Adipocyte-specific hypoxia-inducible factor 2α deficiency exacerbates obesity-induced brown adipose tissue dysfunction and metabolic dysregulation
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Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia-inducible factor 2α (HIF2α) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2α regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte-specific HIF2α-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2α-deficient mice. Together, our findings show that adipocyte HIF2α is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction.
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Local hypoxia is a potent stimulus for new blood vessel formation through pro-angiogenic actions of HIF-1α and HIF-2α.
“Local hypoxia is a potent stimulus for new blood vessel formation through the pro-angiogenic actions of HIF-1α and HIF-2α (24,25).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [25]
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- Authors
- García-Martín, R., Alexaki, V. I., Qin, N., Rubín de Celis, M. F., Economopoulou, M., Ziogas, A., Gercken, B., Kotlabova, K., Phieler, J., Ehrhart-Bornstein, M., Bornstein, S. R., Eisenhofer, G., Breier, G., Blüher, M., Hampe, J., El-Armouche, A., Chatzigeorgiou, A., Chung, K.-J., & Chavakis, T.
- Affiliations
- Technische Universität Dresden (DE)
- Department of Medicine III, Medical Faculty, Technische Universität Dresden, Dresden, Germany
- Center for Regenerative Therapies Dresden (DE)
- Leipzig University (DE)
- Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Dresden, Germany
- German Center for Diabetes Research (DE)
- Corresponding author
- García-Martín, Rubén
- Chavakis, Triantafyllos
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2016-02-01
- Volume
- 36
- Issue
- 3
- Pages
- 376-393
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC4719429
- OpenAlex
- W2260135833
- Semantic Scholar
- 00de7831c48bda3907614daf6ceed809e03bf17b
- Cited by
- 86
- References
- 61
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 9 · 2023: 9 · 2022: 8 · 2021: 16 · 2020: 9 · 2019: 6 · 2018: 6 · 2017: 8 · 2016: 6
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular and Cellular Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- ERC (ENDHOMRET)
- Center for Regenerative Therapies Dresden
- Deutsche Forschungsgemeinschaft (CH279/5-1, CH279/6-2)
- Else Kröner-Fresenius-Stiftung
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- HIF-2α, adipocytes, obesity, angiogenesis, white adipose tissue inflammation, vascular endothelial growth factor, thermogenesis, UCP1, insulin resistance, hepatic steatosis, cold exposure
- MeSH terms
- Uncoupling Protein 1, Endothelial PAS Domain-Containing Protein 1, Animals, Adipose Tissue, Brown, Inflammation, Ion Channels, Male, Obesity, Gene Deletion, Adipocytes, Mice, Knockout, Neovascularization, Physiologic, Thermogenesis, Mitochondrial Proteins, Vascular Endothelial Growth Factor A, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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