Hypothalamic mechanisms mediating estrogenic regulation of energy homeostasis

描述（由申请人提供）： 肥胖症发病率的增加是世界面临的主要健康问题，并且增加对体重调节的理解可能导致对抗肥胖症和相关疾病（例如糖尿病）的有效策略。性激素，雌激素，在维持正常体重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。因此，所提出的研究的一个目的是确定雌激素的抗肥胖作用是否由一种雌激素受体亚型ER（，由特定的脑细胞群，即POMC神经元和SF 1神经元表达）介导。为此，我们将产生具有ER（在POMC神经元和/或SF 1神经元中选择性缺失）的小鼠模型，并评估由雌激素诱导的代谢益处是否在这些动物中被废除。我们还将产生POMC或SF 1神经元缺乏PI 3激酶活性的小鼠，PI 3激酶是一种由雌激素激活的细胞内分子。通过评估雌激素在这些小鼠中的作用，我们将确定PI 3激酶是否是雌激素对能量平衡的作用所必需的。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): The increasing incidence of obesity is a major health issue facing the world and increased understanding of body weight regulation may lead to effective strategies to combat obesity and related disorders, such as diabetes. The sex hormone, estrogen, plays a beneficial role in maintaining normal body weight 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 diseases. Thus, one objective of the proposed study is to determine whether the anti-obesity effects of estrogen are mediated by one estrogen receptor isoform, ER(, expressed by specific populations of brain cells, namely POMC neurons and SF1 neurons. To this end, we will generate mouse models with ER( deleted selectively in POMC neurons and/or SF1 neurons, and assess whether the metabolic benefits induced by estrogen are abrogated in these animals. We will also generate mice whose POMC or SF1 neurons lack activity of PI3 kinase, which is an intracellular molecule activated by estrogen. By assessing effects of estrogen in these mice, we will determine if the PI3 kinase is required for estrogenic actions on energy 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, but also help identify rationale targets for developing more specific estrogen therapies that provide metabolic benefits with no or fewer side effects.