肥胖是世界范围内的健康问题。当脂肪组织分化能力异常抑制时，会导致血浆游离脂肪酸增加并引发其他疾病。共转录因子Yes相关蛋白（YAP）的调节与能量代谢密切相关且可抑制脂肪分化，但缺乏机制及对代谢性疾病影响的研究。申请者结合预实验提出假说：肥胖的过程中，miR-200a，200b，200c以及（或）141表达下降，使YAP的mRNA表达增加，增加的YAP通过与TEAD结合作为协同抑制因子抑制C/EBPα、C/EBPβ和（或）PPARγ的表达从而抑制脂肪分化过程，导致脂肪组织储脂能力下降，血浆中游离脂肪酸增加，引起肝脏脂质沉积、胰岛素抵抗、血脂紊乱等肥胖相关疾病。本项目将用脂肪组织YAP过表达及敲除小鼠从在体及离体水平研究：YAP在脂肪分化中的作用及机制；脂肪中的YAP对肥胖相关代谢性疾病的影响；肥胖发生时YAP的调控机制。旨在发现脂肪组织功能调节的新机制，为肥胖相关代谢性疾病的治疗提供新靶点。

Obesity is a major health problem worldwide. Adipose tissue plays a key role in determining metabolic health. Inhibiting healthy expansion in the white adipose tissue will limit lipid storage, increase free fatty acid in circulation and lead to obesity-related metabolic diseases. Yes-Associated Protein (YAP), a co-transcription factor, was regulated by energy metabolic pathways and reported to inhibit 3T3L-1 preadipocyte differentiation into mature adipocyte. However, the functions of YAP in adipose tissue and obesity-related metabolic diseases and the underlying mechanisms are still unclear and need further investigation. Based on our preliminary data, we hypothesize that in obesity status, the mRNA level of YAP will increase via downregulating miR-200a，200b，200c and/or 141. Increased YAP will inhibit adipocyte differentiation which increases free fatty acid in circulation and leads to fatty liver disease, insulin resistance and dyslipidemia. We will use adipose tissue specific YAP transgenic and knockout mice to elucidate the functions of YAP in adipocyte differentiation and the underlying mechanisms, the role of YAP in obesity-related metabolic disorders and further the mechanisms of regulation of YAP in white adipose tissue in obesity. This study may extend our knowledge of the mechanisms of white adipose tissue dysfunction and potentially contribute to the development of novel therapeutic approaches to obesity-related metabolic diseases.