Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises XXXX Sensitivity in @entity1 Obesity.

@entity1 @entity28 @entity2365 @entity19 @entity409 @entity2690 @entity2041 @entity209 @entity1386
AIMS: Obesity is characterized by a low-grade systemic inflammatory state and @entity1386 ( @entity1386 ) dysfunction, which predispose individuals to the development of @entity2690 resistance (IR) and @entity209 . However, a subset of @entity28 individuals, referred to as @entity28 ( @entity28 ) individuals, are protected from @entity28 -associated @entity209 . Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the @entity2690 -sensitive to the @entity2690 -resistant, @entity28 ( @entity28 ) phenotype. RESULTS: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) @entity1 @entity1386 revealed that both types of cells are altered in the @entity28 state. Specifically, the @entity2041 redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of @entity28 individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced @entity28 @entity19 and in 3T3-L1 adipocytes exposed to @entity2365 . In line with these data, proteasome inhibition significantly impaired @entity2690 signaling in 3T3-L1 adipocytes. INNOVATION: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in @entity1 @entity28 , which, together with oxidative damage, interferes with @entity2690 signaling in these cells. CONCLUSION: Our results suggest that @entity409 and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in @entity28 . Antioxid. Redox Signal. 23, 597-612.
