Obeticholic Acid Rescues Male Reproductive Function in High-Fat Diet-Induced Metabolic Syndrome

Metabolic syndrome (MetS) contributes to male infertility, yet the impact of MetS-targeted therapies on fertility remains unclear. This study investigates the impact of obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, in a high-fat-diet (HFD)-induced MetS mouse model. MetS was induced in male mice by 12-week of HFD feeding. Mice then received OCA (30 mg/kg) or vehicle for 5 weeks. Sperm parameters, testicular and epididymal immune profiles, intestinal bile acid, gut microbiota, and epididymal gene expression were assessed. OCA treatment was associated with higher sperm progressive motility (PR) and lower proportions of epididymal IFN-γ-producing CD4⁺ T helper 1 (Th1) cells. OCA shifted bile acid profile and gut microbiota. Expression of H2bc24 in epididymis increased to levels comparable with control group. These findings indicate that OCA is associated with improved male reproductive parameters in MetS through modulation of bile acid signaling, immune response, and microbiota. OCA may represent a potential therapeutic approach for MetS- associated male infertility.