Distinct Epigenetic Responses to Aging and Short‐Term High‐Fat Diet in Hepatic Lipid Metabolism Genes in Male and Female Mice

ABSTRACT Background and Aims Aging is associated with widespread epigenetic remodelling that contributes to metabolic alterations in the liver. High‐fat diet (HFD) represents a major environmental perturbation affecting hepatic metabolism, yet its specific impact on age‐associated epigenetic changes remains unclear. Here, we investigated in male and female mice whether HFD induces epigenetic changes similar to or distinct from those observed during aging, with a particular focus on DNA methylation (5mC) and hydroxymethylation (5hmC) in key lipid metabolism genes. Methods We combined re‐analysis of published RNA‐sequencing datasets from young and aged mouse livers with targeted epigenetic and metabolic profiling in a short‐term HFD model. Results In our study, we identified a consistent age‐associated transcriptional upregulation of lipogenic genes, including fatty acid synthase ( Fasn ) and stearoyl‐CoA 9‐desaturase ( Scd1 ), accompanied by reduced DNA methylation and gene‐specific alterations in 5hmC. In contrast, HFD exposure resulted in increased gene‐body methylation with reduced expression of these genes, alongside shifts in fatty acid composition indicative of altered lipid metabolism. Analyses of samples from male and female mice showed sex‐specific differences. Notably, the applied HFD model did not induce overt lipid pathology, suggesting that these changes reflect early metabolic adaptation rather than advanced disease states. Conclusions Together, our findings indicate that HFD induces an epigenetic and transcriptional response in hepatic lipid metabolism genes that differs from and in part opposes age‐associated patterns. These results support a model in which short‐term dietary lipid excess triggers distinct regulatory mechanisms rather than simply recapitulating epigenetic aging.