CDK6 Inhibits De Novo Lipogenesis in White Adipose Tissues but not in the Liver

Increased de novo lipogenesis (DNL) in white adipose tissue (WAT) is associated with insulin sensitivity. Under both normal chow diet (NCD) and high fat diet (HFD), mice expressing a kinase inactive Cdk6 allele (Cdk6K43M, K43M) displays an increase in DNL in visceral WAT as compared to WT mice, accompanied by markedly increased lipogenic transcriptional factor CHREBP and lipogenic enzymes in WAT but not in the liver. Treatment of WT mice under HFD by CDK6 inhibitors recapitulates the phenotypes observed in K43M mice. Mechanistically, CDK6 is found to phosphorylate AMPK leading to phosphorylation and inactivation of acetyl-CoA carboxylase, a key enzyme in DNL. CDK6 is also found to phosphorylate CHREBP thus preventing its entry into the nucleus. Ablation of RUNX1 in K43M mature adipocytes reverses most of the phenotypes observed in K43M mice. These results demonstrate a role of CDK6 in DNL and a novel strategy to alleviate metabolic syndromes.