目前肥胖症流行趋势加重，其心血管疾病等并发症造成沉重医疗负担。近年研究提示肥胖受“遗传与环境交互作用”影响，但鲜有明确病因报道。申请人在人群遗传研究中发现，LGR4基因p.A750T点突变与性别交互作用影响中心性肥胖等代谢表型。人源化小鼠模型显示，A750T点突变促进雌性体脂增加、代谢紊乱及棕色脂肪白色化，但在雄性未发现该效应；与人群结果一致。前期研究提示，雄激素受体（AR）信号对肥胖等代谢指标的调节在雌雄两性之间不同，而LGR4在性腺系统可促进AR表达。我们的结果也表明，在白色脂肪组织中LGR4与AR表达高度一致。据此，本课题拟在前期研究基础上利用人源化小鼠模型进一步阐释LGR4基因A750T点突变通过AR调控不同性别脂肪分化和能量平衡的作用及机制，并通过人群随访探究“A750T点突变与性别交互作用”是否增加肥胖发生风险。本项目将为肥胖的个体化、精准化干预提供科学依据。

Obesity is in a worldwide epidemic, and its complications such as cardiovascular diseases impose a heavy burden on individuals and the whole society. Studies suggest that gene and environment impose an interactive effect on obesity, but few reported its mechanism. In the population genetic study, the applicant has found that an A750T mutation of LGR4 interacted with sex on affecting metabolic phenotypes such as central obesity. Furthermore, we constructed a mouse model with A750T mutation. In female mice, A750T mutation significantly promoted body fat increase, metabolic disorder and whitening in brown fat after high-fat diet feeding, but no such effect was observed in male mice. It has been reported in previous literatures that the influence of androgen receptor (AR) signaling on metabolic abnormalities such as obesity is in opposite direction for different sex and that LGR4 elevated AR expression in prostate cells. We further found that the expressions of LGR4 and AR were consistent in the white adipose of mice: higher in visceral fat than in subcutaneous fat, and higher in males than in females. Therefore, we would take a further step to construct a moue model with conditional AR-knockout and perform detailed experiments in primary adipocytes, to fully explain how A750T mutation affect adipocyte differentiation and regulate energy metabolism via AR pathway. Additionally, we would also investigate the association of the interaction effect between A750T mutation and sex on risks of incident obesity in the follow-up study of population cohort. This project would provide scientific evidence for precision approaches on prevention and treatment of obesity.