title: Tumor necrosis-like weak inducer of apoptosis as a proinflammatory cytokine in human adipocyte cells: up-regulation in severe obesity is mediated by inflammation but not hypoxia.
abstract: BACKGROUND
  Adipose tissue hypoxia and endoplasmic reticulum (ER) stress may link the presence of chronic inflammation and macrophage infiltration in severely obese subjects. We previously reported the up-regulation of TNF-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis in adipose tissue of severely obese type 2 diabetic subjects.
  
  
  OBJECTIVE
  The objective of the study was to examine TWEAK and Fn14 adipose tissue expression in obesity, severe obesity, and type 2 diabetes in relation to hypoxia and ER stress.
  
  
  METHODS
  In the obesity study, 19 lean, 28 overweight, and 15 obese nondiabetic subjects were studied. In the severe obesity study, 23 severely obese and 35 control subjects were studied. In the type 2 diabetes study, 11 type 2 diabetic and 36 control subjects were studied. The expression levels of the following genes were analyzed in paired samples of sc and visceral adipose tissue: Fn14, TWEAK, VISFATIN, HYOU1, FIAF, HIF-1a, VEGF, GLUT-1, GRP78, and XBP-1. The effect of hypoxia, inflammation, and ER stress on the expression of TWEAK and Fn14 was examined in human adipocyte and macrophage cell lines.
  
  
  RESULTS
  Up-regulation of TWEAK/Fn14 and hypoxia and ER stress surrogate gene expression was observed in sc and visceral adipose tissue only in our severely obese cohort. Hypoxia modulates TWEAK or Fn14 expression in neither adipocytes nor macrophages. On the contrary, inflammation up-regulated TWEAK in macrophages and Fn14 expression in adipocytes. Moreover, TWEAK had a proinflammatory effect in adipocytes mediated by the nuclear factor-kappaB and ERK but not JNK signaling pathways.
  
  
  CONCLUSIONS
  Our data suggest that TWEAK acts as a pro-inflammatory cytokine in the adipose tissue and that inflammation, but not hypoxia, may be behind its up-regulation in severe obesity.
authors.affiliation: Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas, Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitaria Pere Virgili, Universitat Rovira i Virgili, 43007 Tarragona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Vendrell
authors.forename: Elsa
authors.initials: E
authors.lastname: Maymó-Masip
authors.forename: Francisco
authors.initials: F
authors.lastname: Tinahones
authors.forename: Antonio
authors.initials: A
authors.lastname: García-España
authors.forename: Ana
authors.initials: A
authors.lastname: Megia
authors.forename: Enric
authors.initials: E
authors.lastname: Caubet
authors.forename: Eduardo
authors.initials: E
authors.lastname: García-Fuentes
authors.forename: Matilde R
authors.initials: MR
authors.lastname: Chacón
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D001706:Biopsy; D015153:Blotting, Western; D002460:Cell Line; D015331:Cohort Studies; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D009767:Obesity, Morbid / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000074049:Cytokine TWEAK; D016207:Cytokines; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors