CDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver

• Published in: Nature communications Vol. 15; no. 1; p. 1091
• Main Authors: Hu, Alexander J., Li, Wei, Dinh, Calvin, Zhang, Yongzhao, Hu, Jamie K., Daniele, Stefano G., Hou, Xiaoli, Yang, Zixuan, Asara, John M., Hu, Guo-fu, Farmer, Stephen R., Hu, Miaofen G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/58; 13/1; 13/89; 13/95; 49/88; 49/90; 631/154/555; 631/80/304; 64; 692/53/2421; 692/698/690/2816; 82/29; 82/80; 96; 96/100; 96/44; Ablation; Acetyl-CoA carboxylase; Adipocytes; Adipose tissue; Adipose Tissue, White - metabolism; AMP-activated protein kinase; Animals; Carbohydrates; Cyclin-dependent kinase 6; Cyclin-Dependent Kinase 6 - metabolism; Cyclin-dependent kinases; Diet; High fat diet; Humanities and Social Sciences; Inactivation; Kinases; Lipogenesis; Lipogenesis - genetics; Liver; Liver - metabolism; Metabolic disorders; Metabolic syndrome; Mice; multidisciplinary; Obesity; Phenotypes; Phosphorylation; Proteins; Regulatory sequences; Risk factors; Science; Science (multidisciplinary); Strategy; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45294-z

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. Obesity is a risk factor for diseases. Here, authors found that inhibition of cyclin-dependent kinase 6 increased de novo lipogenesis in the adipose tissues but not in the liver, which may provide a strategy to concur obesity-induced maladies.