Katrien H J Gaens1, Gijs H Goossens1, Petra M Niessen1, Marleen M van Greevenbroek1, Carla J H van der Kallen1, Hans W Niessen1, Sander S Rensen1, Wim A Buurman1, Jan Willem M Greve1, Ellen E Blaak1, Marc A van Zandvoort1, Angelika Bierhaus1, Coen D A Stehouwer1, Casper G Schalkwijk2. 1. From the Department of Internal Medicine and the Laboratory of Metabolism and Vascular Medicine (K.H.J.G., P.M.N., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Cardiovascular Research Institute Maastricht (K.H.J.G., P.M.N., M.M.v.G., C.J.H.v.d.K., M.A.v.Z., C.D.A.S., C.G.S.), Department of Human Biology (G.H.G., E.E.B.), NUTRIM School for Nutrition, Toxicology, and Metabolism (G.H.G., S.S.R., W.A.B., J.W.M.G., E.E.B.), Department of General Surgery (S.S.R., W.A.B., J.W.M.G.), and Department of Biomedical Engineering (M.A.v.Z.), Maastricht University Medical Center, Maastricht, The Netherlands; Department of Pathology and Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Medicine and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany (A.B.). 2. From the Department of Internal Medicine and the Laboratory of Metabolism and Vascular Medicine (K.H.J.G., P.M.N., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Cardiovascular Research Institute Maastricht (K.H.J.G., P.M.N., M.M.v.G., C.J.H.v.d.K., M.A.v.Z., C.D.A.S., C.G.S.), Department of Human Biology (G.H.G., E.E.B.), NUTRIM School for Nutrition, Toxicology, and Metabolism (G.H.G., S.S.R., W.A.B., J.W.M.G., E.E.B.), Department of General Surgery (S.S.R., W.A.B., J.W.M.G.), and Department of Biomedical Engineering (M.A.v.Z.), Maastricht University Medical Center, Maastricht, The Netherlands; Department of Pathology and Cardiac Surgery, Institute for Cardiovascular Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (H.W.N.); and Department of Medicine and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany (A.B.). c.schalkwijk@maastrichtuniversity.nl.
Abstract
OBJECTIVE: Dysregulation of inflammatory adipokines by the adipose tissue plays an important role in obesity-associated insulin resistance. Pathways leading to this dysregulation remain largely unknown. We hypothesized that the receptor for advanced glycation end products (RAGE) and the ligand N(ε)-(carboxymethyl)lysine (CML) are increased in adipose tissue and, moreover, that activation of the CML-RAGE axis plays an important role in obesity-associated inflammation and insulin resistance. APPROACH AND RESULTS: In this study, we observed a strong CML accumulation and increased expression of RAGE in adipose tissue in obesity. We confirmed in cultured human preadipocytes that adipogenesis is associated with increased levels of CML and RAGE. Moreover, CML induced a dysregulation of inflammatory adipokines in adipocytes via a RAGE-dependent pathway. To test the role of RAGE in obesity-associated inflammation further, we constructed an obese mouse model that is deficient for RAGE (ie, RAGE(-/-)/Leptr(Db-/-) mice). RAGE(-/-)/Leptr(Db-/-) mice displayed an improved inflammatory profile and glucose homeostasis when compared with RAGE(+/+)/Leptr(Db-/-) mice. In addition, CML was trapped in adipose tissue in RAGE(+/+)/Leptr(Db-/-) mice but not in RAGE(-/-)/Leptr(Db-/-). RAGE-mediated trapping in adipose tissue provides a mechanism underlying CML accumulation in adipose tissue and explaining decreased CML plasma levels in obese subjects. Decreased CML plasma levels in obese individuals were strongly associated with insulin resistance. CONCLUSIONS: RAGE-mediated CML accumulation in adipose tissue and the activation of the CML-RAGE axis are important mechanisms involved in the dysregulation of adipokines in obesity, thereby contributing to the development of obesity-associated insulin resistance.
OBJECTIVE: Dysregulation of inflammatory adipokines by the adipose tissue plays an important role in obesity-associated insulin resistance. Pathways leading to this dysregulation remain largely unknown. We hypothesized that the receptor for advanced glycation end products (RAGE) and the ligand N(ε)-(carboxymethyl)lysine (CML) are increased in adipose tissue and, moreover, that activation of the CML-RAGE axis plays an important role in obesity-associated inflammation and insulin resistance. APPROACH AND RESULTS: In this study, we observed a strong CML accumulation and increased expression of RAGE in adipose tissue in obesity. We confirmed in cultured human preadipocytes that adipogenesis is associated with increased levels of CML and RAGE. Moreover, CML induced a dysregulation of inflammatory adipokines in adipocytes via a RAGE-dependent pathway. To test the role of RAGE in obesity-associated inflammation further, we constructed an obesemouse model that is deficient for RAGE (ie, RAGE(-/-)/Leptr(Db-/-) mice). RAGE(-/-)/Leptr(Db-/-) mice displayed an improved inflammatory profile and glucose homeostasis when compared with RAGE(+/+)/Leptr(Db-/-) mice. In addition, CML was trapped in adipose tissue in RAGE(+/+)/Leptr(Db-/-) mice but not in RAGE(-/-)/Leptr(Db-/-). RAGE-mediated trapping in adipose tissue provides a mechanism underlying CML accumulation in adipose tissue and explaining decreased CML plasma levels in obese subjects. Decreased CML plasma levels in obese individuals were strongly associated with insulin resistance. CONCLUSIONS:RAGE-mediated CML accumulation in adipose tissue and the activation of the CML-RAGE axis are important mechanisms involved in the dysregulation of adipokines in obesity, thereby contributing to the development of obesity-associated insulin resistance.
Authors: Liang Chen; Zhigang Duan; Lesley Tinker; Haleh Sangi-Haghpeykar; Howard Strickler; Gloria Y F Ho; Marc J Gunter; Thomas Rohan; Craig Logsdon; Donna L White; Kathryn Royse; Hashem B El-Serag; Li Jiao Journal: Cancer Epidemiol Date: 2016-04-18 Impact factor: 2.984
Authors: Camilo G Sotomayor; António W Gomes-Neto; Marco van Londen; Rijk O B Gans; Ilja M Nolte; Stefan P Berger; Gerjan J Navis; Ramón Rodrigo; Henri G D Leuvenink; Casper G Schalkwijk; Stephan J L Bakker Journal: Clin J Am Soc Nephrol Date: 2019-09-17 Impact factor: 8.237