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Abstract
Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1–31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1–31 days gestation) or 50% nutritional requirements (104–127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development induces changes in mechanisms of lipid and glucose metabolism which differ between tissues and sexes dependent on the period of nutritional restriction. Such changes may increase later life obesity and dyslipidaemia risk.
Highlights
The worldwide incidence of obesity nearly doubled between 1980 and 2008, affecting both developed countries and developing societies that are undergoing socio-economic transition [1]
We have investigated epigenetic modifications of hepatic genes regulating metabolic homeostasis and body composition by measuring methylation of imprinting control regions (ICRs) of the insulin-like growth factor (IGF) 2/H19 and insulin-like growth factor-2 receptor (IGF2R) imprinted clusters and of the delta-like homolog 1 (DLK1)/ maternally expressed gene 3 (MEG3) imprinted cluster, which are involved in fetal and early postnatal growth and in adipocyte development, respectively, and have been linked with metabolic abnormalities and changes in adiposity [33,34,35]
The insulin-induced fall in non-esterified fatty acid (NEFA) output during glucose tolerance test (GTT) was reduced (p,0.05) at 2.5 years in sheep exposed to early gestation undernutrition, regardless of post-weaning nutrition (Fig. 1B)
Summary
The worldwide incidence of obesity nearly doubled between 1980 and 2008, affecting both developed countries and developing societies that are undergoing socio-economic transition [1]. Mid- and late-gestation exposure to the Dutch Famine reduced birth weight and glucose tolerance in adulthood, which worsened with obesity [5] while early gestation famine exposure did not affect birth weight, but increased coronary heart disease prevalence and atherogenic risk factors [6,7]. As well as investigating low birth weight and thinness at birth [13,14] it is clear that a range of possible developmental pathways to poor health in adulthood should be considered. These include the periconceptional and fetal periods and/or early postnatal infant life and beyond
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