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疾病和费用正在增加。男性和女性的脂肪分布和患心血管疾病、2型糖尿病、某些癌症和其他疾病的相关风险不同。男性和绝经后女性比年轻女性有更大的风险发展肥胖并发症。下丘脑腹内侧区（ventromedial hypothalamus，VMM）是能量稳态的重要调节器，其腹外侧区（ventrolateral portion，VL VMM）和弓状区（arc，ARC）对激素和其他信号作出反应，控制能量的摄入和消耗。当产生包括VL VMM和ARC的大VMM病变时，动物，特别是雌性，吃更多的食物，消耗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ER α），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的减少是导致体重增加的原因。该提案的目的直接来自这些观察结果，并将确定通过ER α调节ARC和VL VMN中的食物摄入和体重的雌激素信号传导的相对贡献。具体来说，我们将确定通过VL VMN或ARC中的ERa进行雌激素信号传导是否是调节食物摄入量和体重所必需和/或足够的。我们的研究结果将直接关系到增加我们对雌激素调节体重的机制的理解，这将有助于确定绝经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.