Editors' ChoiceMetabolic Disease

An Unexpected Player in Diabetes

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Science Translational Medicine  16 Jul 2014:
Vol. 6, Issue 245, pp. 245ec125
DOI: 10.1126/scitranslmed.3009811

More than one-third of U.S. adults are obese, and three out of four will develop insulin resistance, which leads to glucose buildup and type 2 diabetes. Although chronic low-grade inflammation is a primary driver of insulin resistance in obese individuals, the mechanism of this process remains unclear. Therefore, biomarkers to predict who will develop diabetes are sorely needed. Now, Jais et. al. have found an unexpected candidate: heme oxygenase-1 (HO-1), which turns out to initiate inflammation in the liver and drive metabolic disease.

HO-1 had been thought to be an anti-inflammatory molecule that catalyzes heme breakdown. Indeed, in humans, loss of HO-1 leads to early death, and in mice, loss of HO-1 results in high mortality and increased susceptibility to inflammation. To investigate HO-1’s role in obesity, the authors divided 44 obese individuals into insulin-sensitive and -resistant groups and compared their gene signatures within the liver to those of nonobese healthy individuals. To the authors’ surprise, all insulin-resistant individuals had markedly elevated HO-1 in both the liver and visceral fat, which correlated with inflammation and metabolic dysregulation. Because HO-1 was not previously thought to be proinflammatory, the authors validated their results in five independent studies. In all five, HO-1 was elevated in obese versus lean subjects, in diabetic versus nondiabetic subjects, and even in the obese sibling of monozygotic twin pairs. These data suggest that HO-1 is involved in promoting insulin resistance and might serve as a biomarker to predict the onset of disease.

To test how HO-1 contributes to the development of diabetes, the authors created a mouse in which HO-1 was knocked out in either the liver or macrophages. The results from the liver-specific deletion were consistent with their patient studies, protecting animals from insulin resistance induced by a high-fat diet. But HO-1 depletion in macrophages reduced inflammation and adipocyte size and protected the animals from insulin resistance. They showed improved health despite their high-fat diet–induced obesity. Although more validation is required, these studies suggest that HO-1 expression could identify those obese individuals who will develop insulin resistance and diabetes, allowing treatment to be directed to prediabetics. Even more important is the fact that HO-1’s functional role in driving inflammation and insulin resistance suggests that its inhibition could be a valuable therapeutic strategy to treat metabolic disease.

A. Jais et al., Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell 158, 25–40 (2014). [Abstract]

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