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Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance

Author

Listed:
  • Daniel J. Fazakerley

    (University of Sydney
    University of Cambridge)

  • Julian van Gerwen

    (University of Sydney)

  • Kristen C. Cooke

    (University of Sydney)

  • Xiaowen Duan

    (University of Sydney)

  • Elise J. Needham

    (University of Sydney)

  • Alexis Díaz-Vegas

    (University of Sydney)

  • Søren Madsen

    (University of Sydney)

  • Dougall M. Norris

    (University of Cambridge)

  • Amber S. Shun-Shion

    (University of Cambridge)

  • James R. Krycer

    (University of Sydney
    QIMR Berghofer Medical Research Institute
    Queensland University of Technology)

  • James G. Burchfield

    (University of Sydney)

  • Pengyi Yang

    (University of Sydney
    University of Sydney)

  • Mark R. Wade

    (Lilly Research Laboratories, Division of Eli Lilly and Company)

  • Joseph T. Brozinick

    (Lilly Research Laboratories, Division of Eli Lilly and Company)

  • David E. James

    (University of Sydney
    University of Sydney)

  • Sean J. Humphrey

    (University of Sydney
    Murdoch Children’s Research Institute, The Royal Children’s Hospital)

Abstract

The failure of metabolic tissues to appropriately respond to insulin (“insulin resistance”) is an early marker in the pathogenesis of type 2 diabetes. Protein phosphorylation is central to the adipocyte insulin response, but how adipocyte signaling networks are dysregulated upon insulin resistance is unknown. Here we employ phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults causing insulin resistance, we observe a marked rewiring of the insulin signaling network. This includes both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying dysregulated phosphosites common to multiple insults reveals subnetworks containing non-canonical regulators of insulin action, such as MARK2/3, and causal drivers of insulin resistance. The presence of several bona fide GSK3 substrates among these phosphosites led us to establish a pipeline for identifying context-specific kinase substrates, revealing widespread dysregulation of GSK3 signaling. Pharmacological inhibition of GSK3 partially reverses insulin resistance in cells and tissue explants. These data highlight that insulin resistance is a multi-nodal signaling defect that includes dysregulated MARK2/3 and GSK3 activity.

Suggested Citation

  • Daniel J. Fazakerley & Julian van Gerwen & Kristen C. Cooke & Xiaowen Duan & Elise J. Needham & Alexis Díaz-Vegas & Søren Madsen & Dougall M. Norris & Amber S. Shun-Shion & James R. Krycer & James G. , 2023. "Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36549-2
    DOI: 10.1038/s41467-023-36549-2
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    References listed on IDEAS

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