CNS Circuits Mediating Estrogenic Regulation on Energy and Glucose Homeostasis

描述(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，对体重调节的了解增加可能会导致有效的战略来对抗肥胖和糖尿病。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，因为当女性进入更年期时，患肥胖症和糖尿病的风险会急剧增加。激素替代疗法可能是降低这些风险的一种方法，但雌激素通过其外周组织中的受体发挥作用会产生不必要的影响，如癌症和心脏病。有证据表明，雌激素在大脑中起作用，以减轻体重和改善血糖状况，但这些有益效果背后的机制尚不完全清楚。为此，目前的赠款将追求三个目标。(1)已有研究表明，雌激素通过作用于一种雌激素受体亚型ER1来抑制食物摄取和改善葡萄糖平衡，该受体存在于脑细胞的一个亚群，即POMC神经元中。然而，这些POMC神经元招募的下游神经回路调节雌激素的作用仍不清楚。将建立小鼠模型，在该模型中，POMC产物的受体黑素皮质素4受体(MC4R)将在零背景下在大脑的两个不同位置重新表达。这些模型将被用来确定这些部位的MC4R是否足以调节雌激素的厌食和抗糖尿病作用。(2)ER1在另一组脑细胞(SF1神经元)中的作用被证明增加了能量消耗，但ER1启动的细胞内信号转导实现这一调节的机制尚不清楚。只在SF1神经元中缺失FoxO1的小鼠将被用来确定SF1神经元中的FoxO1是否需要介导能量消耗的雌激素效应。(3)对ER1在其他脑区的功能进行研究。只有在前脑结构杏仁核中ER1缺失的小鼠才会出生。这些小鼠将被用来确定杏仁核中的ER1是否提供了调节能量和葡萄糖平衡的多余机制。因此，这项拟议的研究不仅将增进我们对性激素调节大脑功能以提供体重和血糖协调调节的机制的理解，还将有助于确定合理的靶点，以开发更具体的雌激素疗法，提供没有或更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.