Editors' ChoiceMetabolism

HO-1 Promotes Unhealthy Obesity

Sci. Signal.  15 Jul 2014:
Vol. 7, Issue 334, pp. ec191
DOI: 10.1126/scisignal.2005682

Obesity is a risk factor for type II diabetes, but not all obese people are diabetic. Unhealthy obesity is associated with chronic systemic inflammation. Jais et al. discovered that the mitochondrial heme-metabolizing enzyme HO-1 (heme oxygenase-1, encoded by HMOX1) contributes to unhealthy obesity. The expression of HMOX1 was a predictor of obesity and diabetes in several patient cohorts and was greater in obese siblings of monozygotic twins. In an age- and body mass index–matched cohort, the expression of HMOX1 and the abundance of HO-1 was greater in insulin-resistant, compared with insulin-sensitive, obese patients. Likewise, in a group of mice fed a high-fat diet (HFD) and stratified according to insulin and glucose tolerance, the expression of Hmox1 in liver and adipose tissues correlated with metabolic dysfunction, but not overall body weight. Conditional knockout of Hmox1 in hepatocytes or macrophages in mice did not affect embryonic or postnatal development, liver morphology, basal blood glucose, or tolerance to glucose injection. When fed a HFD, both types of knockout mice had similar weight gain as wild-type mice, but improved sensitivity to insulin injection and reduced hepatic damage. Overexpression of HO-1 in wild-type mice fed a normal diet resulted in decreased glucose tolerance and insulin sensitivity. Macrophage-specific knockout mice fed a HFD had decreased expression of genes encoding inflammatory cytokines in both myeloid cells and hepatocytes, reduced infiltration of proinflammatory M1-type macrophages into epididymal fat, and decreased abundance of other inflammatory markers. Macrophages differentiated ex vivo from bone marrow of the macrophage-specific knockout mice had reduced activation of the transcription factor NF-κB in response to stimulation with the proinflammatory cytokine TNF-α. Ex vivo differentiated macrophages from either type of knockout mice had an aerobic respiratory signature consistent with an anti-inflammatory, M2-type macrophage phenotype. These cells had normal mitochondrial mass, mitochondrial DNA content, and oxidative chain stoichiometry, but increased expression of several genes encoding proteins that detoxify reactive oxygen species (ROS) and increased cytosolic ROS, consistent with the observation that low amounts of ROS can promote mitochondrial respiration. Thus, increased HO-1 is associated with diabetes and may contribute to the progression of insulin resistance in obese patients by promoting chronic inflammation.

A. Jais, E. Einwallner, O. Sharif, K. Gossens, T. T.-H. Lu, S. M. Soyal, D. Medgyesi, D. Neureiter, J. Paier-Pourani, K. Dalgaard, J. C. Duvigneau, J. Lindroos-Christensen, T.-C. Zapf, S. Amann, S. Saluzzo, F. Jantscher, P. Stiedl, J. Todoric, R. Martins, H. Oberkofler, S. Műller, C. Hauser-Kronberger, L. Kenner, E. Casanova, H. Sutterlűty-Fall, M. Bilban, K. Miller, A. V. Kozlov, F. Krempler, S. Knapp, C. N. Lumeng, W. Patsch, O. Wagner, J. A. Pospisilik, H. Esterbauer, Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell 158, 25–40 (2014). [Pubmed]