The Role of Insulin and IGF-1 Receptors in Murine Ovarian Function and Female Fertility

Recent studies have revealed the importance of insulin and insulin-like growth factor type-1 (IGF1) receptors in regulating the proliferation of the supporting Sertoli cells which affects the testis size and the sperm production, thus interfering with the male fertility (Pitetti et al., 2013). To determine the importance of the insulin and IGF1 receptors in the female equivalent granulosa cells and their implication in regulating female’s fertility, we used both X12G granulosa cell line for in vitro experiments, and conditional knock-out mice for in vivo evaluations. Our in-vitro model was useful to prove that prenatal granulosa cells are responsive to insulin and IGF1 at very early stages of development (E12.5) and thus express the receptors for both insulin (INSR) and Igf1 (IGF1R) already at this stage. Previous studies showed that specific deletion of Insr and Igf1r in mouse oocyte was dispensable (Pitetti et al., 2009). To evaluate their importance in somatic cells, we used the Cre/LoxP system, with a specific promoter for granulosa cells guiding the activity of the Cre-Recombinase. We were thus able to conditionally knock out Insr and Igf1r and study their role in ovarian functions. Our genetic evidence shows that mutant mice exhibit longer estrous cycles, have altered morphology of their reproductive tracts, have a depletion of primordial follicles at P60 and have higher germ cell apoptosis during early postnatal stages. However, they have a reduced number of oocyte that matures normally and are fertile yet delivering significantly fewer pups per litter. These observations suggests that the Insulin/IGF signaling pathway in granulosa cells is implicated in normal functioning of the ovarian system but appears to be dispensable for female’s fertility