Glucose-dependent insulinotropic peptide (GIP) suppresses androgen biosynthesis in PCOS mouse models and cellular systems

Objective: To assess the potential therapeutic effects of glucose-dependent insulinotropic peptide (GIP) on hyperandrogenism.

Methods: Polycystic ovary syndrome (PCOS) mouse models induced by dehydroepiandrosterone (DHEA) were established to evaluate the impact of GIP on androgen synthesis in vivo. Additionally, NCI-H295R cells were utilized for in vitro studies to investigate the effects of GIP on androgen synthesis using various techniques, including CCK8, flow cytometry, RT‒qPCR, WB, ELISA, and RNA Sequencing (RNA-seq).

Results: Administration of GIP significantly reduced testosterone secretion in a DHEA-induced PCOS mouse model. Consistent with these findings, GIP treatment decreased testosterone release and downregulated the expression of GIP receptor (GIPR), steroidogenic acute regulatory protein (STAR), Cytochrome P450 family 11 subfamily A member 1 (CYP11A1), and Cytochrome P450 family 17 subfamily A member 1 (CYP17A1) in NCI-H295R cells. Notably, RNA-seq revealed that PSENEN was the most significantly downregulated gene upon GIP stimulation. Knockdown of PSENEN in NCI-H295R cells further decreased testosterone levels in the culture medium, confirming the inhibitory effect of GIP on androgen synthesis.

Conclusions: Our study demonstrated that the administration of GIP reduces androgen synthesis in PCOS mouse models and at the cellular level, suggesting its potential as a novel therapeutic target for managing PCOS.

Glucose-dependent insulinotropic peptide (GIP); PSENEN; androgen synthesis; hyperandrogenism (HA); polycystic ovary syndrome (PCOS).