Brain Estrogen Regulates Energy and Glucose Balance

项目摘要 绝经后妇女循环中17β-雌二醇（E2）的急剧下降与以下因素有关： 肥胖和葡萄糖调节障碍的发展。绝经后妇女服用E2 虽然雌激素治疗可以纠正这些问题，但雌激素治疗往往伴随着副作用，包括生殖 内分泌毒性和乳腺癌。靶向特异性雌激素受体（ER）和ER表达 在人群中使用这种药物可能会产生抗肥胖和抗糖尿病的益处，副作用较少。我们证明 下丘脑腹内侧腹外侧亚部（vlVMH）的雌激素受体α（ERα）是 维持体重和葡萄糖平衡至关重要。在这里，我们试图解开分子和 这些ERα神经元的神经回路机制，通过测试的一般假设，E2敏感 ERαvlVMH神经元检测营养/血糖波动，并招募多个下游神经元， 维持能量和葡萄糖稳态的回路。第一个目标是确定葡萄糖和 ERα vlVMH起源的投射到一些脑区的能量调节作用，包括背侧 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Abcc 8和Ano 4，是否调节放电 ERαvlVMH神经元对血糖和/或进食状态的各种改变的反应;我们还将 检查这些通道对全身能量/葡萄糖平衡的生理功能。第三 目的建立一个新的ERα靶基因Clic 1，并探讨Clic 1在ERαvlVMH中的作用 神经元介导E2的作用以维持能量和葡萄糖平衡。完成这些研究 将阐明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ERα vlVMH起源的神经网络，响应这些变化，因此 恢复能量/葡萄糖稳态。我们还将描述E2调节的分子机制， ERαvlVMH神经元功能和能量/葡萄糖平衡，并可能确定治疗糖尿病的潜在靶点。 与更年期有关的代谢紊乱。

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.