Abstract

BackgroundIntrauterine and postnatal overnutrition program hyperphagia, adiposity and glucose intolerance in offspring. Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene have been linked to increased risk of obesity. FTO is highly expressed in hypothalamic regions critical for energy balance and hyperphagic phenotypes were linked with FTO SNPs. As nutrition during fetal development can influence the expression of genes involved in metabolic function, we investigated the impact of maternal obesity on FTO.MethodsFemale Sprague Dawley rats were exposed to chow or high fat diet (HFD) for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1 (PND1), some litters were adjusted to 3 pups (vs. 12 control) to induce postnatal overnutrition. At PND20, rats were weaned onto chow or HFD for 15 weeks. FTO mRNA expression in the hypothalamus and liver, as well as hepatic markers of lipid metabolism were measured.ResultsAt weaning, hypothalamic FTO mRNA expression was increased significantly in offspring of obese mothers and FTO was correlated with both visceral and epididymal fat mass (P<0.05); body weight approached significance (P = 0.07). Hepatic FTO and Fatty Acid Synthase mRNA expression were decreased by maternal obesity. At 18 weeks, FTO mRNA expression did not differ between groups; however body weight was significantly correlated with hypothalamic FTO. Postnatal HFD feeding significantly reduced hepatic Carnitine Palmitoyltransferase-1a but did not affect the expression of other hepatic markers investigated. FTO was not affected by chronic HFD feeding.SignificanceMaternal obesity significantly impacted FTO expression in both hypothalamus and liver at weaning. Early overexpression of hypothalamic FTO correlated with increased adiposity and later food intake of siblings exposed to HFD suggesting upregulation of FTO may contribute to subsequent hyperphagia, in line with some human data. No effect of maternal obesity was observed on FTO in adulthood.

Highlights

  • Obesity rates are rising dramatically around the globe and its consequences represent a major public health concern [1]

  • Overexpression of hypothalamic fat mass and obesity associated (FTO) correlated with increased adiposity and later food intake of siblings exposed to high fat diet (HFD) suggesting upregulation of FTO may contribute to subsequent hyperphagia, in line with some human data

  • FTO mRNA at weaning was significantly correlated with both visceral (P = 0.005; n = 30; r = 0.459) and epididymal (P = 0.005; n = 30; r = 0.476; Fig. 4 A and B) fat mass; the relationship with body weight approached significance (P = 0.07; n = 30; r = 0.333)

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Summary

Introduction

Obesity rates are rising dramatically around the globe and its consequences represent a major public health concern [1]. The intrauterine environment plays a key role and suboptimal maternal nutrition during gestation is implicated in the development of adult metabolic diseases. It is accepted that nutritional changes during fetal development can predispose individuals to obesity and metabolic disease in adult life, resetting the expression of genes involved in energy homeostasis and altering metabolic function [8,9,10,11]. Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene have been linked to increased risk of obesity. FTO is highly expressed in hypothalamic regions critical for energy balance and hyperphagic phenotypes were linked with FTO SNPs. As nutrition during fetal development can influence the expression of genes involved in metabolic function, we investigated the impact of maternal obesity on FTO

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