Regulation of Food Intake and Body Weight by Hypothalamic ERAlpha

下丘脑 ERAlpha 对食物摄入量和体重的调节

• 批准号: 7148400
• 负责人: Deborah J Clegg
• 金额: $ 28.4万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7148400
• 关键词: appetite regulatory center; behavioral /social science research tag; bioenergetics; body weight; brain regulatory center; estrogen receptors; estrogens; hormone regulation /control mechanism; hormone sensitivity /resistance; hypothalamus; laboratory mouse; laboratory rat; leptin; nutrient intake activity; nutrition related tag; receptor expression; weight control

DESCRIPTION (provided by applicant): Obesity and its associated health disorders and costs are increasing. Fat distribution and the associated risk for developing cardiovascular problems, type-2 diabetes mellitus, certain cancers and other disorders differ for men and women. Men and post-menopausal women have greater risk of developing complications of obesity than younger women. The ventromedial hypothalamus (VMM) is an important regulator of energy homeostasis, and two of its sub-areas, the ventrolateral portion (VL VMM) and the arcuate (ARC) respond to hormones and other signals to control energy intake and expenditure. When large VMM lesions are made that include both the VL VMM and the ARC, animals, especially females, eat more food, burn less energy and become obese. Because both the ARC and the VMN contain dense estrogen receptors (specifically ERa), because reducing estrogen also causes obesity, and because estrogen mediates the sensitivity of the brain to leptin, we hypothesize that when VMM lesions are made, the reduction of estrogen signaling and consequent reduction in leptin signaling are what results in increased body weight. The aims of this proposal follow directly from these observations, and will determine the relative contribution of estrogen signaling through ERa in the regulation of food intake and body weight in the ARC and the VL VMN. Specifically, we will determine if estrogen signaling through ERa in the VL VMN or the ARC is necessary and/or sufficient to regulate food intake and body weight. Our findings will have direct relevance in increasing our understanding of the mechanisms by which estrogen regulates body weight, and this will assist in determining potential therapeutic agents for menopausal women to decrease adiposity and the propensity of diseases associated with obesity.

描述（由申请人提供）：肥胖及其相关的健康障碍和费用正在增加。男性和女性的脂肪分布以及发生心血管问题、2 型糖尿病、某些癌症和其他疾病的相关风险有所不同。男性和绝经后女性比年轻女性患肥胖并发症的风险更大。下丘脑腹内侧区 (VMM) 是能量稳态的重要调节器，其两个子区域：腹外侧部分 (VL VMM) 和弓状区 (ARC) 对激素和其他信号做出反应以控制能量摄入和消耗。当发生包括 VL VMM 和 ARC 在内的大型 VMM 损伤时，动物，尤其是雌性，会吃更多的食物，燃烧更少的能量并变得肥胖。因为ARC和VMN都含有密集的雌激素受体（特别是ERa），因为减少雌激素也会导致肥胖，并且因为雌激素介导大脑对瘦素的敏感性，我们假设当VMM损伤时，雌激素信号的减少和随之而来的瘦素信号减少导致体重增加。该提案的目的直接源于这些观察结果，并将确定通过 ERa 的雌激素信号在 ARC 和 VL VMN 中食物摄入和体重调节中的相对贡献。具体来说，我们将确定通过 VL VMN 或 ARC 中的 ERa 发出的雌激素信号对于调节食物摄入和体重是否是必要和/或充分的。我们的研究结果将直接关系到我们对雌激素调节体重机制的理解，这将有助于确定更年期妇女减少肥胖和肥胖相关疾病倾向的潜在治疗药物。