CNS Circuits Mediating Estrogenic Regulation on Energy and Glucose Homeostasis

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对抗肥胖和糖尿病的有效策略。当女性进入更年期后，患肥胖症和糖尿病的风险急剧增加时，性激素雌激素在维持正常体重和葡萄糖平衡方面起着有益的作用。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引起不必要的影响，例如癌症和心脏病。有证据表明，雌激素在大脑中起到减轻体重和改善血糖水平的作用，但这些有益作用的机制尚不完全清楚。为此目的，本次赠款将实现三个目标。(1)研究表明，雌激素通过作用于雌激素受体ER1来抑制食物摄入并改善葡萄糖平衡，ER1存在于脑细胞亚群中，即POMC神经元中。然而，这些POMC神经元募集的下游神经回路介导雌激素的作用尚不清楚。将生成的小鼠模型中，黑素皮质素4受体（MC4R）， POMC产物的受体，将在零背景下在大脑的两个不同部位重新表达。这些模型将用于确定这些部位的MC4R是否足以介导雌激素的厌氧性和抗糖尿病作用。(2) ER1在另一群脑细胞（SF1神经元）中的作用显示增加能量消耗，但ER1启动的细胞内信号传导实现这种调节尚不清楚。仅在SF1神经元中缺失FoxO1的小鼠将被用来确定SF1神经元中FoxO1是否需要介导雌激素对能量消耗的影响。(3)最后，我们将研究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。这些小鼠将被用来确定杏仁核中的ER1是否提供冗余机制来调节能量和葡萄糖平衡。因此，这项研究不仅将促进我们对性激素调节大脑功能的机制的理解，以提供对体重和葡萄糖的协调调节，而且还有助于确定合理的目标，以开发更具体的雌激素疗法，提供无副作用或较少副作用的代谢益处。

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.