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

ABSTRACT: Here we employed phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults triggering insulin resistance, we observed marked rewiring of the insulin signaling network. This included both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying dysregulated phosphosites common to multiple insults revealed subnetworks containing novel regulators of insulin action, such as MARK2/3, and causal drivers of insulin resistance. The presence of several GSK3 substrates among these phosphosites led us to establish a pipeline for identifying context-specific kinase substrates. This revealed widespread dysregulation of GSK3 signaling. Pharmacological inhibition of GSK3 partially reversed insulin resistance in cells and tissue explants. These data highlight that insulin resistance is multi-nodal signaling defect that includes dysregulated GSK3 activity.

INSTRUMENT(S): Q Exactive HF-X, Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): White Fat Cell, White Adipose Tissue

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Sean Humphrey

LAB HEAD: Sean Humphrey

PROVIDER: PXD032913 | Pride | 2023-02-17

REPOSITORIES: Pride

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			Action	DRS
	20170707_QEHF_SeHu_IR_AdiposeTissue_EasyPhos_A1.raw	Raw
	20170707_QEHF_SeHu_IR_AdiposeTissue_EasyPhos_A10.raw	Raw
	20170707_QEHF_SeHu_IR_AdiposeTissue_EasyPhos_A11.raw	Raw
	20170707_QEHF_SeHu_IR_AdiposeTissue_EasyPhos_A12.raw	Raw
	20170707_QEHF_SeHu_IR_AdiposeTissue_EasyPhos_A2.raw	Raw

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