Brain Estrogen Regulates Energy and Glucose Balance

大脑雌激素调节能量和血糖平衡

基本信息

批准号：
10032667
负责人：
YONG XU
金额：
$ 40.33万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10032667
关键词：
Biochemistry Blood Glucose Body Weight Brain Brain region Clustered Regularly Interspaced Short Palindromic Repeats Diabetes Mellitus Eating Endocrine Energy Metabolism Equilibrium Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogen Therapy Estrogens Female Fiber Functional disorder Gene Deletion Genes Genetic Genetic Transcription Glucose Homeostasis Hypothalamic structure Impairment Ion Channel Lead Medial Mediating Menopause Metabolic Metabolic Diseases Modeling Molecular Molecular Biology Mus Neurons Nutrient Nutritional Obesity Ovarian hormone Ovariectomy Pharmacology Photometry Physiological Pilot Projects Play Population Postmenopause Rest RiboTag Role Signal Transduction Site Structure of nucleus infundibularis hypothalami Testing Toxic effect Woman base blood glucose regulation dorsal raphe nucleus energy balance feeding female sex hormone gain of function malignant breast neoplasm neural circuit neural network novel obesity development obesity treatment optogenetics overexpression patch sequencing prevent recruit reproductive response side effect

项目摘要

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.

项目概要绝经后女性循环 17β-雌二醇 (E2) 的急剧下降与绝经后妇女服用 E2 会导致肥胖和血糖失调。虽然可以纠正这些问题，但雌激素治疗通常会带来副作用，包括生殖副作用内分泌毒性和乳腺癌。针对特定雌激素受体 (ER) 和 ER 表达。我们证明了，它可以产生抗肥胖和抗糖尿病的功效，同时副作用也更少。下丘脑腹内侧区（vlVMH）的雌激素受体-α（ERα）是对于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葡萄糖之间的关系。通过测试 E2 敏感的一般假设，研究这些 ERα 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稳态的电路第一个目标是确定葡萄糖和葡萄糖。 ERαvlVMH 起源的投射对一些大脑区域（包括背侧）的能量调节作用第二个是中缝核（DRN）和下丘脑内侧后弓状核（mpARH）。目的是确定两个离子通道基因，即 Abcc8 和 Ano4 是否调节放电我们还将观察 ERαvlVMH 神经元对血糖和/或进食状态的各种变化的反应；检查这些通道对全身能量/葡萄糖平衡的生理功能。目的是将Clic1建立为新的ERα靶基因，并确定Clic1是否存在于ERαvlVMH中神经元介导 E2 的作用来维持能量和葡萄糖平衡。将揭示 ERαvlVMH 神经元检测能量和葡萄糖动态变化的离子机制平衡，并揭示了源自 ERαvlVMH 的神经网络对这些变化做出反应，因此我们还将描述 E2 调节的分子机制。 ERαvlVMH 神经元功能和能量/葡萄糖平衡，并可能确定治疗的潜在靶点与更年期相关的代谢紊乱。