β-catenin 调控棕色脂肪与骨骼肌相互转化作用及机制研究

棕色脂肪和骨骼肌共同起源于Myf5祖细胞，二者转化机制不清楚。最新研究表明，PRDM16是控制骨骼肌和棕色脂肪相互转化的分子开关。我们前期研究发现，脂肪组织特异性β-catenin敲除小鼠（AP2-BKO）呈现体重减轻，糖耐量改善，棕色脂肪脂滴减少。基因表达谱分析表明，敲除小鼠棕色脂肪出现骨骼肌标志基因高表达，这提示β-catenin缺失促进棕色脂肪向骨骼肌转化，那么β-catenin是否是另一个调控棕色脂肪与骨骼肌命运决定的分子开关呢？本课题拟以AP2-BKO和Adiponectin-Cre-BKO小鼠为主要模型，借助原代细胞分离诱导技术和分子生物学实验，从体内、外水平证明β-catenin调控棕色脂肪和骨骼肌相互转化；进一步证明β-catenin对PRDM16转录复合体的翻译后修饰，从而阐明β-catenin调控二者转化的分子机制。这将为棕色脂肪和骨骼肌转化研究提供新的靶点和理论认识。

Recent data have shown that brown fat and skeletal muscle both derive from the Myf5 cellular lineage, and PRDM16 is identified as a determinant of a brown fat/skeletal muscle switch. We have found that fat tissue specific β-catenin knockout mice (AP2-BKO) showed reduced body weight, improved glucose tolerance and insulin sensitivity. Brown adipocytes of AP2-BKO mice contained a dramatic decrease in lipid droplets.We further performed cDNA micro-array of brown fat of wild-type and AP2-BKO mice, very interestingly, we detected a much increase in muscular specific markers in brown fat of AP2-BKO mice. These results strongly indicated that loss of β-catenin promotes brown fat to skeletal muscle switch. We thus hypothyze that β-catenin may be a novel fator to control brown fat/skeletal muscle switch.In this project, we will use AP2-BKO and Adiponectin-Cre-BKO mice models and apply primary cell isolation and brown adipocyte differentiaiton as well as other biomolecular techniques to further investigate the role of β-catenin in controling brown fat/skeletal muscle switch in vitro and in vivo, and examine the role of β-catenin in regulating the PRDM16-C/EBP-βtranscriptional complex, thereby elucidating the molecular mechanism of β-catenin in controling brown fat/skeletal muscle switch. This study will provide a novel candiate to regulate brown fat/skeletal muscle switch and fullfil the theory of brown fat diferentiation.