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Cell. 2014 Jul 3;158(1):25-40. doi: 10.1016/j.cell.2014.04.043.

Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

Author information

1
Medical University of Vienna, 1090 Vienna, Austria.
2
Medical University of Vienna, 1090 Vienna, Austria; CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
3
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
4
Paracelsus Medical University, 5020 Salzburg, Austria.
5
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; BIOSS Centre of Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany.
6
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, 1200 Vienna, Austria.
7
University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
8
Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
9
Medical University of Vienna, 1090 Vienna, Austria; University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
10
Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria.
11
General Hospital Hallein, 5400 Hallein, Austria.
12
University of Michigan, Ann Arbor, MI 48109, USA.
13
Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. Electronic address: pospisilik@ie-freiburg.mpg.de.
14
Medical University of Vienna, 1090 Vienna, Austria. Electronic address: harald.esterbauer@meduniwien.ac.at.

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.

PMID:
24995976
PMCID:
PMC5749244
DOI:
10.1016/j.cell.2014.04.043
[Indexed for MEDLINE]
Free PMC Article

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