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.
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Many adipokines related to inflammation, such as MIF, MMP2, MMP9, IL-6, Angplt4, PAI-1, VEGF, and leptin, are upregulated by hypoxia.
“These papers suggest that many adipokines that are related to inflammation, such as macrophage migration inhibitory factor (MIF), the matrix metalloproteinases MMP2 and MMP9, IL-6, Angplt4, PAI-1, VEGF, and leptin are all upregulated by hypoxia (22)(23)(24)(25).”
From Adipose tissue remodeling and obesity (2011) · cites this paper as [24]
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- Authors
- Chen, B., Lam, K. S. L., Wang, Y., Wu, D., Lam, M. C., Shen, J., Wong, L., Hoo, R. L. C., Zhang, J., & Xu, A.
- Affiliations
- Tang Du Hospital (CN)
- University of Hong Kong (HK)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Xu, Aimin
- ORCID
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 341
- Issue
- 2
- Pages
- 549-556
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2025710049
- Cited by
- 238
- References
- 53
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 5 · 2020: 11 · 2019: 8 · 2018: 8 · 2017: 12 · 2016: 9 · 2015: 11 · 2014: 15 · 2013: 14 · 2012: 18
- FWCI
- 14.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- Hong Kong Arts Development Council (HKU (7486/04M)
- University of Hong Kong
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- hypoxia, adiponectin, plasminogen activator inhibitor-1, reactive oxygen species, adipocytes, hypoadiponectinemia, HIF-1α, PPARγ, C/EBPα, hydrogen peroxide, obesity, insulin resistance, adipokine dysregulation
- MeSH terms
- Amino Acids, Dicarboxylic, Animals, Hypoxia, Antioxidants, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Hydrogen Peroxide, Immunoassay, RNA, Messenger, Time Factors, Blotting, Western, Signal Transduction, Polymerase Chain Reaction, Reactive Oxygen Species, Plasminogen Activator Inhibitor 1, Adipocytes, Reverse Transcriptase Polymerase Chain Reaction, CCAAT-Enhancer-Binding Protein-alpha, 3T3-L1 Cells, PPAR gamma, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Adiponectin
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