申请人长期致力于肥胖症发病机制研究。组建肥胖课题组，建立完善的、高质量肥胖研究平台，包括中国早发性肥胖研究队列（GOCY）、能量代谢基础研究系列平台以及多种基因修饰小鼠模型。基于队列二代测序，原创性发现LGR4激活变异显著增加肥胖发生风险，借助动物模型揭示LGR4通过调节白色脂肪棕色化参与肥胖发生的机制。发现新肥胖候选致病基因TUT1和NPC1，揭示其低频变异导致肥胖发生的机制。并开展肥胖相关代谢紊乱研究，揭示LGR4 通过调控醛固酮受体途径调节水盐代谢和血压的分子机制，发现LGR4调控脂代谢节律等。以第一或通讯作者在Nat Cell Biol、JASN、JME等期刊发表成果。本项目拟延续前期工作，结合临床队列与动物模型深入探讨LGR4配体RSPO1在米色脂肪分化与体重调节中的作用，阐明RSPO1/LGR4通过经典Wnt通路调控肥胖发生的机制，为减重药物开发提供新靶点，促进临床转化。

The applicant has been engaged in the exploration of the mechanisms of obesity and intervention targets for obesity. Under his leadership, the research group systematically conducted the screening of candidate genes for obesity and further validation with functional study. They found a functional variant of LGR4 gene in a Chinese obese-control study, which significantly increases the risk for human obesity. By analyzing Lgr4 gene knockout mice, they demonstrate that LGR4 promotes energy accumulation and obesity by inhibiting beige adipocyte differentiation through regulating Rb1 expression. They also identified low-frequency variants of NPC1 gene, which dramatically increase the risk for human obesity by 9 folds, and demonstrated NPC1 hypoinsufficiency promotes body weight gain in mice. The research group also conducted studies of the molecular mechanism of obesity-related metabolic syndrome. They found that LGR4 regulates blood pressure by mineralocorticoid receptor signaling pathway. Besides, they first reported the role of LGR4 in regulating plasma lipid rhythms. Based on these major findings, the applicant has published 5 representative papers in high-quality journals on medical science, Nature Cell Biology, Journal of the American Society of Nephrology and Journal of Molecular Endocrinology as first or corresponding author. The total impact factors of the 5 publications are 40.58 and the highest one is 20.06. The applicant has 9 SCI publications in total, which were cited 35+ times by others. This project aims (1) to study the role of the potential LGR4 ligand, RSPO1 in adipocyte differentiation and body weight regulation using gene knockout mouse models; (2) to demonstrate the molecular mechanisms of RSPO1/LGR4/Wnt signaling in regulating beige adipocyte differentiation and obesity. This will not only provide evidence for understanding the mechanisms for obesity, but also provide potential intervention targets for obesity.