Brain Estrogen Regulates Energy and Glucose Balance

大脑雌激素调节能量和血糖平衡

• 批准号: 10256073
• 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
• 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/10256073
• 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 prevention; obesity treatment; optogenetics; overexpression; patch sequencing; recruit; reproductive; response; side effect

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.

项目摘要 绝经后妇女循环17β-雌二醇（E2）的急剧下降与 肥胖和葡萄糖失调的发展。而在绝经后妇女的E2管理 可能会纠正这些问题，雌激素疗法通常与副作用有关，包括生殖 内分泌毒性和乳腺癌。靶向特定的雌激素受体（ER）和表达ER 种群可能会产生抗肥胖，抗糖尿病受益，而副作用较少。我们证明了 雌激素受体-α（ERα）在腹侧下丘脑（VLVMH）的腹外侧细分中 维持体重和葡萄糖平衡至关重要。在这里，我们试图揭开分子和 通过检验E2敏感的一般假设，这些ERα神经元的神经通路机制 ERαVLVMH神经元检测营养/血糖波动，并募集多个下游神经元 电路以维持能量和葡萄糖稳态。第一个目标是确定葡萄糖和 ERαVLVMH原始项目的能量调节作用，包括背侧包括背部 Raphe Nuclei（DRN）和下丘脑（MPARH）的培养基弧形核心。第二个 目的是确定两个离子通道基因（即ABCC8和ANO4）是否调节点火 ERαVLVMH神经元对血糖和/或喂养状态的各种改变的反应；我们也会 检查这些通道在全身能量/葡萄糖平衡上的物理功能。第三 目的是将Clic1建立为新型ERα靶基因，并确定ERαVLVMH中的Clic1是否 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 ERαVLVMH神经元检测能量和葡萄糖的动态变化的离子机制将揭开离子机制 平衡并揭示了响应这些变化的ERαVLVMH原始神经网络，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，并可能确定治疗的潜在靶标 与更年期相关的代谢障碍。