FXR maintains primordial follicle dormancy via regulating FoxO3 expression

Farnesoid X receptor (FXR), a ligand-dependent nuclear receptor predominantly expressed in enterohepatic tissues, is also present in the ovary; however, its role in female reproduction remains unclear. In this study, we investigated the role of FXR in regulating the ovarian reserve using a novel FXR knockout (FXR-KO) mouse. FXR-KO mice exhibited an increased number of ovulated oocytes, associated with an enlarged pool of secondary follicles, suggesting enhanced recruitment from the primordial follicle pool. During the neonatal period, FXR-KO ovaries showed accelerated primordial follicle activation, evidenced by increased Forkhead box O3 (FOXO3) nuclear exclusion, while pharmacological activation of FXR suppressed this process in wild-type ovaries. Mechanistically, FXR directly bound to the FoxO3 promoter, increasing its expression without altering FOXO3 phosphorylation, indicating transcriptional regulation. In vitro, activation of FXR in granulosa cells by an agonist upregulated cell cycle inhibitors and suppressed proliferation, suggesting FXR maintains primordial follicle dormancy by restraining granulosa cell differentiation and potentially enhancing oocyte quiescence. These findings identify FXR as a novel regulator of ovarian reserve maintenance, highlighting its potential as a pharmacological target to modulate reproductive lifespan and fertility management in mammals.