Diet-Induced Obesity Reprograms Testicular Transcriptome and Epigenome: Insights from Single-Nucleus Multiome Analysis
Obesity impairs male reproductive health, but the underlying cellular and epigenomic mechanisms remain unclear. Using single-nucleus RNA sequencing and ATAC sequencing in testes from mice with diet-induced obesity, we identify widespread transcriptional and chromatin alterations across testicular resident somatic and germ cells. Leydig and Sertoli cells exhibit dysregulation of steroidogenic and CREB dependent signaling, while germ cells show a profound loss of CREM and A-MYB driven gene expression together with reduced chromatin accessibility. Treatment with the SGLT2 inhibitor canagliflozin restores systemic metabolic homeostasis and, despite minimal direct testicular SGLT2 expression, partially rescues disrupted CREB CREM A-MYB mediated transcriptional networks, chromatin accessibility at key promoters, and germ cell differentiation. Experiments in cultured cell models suggest that both lipid excess and chronic insulin exposure impair CREB and CREM signaling and induce obesity associated transcriptional changes. These findings uncover a coordinated metabolic epigenetic axis linking obesity to impaired spermatogenesis and suggest that improvements in systemic metabolism can reprogram the sperm epitranscriptome and partially reverse obesity associated male subfertility.