Astrocyte Specific Insulin Receptor Deletion Contributes to Reproductive and Metabolic Dysregulation in Mice

Abstract

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.