School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, USA.
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, USA.
Mol Cell Endocrinol. 2020 Dec 1;518:111000. doi: 10.1016/j.mce.2020.111000. Epub 2020 Aug 25.
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.
低血糖会导致体内下丘脑星形胶质细胞糖原代谢出现性别依赖性变化。核内星形胶质细胞雌激素受体（ER）与膜内星形胶质细胞雌激素受体（ER）在糖饥饿调节糖原中的作用尚不清楚。在此，我们在糖饥饿时用选择性 ER 拮抗剂处理原代下丘脑星形胶质细胞培养物，以研究 ER 是否介导糖饥饿对糖原的性别特异性反应的假设。结果表明，糖饥饿下调糖原合酶表达是通过两性中的跨膜 G 蛋白偶联 ER-1（GPER）信号传导和雌性中的雌激素受体（ER）-β（ERβ）活性介导的。糖饥饿抑制糖原磷酸化酶涉及雌性中的 GPER 和 ERβ，但雄性中涉及 ER 独立机制。GPER、ERβ 和 ER-α（ERα）分别抑制或刺激雄性与雌性星形胶质细胞中的 AMPK 蛋白表达。GPER 激活拮抗了雄性神经胶质细胞中磷酸化 AMPK 谱的糖饥饿增加，而 GPER 和 ERβ 则抑制了雌性中的磷酸化 AMPK 谱。在葡萄糖缺乏期间，两性中的 ERα 和 GPER 含量均下调，而 ERβ 水平不变（雄性）或增加（雌性）。糖饥饿相应地增加或减少了雄性与雌性星形胶质细胞中的糖原含量；在雄性中，ER 拮抗作用逆转了这种反应，但在雌性中没有。结果确定了在这种底物燃料缺乏时参与性别相似与性别特异性星形胶质细胞蛋白反应的不同 ER 变体。值得注意的是，糖饥饿会引发 GPER 和 ERβ 对特定神经胶质蛋白谱的特定方向的开关或增益效应。结果推断 ER 对于雄性中糖饥饿调节星形胶质细胞糖原积累至关重要。另一方面，雌二醇可能独立于 ER 信号作用于女性以分解这种储备。
