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风险因素，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。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，因为女性在进入更年期时患肥胖症和糖尿病的风险显着增加。激素替代疗法可能是降低这些风险的一种方法，但雌激素通过其受体在外周组织中的作用会引起不必要的影响，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谱，但这些有益作用的机制尚未完全了解。为此，本次赠款将实现三个目标。(1)已经表明，雌激素通过作用于存在于脑细胞亚群（即POMC神经元）中的一种雌激素受体亚型ER 1来抑制食物摄入并改善葡萄糖平衡。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仍然未知。将产生小鼠模型，其中黑皮质素4受体（MC4R）（POMC产物的受体）将在空白背景下在脑的两个不同部位中重新表达。这些模型将用于确定这些部位中的MC4R是否足以介导雌激素的促孕和抗糖尿病作用。(2)ER 1在另一群脑细胞（SF 1神经元）中的作用显示出增加能量消耗，但ER 1启动的细胞内信号传导以实现这种调节尚不清楚。将使用仅在SF 1神经元中缺失FoxO1的小鼠来确定SF 1神经元中的FoxO1是否需要介导对能量消耗的雌激素效应。(3)最后，将检查ER 1在其他脑部位的功能。将产生仅在前脑结构杏仁核中缺失ER 1的小鼠。这些小鼠将用于确定杏仁核中的ER 1是否提供了调节能量和葡萄糖平衡的冗余机制。因此，拟议的研究不仅将促进我们对性激素调节大脑功能以协调调节体重和葡萄糖的机制的理解，而且还有助于确定开发更具体的雌激素治疗的合理目标，这些治疗提供代谢益处，没有或很少副作用。

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.