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

• Published in: The journal of clinical endocrinology and metabolism 2010-06, Vol.95 (6), p.2983-2992
• Main Authors: Vendrell, Joan, Maymó-Masip, Elsa, Tinahones, Francisco, García-España, Antonio, Megia, Ana, Caubet, Enric, García-Fuentes, Eduardo, Chacón, Matilde R.
• Format: Article
• Language: English
• Subjects: Adipocytes - metabolism; Adipose Tissue - metabolism; Biological and medical sciences; Biopsy; Blotting, Western; Cell Line; Cohort Studies; Cytokine TWEAK; Cytokines - metabolism; Diabetes Mellitus, Type 2 - metabolism; Endocrinopathies; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Gene Expression; Humans; Hypoxia - metabolism; Inflammation - metabolism; Macrophages - metabolism; Medical sciences; Obesity, Morbid - metabolism; Receptors, Tumor Necrosis Factor - genetics; Signal Transduction - genetics; Signal Transduction - physiology; Tumor Necrosis Factors - antagonists & inhibitors; Tumor Necrosis Factors - metabolism; TWEAK Receptor; Up-Regulation; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2009-2481

Context: 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. Objectives: 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. Design: 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-κB 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. Inflammation but not hypoxia may be behind the up-regulation of TWEAK/Fn14 gene expression levels in SAT and VAT adipose tissue depots of severely obese patients.