Interleukin-1 Receptor-Associated Kinase-3 Is a Key Inhibitor of Inflammation in Obesity and Metabolic Syndrome

<div><h3>Background</h3><p>Visceral obesity is associated with the rising incidence of type 2 diabetes and metabolic syndrome. Low-grade chronic inflammation and oxidative stress synergize in obesity and obesity-induced disorders.</p> <h3>Objective</h3><p>We searched a cluster of molecules that support interactions between these stress conditions in monocytes.</p> <h3>Methods</h3><p><em>RNA</em> expressions in blood monocytes of two independent cohorts comprising 21 and 102 obese persons and 46 age-matched controls were determined by microarray and independently validated by quantitative RT-PCR analysis. The effect of three-month weight loss after bariatric surgery was determined. The effect of <em>RNA</em> silencing on inflammation and oxidative stress was studied in human monocytic THP-1 cells.</p> <h3>Results</h3><p><em>Interleukin-1 receptor-associated kinase-3</em> (<em>IRAK3</em>), key inhibitor of IRAK/NFκB-mediated chronic inflammation, is downregulated in monocytes of obese persons. Low <em>IRAK3</em> was associated with high <em>superoxide dismutase-2</em> (<em>SOD2</em>), a marker of mitochondrial oxidative stress. A comparable expression profile was also detected in visceral adipose tissue of the same obese subjects. Low <em>IRAK3</em> and high <em>SOD2</em> was associated with a high prevalence of metabolic syndrome (odds ratio: 9.3; sensitivity: 91%; specificity: 77%). By comparison, the odds ratio of high-sensitivity C-reactive protein, a widely used marker of systemic inflammation, was 4.3 (sensitivity: 69%; specificity: 66%). Weight loss was associated with an increase in <em>IRAK3</em> and a decrease in <em>SOD2</em>, in association with a lowering of systemic inflammation and a decreasing number of metabolic syndrome components. We identified the increase in reactive oxygen species in combination with obesity-associated low adiponectin and high glucose and interleukin-6 as cause of the decrease in IRAK3 in THP-1 cells <em>in vitro</em>.</p> <h3>Conclusion</h3><p>IRAK3 is a key inhibitor of inflammation in association with obesity and metabolic syndrome. Our data warrant further evaluation of IRAK3 as a diagnostic and prognostic marker, and as a target for intervention.</p>