Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats

Thanuja Gali Ramamoorthy,Charlotte Sefton,Erika Harno,Christopher Murgatroyd,Anne White,Tiffany-Jayne Allen,Alison Davies

doi:10.1038/s41366-018-0094-1

Abstract

Background and objectiveMaternal overnutrition has been implicated in affecting the offspring by programming metabolic disorders such as obesity and diabetes, by mechanisms that are not clearly understood. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring’s hypothalamic Pomc gene, coding a key factor in the control of energy balance. Further, it aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition.MethodsEight-week-old female Sprague–Dawley rats were fed HF diet or low-fat (LF) diet for 6 weeks before mating, and throughout gestation and lactation. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet.ResultsWith maternal HF diet, offspring at weaning had rapid early weight gain, increased adiposity, and hyperleptinemia. The programmed adult offspring, subsequently fed LF diet, retained the increased body weight. Maternal HF diet combined with offspring HF diet caused more pronounced hyperphagia, fat mass, and insulin resistance. The ARC Pomc gene from programmed offspring at weaning showed hypermethylation in the enhancer (nPE1 and nPE2) regions and in the promoter sequence mediating leptin effects. Interestingly, hypermethylation at the Pomc promoter but not at the enhancer region persisted long term into adulthood in the programmed offspring. However, there were no additive effects on methylation levels in the regulatory regions of Pomc in programmed offspring fed a HF diet.ConclusionMaternal overnutrition programs long-term epigenetic alterations in the offspring’s hypothalamic Pomc promoter. This predisposes the offspring to metabolic disorders later in life.

Highlights

The prevalence of obesity and other associated metabolic disorders has markedly increased globally, resulting from a Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.complex interaction between multiple factors including genetic, physiological, behavioral and environmental influences
Data from epidemiological and animal studies have suggested that susceptibility to metabolic disorders such as obesity, diabetes, and cardiovascular disease in adulthood can be influenced by early life environment [1]
Energy homeostasis is regulated by neurohormonal signals, which are directly related to nutritional state, especially leptin, a key hormone acting on POMC and neuropeptide Y (NPY) neurons [10, 11]

Summary

Introduction

The hypothalamic neuropeptides produced by neurons located in the Arcuate nucleus (ARC) have a key role in energy balance regulation [5, 6]. Energy homeostasis is regulated by neurohormonal signals, which are directly related to nutritional state, especially leptin, a key hormone acting on POMC and NPY neurons [10, 11]. This study aimed to determine the long-term impact of maternal high-fat (HF) diet feeding on epigenetic changes in the offspring’s hypothalamic Pomc gene, coding a key factor in the control of energy balance. It aimed to study the additional effects of postnatal overnutrition on epigenetic programming by maternal nutrition. At postnatal day 21, samples were collected from a third offspring and the remainder were weaned onto LF diet for 5 weeks, after which they were either fed LF or HF diet for 12 weeks, resulting in four groups of offspring differing by their maternal and postweaning diet

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