Metformin and exenatide upregulate hepatocyte nuclear factor-4α, sex hormone binding globulin levels and improve hepatic triglyceride deposition in polycystic ovary syndrome with insulin resistance rats

To explore the efficacy and underlying mechanisms of metformin and exenatide in reversing reproductive and metabolic disturbances in letrozole combined with high-fat diet-induced polycystic ovary syndrome (PCOS) rats.Rats with PCOS and insulin resistance (IR) were induced by intra-gastric instillation of letrozole combined with a high-fat diet and verified by histological screening of vaginal exfoliated cells. After metformin and exenatide supplementation, body weight, chow intake and ovarian morphology were observed. Serum biochemical profiles were analyzed using ELISA, while the levels of key anabolism-related proteins, including sex hormone binding globulin (SHBG), hepatocyte nuclear factor-4α (HNF-4α), PI3K, and AKT, were determined using western blotting.The estrus cycle and ovarian morphology of rats with PCOS and IR were significantly recovered following metformin and exenatide treatment, with decreased body weight and chow intake. Furthermore, PCOS-induced changes in metabolic disorders including IR and hepatic triglyceride (TG) deposition, and hyperandrogenemia were reversed by treatment with both drugs. Specifically, the levels of HNF-4α and SHBG in liver tissue of rats with PCOS and IR were upregulated significantly.Both metformin and exenatide could recover the estrous cycle and ovarian morphology, reduce body weight and high-fat chow intake, and improve glycolipid metabolism disorders and hyperandrogenemia in PCOS with IR rat models. Interestingly, our findings also highlight the potential of both therapeutic agents for improving IR by regulating the liver PI3K/AKT pathway, reducing the deposition of hepatic TG, as well as upregulating the levels of SHBG and HNF-4α in PCOS with IR rat liver tissue.