title: Interleukin-1 receptor-associated kinase-3 is a key inhibitor of inflammation in obesity and metabolic syndrome.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Atherosclerosis and Metabolism Unit, Department of Cardiovascular Diseases, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hulsmans
authors.forename: Benjamine
authors.initials: B
authors.lastname: Geeraert
authors.forename: Dieuwke
authors.initials: D
authors.lastname: De Keyzer
authors.forename: Ann
authors.initials: A
authors.lastname: Mertens
authors.forename: Matthias
authors.initials: M
authors.lastname: Lannoo
authors.forename: Bart
authors.initials: B
authors.lastname: Vanaudenaerde
authors.forename: Marc
authors.initials: M
authors.lastname: Hoylaerts
authors.forename: Nora
authors.initials: N
authors.lastname: Benhabilès
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics; D000328:Adult; D002460:Cell Line; D002478:Cells, Cultured; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D053592:Interleukin-1 Receptor-Associated Kinases; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C507771:IRAK3 protein, human