Abstract
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 [IRKOGFAP] mice). IRKOGFAP males and females showed a delay in balanopreputial separation or vaginal opening and first estrous, respectively. In adulthood, IRKOGFAP female mice also exhibited longer, irregular estrus cycles, decreased pregnancy rates, and reduced litter sizes. IRKOGFAP 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.
Highlights
These findings are the first demonstration that astrocytes and a metabolic signal collaborate to permit the maturation of the reproductive axis and adult fertility
Mice with insulin receptor (IR) ablated from astrocytes in the mediobasal hypothalamus became insulin and glucose intolerant [10]. These findings suggest that IRs on hypothalamic astrocytes play a role in regulating glucose metabolism
To assess whether Cre expression was restricted to astrocytes in the resulting mice, we crossed experimental mice with tdTomato-loxP reporter mice, which express red fluorescent protein (RFP) in a cre-dependent manner
Summary
Because energy is required to locate a mate, maintain a pregnancy, and rear young, fertility is modulated by the status of energy stores [1,2,3]. Excessive energy expenditure or insufficient caloric intake in humans and rodents delays the pubertal transition and reduces fertility [4, 5]. The pancreatic hormone insulin serves as one metabolic signal linking hypothalamic function with metabolic state [7,8,9]. Mice with IR ablated from astrocytes in the mediobasal hypothalamus became insulin and glucose intolerant [10]. These findings suggest that IRs on hypothalamic astrocytes play a role in regulating glucose metabolism
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