Brain Estrogen Regulates Energy and Glucose Balance

项目总结 绝经后妇女血液中17β-雌二醇(E_2)的急剧下降与 肥胖和血糖失调的发展。绝经后妇女服用雌二醇组 可以纠正这些问题，雌激素治疗往往与副作用有关，包括生殖 内分泌毒性与乳腺癌。靶向雌激素受体与雌激素受体的表达 人群可能会产生抗肥胖和抗糖尿病的好处，副作用更少。我们演示了 下丘脑腹内侧亚区(V1VMH)内雌激素受体-α(ER-α)是 维持体重和葡萄糖平衡所必需的。在这里，我们试图解开分子和 通过检验雌激素敏感的一般假说来研究这些ER-α神经元的神经回路机制 ERαvlVMH神经元检测营养/血糖波动，并招募多个下游神经元 维持能量和葡萄糖动态平衡的回路。第一个目标是确定葡萄糖和 内质网αv1VMH对包括背侧在内的几个脑区的能量调节作用 中缝核(DRN)和下丘脑内侧后弓状核(MpARH)。第二 目的是确定两个离子通道基因，即Abcc8和Ano4是否调节放电 ERαvlVMH神经元对血糖和/或摄食状态的各种变化的反应；我们还将 研究这些通道在全身能量/葡萄糖平衡中的生理功能。第三 目的：建立一个新的ERα靶基因clic1，并研究其在ERαvlVMH中的作用。 神经元介导E2维持能量和葡萄糖平衡的作用。完成这些研究 将揭开ERαvlVMH神经元检测能量和葡萄糖动态变化的离子机制 平衡并揭示ERαvlVMH起源的神经网络对这些变化做出反应，因此 恢复能量/葡萄糖动态平衡。我们还将描述E2调控的分子机制 ERαv1 VMH神经元功能和能量/糖平衡，并可能识别潜在的治疗靶点 与更年期相关的代谢紊乱。

PROJECT SUMMARY Dramatic decline in circulating 17β-estradiol (E2) in post-menopausal women has been associated with development of obesity and glucose dysregulations. While E2 administration in post-menopausal women may correct these issues, the estrogen therapy is often associated with side effects, including reproductive endocrine toxicity and breast cancer. Targeting specific estrogen receptors (ERs) and ER-expressing populations may produce anti-obesity and anti-diabetes benefits with fewer side effects. We demonstrated that estrogen receptor-α (ERα) in the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH) is essential to maintain body weight and glucose balance. Here we seek to unravel the molecular and neurocircuitry mechanisms for these ERα neurons by testing a general hypothesis that E2-sensitive ERαvlVMH neurons detect nutritional/glycemic fluctuations, and recruit multiple downstream neural circuits to maintain energy and glucose homeostasis. The first objective is to determine the glucose and energy-regulatory effects of the ERαvlVMH-originated projections to a few brain regions, including the dorsal Raphe nuclei (DRN) and medial posterior arcuate nucleus of the hypothalamus (mpARH). The second objective is to determine whether two ionic channel genes, namely, Abcc8 and Ano4, regulate the firing responses of ERαvlVMH neurons to various alterations in blood glucose and/or feeding states; we will also examine the physiological functions of these channels on whole-body energy/glucose balance. The third objective is to establish Clic1 as a novel ERα target gene, and to determine whether Clic1 in ERαvlVMH neurons mediates actions of E2 to maintain energy and glucose balance. Accomplishment of these studies will unravel ionic mechanisms by which ERαvlVMH neurons detect dynamic changes in energy and glucose balance, and reveal the ERαvlVMH-originated neural networks that respond to these changes and therefore restore energy/glucose homeostasis. We will also delineate molecular mechanisms by which E2 regulates ERαvlVMH neuron functions and energy/glucose balance, and may identify potential targets for treatment of metabolic disorders associated with menopause.