Periovulatory insulin signaling is essential for ovulation, granulosa cell differentiation, and female fertility

Recent studies have demonstrated an essential role for insulin signaling in folliculogenesis as conditional ablation of Igf1r in primary follicles elicits defective follicle-stimulating hormone responsiveness blocking development at the preantral stage. Thus the potential role of insulin action in the periovulatory window and in the corpus luteum is unknown. To examine this, we generated conditional Insr,Igf1r, and double receptor knockout mice driven by Pgr-Cre. These models escape the preantral follicle block and in response to superovulatory gonadotropins exhibit normal distribution of ovarian follicles and corpora lutea. However, single ablation of Igf1r leads to subfertility and mice lacking both receptors are infertile. Double knockout mice have impaired oocyte development and ovulation. While some oocytes are released and fertilized, subsequent embryo development is retarded, and the embryos potentially fail to thrive due to lack of luteal support. In support of this, we found reduced expression of key enzymes in the steroid synthesis pathway and reduced serum progesterone. In addition to metabolic and steroidogenic pathways, RNA-sequencing analysis revealed transcription factor-3 as an important transcription factor downstream of insulin signaling. Collectively, these results highlight the importance of growth factors of the insulin family during two distinct windows of follicular development, ovulation, and luteinization.