Gene expression and DNA methylation as mechanisms of disturbed metabolism in offspring after exposure to a prenatal HF diet

Sven H Rouschop,Tanja Karl,Angela Risch,Petronella A Van Ewijk,Vera B Schrauwen-Hinderling,Antoon Opperhuizen,Frederik J Van Schooten,Roger W Godschalk

doi:10.1194/jlr.m092593

Abstract

Exposure to a prenatal high-fat (HF) diet leads to an impaired metabolic phenotype in mouse offspring. The underlying mechanisms, however, are not yet fully understood. Therefore, this study investigated whether the impaired metabolic phenotype may be mediated through altered hepatic DNA methylation and gene expression. We showed that exposure to a prenatal HF diet altered the offspring’s hepatic gene expression of pathways involved in lipid synthesis and uptake (SREBP), oxidative stress response [nuclear factor (erythroid-derived 2)-like 2 (Nrf2)], and cell proliferation. The downregulation of the SREBP pathway related to previously reported decreased hepatic lipid uptake and postprandial hypertriglyceridemia in the offspring exposed to the prenatal HF diet. The upregulation of the Nrf2 pathway was associated with increased oxidative stress levels in offspring livers. The prenatal HF diet also induced hypermethylation of transcription factor (TF) binding sites upstream of lipin 1 (Lpin1), a gene involved in lipid metabolism. Furthermore, DNA methylation of Lpin1 TF binding sites correlated with mRNA expression of Lpin1. These findings suggest that the effect of a prenatal HF diet on the adult offspring’s metabolic phenotype are regulated by changes in hepatic gene expression and DNA methylation.

Highlights

Exposure to a prenatal high-fat (HF) diet leads to an impaired metabolic phenotype in mouse offspring
At 12 weeks of age, HF/HF offspring displayed postprandial hypertriglyceridemia and an impaired clearance of lipids from the blood into the liver after a HF meal [24]. To study whether this impaired metabolic phenotype in HF/HF offspring was related to alterations in hepatic gene expression, a microarray was performed on offspring livers at 12 and 28 weeks of age
We studied the effect of a combined paternal and maternal HF diet on hepatic DNA methylation and gene expression in adult mouse offspring. We showed that this prenatal HF diet altered hepatic DNA methylation and gene expression of pathways involved in lipid metabolism, oxidative stress response, and cell proliferation

Summary

Introduction

Exposure to a prenatal high-fat (HF) diet leads to an impaired metabolic phenotype in mouse offspring. Gene expression and DNA methylation as mechanisms of disturbed metabolism in offspring after exposure to a prenatal HF diet. A paternal HF diet before conception is able to increase the offspring’s bodyweight and fat mass and impair its lipid and glucose metabolism [14, 15]. Both maternal and paternal HF diet have been shown to induce nonalcoholic fatty liver disease in mouse offspring, indicated by increased liver size, excessive accumulation of cholesterol and triglycerides

Methods

Results

Conclusion