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.

中文翻译：

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A2 去甲肾上腺素能神经元多巴胺-β-羟化酶和雌激素受体变异蛋白和 5'-AMP 激活蛋白激酶的性别特异性驯化对大鼠复发性低血糖的反应

后脑雌激素受体 (ER) 对反调节激素和下丘脑葡萄糖调节递质和糖原代谢对低血糖的反应施加性别二态性控制。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) 蛋白对女性复发性胰岛素诱导低血糖 (RIIH) 的适应。目前的研究调查了 A2 ER 变异适应 RIIH 的性别二态模式与差异 A2 DBH 和 5'-AMP 活化蛋白激酶 (AMPK) 对 RIIH 的适应相关的前提。注射一或四次胰岛素后，对雄性和雌性大鼠的 A2 神经元进行激光弹射显微解剖，用于蛋白质印迹分析。A2 pAMPK 和 DBH 水平在男性中增加，但在单次胰岛素给药后在女性中受到抑制。ER-α (ERα) 和-β (ERβ) 蛋白谱在每个性别中都不受急性低血糖的影响或降低，而 G 蛋白相关的 ER-1 (GPER) 反应性因性别而异。先前的低血糖降低了每个性别的基础 A2 ERα/GPER 和升高的 ERβ 含量，但仅降低了雌性大鼠的 pAMPK 和 DBH 水平。重新引入的低血糖抑制了每个性别的 A2 ERβ 水平，但仅改变了男性的 DBH (↓)、ERα (↓) 和 GPER (↑) 水平。数据记录了 A2 DBH 适应 RIIH 的性别差异，例如男性从阳性反应到阴性反应的转变与女性阴性反应性的丧失，以及两性的 AMPK 激活减弱。在低血糖发作之间，每个性别的 A2 神经元可能对 ERα/GPER 信号的敏感性降低，但对 ERβ 输入的接受性增强。