高脂饮食通过调节下丘脑LKB1诱导食源性肥胖发生的机制研究

肝激酶B1（LKB1）是AMPK的重要激酶，参与调节细胞代谢，其在肥胖发生中的作用及机制尚待深入探讨。NAD+是近年肥胖治疗的靶点之一。下丘脑持续性炎症反应是肥胖发生的主要原因。本课题组前期工作提示高脂饮食（HFD）降低下丘脑LKB1水平，LKB1可能对POMC神经元有保护作用。为揭示HFD降低下丘脑LKB1的原因，和LKB1对POMC神经元的主要作用及机制，本项目拟利用细胞实验，明确高脂引起的NAD+-SIRT1-PPARγ的下降是否导致LKB1降低，明确PPARγ是否直接调控LKB1的转录，观察LKB1在高脂诱导的炎症环境中对POMC神经元细胞系的作用及机制；在动物实验中，利用体视学计数、激光捕获显微切割等技术，系统的观察生理状态下LKB1对POMC神经元功能的影响；验证在细胞实验中观察到的机制。本项目拟对POMC神经元的LKB1进行较为系统的研究，为肥胖的发病机制和治疗提供新理论。

Liver kinase B1 (LKB1) is an important kinase of AMPK, which is involved in the regulation of cell metabolism. Its role and mechanism in the development of obesity need to be further explored. NAD + is one of the targets of obesity treatment in recent years. Persistent inflammation of the hypothalamus is the main cause of obesity. Our previous work suggested that high-fat diet (HFD) reduced the level of LKB1 in hypothalamus, which might have protective effect on POMC neurons. In order to reveal the reason why HFD reduces LKB1 in hypothalamus, and the main effect and mechanism of LKB1 on POMC neurons, this project intends to use cell experiment to determine whether the decrease of NAD + - SIRT1-PPAR γ caused by high fat causes the decrease of LKB1, to determine whether PPAR γ directly regulates the transcription of LKB1, and to observe the effect and mechanism of LKB1 on POMC neuron cell line in the inflammatory environment induced by high fat; in animal experiment In addition, the effects of LKB1 on the function of POMC neurons in physiological state were systematically observed by stereological counting and laser capture microdissection, and the mechanism observed in cell experiments was verified. In this project, LKB1 of POMC neurons will be studied systematically to provide a new theory for the pathogenesis and treatment of obesity.