Chronic Energy Restriction Is Associated with Impaired Follicular Development and Hepatic Bile Acid Remodeling in Mice

Chronic energy restriction (ER) can impair female reproductive function, but the peripheral metabolic mechanisms by which sustained energy deficiency disrupts follicular development remain poorly understood. This study aimed to determine whether hepatic bile acid (BA) remodeling contributes to the link between systemic energy availability and ovarian dysfunction. A chronic ER mouse model was established by reducing energy intake by 50% for 44 days. Multi-omics approaches, including hepatic transcriptomics, untargeted metabolomics, and targeted BA metabolomics, were integrated with ovarian functional analyses. ER significantly reduced ovarian weight, impaired follicular development, and decreased circulating concentrations of reproductive hormones. Hepatic transcriptomic and metabolomic analyses revealed extensive metabolic remodeling, with marked enrichment of BA-related pathways and increased expression of CYP7A1, suggesting increased hepatic BA synthetic capacity. Targeted BA profiling demonstrated elevated hepatic and circulating BA levels, including increased concentrations of several farnesoid X receptor (FXR)-activating BAs. Furthermore, ovarian FXR expression was increased, accompanied by decreased expression of key steroidogenic regulators, including SRB1, StAR, CYP11A1, and HSD3B1, consistent with reduced ovarian steroidogenic activity. These findings suggest that altered BA metabolism and increased ovarian FXR expression may contribute to reproductive dysfunction under chronic ER.