Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring.

Madeline Rose Keleher,Ting Wang,Samir El Idrissi,Daofeng Li,Cassondra Pavlatos,James M Cheverud,Shyam Shah,Xiaoyun Xing,Rabab Zaidi,M Elsa Oakley

doi:10.1371/journal.pone.0192606

Madeline Rose Keleher, Ting Wang + Show 8 more

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https://doi.org/10.1371/journal.pone.0192606

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Abstract

We investigated maternal obesity in inbred SM/J mice by assigning females to a high-fat diet or a low-fat diet at weaning, mating them to low-fat-fed males, cross-fostering the offspring to low-fat-fed SM/J nurses at birth, and weaning the offspring onto a high-fat or low-fat diet. A maternal high-fat diet exacerbated obesity in the high-fat-fed daughters, causing them to weigh more, have more fat, and have higher serum levels of leptin as adults, accompanied by dozens of gene expression changes and thousands of DNA methylation changes in their livers and hearts. Maternal diet particularly affected genes involved in RNA processing, immune response, and mitochondria. Between one-quarter and one-third of differentially expressed genes contained a differentially methylated region associated with maternal diet. An offspring high-fat diet reduced overall variation in DNA methylation, increased body weight and organ weights, increased long bone lengths and weights, decreased insulin sensitivity, and changed the expression of 3,908 genes in the liver. Although the offspring were more affected by their own diet, their maternal diet had epigenetic effects lasting through adulthood, and in the daughters these effects were accompanied by phenotypic changes relevant to obesity and diabetes.

Highlights

A mother’s diet—from its fat and protein content to its richness in methyl donors while DNA methylation is being established in the developing fetus—can directly affect her offspring’s epigenome [1,2,3,4]
A general linear model showed that the weekly weights, diabetes-related traits, and necropsy traits were all significantly affected by maternal diet (F36,32 = 3.0, p = 0.001), offspring diet (F36,32 = 28.2, p = 4.17 x 10−16), sex (F36,32 = 18.4, p = 2.36 x 10−13), and an offspring-diet-by-sex interaction (F36,32 = 4.4, p = 3.0 x 10−5) (Table 1)
Independent of maternal diet, an offspring high-fat (HF) diet induced a vast array of changes in the SM/J mice: it increased body and organ weights; reduced sensitivity to insulin; increased the serum levels of leptin, insulin, triglycerides, glucose, and free fatty acids; increased the lengths and weights of the long bones; and changed the expression of 3,908 genes in the liver

Summary

Introduction

A mother’s diet—from its fat and protein content to its richness in methyl donors while DNA methylation is being established in the developing fetus—can directly affect her offspring’s epigenome [1,2,3,4]. Maternal diet is important to study since half of United States mothers have pre-pregnancy weights classifying them as overweight or obese [5]. Babies of obese women have a higher risk of stillbirth [6, 7], neural-tube defects [8, 9], and are born with more body fat, more leptin in their cord blood, and increased inflammatory cytokine levels [10]. Maternal high-fat diet associated with altered gene expression, DNA methylation, obesity in mouse offspring. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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