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Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man

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Jais,  Alexander
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Einwallner,  Elisa
Max Planck Society;

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Tsai-Hsiu Lu,  Tess
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Medgyesi,  David
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Dalgaard,  Kevin
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Pospisilik,  J. Andrew
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Jais, A., Einwallner, E., Sharif, O., Gossens, K., Tsai-Hsiu Lu, T., Soyal, S. M., et al. (2014). Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man. Cell, 158, 25-40.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-884B-D
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.