CDK6 inhibits white to beige fat transition by suppressing RUNX1

Xiaoli Hou,Yongzhao Zhang,Stefano G Daniele,Wenhui Zhou,Jinfeng Wang,Alexander J Hu,Andrew S Greenberg,Jamie K Hu,Stephen R Farmer,Wei Li,Jinghao Sheng,Yongsheng Fan,Miaofen G Hu,Chi Luo

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.

Highlights

Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects
A protein produced by fatty tissue and considered to regulate fat storage, Cyclin-dependent Kinase 6 (CDK6) mRNA and protein were selectively up-regulated in inguinal WAT (iWAT) and epididymal WAT (eWAT) but not in brown adipose tissues (BAT) in C57BL/6J mice under an high-fat diet (HFD) compared to the mice under a normal chow diet (NCD) (Supplementary Fig. 1b, c)
We provided biochemical and physiological data demonstrating that CDK6, and its kinase domain, is critical for adipocyte biology and metabolism

Summary

Introduction

Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. 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. The activation of beige cells is associated with a protection against obesity and metabolic diseases in rodent models and correlated with leanness in human[1,2]. While at first it may seem plausible to treat humans with β3-AR agonists, differences between rodent and human receptor physiology lead to significant off target effects[6,7] This has halted the development of β3-AR agonists as a viable treatment for obesity-related metabolic diseases. The molecular roles that CDK6 and RUNX1 play in obesity and its associated metabolic diseases remains largely unexplored

Methods

Results

Conclusion