Induction of Foxo3a by nutrient deprivation regulates folliculogenesis

Abstract

The transcription factor Foxo3a impacts apoptosis, metabolism, and cell proliferation/differentiation, and is critical in ovarian folliculogenesis. Mice overexpressing Foxo3a in the ovary are infertile due to lack of follicular development, while Foxo3a−/− mice display infertility resulting from global follicular activation. Our cell culture data show that Foxo3a mRNA and protein expression is induced by both essential amino acid and glucose deprivation. We hypothesized that nutrient deprivation in mice would similarly upregulate Foxo3a expression, and potentially block follicular development. 5‐week‐old C57/B6 female mice were injected daily with 2‐deoxyglucose (2‐DG), a glucose‐deprivation mimetic, at increasing concentrations (100mg/kg, 300mg/kg, 600mg/kg or PBS). After two weeks, one ovary was used for RNA analysis, which showed that 100mg/kg 2‐DG caused a 4‐fold increase in Foxo3a mRNA. The contralateral ovary was formalin‐fixed and sectioned, and follicles were counted and classified. Mice treated with 100mg/kg 2‐DG had a 58% decrease in percentage of early‐stage primary follicles, while treatment with 600mg/kg 2‐DG resulted in a 32% decrease in these follicles. Our data demonstrate that nutrient deprivation induces Foxo3a in a mouse model, and that this induction results in a decrease of early‐stage activated follicles.Research Support: McKnight Brain Institute Research Fund