CNS Circuits Mediating Estrogenic Regulation on Energy and Glucose Homeostasis

中枢神经系统回路介导雌激素对能量和血糖稳态的调节

基本信息

批准号：
8338904
负责人：
YONG XU
金额：
$ 30.02万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-27 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8338904
关键词：
Address Adverse effects Agonist American Amygdaloid structure Animals Arts Body Weight Brain Brain region Breast Cardiovascular Diseases Cessation of life Choline O-Acetyltransferase Coupled Cytoplasm Development Diabetes Mellitus Eating Energy Metabolism Equilibrium Estradiol Estrogen Receptor 2 Estrogen Receptors Estrogen Replacement Therapy Estrogen Therapy Estrogens Etiology Event Exclusion Fatty acid glycerol esters Feeding behaviors Female Functional disorder Gene Targeting Genes Glucose Glucose Intolerance Gonadal Steroid Hormones Grant Heart Diseases Homeostasis Hormone replacement therapy Hyperphagia Hypothalamic structure Individual Insulin Lead Malignant Neoplasms Mediating Mediator of activation protein Melanocortin 4 Receptor Menopause Metabolic Methods Mind Modeling Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Ovarian hormone Overweight Peripheral Phenotype Physical activity Play Population Postmenopause Prevalence Property Prosencephalon Protein Isoforms Recruitment Activity Regulation Replacement Therapy Research Risk Risk Factors Role Series Signal Pathway Signal Transduction Site Structure System Technology Testing Tissues Woman blood glucose regulation brain cell combat design diabetic effective therapy feeding global health heart disease risk improved insulin sensitivity male malignant breast neoplasm mouse model mutant neural circuit novel premature programs receptor relating to nervous system research study restoration transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Obesity is a major risk factor for type II diabetes and cardiovascular disease and increased understanding of body weight regulation may lead to effective strategies to combat obesity and diabetes. The sex hormone, estrogen, plays a beneficial role in maintaining normal body weight and glucose balance as women show dramatically increased risks for developing obesity and diabetes when they enter menopause. Hormone replacement therapy may be a way to reduce these risks, but actions of estrogen via its receptors in the peripheral tissues cause unwanted effects, such as cancer and heart disease. Evidence indicates that estrogen acts in the brain to reduce body weight and improve glucose profile, but the mechanisms underlying these beneficial effects are not fully understood. To this end, three objectives will be pursued in the current grant. (1) It has been shown that estrogen suppresses food intake and improves glucose balance by acting upon one estrogen receptor isoforms, ER1, present in a subset of brain cells, namely POMC neurons. However, the downstream neural circuits recruited by these POMC neurons to mediate effects of estrogen remain unknown. Mouse models will be generated in which melanocortin 4 receptor (MC4R), the receptor for the POMC product, will be re-expressed in two distinct site of the brain at the null background. These models will be used to determine if MC4R in these sites is sufficient to mediate anorexigenic and anti-diabetic effects of estrogen. (2) Actions of ER1 in another population of brain cells (SF1 neurons) are shown to increase energy expenditure, but the intracellular signaling initiated by ER1 to achieve this regulation are unclear. Mice with FoxO1 deleted only in SF1 neurons will be used to determine if FoxO1 in SF1 neurons is required to mediate estrogenic effects on energy expenditure. (3) Finally, the functions of ER1 in other brain sites will be examined. Mice will be generated with ER1 deleted only in a forebrain structure, amygdala. These mice will be used to determine if ER1 in the amygdala provides redundant mechanisms to regulate energy and glucose balance. Thus, the proposed study will not only advance our understanding about the mechanisms by which sex hormone regulates brain functions to provide a coordinated regulation of body weight and glucose, but also help identify rational targets for developing more specific estrogen therapies that provide metabolic benefits with no or fewer side effects.

描述（由申请人提供）：肥胖是 II 型糖尿病和心血管疾病的主要危险因素，增加对体重调节的了解可能会导致制定对抗肥胖和糖尿病的有效策略。性激素雌激素在维持正常体重和血糖平衡方面发挥着有益作用，因为女性在进入更年期时患肥胖和糖尿病的风险显着增加。激素替代疗法可能是降低这些风险的一种方法，但雌激素通过其在外周组织中的受体的作用会导致不良影响，例如癌症和心脏病。有证据表明，雌激素在大脑中发挥作用，可以减轻体重并改善血糖状况，但这些有益作用的机制尚不完全清楚。为此，本次赠款将实现三个目标。 (1) 研究表明，雌激素通过作用于脑细胞子集（即 POMC 神经元）中的一种雌激素受体亚型 ER1 来抑制食物摄入并改善葡萄糖平衡。然而，这些 POMC 神经元招募的下游神经回路来介导雌激素的作用仍然未知。将生成小鼠模型，其中黑皮质素 4 受体 (MC4R)（POMC 产物的受体）将在空背景下大脑的两个不同位点重新表达。这些模型将用于确定这些位点的 MC4R 是否足以介导雌激素的厌食和抗糖尿病作用。 (2) ER1 在另一群脑细胞（SF1 神经元）中的作用被证明会增加能量消耗，但 ER1 启动的细胞内信号传导以实现这种调节尚不清楚。仅在 SF1 神经元中删除 FoxO1 的小鼠将用于确定 SF1 神经元中的 FoxO1 是否需要介导雌激素对能量消耗的影响。 (3)最后，将检查ER1在大脑其他部位的功能。小鼠将只在前脑结构杏仁核中删除 ER1。这些小鼠将用于确定杏仁核中的 ER1 是否提供调节能量和葡萄糖平衡的冗余机制。因此，拟议的研究不仅将增进我们对性激素调节大脑功能以协调体重和血糖的机制的理解，而且有助于确定合理的目标，以开发更具体的雌激素疗法，这些疗法可以在不影响代谢的情况下提供代谢益处。或更少的副作用。