title: Decrease of miR-146b-5p in monocytes during obesity is associated with loss of the anti-inflammatory but not insulin signaling action of adiponectin.
abstract: BACKGROUND
  Low adiponectin, a well-recognized antidiabetic adipokine, has been associated with obesity-related inflammation, oxidative stress and insulin resistance. Globular adiponectin is an important regulator of the interleukin-1 receptor-associated kinase (IRAK)/NFκB pathway in monocytes of obese subjects. It protects against inflammation and oxidative stress by inducing IRAK3. microRNA (miR)-146b-5p inhibits NFκB-mediated inflammation by targeted repression of IRAK1 and TNF receptor-associated factor-6 (TRAF6). Therefore, we measured the expression of miR-146b-5p in monocytes of obese subjects. Because it was low we determined the involvement of this miR in the anti-inflammatory, antioxidative and insulin signaling action of globular adiponectin.
  
  
  METHODS
  miR-146b-5p expression in monocytes of obese subjects was determined by qRT-PCR. The effect of miR-146b-5p silencing on molecular markers of inflammation, oxidative stress and insulin signaling and the association with globular adiponectin was assessed in human THP-1 monocytes.
  
  
  RESULTS
  miR-146b-5p was downregulated in monocytes of obese persons. Low globular adiponectin decreased miR-146b-5p and IRAK3 in THP-1 monocytes, associated with increased mitochondrial reactive oxygen species (ROS). Intracellular ROS and insulin receptor substrate-1 (IRS1) protein were unchanged. Silencing of miR-146b-5p with an antisense inhibitor resulted in increased expression of IRAK1 and TRAF6 leading to more NFκB p65 DNA binding activity and TNFα. As a response IRAK3 and IRS1 protein increased. Mitochondrial and intracellular ROS production did not increase despite more inflammation. In addition, exposure of miR-146b-5p-depleted THP-1 monocytes to high levels of globular adiponectin resulted in an increased production of TNFα and intracellular ROS. Still, they did not lose their potential to increase IRAK3 and IRS1 protein and to decrease mitochondrial ROS.
  
  
  CONCLUSIONS
  miR-146b-5p, decreased in monocytes during obesity, is a major mediator of the anti-inflammatory action of globular adiponectin. It appears not to be involved in insulin signaling possibly by protective response of IRAK3 and lack of mitochondrial ROS production.
authors.affiliation: Atherosclerosis and Metabolism Unit, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Hulsmans
authors.forename: Els
authors.initials: E
authors.lastname: Van Dooren
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Paul
authors.initials: P
authors.lastname: Holvoet
mesh_terms: D052242:Adiponectin / Q000097:blood / Q000378:metabolism*; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000097:blood; D007328:Insulin / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000097:blood*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
chemical_list: D052242:Adiponectin; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D007328:Insulin; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D048029:TNF Receptor-Associated Factor 6; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases