title: Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation.
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.
authors.affiliation: Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany rubenggmm@hotmail.com triantafyllos.chavakis@uniklinikum-dresden.de.
authors.forename: Rubén
authors.initials: R
authors.lastname: García-Martín
authors.affiliation: Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Vasileia I
authors.initials: VI
authors.lastname: Alexaki
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Nan
authors.initials: N
authors.lastname: Qin
authors.affiliation: Department of Medicine III, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: María F
authors.initials: MF
authors.lastname: Rubín de Celis
authors.affiliation: Department of Ophthalmology, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Matina
authors.initials: M
authors.lastname: Economopoulou
authors.affiliation: Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Ziogas
authors.affiliation: Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Gercken
authors.affiliation: Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Klara
authors.initials: K
authors.lastname: Kotlabova
authors.affiliation: Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Phieler
authors.affiliation: Department of Medicine III, Medical Faculty, Technische Universität Dresden, Dresden, Germany Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Ehrhart-Bornstein
authors.affiliation: Department of Medicine III, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Graeme
authors.initials: G
authors.lastname: Eisenhofer
authors.affiliation: Department of Psychiatry, Medical Faculty, Technische Universität Dresden, Dresden, Germany Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.affiliation: Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Department of Medicine I, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.affiliation: Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
authors.affiliation: 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.
authors.forename: Antonios
authors.initials: A
authors.lastname: Chatzigeorgiou
authors.affiliation: Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany.
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology*; D002001:Adipose Tissue, Brown / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D007249:Inflammation / Q000150:complications; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D022722:Thermogenesis; D000071256:Uncoupling Protein 1; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071256:Uncoupling Protein 1; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C000604372:Ucp1 protein, mouse