|Hou, Xiaoli - Tufts University|
|Zhang, Yongzhao - Tufts University|
|Li, Wei - Tufts University|
|Hu, Alexander - Tufts University|
|Luo, Chi - Dana-Farber Cancer Institute|
|Zhou, Wenhui - Tufts University|
|Hu, Jamie - Tufts University|
|Daniele, Stefano - Yale University|
|Wang, Jinfeng - Tufts University|
|Sheng, Jinghao - Tufts University|
|Fan, Yongsheng - Zhejiang University|
|Greenberg, Andrew - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Farmer, Stephen - Boston University|
|Hu, Miaofen - Tufts University|
Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/14/2018
Publication Date: 3/9/2018
Citation: Hou, X., Zhang, Y., Li, W., Hu, A.J., Luo, C., Zhou, W., Hu, J.K., Daniele, S.G., Wang, J., Sheng, J., Fan, Y., Greenberg, A., Farmer, S.R., Hu, M.G. 2018. CDK6 inhibits white to beige fat transition by suppressing RUNX1. Nature Communications. 9:1023. https://doi.org/10.1038/s41467-018-03451-1.
DOI: https://doi.org/10.1038/s41467-018-03451-1 Interpretive Summary: Obesity is reaching epidemic levels, which has led to an urgent need to identify new pathways to protect against diet-induced obesity. This paper demonstrates that reductions in the levels of a protein called CDK6 in the fat cells of mice results in increased levels of another fat cell protein called RUNX1. Increased levels of the protein RUNX1 altered fat cells from just storing fat to actually metabolizing and burning fat so that the mice were protected against diet-induced obesity. Future studies will be directed to determine what dietary factors increase RUNX1 expression in fat cells and could protect against the development of obesity in humans.
Technical Abstract: 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 Pgc1a 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.