脂肪组织中Yes相关蛋白的功能及机制以及其在肥胖相关代谢性疾病中的作用

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.

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。

肥胖是世界范围内的健康问题，脂肪组织功能在肥胖相关代谢性疾病中发挥了重要作用。Yes相关蛋白（YAP）是Hippo信号通路的核心成员，具有重要的生理及病理生理功能。本项目研究了YAP在脂肪组织中的功能以其与代谢性疾病的关系。我们发现YAP高表达于棕色脂肪组织和米色脂肪组织。米色脂肪形成过程中YAP的表达增加不是由Hippo通路所调控，而是由寒冷刺激下调miR-429所致。YAP是miR-429的靶基因，miR-429在体内外均可调控YAP的表达。进一步发现YAP-TEADs的抑制剂可显著抑制寒冷刺激引起的米色脂肪形成，表明YAP通过与转录因子TEADs结合促进米色脂肪形成。通过构建脂肪组织特异性过表达YAP的转基因小鼠，我们发现脂肪组织过表达YAP可以通过提高解偶联蛋白1（UCP1）的基础表达水平，促进小鼠能量消耗。但是在YAP过表达的年轻小鼠中发现，皮下白色脂肪组织(sWAT)棕色化程度无明显变化。然而，中年小鼠sWAT中YAP的基础表达水平以及寒冷刺激诱导的表达水平均明显低于年轻小鼠。脂肪组织过表达YAP则改善了中年小鼠的米色脂肪形成障碍。除此之外，脂肪组织过表达YAP改善了高脂饮食导致的肝脏脂质沉积。综上所述，寒冷刺激引起的皮下脂肪组织miR-429的下调增加了YAP的表达，YAP通过与TEADs协同作用上调UCP1的表达。在年龄增加的过程中，皮下脂肪组织中YAP的基础表达水平下降，寒冷刺激引起的miR-429的下调也受到阻滞，YAP表达上调受到抑制，导致棕色化受损。本项目进一步阐明了米色脂肪形成机制，研究了YAP在米色脂肪形成中的作用及调控机制，以及靶向脂肪组织中miR-429-YAP通路对年龄相关米色脂肪形成障碍的改善作用。研究成果发表5篇SCI论文。