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Impact of insulin on ovarian function
The ovary is the female gonad responsible for gamete production, as well as 17β-estradiol and progesterone synthesis. A finite number of primordial follicles are present at of birth, and these serve as the follicular pool. The number of follicles decline over the female’s lifetime and once depleted, follicles cannot be replaced, because the process of follicular growth is irreversible; once follicles are recruited from the dormant phase into the growing pool they either undergo cell death or they are selected for further growth and eventually ovulation. Unlike the cyclic recruitment of follicles to ovulation, initial primordial follicular activation is independent of pituitary gonadotropins. Several lines of evidence have identified phosphatidylinositol-3 kinase (PI3K) as a locally-produced ovarian factor regulating individual primordial follicle activation. An overall balance among dormancy, activation and death of primordial follicles is a major determining factor contributing to the duration of a female’s reproductive lifespan. Insulin can influence the rate at which primordial follicles are activated and can regulate steroidogenesis through PI3K. Hyperinsulinemia is a biological link between two major physiological conditions in which compromised reproduction is a phenotype: obesity and heat stress. Our work uses three models of hyperinsulinemia to study the impact of elevated insulin on ovarian signaling pathways that contribute to reproductive success: 1) high fat diet obesity induced mice; 2) lethal yellow genetic mouse model of obesity and; 3) heat-stressed gilts. We show that the insulin receptor is localized to the oocyte, granulosa and theca cells. We have also demonstrated altered ovarian PI3K and steroidogenic pathway signaling in these three physiological models. In addition, we have discovered that metabolism of reproductive toxicants is affected by hyperinsulinemia and that low levels of DNA damage are induced in the ovary of obese hyperinsulinemic females. In summary, during hyperinsulinemia, the ovary remains insulin sensitive and we hypothesize that this sensitivity contributes to compromised reproductive capacity in females.
Keywords: Ovary, Insulin, Oocyte