Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation

Rubén García-Martín; Vasileia I Alexaki; Nan Qin; María F Rubín de Celis; Matina Economopoulou; Athanasios Ziogas; Bettina Gercken; Klara Kotlabova; Julia Phieler; Monika Ehrhart-Bornstein; Stefan R Bornstein; Graeme Eisenhofer; Georg Breier; Matthias Blüher; Jochen Hampe; Ali El-Armouche; Antonios Chatzigeorgiou; Kyoung-Jin Chung; Triantafyllos Chavakis

doi:10.1128/MCB.00430-15

Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation

Mol Cell Biol. 2015 Nov 16;36(3):376-93. doi: 10.1128/MCB.00430-15. Print 2016 Feb 1.

Authors

Rubén García-Martín¹, Vasileia I Alexaki², Nan Qin³, María F Rubín de Celis⁴, Matina Economopoulou⁵, Athanasios Ziogas², Bettina Gercken², Klara Kotlabova², Julia Phieler², Monika Ehrhart-Bornstein⁶, Stefan R Bornstein⁴, Graeme Eisenhofer³, Georg Breier⁷, Matthias Blüher⁸, Jochen Hampe⁹, Ali El-Armouche¹⁰, Antonios Chatzigeorgiou¹¹, Kyoung-Jin Chung², Triantafyllos Chavakis¹²

Affiliations

¹ Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany rubenggmm@hotmail.com triantafyllos.chavakis@uniklinikum-dresden.de.
² Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
³ Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁴ Department of Medicine III, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁵ Department of Ophthalmology, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
⁶ Department of Medicine III, Medical Faculty, Technische Universität Dresden, Dresden, Germany Center for Regenerative Therapies Dresden, Dresden, Germany.
⁷ Department of Psychiatry, Medical Faculty, Technische Universität Dresden, Dresden, Germany Center for Regenerative Therapies Dresden, Dresden, Germany.
⁸ Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
⁹ Department of Medicine I, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
¹⁰ Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
¹¹ Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, and German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
¹² Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany Center for Regenerative Therapies Dresden, Dresden, Germany Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, and German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany rubenggmm@hotmail.com triantafyllos.chavakis@uniklinikum-dresden.de.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipocytes / metabolism
Adipocytes / pathology*
Adipose Tissue, Brown / blood supply
Adipose Tissue, Brown / metabolism
Adipose Tissue, Brown / physiopathology*
Animals
Basic Helix-Loop-Helix Transcription Factors / genetics*
Basic Helix-Loop-Helix Transcription Factors / metabolism
Gene Deletion*
Inflammation / complications
Ion Channels / metabolism
Male
Mice
Mice, Knockout
Mitochondrial Proteins / metabolism
Neovascularization, Physiologic
Obesity / complications
Obesity / genetics*
Obesity / metabolism
Obesity / physiopathology*
Thermogenesis
Uncoupling Protein 1
Vascular Endothelial Growth Factor A / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
Ion Channels
Mitochondrial Proteins
Ucp1 protein, mouse
Uncoupling Protein 1
Vascular Endothelial Growth Factor A
endothelial PAS domain-containing protein 1