title: Role of the ubiquitin-proteasome system and autophagy in regulation of insulin sensitivity in serum-starved 3T3-L1 adipocytes.
abstract: The ubiquitin-proteasome system (UPS) and autophagy are two conserved intracellular proteolytic pathways, responsible for degradation of most cellular proteins in living cells. Currently, both the UPS and autophagy have been suggested to be associated with pathogenesis of insulin resistance and diabetes. However, underlying mechanism remains largely unknown. The purpose of the present study is to investigate the impact of the UPS and autophagy on insulin sensitivity in serum-starved 3T3-L1 adipocytes. Our results show that serum depletion resulted in activation of the UPS and autophagy, accompanied with increased insulin sensitivity. Inhibition of the UPS with bortezomib (BZM), a highly selective, reversible 26S proteasome inhibitor induced compensatory activation of autophagy but did not affect significantly insulin action. Genetic and pharmacological inhibition of autophagy dramatically mitigated serum starvation-elevated insulin sensitivity. In addition, autophagy inhibition compromised UPS function and led to endoplasmic reticulum (ER) stress and unfolded protein response (UPR). Inability of the UPS by BMZ exacerbated autophagy inhibition-induced ER stress and UPR. These results suggest that protein quality control maintained by the UPS and autophagy is required for preserving insulin sensitivity. Importantly, adaptive activation of autophagy plays a critical role in serum starvation-induced insulin sensitization in 3T3-L1 adipocytes.
authors.affiliation: Department of Pathology & Pathophysiology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
authors.forename: Yemin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mao
authors.initials: M
authors.lastname: Ye
authors.forename: Leyuan Jack
authors.initials: LJ
authors.lastname: Chen
authors.forename: Mingxin
authors.initials: M
authors.lastname: Li
authors.forename: Zhao
authors.initials: Z
authors.lastname: Tang
authors.forename: Changhua
authors.initials: C
authors.lastname: Wang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000069286:Bortezomib / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology
chemical_list: D061988:Proteasome Inhibitors; D025801:Ubiquitin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex