Abstract
BackgroundVisceral 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.ObjectiveWe searched a cluster of molecules that support interactions between these stress conditions in monocytes.Methods RNA 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 RNA silencing on inflammation and oxidative stress was studied in human monocytic THP-1 cells.Results Interleukin-1 receptor-associated kinase-3 (IRAK3), key inhibitor of IRAK/NFκB-mediated chronic inflammation, is downregulated in monocytes of obese persons. Low IRAK3 was associated with high superoxide dismutase-2 (SOD2), a marker of mitochondrial oxidative stress. A comparable expression profile was also detected in visceral adipose tissue of the same obese subjects. Low IRAK3 and high SOD2 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 IRAK3 and a decrease in SOD2, 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 in vitro.ConclusionIRAK3 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.
Highlights
Chronic low-grade inflammation is considered to have a pivotal role in the development of obesity and associated metabolic diseases such as insulin resistance, type 2 diabetes (T2DM) and the metabolic syndrome and cardiovascular disease [1,2]
Interleukin-1 receptor-associated kinase-3 (IRAK3) is a key inhibitor of inflammation in association with obesity and metabolic syndrome
A cluster of risk factors for cardiovascular disease and T2DM including raised blood pressure, dyslipidemia, raised fasting glucose, and central obesity have become known as the metabolic syndrome
Summary
Chronic low-grade inflammation is considered to have a pivotal role in the development of obesity and associated metabolic diseases such as insulin resistance, type 2 diabetes (T2DM) and the metabolic syndrome and cardiovascular disease [1,2]. It is recognized that maladaptive production of various adipocytokines (e.g. adiponectin, resistin, visfatin, and leptin) and pro-inflammatory cytokines, such as tumor necrosis factor-a (TNFa) and interleukin (IL)-6 and IL-1, are implicated in the development of obesity-related systemic inflammation and insulin resistance. The plasma levels of the adipocytokine adiponectin are significant lower in obese individuals and have been associated with inflammation, insulin resistance and the development of cardiovascular disease. Adiponectin is present in the plasma in its full length, forming homomultimers, and as globular adiponectin, a shorter product formed by macrophage-dependent elastase cleavage [3]. Low-grade chronic inflammation and oxidative stress synergize in obesity and obesity-induced disorders
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