The rise of soluble TWEAK levels in severely obese subjects after bariatric surgery may affect adipocyte-cytokine production induced by TNFα.

CONTEXT 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. OBJECTIVES 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. DESIGN 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. CONCLUSION The decrease of sTWEAK in severely obese patients may favor the proinflammatory activity elicited by TNFα.

Journal Article; Research Support, Non-U.S. Gov't;

This work was supported by projects from the Fondo de Investigación Sanitaria: Grant PI 11/00049 (to M.R.CH), Grant PI08/0733 (to M.R.C.), Grant SAF2012-36186 (to S.F.-V.) and from the Project Consolider Ingenio Grant CSD-2010-00065 (to A.G.-E.). S.F.-V. acknowledges support from the “Miguel Servet” tenure track program (Grant CP10/00438) from the Fondo de Investigación Sanitaria. All support from the Fondo de Investigación Sanitaria are cofinanced by the European Regional Development Fund. A.G.-E., M.R.C., and E.G.-F. are supported by the Research Stabilization Programme of the Instituto de Salud Carlos III. M.R.C. and A.G.-E. are also cofinanced by Institut Català de Salut in Catalonia (Spain). M.M.R. and L.G.-S. are financed by a fellowship “Juan de la Cierva” from the Spanish Ministry of Science and Innovation (Grant JCI-2011-11488 and JCI-2009-04086, respectively). E.-M.-M. is supported by the Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas.