In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model

Abstract

Objective Data from animal models show that in utero exposure to a maternal high fat diet (HFD) renders susceptibility of these offspring to the adult onset of metabolic syndrome. We and others have previously shown that epigenetic modifications to histones may serve as a molecular memory of the in utero exposure, rendering risk of adult disease. Because mice heterozygous for GLUT4 (insulin sensitive glucose transporter) born to wild-type (WT) mothers demonstrate exacterbated metabolic syndrome when exposed to a high fat diet in utero, we sought to analyze the genome-wide epigenetic changes which occur in the fetal liver in susceptible offspring. Study Design WT and Glut4+/− (G4+/−) offspring of WT mothers exposed either to a control or a HF diet in utero were studied. Immunoblotting was used to measure hepatic histone modifications of fetal and 5 week animals. Chromatin immunoprecipitation (ChIP) followed by hybridization to chip arrays (ChIP on chip) was utilized to detect genome-wide changes of histone modifications with HFD exposure. Results We found that levels of hepatic H3K14ac and H3K9me3 significantly increased with HFD exposure in WT and G4+/− fetal and 5 week offspring. Pathway analysis of our ChIP on chip data reveal differential H3K14ac and H3K9me3 enrichment along pathways which regulate lipid metabolism, specifically in the promoter regions of Pparg, Ppara, Rxra and Rora. Conclusion We conclude that HFD exposure in utero is associated with functional alterations to fetal hepatic histone modifications in both WT and G4+/− offspring, some which persist up to 5 weeks of age.

Epigenetics and Metabolism

“…In accordance with differential expression of Sirt1, Gcn5, Hdac1, and Hdac3, enrichment of histone acetylation, and also histone methylation, was observed at promoters of genes important for lipid metabolism in livers of fetal and 5-week offspring. 206,207 Similar histone lysine modifications were associated with developmentally programmed changes in leptin and adiponectin expression in adipose tissue.…”

The Omics of Obesity

“…Therefore, epigenetic modifications are hypothesised to be trans-generational and have been shown to be reversible whereby specific epigenetic marks can be turned on or off depending on the stimuli (Bishop et al). Most of these studies have been performed in animal models including mice [24,25], rats [26,27], Macaque [28], drosophila [29] and sheep [23,30,31]. The effects of the in utero environment on foetal programming in humans have not been well explored.…”

“…Proteomics can also be further enhanced by analysing sub-cellular compartments such as mitochondria. In a study comparing lean versus obese mice, Nesteruk et al [25] purified isolated mitochondria from both liver and skeletal muscle and analysed mitochondrial-associated proteins via mass spectrometry. Analysis identified 1,675 liver and 704 muscle mitochondria-associated proteins and of these, 221 liver and 44 muscle proteins were differentially expressed between the lean and obese groups [25].…”

“…In a study comparing lean versus obese mice, Nesteruk et al [25] purified isolated mitochondria from both liver and skeletal muscle and analysed mitochondrial-associated proteins via mass spectrometry. Analysis identified 1,675 liver and 704 muscle mitochondria-associated proteins and of these, 221 liver and 44 muscle proteins were differentially expressed between the lean and obese groups [25]. Analysis of"sub-proteomes" such as the ones at the mitochondrial proteome may be used more in the future to identify cellular compartmentspecific changes associated with obesity.…”

The Impact of Traditional Food and Lifestyle Behavior on Epigenetic Burden of Chronic Disease

“…Global hypomethylation of germ cell DNA in F0 mice Altered testes mRNA (414 genes involved in nitric oxide and ROS pathways, Sertoli cell junction signaling, EIF2 signaling, NF-κβ signaling and inflammatory response, lipid metabolism, and carbohydrate metabolism), and sperm and testes microRNA (11 microRNAs mostly involved in metabolic disease, cell death, production of ROS, DNA replication, NF-κB signaling, p53 signaling, recombination and repair, lipid metabolism, spermatogenesis, and embryonic development) expression Mice High fat diet during pregnancy and lactation [143,170,173,175,180,186,192,195,196,198,200] Increased body weight, body fat content, inflammatory markers and serum insulin and leptin concentrations [181] Increased body weight in female mice in F1 and F2 generations (most severe in F2)…”