Effects of High Fat Diets on Metabolic Gene Expression in the Liver and Adipose of the Offspring through Multi‐generations via Epigenetic Alterations

The epigenetic modification is established and altered in a sensitive manner to environment factors such as diet during development. The modification is long-lasting through the life cycle and even can be transmitted to offspring. Here, we show that paternal high fat diet (HFD) induce metabolic disturbance as well as epigenetic changes in gametes and the effects are transmitted to the next two generations. The founder (F0) male mice were exposed to HFD for 13 weeks from 5wk of age, resulting in glucose intolerance and insulin resistance, and were bred with female mice fed with control diet. F1 female progeny of HFD F0 showed high fasting glucose at 8wk of age and glucose intolerance at 18wk, although all the progeny were fed with control diet. Even stronger phenotypes of impaired glucose metabolism appeared in F2 female progeny born to the F1 female. The transmission of metabolic phenotypes was associated with changes in expression of metabolic regulating genes. In both HFD F0 and F1 female there were increased glucose and fatty acid metabolism-related gene such as Gck, Fasn, and Pparα in liver and decreased Pparγ in adipose tissue, which means progressing insulin resistance and decreased fat storage capacity, respectively. In order to understand the underlying mechanism, DNA methylation status of F0 sperm was analyzed. A HFD reduced global DNA methylation in sperms, indicated by DNA methylation levels in repetitive elements. In conclusion, paternal exposure to HFD induced transgenerational effects on impaired glucose intolerance and altered metabolic gene expression in liver and adipose through multi-generations, possibly through epigenetic alterations in gametes.