基于新GPCR突变的肥胖小鼠模型鉴定与研究

Obesity is a rapidly increasing health threat related to cardiovascular diseases, diabetes, and cancer. Only small progresses have been achieved in efficient interference of overweight and obesity in modern society, due to the lack of mechanistic understanding of this process. Limited choices of animal models further delayed the study in the field. We found loss-of-function mutation of an orphan G protein-coupled receptor (GPCR) led to severe obesity in mice. The mutants exhibited different metabolic related phenotypes than popular obese mouse models, indicating the potential of this strain to act as a novel animal model of obesity. In addition, the nature of GPCR itself makes this protein a good candidate as therapeutic targets. We propose detailed characterization of development and progress of obesity and related phenotypes, as well as the effect brought by diet or different genetic backgrounds in the strain. We also propose analysis targeting pathphysiological mechanisms and potention contribution of GPCR mutations to human obesity. Finally, we propose to test the potential value of this GPCR as an obesity intervention target in transgenic mice. This study will establish a new animal model for obesity. It will also deepen our knowledge of the biological mechanisms underlying obesity, and provide new hints for disease intervention.

肥胖是现代社会面临的重大健康挑战，缺乏持久有效干预方法。肥胖小鼠模型选择有限，难以满足疾病机理和干预研究需要。我们发现一种未知功能G蛋白偶联受体(GPCR)突变小鼠显著肥胖，相关表型与常用肥胖小鼠品系存在差异，可望成为新的肥胖动物模型。作为GPCR家族的一员，该基因也有成为干预靶标的良好潜力。本项目将深入分析突变小鼠肥胖及相关表型的发生发展，掌握饮食等外界环境和不同遗传背景对表型的可能影响，分析突变小鼠肥胖的病理生理机制，探索该GPCR作为药物靶点的可行性和基因突变对人群肥胖的贡献。项目工作将鉴定一种新的肥胖动物模型，为进一步了解肥胖发生发展分子机制，寻找肥胖干预方法提供新的视角与线索。

肥胖是现代社会面临的重大健康挑战，但缺乏持久有效干预方法。肥胖小鼠模型选择有限，难以满足疾病机理和干预研究需要。我们发现G蛋白偶联受体GPR45突变造成小鼠显著肥胖。为研究GPR45突变小鼠作为新的肥胖动物模型的价值，以及GPR45充当肥胖干预靶标的潜力，项目分析了基因突变小鼠肥胖及相关表型的发生发展过程，检验了饮食等外界环境和不同遗传背景对表型的可能影响，研究了突变小鼠肥胖的病理生理机制。.项目研究发现GPR45突变出生后三周内即发生肥胖，并可进一步引发糖代谢异常和脂肪肝。GPR45失活可通过JAK2/STAT3通路影响下丘脑POMC基因活性，虽不影响进食，但减少小鼠能量消耗。GPR45突变引发小鼠肥胖不受小鼠遗传背景影响，但会在高脂饮食下加剧，改变GPR45信号通路活性可以逆转小鼠肥胖。这些结果显示，GPR45可以用于培育新的肥胖动物模型，并有作为干预肥胖靶点的潜力。.同时，项目组制备了小鼠GPR45抗体，培育了融合YFP标记的GPR45基因敲入小鼠，引进并检验了用于下丘脑神经元发育及功能研究的一批工具品系，为进一步探索GPR45对神经发育和神经调控代谢功能的机制奠定了扎实基础。