Browning of White Adipose Tissue with Roscovitine Induces a Distinct Population of UCP1+ Adipocytes

Abstract

Brown-like adipocytes exist in several adipose depots including white (WAT) as well as brown (BAT). Activation of these UCP1⁺ cells is a potential therapeutic strategy to combat obesity. Studies have shown that posttranslational modifications of PPARγ regulate select adipocyte programs. Deacetylation of K268 and K293 in the ligand-binding domain of PPARγ by Sirt1 induces browning of WAT. Phosphorylation of S273 of PPARγ by CDK5 or ERK stimulates a diabetogenic program of gene expression in WAT. Here, we report that roscovitine, a CDK inhibitor, prevents S273 phosphorylation and promotes formation of UCP1⁺ (brite) adipocytes in WAT. It also enhances energy expenditure as well as prevents diet-induced obesity and insulin resistance. Analysis of fluorescence-activated cell-sorted UCP1⁺ adipocytes shows that the mRNA signature of brite adipocytes is distinct from beige adipocytes, which arise through catecholamine signaling. These results suggest that brown-like adipocytes in WAT may arise from multiple origins.