title: Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.
abstract: Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of "healthy" versus "unhealthy" obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from "healthy" versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jais
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Elisa
authors.initials: E
authors.lastname: Einwallner
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria; CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Omar
authors.initials: O
authors.lastname: Sharif
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Gossens
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Tess Tsai-Hsiu
authors.initials: TT
authors.lastname: Lu
authors.affiliation: Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Selma M
authors.initials: SM
authors.lastname: Soyal
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; BIOSS Centre of Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Medgyesi
authors.affiliation: Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria.
authors.forename: Jamile
authors.initials: J
authors.lastname: Paier-Pourani
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Kevin
authors.initials: K
authors.lastname: Dalgaard
authors.affiliation: University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: J Catharina
authors.initials: JC
authors.lastname: Duvigneau
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Josefine
authors.initials: J
authors.lastname: Lindroos-Christensen
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Thea-Christin
authors.initials: TC
authors.lastname: Zapf
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Amann
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria; CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Simona
authors.initials: S
authors.lastname: Saluzzo
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Jantscher
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
authors.forename: Patricia
authors.initials: P
authors.lastname: Stiedl
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Jelena
authors.initials: J
authors.lastname: Todoric
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria; CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Rui
authors.initials: R
authors.lastname: Martins
authors.affiliation: Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Hannes
authors.initials: H
authors.lastname: Oberkofler
authors.affiliation: University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
authors.forename: Simone
authors.initials: S
authors.lastname: Müller
authors.affiliation: Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Hauser-Kronberger
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria; University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
authors.forename: Emilio
authors.initials: E
authors.lastname: Casanova
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Hedwig
authors.initials: H
authors.lastname: Sutterlüty-Fall
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.affiliation: General Hospital Hallein, 5400 Hallein, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Miller
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kozlov
authors.affiliation: General Hospital Hallein, 5400 Hallein, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Krempler
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria; CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.affiliation: University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Carey N
authors.initials: CN
authors.lastname: Lumeng
authors.affiliation: Paracelsus Medical University, 5020 Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Oswald
authors.initials: O
authors.lastname: Wagner
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. Electronic address: pospisilik@ie-freiburg.mpg.de.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.affiliation: Medical University of Vienna, 1090 Vienna, Austria. Electronic address: harald.esterbauer@meduniwien.ac.at.
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008659:Metabolic Diseases / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse