Journal
CELL
Volume 158, Issue 1, Pages 25-40Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.04.043
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Funding
- Vienna Science and Technology Fund
- Max-Planck Society
- Austrian Diabetes Association
- Medical Scientific Fund of the Mayor of the City of Vienna
- Osterreichische Gesellschaft fur Laboratoriumsmedizin und Klinische Chemie
- National Institutes of Health [DK090262]
- Austrian Science Fund (FWF) [V344] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [V 344] Funding Source: researchfish
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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-kappa B amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.
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