Insulin resistance and obesity are associated with reduced gonadotropin-releasing hormone (GnRH) release and infertility. Mice that lack insulin receptors (IRs) throughout development in both neuronal and non-neuronal brain cells are known to exhibit subfertility due to hypogonadotropic hypogonadism. However, attempts to recapitulate this phenotype by targeting specific neurons have failed. To determine whether astrocytic insulin sensing plays a role in the regulation of fertility, we generated mice lacking IRs in astrocytes (astrocyte-specific insulin receptor deletion [IRKO GFAP ] mice). IRKO GFAP males and females showed a delay in balanopreputial separation or vaginal opening and first estrous, respectively. In adulthood, IRKO GFAP female mice also exhibited longer, irregular estrus cycles, decreased pregnancy rates, and reduced litter sizes. IRKO GFAP mice show normal sexual behavior but hypothalamic-pituitary-gonadotropin (HPG) axis dysregulation, likely explaining their low fecundity. Histological examination of testes and ovaries showed impaired spermatogenesis and ovarian follicle maturation. Finally, reduced prostaglandin E synthase 2 (PGES2) levels were found in astrocytes isolated from these mice, suggesting a mechanism for low GnRH/luteinizing hormone (LH) secretion. These findings demonstrate that insulin sensing by astrocytes is indispensable for the function of the reproductive axis. Additional work is needed to elucidate the role of astrocytes in the maturation of hypothalamic reproductive circuits.

Insulin resistance and obesity are associated with infertility and reduced GnRH release. It has been previously shown that male and female mice lacking insulin signaling in all cell types of the brain during development exhibit subfertility and develop diet‐sensitive obesity, mild insulin resistance and elevated insulin and leptin plasma levels. To determine whether astrocyte insulin sensing plays an important role in the regulation of fertility, we generated mice lacking insulin receptors in astrocytes (GLIRKO mice). GLIRKO males and females showed a delay in balanopreputial separation or vaginal opening and first estrous, respectively. GLIRKO female mice also exhibited longer estrus cycle lengths and irregular estrous cyclicity. In addition, these mice exhibited decrease in pregnancy rate and litter size, and thus decreased fertility. Histological examination of testes and ovaries showed impaired spermatogenesis and ovarian follicle maturation. GLIRKO mice also show hypothalamic hypogonadism, but normal sexual behavior, which confirms that the observed subfertility phenotype is due to HPG axis dysregulation. GLIRKO male mice displayed higher body weight and growth, and significant differences in body composition at 7 months of age. These mice also showed insulin resistance at 2 months and both insulin and glucose intolerance at 7 months of age. Histological analysis showed altered liver morphology with higher fat droplets. GLIRKO mice displayed significant decrease in energy expenditure, and a striking decrease in body temperature during fed state and overnight fasting conditions. However, when fasted mice were exposed to 4C, they were able to mount a robust thermogenic response and rapidly increase body temperature. These observations support the idea that astrocytic population that integrate information about energy stores to regulate body temperature is different from those required to respond to a cold challenge. Overall, our findings suggest that impaired insulin sensing in astrocytes delays the initiation of puberty and affects adult reproductive function. They also suggest that that astrocytic insulin signaling regulate body weight, systematic glucose metabolism and regulate thermogenic responses to nutritional and cold challengesSupport or Funding InformationThis project is supported by NIH R01 HD081792 grant to Dr. Jennifer W. HillThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.