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[Obesity Discussion]

Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes.

Authors: Chen, Baoying1,2
Lam, Karen S.L.1
Wang, Yu3
Wu, Donghai4
Lam, Michael C.1
Shen, Jiangang5
Wong, Laiching1
Hoo, Ruby L.C.1
Zhang, Jialiang1
Xu, Aimin1,3 amxu@hkucc.hku.hk
Source: Biochemical & Biophysical Research Communications; Mar2006, Vol. 341 Issue 2, p549-556, 8p

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 1a (HIF-1a), 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 (PPAR?) and CCAAT/enhancer binding protein (C/EBPa), but had no effect on HIF-1a, whereas hypoxia stabilized HIF-1a and decreased expression of C/EBPa, but not PPAR?. 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.

Author Affiliations:
Department of Medicine, University of Hong Kong, Hong Kong, China
Department of Radiology, Tangdu Hospital, Fourth Military Medical University, China
The Genome Research Center, University of Hong Kong, Hong Kong, China
Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, China
School of Chinese Medicine, University of Hong Kong, China