Glucagon-like peptide-1 receptor agonists ameliorate polycystic ovarian syndrome in mice by regulating the irisin level and activating the BMP4-Smad signaling pathway

Abstract Polycystic ovarian syndrome (PCOS) is a multifaceted reproductive endocrine illness marked by ovulatory dysfunction, with various causes and symptoms; it is well-accepted that hyperandrogenism and glucose metabolism disturbances significantly contribute to its progression. Our prior research demonstrated that GLP-1 receptor agonists (GLP-1RAs) could ameliorate the symptoms of PCOS mice. GLP-1RAs have the ability to control irisin expression. However, it remains ambiguous if irisin contributes to the amelioration of PCOS through GLP-1RAs. Androgen excess is a primary component influencing the phenotypic characteristics of PCOS. Evidence shows that BMP4 downregulates the CYP17A1 protein level by activating the Smad pathway, thereby inhibiting androgen synthesis. However, the relationship between irisin and BMP4 in regulating PCOS by GLP-1RAs is unclear. This study used DHEA to induce a mouse model of PCOS. After the intervention with GLP-1RAs and the integrin blocker cRGDyk (an integrin blocker that disrupts irisin signaling), the relevant indexes of mice in each group were measured. We found that the ameliorating effect of GLP-1RAs on PCOS was attenuated by the combined application of the cRGDyk. Notably, after GLP-1RAs intervention, the BMP4-Smad signaling pathway was activated, and testosterone levels were significantly reduced in mice with polycystic ovary syndrome. However, this activation effect disappeared after combined use with the integrin blocker. Our study elucidates the importance of GLP-1RAs in the control of PCOS by regulating irisin and the BMP4-Smad signaling pathway. Our investigation will enhance future comprehension of PCOS from a metabolic viewpoint and investigate therapy alternatives.