Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Leuven, Belgium.
PLoS One. 2012;7(1):e30414. doi: 10.1371/journal.pone.0030414. Epub 2012 Jan 17.
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.
We searched a cluster of molecules that support interactions between these stress conditions in monocytes.
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.
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.
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.
内脏型肥胖与 2 型糖尿病和代谢综合征的发病率上升有关。在肥胖和肥胖引起的疾病中，低度慢性炎症和氧化应激协同作用。
我们搜索了一组支持单核细胞中这些应激条件相互作用的分子。
通过微阵列和独立的定量 RT-PCR 分析，确定了来自两个独立队列的 21 名和 102 名肥胖者以及 46 名年龄匹配的对照者的血液单核细胞中的 RNA 表达。确定了减肥手术后三个月体重减轻的效果。在人单核细胞 THP-1 细胞中研究了 RNA 沉默对炎症和氧化应激的影响。
白细胞介素-1 受体相关激酶-3（IRAK3）是 IRAK/NFκB 介导的慢性炎症的关键抑制剂，在肥胖者的单核细胞中下调。低 IRAK3 与超氧化物歧化酶-2（SOD2）相关，SOD2 是线粒体氧化应激的标志物。在同一肥胖受试者的内脏脂肪组织中也检测到类似的表达谱。低 IRAK3 和高 SOD2 与代谢综合征的高患病率相关（比值比：9.3；敏感性：91%；特异性：77%）。相比之下，广泛用于全身炎症标志物的高敏 C 反应蛋白的比值比为 4.3（敏感性：69%；特异性：66%）。体重减轻与 IRAK3 增加和 SOD2 减少相关，与全身炎症降低和代谢综合征成分减少相关。我们发现，活性氧的增加与肥胖相关的低脂联素、高葡萄糖和白细胞介素-6 一起，导致 THP-1 细胞中 IRAK3 的减少。
IRAK3 是炎症与肥胖和代谢综合征相关的关键抑制剂。我们的数据证明了 IRAK3 作为诊断和预后标志物以及干预靶点的进一步评估。
