Prohibitin-induced obesity leads to anovulation and polycystic ovary in mice

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and the most common cause of female infertility. However, the etiology of the disease and the mechanisms by which this disorder progress remain unclear. Here we report that a transgenic obese mouse (Mito-Ob) developed by overexpressing prohibitin in adipocytes develops polycystic ovaries. Initially, the female Mito-Ob mice were equally fertile to their wild-type littermates. Mito-Ob mice begin to gain weight after puberty, become significantly obese between 3-6 months of age, and roughly 25% of them become infertile by 9 months of age. Despite obesity, female Mito-Ob mice maintained glucose homeostasis and insulin sensitivity similar to their wild-type littermates. Mito-Ob mice showed morphologically distinct polycystic ovaries and elevated estradiol, but normal testosterone and insulin levels. Histological analysis of the ovaries showed signs of impaired follicular dynamics like preantral follicular arrest and reduced number, or absence of corpus luteum. The ovaries in infertile Mito-Ob mice were found closely surrounded by periovarian adipose tissue suggesting a potential role in anovulation. Collectively, these data suggest that elevated estradiol and obesity per se may lead to anovulation and polycystic ovaries independent of hyperinsulinemia and hyperandrogenism. As obesity often coexists with other abnormalities known to be involved in the development of PCOS such as insulin resistance, compensatory hyperinsulinemia, and hyperandrogenism, the precise role of these factors in the disease process remain unclear. The Mito-Ob mice provide an opportunity to study the effect of obesity on anovulation and ovarian cyst formation independent of the major drivers of obesity-linked PCOS.