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Rescue of obesity‐induced infertility in female mice due to an ovarian theca cell‐specific knockout of the insulin receptor

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 two‐fold; first, to determine whether insulin signaling in the ovary played a role in the development or function of reproductive function, and secondly, to explore whether the ovary is also a target for the pathophysiologic affects of high insulin in obesity. We disrupt the IR gene specifically in the theca cells of the ovaries (ThIRKO mouse). No changes in reproductive development or function were observed in lean ThIRKO 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). As expected, there was a significantly higher fasted glucose and body mass in WT and ThIRKO DIO mice compared to WT and ThIRKO lean mice. DIO WT mice were infertile and experienced increased circulating testosterone levels. By contrast, ThIRKO mice exhibited improved estrous cyclicity and fertility with comparable testosterone level as lean mice. These results confirm that the ovary is a target of the high levels of insulin in obesity. It highlights an important role for insulin signaling in the ovary in the development of infertility in DIO and that the reproductive axis maintains insulin sensitivity even in the setting of peripheral insulin resistance.