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

Alexander J. Hu, Wei Li, Calvin Dinh, Yongzhao Zhang, Jamie K. Hu, Stefano G. Daniele, Xiaoli Hou, Zixuan Yang, John M. Asara, Guo-fu Hu, Stephen R. Farmer and Miaofen G. Hu ()
Additional contact information
Alexander J. Hu: Division of Hematology and Oncology, Tufts Medical Center
Wei Li: Division of Hematology and Oncology, Tufts Medical Center
Calvin Dinh: Division of Hematology and Oncology, Tufts Medical Center
Yongzhao Zhang: Division of Hematology and Oncology, Tufts Medical Center
Jamie K. Hu: Division of Hematology and Oncology, Tufts Medical Center
Stefano G. Daniele: MD-PhD program, 333 Cedar St
Xiaoli Hou: Division of Hematology and Oncology, Tufts Medical Center
Zixuan Yang: Division of Hematology and Oncology, Tufts Medical Center
John M. Asara: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School
Guo-fu Hu: Division of Hematology and Oncology, Tufts Medical Center
Stephen R. Farmer: Boston University School of Medicine, Department of Biochemistry, 72E Concord St
Miaofen G. Hu: Division of Hematology and Oncology, Tufts Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45294-z

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