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 Mar 15;504:110703. doi: 10.1016/j.mce.2020.110703. Epub 2020 Jan 11.
Brain astrocytes are implicated in estrogenic neuroprotection against bio-energetic insults, which may involve their glycogen energy reserve. Forebrain estrogen receptors (ER)-alpha (ERα) and -beta (ERβ) exert differential control of glycogen metabolic enzyme [glycogen synthase (GS); phosphorylase (GP)] expression in hypoglycemic male versus female rats. Studies were conducted using a rat hypothalamic astrocyte primary culture model along with selective ER agonists to investigate the premise that estradiol (E) exerts sex-dimorphic control over astrocyte glycogen mass and metabolism. Female astrocyte GS and GP profiles are more sensitive to E stimulation than the male. E did not regulate expression of phospho-GS (inactive enzyme form) in either sex. Data also show that transmembrane G protein-coupled ER-1 (GPER) signaling is implicated in E control of GS profiles in each sex and alongside ERα, GP expression in females. E increases total 5'-AMP-activated protein kinase (AMPK) protein in female astrocytes, but stimulated pAMPK (active form) expression with equivalent potency via GPER in females and ERα in males. In female astrocytes, ERα protein was up-regulated at a lower E concentration and over a broader dosage range compared to males, whereas ERβ was increased after exposure to 1-10 nM versus 100 pM E2 levels in females and males, respectively. GPER profiles were stimulated by E in female, but not male astrocytes. E increased astrocyte glycogen content in female, but not male astrocytes; selective ERβ or ERα stimulation elevated glycogen levels in the female and male, respectively. Outcomes imply that dimorphic astrocyte ER and glycogen metabolic responses to E may reflect, in part, differential steroid induction of ER variant expression and/or regulation of post-receptor signaling in each sex.
脑星形胶质细胞参与雌激素对生物能量损伤的神经保护作用，这可能涉及到它们的糖原能量储备。前脑雌激素受体（ER）-α（ERα）和 -β（ERβ）对低血糖雄性和雌性大鼠的糖原代谢酶[糖原合酶（GS）；磷酸化酶（GP）]表达发挥不同的控制作用。使用大鼠下丘脑星形胶质细胞原代培养模型和选择性 ER 激动剂进行研究，以研究雌二醇（E）对星形胶质细胞糖原质量和代谢产生性别二态控制的前提。雌性星形胶质细胞的 GS 和 GP 谱对 E 的刺激比雄性更敏感。E 对两种性别的磷酸化 GS（无活性酶形式）的表达没有调节作用。数据还表明，跨膜 G 蛋白偶联 ER-1（GPER）信号参与 E 对每一种性别 GS 谱的控制以及 ERα，GP 在雌性中的表达。E 增加雌性星形胶质细胞中总 5'-AMP 激活蛋白激酶（AMPK）蛋白，但通过 GPER 在雌性和 ERα在雄性中以同等效力刺激 pAMPK（活性形式）的表达。在雌性星形胶质细胞中，ERα 蛋白在较低的 E 浓度和较宽的剂量范围内上调，而 ERβ 在雌性中暴露于 1-10 nM 与 100 pM E2 水平后增加，而在雌性和雄性中分别增加。GPER 谱在雌性星形胶质细胞中被 E 刺激，但在雄性星形胶质细胞中则没有。E 增加了雌性星形胶质细胞中的糖原含量，但对雄性星形胶质细胞则没有；选择性 ERβ 或 ERα 刺激分别提高了雌性和雄性的糖原水平。结果表明，E 对雌性和雄性星形胶质细胞 ER 和糖原代谢反应的二态性可能部分反映了甾体激素对 ER 变体表达的差异诱导和/或在每个性别中对受体后信号的调节。
