Paternally multi-generational high-fat diet causes obesity and metabolic disorder through intergenerational DNA methylation

Tianyi Guo¹Zuomin Hu²Liyuan Bao¹Yunyun Cao²Zhongxing Chu²Mingzhi Wang¹Yan Li³Feijun Luo^2*

• ¹Changzhi Medical College, Changzhi, China
• ²Central South University Forestry and Technology, Changsha, China
• ³Heping Hospital Affiliated to Changzhi Medical College, Changzhi, China

Objective: Paternal high-fat diet (HFD) has detrimental effects on offspring. However, the extent of comprehensive damage and the underlying mechanisms associated with sustained multigenerational HFD exposure remain unclear. This study aims to investigate intergenerational progressive accumulation of obesity and glycolipid metabolic disorders, as well as mechanisms mediated by DNA methylation. Methods: We performed a novel paternally multi-generational HFD consumption model in male C57BL/6J mice, while excluding maternal gestational effects and any confounding influences from females. The body weight and glycolipid metabolism indicators of each generation male mice were determined. The intergenerational transmission of CpG methylation and gene expression variation were detected through mRNA microarray, methylated DNA immunoprecipitation (MeDIP)-chip, bisulfite sequencing, RT-qPCR and Western blot etc. analysis, to indicate genes involved in glycolipid metabolism related with the intergenerational reprogramming. Results: The HFD caused intergenerational accumulation of body weight increase, disturbance of glycolipid metabolism and insulin insensitivity in male offspring. MeDIP/gene-chip results indicated that paternal HFD significantly modified gene expression and DNA methylation profiles in liver or sperm of offspring. Majority of differential genes exhibited hypermethylation in promoter regions and reduced expression in liver, which were linked to glucolipid metabolic signaling pathway. The elevated promoter methylation and expression states of Spns2, Lonp1 and Hk1, which are involved in glycolipid metabolism, were inherited by offsprings. Conclusion: This research shows that paternal sustained multi-generational HFD could induce intergenerational progressive accumulation of obesity and metabolic disorder through DNA methylation regulation, and identifies the target genes related with the intergenerational reprogramming, which provides new insights for establishment of healthy diets and lifestyles.