title: The rise of soluble TWEAK levels in severely obese subjects after bariatric surgery may affect adipocyte-cytokine production induced by TNFα.
abstract: BACKGROUND
  Soluble TNF-like weak inducer of apoptosis (sTWEAK) is generated by the intracellular proteolytic cleavage of full-length membrane-bound TNF-like weak inducer of apoptosis (mTWEAK). sTWEAK levels are reduced in diseases with an inflammatory component. Additionally, sTWEAK hampers TNFα activity in human cells.
  
  
  OBJECTIVE
  The objectives of the study were as follows: 1) to determine circulating sTWEAK in severe obesity and after bariatric surgery; 2) to study m/sTWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) protein expression in sc adipose tissue (SAT) of severely obese subjects, in SAT stromal vascular fraction (SVF), and isolated adipocytes and in human monocyte-derived macrophages; and 3) to explore, on human adipocytes, the sTWEAK effect on TNFα proinflammatory activity.
  
  
  METHODS
  sTWEAK levels were measured in cohort 1: severely obese subjects (n = 23) and a control group (n = 35); and in cohort 2: (n = 23) severely obese subjects before and after surgery. The m/sTWEAK and Fn14 expressions were determined in SAT biopsies, SVF, and isolated adipocytes from severely obese and control subjects and in human monocyte-derived macrophages. In human primary cultured adipocytes, sTWEAK pretreated and TNFα challenged, IL-6, IL-8, and adiponectin protein and gene expressions were determined and nuclear factor-κ B and MAPK signaling analyzed.
  
  
  RESULTS
  sTWEAK levels were reduced in severely obese subjects. After surgery, sTWEAK levels rose in 69% of patients. mTWEAK protein expression was increased in SAT and SVF of severely obese subjects, whereas Fn14 was up-regulated in isolated adipocytes. M2 human monocyte-derived macrophages overexpress mTWEAK. In human adipocytes, sTWEAK down-regulates TNFα cytokine production by hampering TNFα intracellular signaling events.
  
  
  CONCLUSIONS
  The decrease of sTWEAK in severely obese patients may favor the proinflammatory activity elicited by TNFα.
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, 28027 Madrid, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Maymó-Masip
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Veledo
authors.forename: Antonio
authors.initials: A
authors.lastname: Garcia España
authors.forename: Ana
authors.initials: A
authors.lastname: Vázquez-Carballo
authors.forename: Francisco Jóse
authors.initials: FJ
authors.lastname: Tinahones
authors.forename: Eduardo
authors.initials: E
authors.lastname: García-Fuentes
authors.forename: Lourdes
authors.initials: L
authors.lastname: Garrifo-Sanchez
authors.forename: Maria del Mar
authors.initials: Mdel M
authors.lastname: Rodriguez
authors.forename: Joan
authors.initials: J
authors.lastname: Vendrell
authors.forename: Matilde R
authors.initials: MR
authors.lastname: Chacón
mesh_terms: D017667:Adipocytes / Q000276:immunology*; D000328:Adult; D050110:Bariatric Surgery; D015992:Body Mass Index; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000096:biosynthesis*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000276:immunology* / Q000601:surgery; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D048069:Tumor Necrosis Factors / Q000097:blood*
chemical_list: D000074049:Cytokine TWEAK; D016207:Cytokines; D005230:Fatty Acids, Nonesterified; C109743:TNFSF12 protein, human; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors