肥胖是当今全球需共同面对的健康问题。雌激素具有调控女性体重及增加糖耐量、改善胰岛素敏感性的作用，但雌激素可能增加心脏疾患及乳腺癌的风险，限制了其临床应用。因此，确定调节体重及血糖的关键雌激素受体亚型、受体作用部位及下游信号通路将对研制高选择性且副作用少的肥胖及糖尿病治疗方法带来极大帮助。既往研究发现雌激素受体α（ERα）参与了下丘脑POMC神经元调控能量及葡萄糖代谢稳态，但对于ERα作用的信号通路目前尚不清楚。本研究拟通过利用条件性基因调控Cre-loxP技术构建下丘脑阿片-促黑素细胞皮质素原（pro-opriomelanocortin,POMC）神经元PI3K信号通路被特异性敲除的小鼠模型,探索ERα-PI3K信号通路是否参与了雌激素介导的POMC神经元调控能量及葡萄糖平衡的作用。本研究的开展将为今后寻找高选择性且低副作用的治疗肥胖及糖尿病新方法提供坚实的理论基础。

Obesity is now recognized as a serious global health problem .The ovarian steroid estrogen contributes to normal body weight regulation and glucose homeostasis in females. However, current estrogen replacement therapy is often associated with increased risk of heart diseases and breast cancer.Therefore, identification of the critical estrogen receptor (ER) isoforms, ER sites and the downstream mechanisms that mediate the anti-obesity and anti-diabetic properities of esotrogen may facility development of highly selective therapies that can treat obesity and diabetes and cause no of fewer side effects.Previous studies showed that ERαin POMC neurons is required to mediated the effects of body weight, food intake and glucose homeostasis.However, the ERα signaling pathway in POMC neurons is not clear. In this study, we are going to take advantage of Cre-loxP technique to generate a mouse model which PI3K signaling pathway in POMC neurons is specific deleted.Then we will usie this mouse model to investigate if ERα-PI3K signaling pathway in POMC neurons is required to mediate the effects of estrogen to suppress body weight and improve insulin sensitivity and glucose tolerance. This study will supply solid theary basis of develpoment high selective therapies with low side effects in treating obesity and diabetes.