Altered circadian clock as a novel therapeutic target for constant darkness-induced insulin resistance and hyperandrogenism of polycystic ovary syndrome

Abstract

The mechanisms underlying metabolic and reproductive dysfunction caused by arrhythmic circadian clock and their involvement in polycystic ovary syndrome (PCOS) are not understood. Here, we addressed this issue using rats with constant light or darkness exposure for 8 weeks and human leukocytes and serum of PCOS and non-PCOS patients. Additionally, we utilized HepG2 cells and KGN cells to verify the molecular mechanisms. The arrhythmic expressions of circadian clock genes due to constant darkness induced the metabolic and reproductive hallmarks of PCOS in rats. After exposure to constant darkness, decreased brain and muscle ARNT-like protein 1 (BMAL1) promoted insulin resistance via glucose transporter 4 (GLUT4), and decreased period (PER) 1 and PER2 promoted androgen excess via insulin-like growth factor-binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) in the liver. Hyperinsulinemia and hyperandrogenism shared a bidirectional link promoting aberrant expression of circadian genes and inducing apoptosis of ovarian granulosa cells. Notably, the altered expressions of circadian clock genes in darkness-treated rats matched those of PCOS patients. Furthermore, melatonin treatment relieved the hyperinsulinemia and hyperandrogenism of darkness-treated rats via BMAL1, PER1, and PER2. Restoring normal light/dark exposure for 2 weeks reversed these conditions via BMAL1. In conclusion, our findings elucidated the critical function of circadian clock genes, especially BMAL1, PER1, and PER2 in PCOS, which might aid the development of feasible preventive and therapeutic strategies for PCOS in women with biorhythm disorder.