肥胖发生与能量稳态的失衡有关，下丘脑弓状核神经元是调节能量平衡的关键部位。Ago2作为RISC的核心元件，参与机体重要的生理及病理过程,与肥胖症的发生密切相关。我们前期研究显示，在小鼠Vglut2兴奋性神经元中特异敲除Ago2基因，小鼠变瘦，胰岛素敏感性提高，能量消耗增加，提高机体产热；在Vgat抑制性神经元中特异敲除Ago2基因并不影响体能代谢；进一步在下丘脑POMC神经元中特异敲除Ago2基因，提高小鼠对胰岛素的敏感性，增加机体能耗，起到减轻体重的效果。由此，我们推测Ago2在下丘脑弓状核神经元中对于能量平衡和脂质代谢具有重要功能。本项目将利用多种基因工程小鼠，结合基因重组、TSE小鼠能量代谢监测、免疫荧光染色、免疫沉淀、扫描电镜、电生理等方法，研究POMC和AgRP神经元中Ago2的功能，揭示Ago2对于肥胖及代谢疾病的影响和作用机制，将为进一步发现肥胖的病因与治疗提供重要理论基础。

Obesity is related to energy imbalance between intake and expenditure. The neurons in the arcuate nuclei of the hypothalamus play key role in the energy homeostasis. As a core element of RNA-induced silencing complex, Ago2 has been involved in many physiological and pathological processes and is strongly linked to the obesity. In our previous study, mice with elimination of Ago2 in Vglut2 excitatory neurons have decreased body weight, improved overall insulin sensitivity and increased energy expenditure. While, deletion of Ago2 in Vgat inhibitory neurons has no effect on the energy homeostasis. Furthermore, mice with conditional deletion of Ago2 in POMC neurons exhibit increased insulin sensitivity and energy expenditure, and decreased body weight. Based on those results, we hypothesized that Ago2 expressing in the hypothalamic Arc neurons play an important role in the energy balance and lipid metabolism. In present project, we will use several genetically engineered mice and different advanced bio-techniques, such as genetic engineering, TSE Phenomaster metabolic cages, immunofluorescence, immunoprecipitation, electron microscope and electrophysiology. We will investigate the function of Ago2 in the POMC and AgRP neurons. This project will explore the functional mechanisms of Ago2 on the obesity and further provide basic research data for the potential clinic treatment of obesity.