Hou Xiaoli, Zhang Yongzhao, Li Wei, Hu Alexander J, Luo Chi, Zhou Wenhui, Hu Jamie K, Daniele Stefano G, Wang Jinfeng, Sheng Jinghao, Fan Yongsheng, Greenberg Andrew S, Farmer Stephen R, Hu Miaofen G
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA.
Zhejiang Chinese Medical University, Center for Analysis and Testing, 548 Bin-Wen Road, Hangzhou, 310053, P. R. China.
Nat Commun. 2018 Mar 9;9(1):1023. doi: 10.1038/s41467-018-03451-1.
Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6 mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1α by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases.
白色脂肪组织库会促进代谢疾病的发展，而棕色和米色脂肪组织则具有有益的代谢作用。在此我们表明，细胞周期蛋白依赖性激酶6（CDK6）调节米色脂肪细胞的形成。我们证明，缺乏CDK6蛋白或其激酶结构域（K43M）的小鼠表现出米色细胞形成显著增加、能量消耗增强、葡萄糖耐量改善以及胰岛素敏感性提高，并且对高脂饮食诱导的肥胖更具抵抗力。在Cdk6成熟或前体细胞中重新表达CDK6，或在K43M成熟或前体细胞中敲除RUNX1，可逆转这些表型。此外，RUNX1通过结合近端启动子区域正向调节解偶联蛋白1（Ucp-1）和过氧化物酶体增殖物激活受体γ辅激活因子1α（Pgc1α）的表达。我们的研究结果表明，CDK6激酶活性通过抑制RUNX1负向调节储存脂肪的细胞向燃烧脂肪的细胞的转化，并表明CDK6可能是治疗肥胖及相关代谢疾病的一个治疗靶点。
