Hypoglycemia causes sex-reliant changes in hypothalamic astrocyte glycogen metabolism in vivo. The role of nuclear versus membrane astrocyte estrogen receptors (ER) in glucoprivic regulation of glycogen is unclear. Here, primary hypothalamic astrocyte cultures were treated with selective ER antagonists during glucoprivation to investigate the hypothesis that ER mediate sex-specific glycogen responses to glucoprivation. Results show that glucoprivic down-regulation of glycogen synthase expression is mediated by transmembrane G protein-coupled ER-1 (GPER) signaling in each sex and estrogen receptor (ER)-beta (ERβ) activity in females. Glucoprivic inhibition of glycogen phosphorylase involves GPER and ERβ in females, but ER-independent mechanisms in males. GPER, ERβ, and ER-alpha (ERα) inhibit or stimulate AMPK protein expression in male versus female astrocytes, respectively. Glucoprivic augmentation of phospho-AMPK profiles in male glia was opposed by GPER activation, whereas GPER and ERβ suppress this protein in females. Astrocyte ERα and GPER content was down-regulated in each sex during glucose deficiency, whereas ERβ levels was unaltered (males) or increased (females). Glucoprivation correspondingly elevated or diminished male versus female astrocyte glycogen content; ER antagonism reversed this response in males, but not females. Results identify distinctive ER variants involved in sex-similar versus sex-specific astrocyte protein responses to withdrawal of this substrate fuel. Notably, glucoprivation elicits a directional switch or gain-of-effect of GPER and ERβ on specific glial protein profiles. Outcomes infer that ERs are crucial for glucoprivic regulation of astrocyte glycogen accumulation in males. Alternatively, estradiol may act independently of ER signaling to disassemble this reserve in females.

低血糖导致体内下丘脑星形胶质细胞糖原代谢的性别依赖变化. 核与膜星形胶质细胞雌激素受体 (ER) 在糖原的 glucoprivic 调节中的作用尚不清楚。在这里，原代下丘脑星形胶质细胞培养物在葡萄糖剥夺期间用选择性 ER 拮抗剂处理，以研究 ER 介导对葡萄糖剥夺的性别特异性糖原反应的假设。结果表明，糖原合酶表达的糖原性下调是由跨膜 G 蛋白偶联的 ER-1 (GPER) 信号在雌性中和雌激素受体 (ER)-β (ERβ) 活性介导的。糖原磷酸化酶的糖原抑制涉及女性的 GPER 和 ERβ，但男性的 ER 非依赖性机制。GPER、ERβ 和 ER-α (ERα) 分别抑制或刺激雄性和雌性星形胶质细胞中的 AMPK 蛋白表达。GPER 激活反对雄性神经胶质中磷酸化 AMPK 谱的 Glucoprivic 增强，而 GPER 和 ERβ 抑制雌性中的这种蛋白质。在葡萄糖缺乏期间，每个性别的星形胶质细胞 ERα 和 GPER 含量均下调，而 ERβ 水平未改变（男性）或增加（女性）。Glucoprivation 相应地升高或减少男性与女性星形胶质细胞糖原含量；ER 拮抗剂在男性中逆转了这种反应，但在女性中则不然。结果确定了独特的 ER 变体，这些变体涉及对这种底物燃料撤回的性别相似与性别特异性星形胶质细胞蛋白反应。值得注意的是，葡萄糖剥夺引起 GPER 和 ERβ 对特定神经胶质蛋白谱的定向转换或增益效应。结果推断，ERs 对雄性星形胶质细胞糖原积累的糖化调节至关重要。