Follicle-dependent differential localization of adipokines in the letrozole-induced hyperandrogenized mouse ovary

This study investigated whether ovarian adipokines exhibit uniform or stage-specific expression patterns across different follicular stages under hyperandrogenic conditions using a letrozole-induced polycystic ovary syndrome (PCOS) mouse model. Adult female mice received oral letrozole treatment for 21 days to induce hyperandrogenism, and ovarian tissues were analyzed by immunohistochemistry and western blot to examine the localization and expression of adiponectin (ADPN), adipoR1, adipoR2, leptin (Ob), leptin receptor (ObR), apelin (APLN), apelin receptor (APJ), chemerin, CMKLR1, and visfatin. Intense immunostaining for Ob, ObR, APJ, APLN, adipoR2, and visfatin was observed in primary, secondary, and Graafian follicles, whereas ADPN, adipoR1, and CMKLR1 showed reduced reactivity. In follicular cysts, adipoR2, APLN, APJ, and Ob were markedly upregulated compared with the corpus luteum of control ovaries, whereas ADPN, adipoR1, chemerin, CMKLR1, and ObR were downregulated. These findings indicate that hyperandrogenism disrupts adipokine signaling in a follicle-dependent manner, with differential expression patterns contributing to altered follicular maturation and cyst formation. The enhanced activation of adiponectin, apelin, and leptin signaling observed in cystic follicles may indicate disrupted adipokine-mediated regulation of ovarian physiology in letrozole-induced PCOS. Given the established roles of these adipokines in folliculogenesis and steroidogenesis, their dysregulation may contribute to follicular arrest and impaired ovarian function. These alterations are likely reflective responses to an altered endocrine and metabolic environment rather than direct causal mechanisms. Nonetheless, they may participate in the pathophysiological processes underlying cyst formation in PCOS.