CDK6 inhibits white to beige fat transition by suppressing RUNX1

Nat Commun. 2018 Mar 9;9(1):1023. doi: 10.1038/s41467-018-03451-1.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipose Tissue, Brown / physiology*
  • Adipose Tissue, White / physiology*
  • Animals
  • Body Composition
  • Cell Differentiation
  • Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors*
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Crosses, Genetic
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase 6 / metabolism*
  • Diet, High-Fat
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Glucose Tolerance Test
  • Male
  • Metabolic Diseases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / genetics
  • Obesity / metabolism
  • Oxygen Consumption
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Phenotype
  • Uncoupling Protein 1 / metabolism

Substances

  • Core Binding Factor Alpha 2 Subunit
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Runx1 protein, mouse
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Cdk6 protein, mouse
  • Cyclin-Dependent Kinase 6