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

• Liver and adipose tissue HO-1 levels predict unhealthy obesity in humans
• Hepatic and macrophage HO-1 deletion independently prevent metabolic disease
• HO-1 sets NF-κB and insulin receptor signaling thresholds
• HO-1 suppresses mitochondrial OxPhos and skews ROS signaling

SummaryObesity 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.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (3371 K)

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