Obesity induced infertility rescued by ovarian theca cellspecific knockout of the insulin receptor.

Many prevalent health problems are associated with obesity. Women with Type 2DM or PCOS present with elevated LH and androgen levels, anovulation and insulin resistance in metabolic tissues. The aims of these studies were to determine whether insulin signaling in the ovary played a role in the development or function of reproductive function, and to explore whether insulin exerts pathophysiologic effects at the level of the ovary in obesity. We disrupt the IR gene specifically in the theca cells of the ovaries. No changes in reproductive development or function were observed in lean KO female mice suggesting that insulin signaling in the theca cell is not essential for reproduction. To explore the effect of insulin signaling in the ovary in obesity we made mice obese (DIO) by feeding them a high fat diet. DIO WT mice were infertile and experienced increased circulating testosterone levels. By contrast, KO mice exhibited improved estrous cyclicity and fertility with comparable testosterone level as lean mice. In vitro study using a whole ovary culture model shows how HCG and insulin interact with each other to enhance androstenedione secretion. These results confirm that the high levels of insulin in obesity exert insulin action on the ovary contributing to infertility and indicate that the reproductive axis maintains insulin sensitivity even in the setting of peripheral insulin resistance.