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

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. Burchfield, Pengyi Yang, Mark R. Wade, Joseph T. Brozinick, David E. James () and Sean J. Humphrey ()
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Daniel J. Fazakerley: University of Sydney
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
James G. Burchfield: University of Sydney
Pengyi Yang: 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
Sean J. Humphrey: University of Sydney

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36549-2

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