Why some obese people are still healthy

Heme Oxygenase-1 Drives Inflammation in Mice and Men.

Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, thetwo 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-kB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.

Cell 158, 25-40, July 3,2014