Maternal High Fat Programs Hepatic Il‐6 Expression Through Differential DNA Methylation in Male Pups

Abstract

Environmental stressors such as dietary high fat (HF) are known to disrupt maternal programming, which leads to metabolic disorders in the offspring later in life. Maternal high-fat diet leads to chronic inflammation which stimulates a hepatic inflammatory response characterized by higher circulating levels of Interleukin-6 (Il-6), thus compromising the functions of hepatocytes. The aim of our study was to examine the programming effect of maternal high fat diet on the Il-6 gene. Female Sprague-Dawley rats were fed with either control (C) or HF diet, and after weaning the pups were given either C or HF diet, generating the four groups of rats on control diet (C/C), maternal high-fat (HF/C), prenatal high-fat (HF/C), and lifelong high-fat diets (HF/HF). mRNA expression analysis showed a significant increase on hepatic Il-6 in HF/C and HF/HF groups, compared to C/C. Methylated DNA Immunoprecipitation analysis showed a marked reduction of methylation between exons 2 and 4 of the Il-6 gene in HF/C and HF/HF. The hypomethylation of these regions of the gene is correlated with the increase in gene expression. This study demonstrates a maternal effect on the epigenetic programming in pup's hepatic pro-inflammatory response, through DNA hypomethyation of elements within the Il-6 gene, which in turn promotes the deterioration of hepatic function. This project was supported in part by the USDA Cooperative State Research, Education and Extension Service, Hatch project number # ILLU-698-394