Cited by 86Adipose Tissue and MetabolismAdipokines, Inflammation, and Metabolic DiseasesCardiovascular Disease and Adiposity

Adipocyte-specific hypoxia-inducible factor 2α deficiency exacerbates obesity-induced brown adipose tissue dysfunction and metabolic dysregulation

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García-Martín, Rubén, Alexaki, Vasileia I., Qin, Nan, Rubín de Celis, María F., Economopoulou, Matina, Ziogas, Athanasios, Gercken, Bettina, Kotlabova, Klara +11 more·2016·Molecular and Cellular Biology

Abstract

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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  1. Matthias A, 2000, UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty scid-induced thermogenesis. J Biol Chem, 275, 25073

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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
Venue
Molecular and Cellular Biology
Published
2016-02-01
Volume
36
Issue
3
Pages
376-393
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W2260135833
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
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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