School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, United States.
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, 71201, United States.
J Chem Neuroanat. 2020 Nov;109:101845. doi: 10.1016/j.jchemneu.2020.101845. Epub 2020 Jun 26.
Hindbrain estrogen receptors (ER) impose sex-dimorphic control of counter-regulatory hormone and hypothalamic glucoregulatory transmitter and glycogen metabolic responses to hypoglycemia. A2 noradrenergic neurons are estradiol- and metabolic-sensitive. Estradiol controls dopamine-beta-hydroxylase (DBH) protein habituation to recurrent insulin-induced hypoglycemia (RIIH) in females. Current research investigated the premise that sex-dimorphic patterns of A2 ER variant acclimation to RIIH correlate with differential A2 DBH and 5'-AMP-activated protein kinase (AMPK) adaptation to RIIH. A2 neurons were laser-catapult-microdissected from male and female rats after one or four insulin injections for Western blot analysis. A2 pAMPK and DBH levels were increased in males, but suppressed in females after single insulin dosing. ER-alpha (ERα) and -beta (ERβ) protein profiles were unaffected or decreased by acute hypoglycemia in each sex, whereas G protein-linked ER-1 (GPER) reactivity varied by sex. Antecedent hypoglycemia diminished basal A2 ERα/GPER and elevated ERβ content in each sex, yet reduced pAMPK and DBH levels in female rats only. Reintroduced hypoglycemia suppressed A2 ERβ levels in each sex, but altered DBH (↓), ERα (↓), and GPER (↑) levels in males only. Data document sex differences in A2 DBH adaptation to RIIH, e.g. a shift from positive-to-negative response in males versus loss of negative reactivity in females, as well as attenuated AMPK activation in both sexes. Between hypoglycemic episodes, A2 neurons in each sex likely exhibit diminished sensitivity to ERα/GPER signaling, but heightened receptivity to ERβ input. RIIH-induced changes in ERα and GPER expression in male but not female may contribute to DBH suppression (males) versus no change (females) relative to adapted baseline expression.
后脑雌激素受体（ER）对激素和下丘脑糖调节递质的反馈调节以及对低血糖的糖原代谢反应施加性别二态控制。A2 去甲肾上腺素能神经元对雌二醇和代谢敏感。雌二醇控制多巴胺-β-羟化酶（DBH）蛋白对反复胰岛素诱导的低血糖（RIIH）的适应。目前的研究调查了这样一个前提，即 A2 ER 变体对 RIIH 的适应的性别二态模式与 A2 DBH 和 5'-AMP 激活蛋白激酶（AMPK）对 RIIH 的适应的差异相关。在雄性和雌性大鼠接受一次或四次胰岛素注射后，使用激光弹射微切割 A2 神经元进行 Western blot 分析。单次胰岛素给药后，雄性 A2 神经元中的 pAMPK 和 DBH 水平增加，但雌性 A2 神经元中的 pAMPK 和 DBH 水平受到抑制。在每个性别中，急性低血糖对 ER-α（ERα）和 -β（ERβ）蛋白谱没有影响或降低，而 G 蛋白偶联的 ER-1（GPER）反应性因性别而异。先前的低血糖症降低了每个性别中 A2 的基础 ERα/GPER 和升高的 ERβ含量，但仅降低了雌性大鼠的 pAMPK 和 DBH 水平。重新引入的低血糖症降低了每个性别中 A2 的 ERβ 水平，但仅改变了雄性大鼠的 DBH（↓）、ERα（↓）和 GPER（↑）水平。数据记录了 A2 DBH 对 RIIH 的适应存在性别差异，例如雄性从阳性反应转变为阴性反应，而雌性则失去阴性反应，以及两性的 AMPK 激活减弱。在低血糖发作之间，每个性别中的 A2 神经元可能表现出对 ERα/GPER 信号的敏感性降低，但对 ERβ输入的反应性增强。RIIH 诱导的雄性中 ERα 和 GPER 表达的变化，但雌性中没有变化，可能导致与适应基线表达相比，DBH 抑制（雄性）而不是无变化（雌性）。
