Regulation of Food Intake and Body Weight by Hypothalamic ERAlpha

描述（由申请人提供）：肥胖及其相关的健康障碍和成本正在增加。男性和女性的脂肪分布以及与之相关的患心血管疾病、2型糖尿病、某些癌症和其他疾病的风险是不同的。男性和绝经后的女性比年轻女性患肥胖症并发症的风险更大。下丘脑腹内侧区（VMM）是调节能量稳态的重要区域，其两个亚区腹外侧区（VL VMM）和弓形区（ARC）响应激素和其他信号来控制能量的摄入和消耗。当包括VL VMM和ARC的大VMM病变发生时，动物，特别是雌性，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），因为雌激素的减少也会导致肥胖，因为雌激素介导大脑对瘦素的敏感性，我们假设当VMM发生病变时，雌激素信号的减少和随之而来的瘦素信号的减少是导致体重增加的原因。本研究的目的直接来自于这些观察结果，并将确定雌激素信号通过ERa在ARC和VL VMN中调节食物摄入和体重的相对贡献。具体地说，我们将确定雌激素信号通过上下腔静脉网络或ARC中的ERa是否必要和/或充分调节食物摄入和体重。我们的研究结果将与增加我们对雌激素调节体重的机制的理解直接相关，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。

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.