Advanced oxidation protein products induce inflammatory response and insulin resistance in cultured adipocytes via induction of endoplasmic reticulum stress.
Accumulation of advanced oxidation protein products (AOPPs) is prevalent in metabolic syndrome and type 2 diabetes. Adipocyte dysfunction has been recognized as a link between these conditions. To examine the effect of AOPPs on adipocyte perturbation, 3T3-L1 adipocytes were treated with increased levels of AOPPs as seen in these conditions. Exposure of adipocytes to AOPPs induced overexpression of tumor necrosis factor α and interleukin-6. This inflammatory response was completely blocked by nuclear factor-κB inhibitor SN50. AOPPs challenge also impaired insulin signaling, which was partly prevented by SN50. Treatment with AOPPs triggered endoplasmic reticulum (ER) stress, revealed by phosphorylation of PKR-like eukaryotic initiation factor 2α kinase, eukaryotic translational initiation factor 2α, inositol-requiring enzyme 1 and c-jun N-terminal kinase, and by overexpression of glucose regulated protein 78. AOPPs-induced ER stress was mediated by reactive oxygen species (ROS) generated by activation of NADPH oxidase since it was prevented by NADPH oxidase inhibitors or ROS scavenger. Treating the cells with inhibitors of NADPH oxidase or ER stress could completely abolish AOPPs-induced overexpression of adipocytokines and insulin resistance, suggesting that AOPPs induced adipocyte perturbation probably through induction of ROS-dependent ER stress. Our data identified AOPPs as a class of important mediator of adipocyte perturbation. Accumulation of AOPPs might be involved in adipocyte dysfunction as seen in metabolic syndrome and type 2 diabetes.
Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
Qiu Gen
QG
Zhou
Min
M
Zhou
Ai Ju
AJ
Lou
Di
D
Xie
Fan Fan
FF
Hou
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D001798:Blood Proteins; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D010455:Peptides; D017382:Reactive Oxygen Species; C118258:SN50 peptide; D014409:Tumor Necrosis Factor-alpha; D019255:NADPH Oxidases; D019892:eIF-2 Kinase; D048031:JNK Mitogen-Activated Protein Kinases