下丘脑GPR45与leptin信号互作机制研究

肥胖是现代社会面临的重大健康挑战。我们用基因突变小鼠筛选肥胖相关基因时，发现G蛋白偶联受体GPR45失活抑制下丘脑JAK2/STAT3通路，影响弓形核POMC表达及POMC神经元活性，虽不改变进食，但导致个体能量消耗减少和肥胖。我们进一步发现GPR45与瘦素（leptin）信号存在明确功能互作。Leptin是下丘脑调控代谢的主要信号系统，可通过POMC神经元影响进食、产热和能量消耗，失活可致严重肥胖，但其功能多样性具体机制还不明确。我们的发现为解析leptin信号多样性提供了新视角。本项目将分析GPR45和leptin受体LepR突变小鼠的代谢变化，下丘脑GPR45和LepR的组织细胞分布，以及分子和细胞水平的互作方式，明确下丘脑GPR45与leptin信号间的影响方式、交汇节点和分子调控，了解其对神经元发育和功能及个体代谢的影响，为下丘脑代谢调控机制提供新知识，为干预肥胖提供新启示。

Obesity is one of the most prominent health threats in modern society. We have identified GPR45 through a genetic screen for obese loci in mice. GPR45 encodes an orphan G protein coupled receptor that mainly expresses in the centeral nervous system. Hypothalamic JAK2/STAT3 signaling is suppressed in GPR45 mutants, so do POMC expression and the neuronal activity of POMC neurons. GPR45 disruption does not interfere with food intake, but reduces energy expenditure, which leads to obesity in young animals. Our further analysis detected genetic interactions between GPR45 and leptin signaling, as animals bearing mutations of both GPR45 and leptin receptor (LepR) exhibit obesity LepR dependently. Leptin/LepR signaling is well known as the major signaling systems involved in hypothalamic regulation of energy metabolism. Deleting LepR in POMC neurons causes not only morbid obesity, but also hyperphagia, decreased thermogenesis, and reduced energy expenditure. Given overlapped phenotypes and clear genetic interaction we found, GPR45 provides an unique opportunity to dissect cellular and molecular mechanism underlying complex fucntions of leptin singaling and POMC neurons. Thus, we propose detailed phenotypic, cellular, expressional, and molecular analysis of the interaction between GPR45 and leptin signaling in mutant animals and cultured cells. By revealing the mechanisms regulating GPR45 and leptin signal crosstalk, we shall deepen our understanding of hypothalamic functions in metabolic regulation, and may find new insights benefiting the campaign against obesity.