al. 2008

Journal of Endocrinology

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Human overnutrition has caused a rise in the prevalence of obesity in recent years. In addition to the deleterious effects of obesity during childhood, long-term effects in adulthood have been described as well. For instance, cardiovascular diseases and type 2 diabetes are among the diseases associated with a history of obesity. Altered insulin secretion and action have been described as important links between these diseases and obesity. Insulin acts as a unique anabolic hormone providing regulation of wholebody glucose homeostasis and peripheral tissue glucose uptake in tissues such as the heart. In this study, we examined insulin signaling in the heart of obese animals using an experimental model of inducing overweight adult animals by overnutrition in early life. In these animals, overfeeding during lactation was able to induce a significant increase in body weight starting at the 10th day of life, and this increased weight persisted until adulthood. Impairment in glucose tolerance, hyperinsulinemia, and an increased insulin/glucose ratio were also observed in these animals. Moreover, an increased heart weight/tibia length ratio was also observed, indicating an enlarged heart size. The overfed animals also had decreased insulin sensitivity in the heart, as confirmed by decreased insulin receptor (IR)-b and IR substrate-1 (Irs1) phosphorylation, increased phosphatase, non-receptor type 1 (Ptpn1)-IR-b association, decreased -Irs1-associated activity, and reduction in anti-phospho Akt1 phosphorylation. In conclusion, our findings showed that overnutrition during early life induced obesity and insulin resistance in the adult offspring, and further increased heart size and impaired cardiac insulin signaling, putatively due to an increase in Ptpn1 activity.

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Maternal hyperinsulinemia predisposes rat fetuses for hyperinsulinemia, and adult-onset obesity and maternal mild food restriction reverses this phenotype

Cited by 71 publications

References 35 publications

Diet-Induced Obesity in Female Mice Leads to Offspring Hyperphagia, Adiposity, Hypertension, and Insulin Resistance

Diet-Induced Obesity in Female Mice Leads to Offspring Hyperphagia, Adiposity, Hypertension, and Insulin Resistance

Sexual dimorphism in environmental epigenetic programming

Early overnutrition impairs insulin signaling in the heart of adult Swiss mice

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