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

Research paper by Alexander A Jais, Elisa E Einwallner, Omar O Sharif, Klaus K Gossens, Tess Tsai-Hsiu TT Lu, Selma M SM Soyal, David D Medgyesi, Daniel D Neureiter, Jamile J Paier-Pourani, Kevin K Dalgaard, J Catharina JC Duvigneau, Josefine J Lindroos-Christensen, Thea-Christin TC Zapf, Sabine S Amann, Simona S Saluzzo, et al.

Indexed on: 06 Jul '14Published on: 06 Jul '14Published in: Cell



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.