Obesity-induced inflammatory miR-133a mediates apoptosis of granulosa cells and causes abnormal folliculogenesis: Role of miR-133a in folliculogenesis

Obesity has been reported to promote disordered folliculogenesis, but the exact molecular mechanisms are still not fully understood. In this study, we find that miR-133a is involved in obesity-induced follicular development disorder. After feeding with a high-fat diet (HFD) and fructose water for nine weeks, the mouse body weight is significantly increased, accompanied by an inflammatory state and increased expression of miR-133a in the adipose tissues and ovaries as well as accelerated follicle depletion. Although miR-133a is increased in the fat and ovaries of HFD mice, the increased miR-133a in the HFD ovaries is not derived from exosome transferred from obese adipose tissues but is synthesized by ovarian follicular cells in response to HFD-induced inflammation. In vivo experiments show that intrabursal injection of miR-133a agomir induces a decrease in primordial follicles and an increase in antral follicles and atretic follicles, which is similar to HFD-induced abnormal folliculogenesis. Overexpression of miR-133a modestly promotes granulosa cell apoptosis by balancing the expression of anti-apoptotic proteins such as C1QL1 and XIAP and pro-apoptotic proteins such as PTEN. Overall, this study reveals the function of miR-133a in obesity-induced ovarian folliculogenesis dysfunction and sheds light on the etiology of female reproductive disorders.