Mark Colin Gissler1, Nathaly Anto-Michel2, Jan Pennig1, Philipp Scherrer1, Xiaowei Li1, Timoteo Marchini1, Katharina Pfeiffer1, Carmen Härdtner1, Tijani Abogunloko1, Timothy Mwinyella1, Lucia Sol Mitre1, Lisa Spiga1, Christoph Koentges1,3, Christian Smolka1, Dominik von Elverfeldt4, Natalie Hoppe1, Peter Stachon1, Bianca Dufner1, Timo Heidt1, Sven Piepenburg1, Ingo Hilgendorf1, Jan-Inge Bjune5,6,7, Simon N Dankel5,6,7, Gunnar Mellgren5,6,7, Gabriel Seifert8, Steffen U Eisenhardt9, Heiko Bugger2, Constantin von Zur Muhlen1, Christoph Bode1, Andreas Zirlik2, Dennis Wolf1, Florian Willecke1,10. 1. Cardiology and Angiology I, University Heart Center, Faculty of Medicine, University of Freiburg, Germany (M.C.G., J.P., P.S., X.L., T. Marchini, K.P., C.H., T.A., T. Mwinyella, L.S.M., L.S., C.K., C.S., N.H., P.S., B.D., T.H., S.P., I.H., C.v.z.M., C.B., D.W., F.W.). 2. Department of Cardiology, Medical University of Graz, Austria (N.A.M., H.B., A.Z.). 3. Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. (C.K.). 4. Department of Radiology, Medical Physics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. (D.v.E.). 5. Center for Diabetes Research, University of Bergen, Norway. (J.-I.B., S.N.D., G.M.). 6. Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Norway. (J.-I.B., S.N.D., G.M.). 7. Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway (J.-I.B., S.N.D., G.M.). 8. Department of General and Visceral Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. (G.S.). 9. Department of Plastic and Hand Surgery, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Breisgau, Germany (S.U.E.). 10. Clinic for General and Interventional Cardiology/Angiology, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum, Bad Oeynhausen, Germany (F.W.).
Abstract
OBJECTIVE: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor-associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5-/- mice consumed a high-fat diet for 18 weeks. Traf5-/- mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5-/- mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5-/- mice revealed an increase in cytotoxic T cells, CD11c+ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNFα, MIP (macrophage inflammatory protein)-1α, MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5-deficient adipocytes but not in Traf5-deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. CONCLUSIONS: We show that a genetic deficiency of TRAF5 in mice diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.
OBJECTIVE: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor-associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5-/- mice consumed a high-fat diet for 18 weeks. Traf5-/- mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5-/- mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5-/- mice revealed an increase in cytotoxic T cells, CD11c+ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNFα, MIP (macrophage inflammatory protein)-1α, MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5-deficient adipocytes but not in Traf5-deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obesepatients and mice and recovered in adipose tissue of obesepatients one year after bariatric surgery. CONCLUSIONS: We show that a genetic deficiency of TRAF5 in mice diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.