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Hyperactivation of the Insulin Signaling Pathway Improves Intracellular Proteostasis by Coordinately Up-regulating the Proteostatic Machinery in Adipocytes


Hyperinsulinemia, which is associated with aging and metabolic disease, may lead to defective protein homeostasis (proteostasis) due to hyperactivation of insulin-sensitive pathways such as protein synthesis. We investigated the effect of chronic hyperinsulinemia on proteostasis by generating a time-resolved map of insulin-regulated protein turnover in adipocytes using metabolic pulse-chase labeling and high resolution mass spectrometry. Hyperinsulinemia increased the synthesis of nearly half of all detected proteins and did not affect protein degradation despite suppressing autophagy. Unexpectedly, this marked elevation in protein synthesis was accompanied by enhanced protein stability and folding and not by markers of proteostasis stress such as protein carbonylation and aggregation. The improvement in proteostasis was attributed to a coordinate up-regulation of proteins in the global proteostasis network, including ribosomal, proteasomal, chaperone, and endoplasmic reticulum/mitochondrial unfolded protein response proteins. We conclude that defects associated with hyperactivation of the insulin signaling pathway are unlikely attributed to defective proteostasis because up-regulation of protein synthesis by insulin is accompanied by up-regulation of proteostatic machinery.

Type Journal
ISBN 1083-351X (Electronic) 0021-9258 (Linking)
Authors Minard, A. Y. ; Wong, M. K. ; Chaudhuri, R. ; Tan, S. X. ; Humphrey, S. J. ; Parker, B. L. ; Yang, J. Y. ; Laybutt, D. R. ; Cooney, G. J. ; Coster, A. C. ; Stockli, J. ; James, D. E.;
Published Date 2016-12-01
Published Volume 291
Published Issue 49
Published Pages 25629-25640
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version