CDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver.
Alexander J HuWei LiCalvin DinhYongzhao ZhangJamie K HuStefano G DanieleXiaoli HouZixuan YangJohn M AsaraGuo-Fu HuStephen R FarmerMiaofen G HuPublished in: Nature communications (2024)
Increased de novo lipogenesis (DNL) in white adipose tissue is associated with insulin sensitivity. Under both Normal-Chow-Diet and High-Fat-Diet, mice expressing a kinase inactive Cyclin-dependent kinase 6 (Cdk6) allele (K43M) display an increase in DNL in visceral white adipose tissues (VAT) as compared to wild type mice (WT), accompanied by markedly increased lipogenic transcriptional factor Carbohydrate-responsive element-binding proteins (CHREBP) and lipogenic enzymes in VAT but not in the liver. Treatment of WT mice under HFD with a CDK6 inhibitor recapitulates the phenotypes observed in K43M mice. Mechanistically, CDK6 phosphorylates AMP-activated protein kinase, leading to phosphorylation and inactivation of acetyl-CoA carboxylase, a key enzyme in DNL. CDK6 also phosphorylates CHREBP thus preventing its entry into the nucleus. Ablation of runt related transcription factor 1 in K43M mature adipocytes reverses most of the phenotypes observed in K43M mice. These results demonstrate a role of CDK6 in DNL and a strategy to alleviate metabolic syndromes.
Keyphrases
- high fat diet induced
- insulin resistance
- high fat diet
- adipose tissue
- wild type
- cell cycle
- protein kinase
- transcription factor
- gene expression
- metabolic syndrome
- cell proliferation
- physical activity
- cell death
- cancer therapy
- drug delivery
- oxidative stress
- signaling pathway
- heat shock protein
- replacement therapy
- genome wide identification