Regulation of testicular steroidogenesis by Foxa3 via transcriptional modulation of ERα signaling in type 2 diabetes mellitus (T2DM).

摘要: Although both insulin and estrogen receptor α (ERα) are known to exert inhibitory effects on testicular steroidogenesis, it remains unknown whether these pathways regulate testosterone (T) production under certain pathological conditions [e.g., type 2 diabetes mellitus (T2DM)] in a coordinated manner. Here, we found that the expression of forkhead box protein A3 (Foxa3), an essential transcriptional regulator engaged adipogenesis energy metabolism, was significantly down-regulated Leydig cells (LCs) from T-deficient T2DM mice. Functionally, upon hCG stimulation, Foxa3 recruits Esr1 promoter suppresses transactivation gene. Disruption this recruitment by T2DM-elicited hyperinsulinemia led abnormal activation ERα pathway, inhibited steroidogenic enzyme genes expression, thus caused inadequate T production. Therapeutically, insulin-impaired ablation-compromised steroidogenesis were effectively rescued pharmacological inhibitor pathway. These findings reveal obligatory coregulatory role regulation Foxa3/ERα cascade, at least part, pathogenesis androgen deficiency T2DM.