Letter | Published:

Cyclin D1–Cdk4 controls glucose metabolism independently of cell cycle progression

Nature volume 510, pages 547551 (26 June 2014) | Download Citation

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Abstract

Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis1,2,3; dysregulation of this axis causes diabetes2,4. PGC-1α (peroxisome-proliferator-activated receptor-γ coactivator-1α) links insulin signalling to the expression of glucose and lipid metabolic genes5,6,7. The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1α and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1α8,9. Although insulin is a mitogenic signal in proliferative cells10,11, whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1–cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1α acetylation. Insulin/GSK-3β (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1–Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1α activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1–Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.

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Acknowledgements

We thank all the members of the Puigserver laboratory for discussions and suggestions about this project. We also appreciate the consultations with and efforts by M. Jedrychowski and S. Gygi for proteomic analysis. Y.L. was supported in part by a 21st Century Leaders scholarship from Ewha Womans University. J.E.D. was supported in part by a National Research Service Award Kirschstein Fellowship from the National Institutes of Health (NIH). The participating researchers were supported with funds from the Dana-Farber Cancer Institute and with grants from the American Diabetes Association, Department of Defense, NIH/National Institute of Diabetes and Digestive and Kidney Diseases (RO1069966 and R24DK080261-06), NIH (RO3 MH092174) awarded to P.P., NIH (RO1 CA108420) awarded to P.S. and NIH (DK059635) awarded to Yale’s Mouse Metabolic Phenotyping Center/G.I.S.

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Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Yoonjin Lee
    • , John E. Dominy
    • , Yoon Jong Choi
    • , Helen Chim
    • , Ji-Hong Lim
    • , Francisca Vazquez
    • , Piotr Sicinski
    •  & Pere Puigserver
  2. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Yoonjin Lee
    • , John E. Dominy
    • , Helen Chim
    • , Ji-Hong Lim
    • , Francisca Vazquez
    •  & Pere Puigserver
  3. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Yoonjin Lee
  4. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Yoon Jong Choi
    •  & Piotr Sicinski
  5. Yale’s Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA

    • Michael Jurczak
    • , Joao Paulo Camporez
    • , Hai-Bin Ruan
    • , Xiaoyong Yang
    •  & Gerald I. Shulman
  6. Chemical Biology Platform, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02141, USA

    • Nicola Tolliday

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Contributions

P.P. and Y.L. conceived the project. Y.L. designed and performed most of the experiments aided by discussions with P.P. J.E.D. also contributed to the design and discussions of the manuscript. Additional advice in the design and execution of the experiments was provided by F.V. and J.-H.L. H.C. assisted with mice experiments. Y.J.C. and P.S. provided D1 fl/fl mice and helped with BrdU incorporation and Ki-67 staining experiments. M.J., J.P.C., H.-B.R., X.Y. and G.I.S. performed hyperinsulinemic–euglycemic clamp experiments, and analysed, interpreted and discussed the data. N.T. assisted with performance and analysis of chemical screening. Y.L. and P.P. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Pere Puigserver.

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DOI

https://doi.org/10.1038/nature13267

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