title: Hyperactivation of the Insulin Signaling Pathway Improves Intracellular Proteostasis by Coordinately Up-regulating the Proteostatic Machinery in Adipocytes.
abstract: 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.
authors.affiliation: From The Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|Charles Perkins Centre, School of Life Environmental Sciences.
authors.forename: Annabel Y
authors.initials: AY
authors.lastname: Minard
authors.affiliation: From The Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.|Charles Perkins Centre, School of Life Environmental Sciences.|School of Physics.
authors.forename: Martin K L
authors.initials: MK
authors.lastname: Wong
authors.affiliation: Charles Perkins Centre, School of Life Environmental Sciences.
authors.forename: Rima
authors.initials: R
authors.lastname: Chaudhuri
authors.affiliation: From The Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Shi-Xiong
authors.initials: SX
authors.lastname: Tan
authors.affiliation: Charles Perkins Centre, School of Life Environmental Sciences.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Humphrey
authors.affiliation: Charles Perkins Centre, School of Life Environmental Sciences.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Parker
authors.affiliation: School of Mathematics and Statistics, and.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Yang
authors.affiliation: From The Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: D Ross
authors.initials: DR
authors.lastname: Laybutt
authors.affiliation: Charles Perkins Centre, School of Life Environmental Sciences.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.affiliation: Department of Applied Mathematics, School of Mathematics and Statistics, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Adelle C F
authors.initials: AC
authors.lastname: Coster
authors.affiliation: Charles Perkins Centre, School of Life Environmental Sciences.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Stöckli
authors.affiliation: Charles Perkins Centre, School of Life Environmental Sciences, david.james@sydney.edu.au.|School of Medicine, University of Sydney, Sydney, New South Wales 2006, Australia, and.
authors.forename: David E
authors.initials: DE
authors.lastname: James
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D006946:Hyperinsulinism / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D014176:Protein Biosynthesis; D050050:Protein Carbonylation; D059748:Proteolysis; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: D007328:Insulin
keywords: adipocyte; insulin; insulin resistance; proteomics; proteostasis; pulse-chase SILAC