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

Author

Listed:
  • Alexander J. Hu

    (Division of Hematology and Oncology, Tufts Medical Center
    Harvard Medical School, Brigham and Women’s Hospital)

  • Wei Li

    (Division of Hematology and Oncology, Tufts Medical Center
    National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy)

  • 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
    Dermatology. 1295 NW 14th St. University of Miami Hospital South Bldg. Suites K-M)

  • Stefano G. Daniele

    (MD-PhD program, 333 Cedar St)

  • Xiaoli Hou

    (Division of Hematology and Oncology, Tufts Medical Center
    Zhejiang Chinese Medical University, Center for Analysis and Testing, 548 Bin-Wen Road)

  • Zixuan Yang

    (Division of Hematology and Oncology, Tufts Medical Center
    TUFTS University Friedman School of Nutrition Science and Policy, TUFTS University, 150 Harrison Avenue)

  • 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)

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.

Suggested Citation

  • 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 & Miaofen G. Hu, 2024. "CDK6 inhibits de novo lipogenesis in white adipose tissues but not in the liver," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45294-z
    DOI: 10.1038/s41467-024-45294-z
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    References listed on IDEAS

    as
    1. Yuefeng Tang & Martina Wallace & Joan Sanchez-Gurmaches & Wen-Yu Hsiao & Huawei Li & Peter L. Lee & Santiago Vernia & Christian M. Metallo & David A. Guertin, 2016. "Adipose tissue mTORC2 regulates ChREBP-driven de novo lipogenesis and hepatic glucose metabolism," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
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