Background Ventromedial hypothalamic nucleus (VMN) gluco-regulatory transmission is subject to sex-specific control by estradiol. The VMN is characterized by high levels of aromatase expression. Methods The aromatase inhibitor letrozole (LZ) was used with high-resolution microdissection/Western blot techniques to address the hypothesis that neuroestradiol exerts sex-dimorphic control of VMN neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase 65/67 (GAD) protein expression. Glycogen metabolism impacts VMN nNOS and GAD profiles; here, LZ treatment effects on VMN glycogen synthase (GS) and phosphorylase brain- (GPbb; glucoprivic-sensitive) and muscle (GPmm; norepinephrine-sensitive) variant proteins were examined. Results VMN aromatase protein content was similar between sexes. Intracerebroventricular LZ infusion of testes-intact male and ovariectomized, estradiol-replaced female rats blocked insulin-induced hypoglycemic (IIH) up-regulation of this profile. LZ exerted sex-contingent effects on basal VMN nNOS and GAD expression, but blocked IIH-induced NO stimulation and GAD suppression in each sex. Sex-contingent LZ effects on basal and hypoglycemic patterns of GPbb and GPmm expression occurred at distinctive levels of the VMN. LZ correspondingly down- or up-regulated baseline pyruvate recycling pathway marker protein expression in males (glutaminase) and females (malic enzyme-1), and altered INS effects on those proteins. Conclusions Results infer that neuroestradiol is required in each sex for optimal VMN metabolic transmitter signaling of hypoglycemic energy deficiency. Sex differences in VMN GP variant protein levels and sensitivity to aromatase may correlate with sex-dimorphic glycogen mobilization during this metabolic stress. Neuroestradiol may also exert sex-specific effects on glucogenic amino acid energy yield by actions on distinctive enzyme targets in each sex.

中文翻译：

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大鼠腹内侧下丘脑核糖调节递质和糖原代谢酶蛋白表达的性别二态性神经雌二醇调节

背景 腹内侧下丘脑核 (VMN) 葡萄糖调节传递受雌二醇的性别特异性控制。VMN 的特点是高水平的芳香酶表达。方法 芳香酶抑制剂来曲唑 (LZ) 与高分辨率显微切割/蛋白质印迹技术一起使用，以解决神经雌二醇对 VMN 神经元一氧化氮合酶 (nNOS) 和谷氨酸脱羧酶 65/67 (GAD) 蛋白表达施加性别二态性控制的假设. 糖原代谢影响 VMN nNOS 和 GAD 谱；在这里，检查了 LZ 治疗对 VMN 糖原合酶 (GS) 和磷酸化酶脑（GPbb；葡萄糖敏感）和肌肉（GPmm；去甲肾上腺素敏感）变异蛋白的影响。结果 VMN 芳香酶蛋白含量在两性之间相似。睾丸完好的雄性和去卵巢、雌二醇替代的雌性大鼠的脑室内 LZ 输注阻止了胰岛素诱导的低血糖 (IIH) 上调。LZ 对基础 VMN nNOS 和 GAD 表达产生性别影响，但在每个性别中都阻止了 IIH 诱导的 NO 刺激和 GAD 抑制。LZ 对 GPbb 和 GPmm 表达的基础和低血糖模式的影响发生在 VMN 的不同水平上。LZ 相应地下调或上调雄性（谷氨酰胺酶）和雌性（苹果酸酶-1）中基线丙酮酸再循环途径标记蛋白的表达，并改变了 INS 对这些蛋白质的影响。结论 结果表明，对于低血糖能量缺乏的最佳 VMN 代谢递质信号传导，每个性别都需要神经雌二醇。VMN GP 变异蛋白水平的性别差异和对芳香酶的敏感性可能与这种代谢压力期间的性别二态性糖原动员相关。神经雌二醇还可以通过作用于不同性别的不同酶靶点，对生糖氨基酸能量产量产生性别特异性影响。