title: Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes.
abstract: Low plasma levels of adiponectin (hypoadiponectinemia) and elevated circulating concentrations of plasminogen activator inhibitor (PAI)-1 are causally associated with obesity-related insulin resistance and cardiovascular disease. However, the mechanism that mediates the aberrant production of these two adipokines in obesity remains poorly understood. In this study, we investigated the effects of hypoxia and reactive oxygen species (ROS) on production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Quantitative PCR and immunoassays showed that ambient hypoxia markedly suppressed adiponectin mRNA expression and its protein secretion, and increased PAI-1 production in mature adipocytes. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1alpha (HIF-1alpha), mimicked the hypoxia-mediated modulations of these two adipokines. Hypoxia caused a modest elevation of ROS in adipocytes. However, ablation of intracellular ROS by antioxidants failed to alleviate hypoxia-induced aberrant production of adiponectin and PAI-1. On the other hand, the antioxidants could reverse hydrogen peroxide (H2O2)-induced dysregulation of adiponectin and PAI-1 production. H2O2 treatment decreased the expression levels of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBPalpha), but had no effect on HIF-1alpha, whereas hypoxia stabilized HIF-1alpha and decreased expression of C/EBPalpha, but not PPARgamma. Taken together, these data suggest that hypoxia and ROS decrease adiponectin production and augment PAI-1 expression in adipocytes via distinct signaling pathways. These effects may contribute to hypoadiponectinemia and elevated PAI-1 levels in obesity, type 2 diabetes, and cardiovascular diseases.
authors.affiliation: Department of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Baoying
authors.initials: B
authors.lastname: Chen
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Lam
authors.forename: Jiangang
authors.initials: J
authors.lastname: Shen
authors.forename: Laiching
authors.initials: L
authors.lastname: Wong
authors.forename: Ruby L C
authors.initials: RL
authors.lastname: Hoo
authors.forename: Jialiang
authors.initials: J
authors.lastname: Zhang
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin / Q000096:biosynthesis* / Q000378:metabolism; D000600:Amino Acids, Dicarboxylic / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007118:Immunoassay; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D052242:Adiponectin; D000600:Amino Acids, Dicarboxylic; D000975:Antioxidants; D022763:CCAAT-Enhancer-Binding Protein-alpha; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; C040947:oxalylglycine