SAT-024 Astrocyte Insulin-Like Peptide Signaling and Control of Murine Sexual Maturation/Function

Abstract Disclosure: L.D. Jaramillo: None. J.W. Hill: None. K. Smedlund: None. I. Manaserh: None. While metabolic disorders such as obesity and type 2 diabetes cause significant metabolic dysregulation, they also negatively impact fertility. Insulin and insulin-like growth factor-1 (IGF-1) signaling are two globally significant metabolic hormones that connect energetic status with the neuroendocrine control of fertility. To determine whether astrocytic insulin sensing plays a role in the regulation of the hypothalamic-pituitary-gonadotropin (HPG), we generated mice lacking IRs in astrocytes (GFAP-specific insulin receptor deletion [IRKOGFAP] mice). IRKOGFAP mice show normal sexual behavior but HPG axis dysregulation accompanied by impaired spermatogenesis and ovarian follicle maturation, leading to delays in sexual maturation in both sexes and low fecundity. Interestingly, astrocytes isolated from these mice had reduced prostaglandin E synthase 2 (PGES2) levels, suggesting a mechanism for low GnRH/luteinizing hormone (LH) secretion. In ongoing in vitro studies using hypothalamic primary astrocyte cultures, IGF-1 treatment elevated PGE2 levels, while co-treatment with a known FOXO inhibitor reduced PGE2 level. These findings demonstrate that insulin-like peptide signaling sensing by astrocytes is indispensable for the function of the reproductive axis. Ongoing work will elucidate the role of astrocytes in the maturation of hypothalamic reproductive circuits. Presentation: Saturday, July 12, 2025