Nε-(carboxymethyl)lysine-receptor for advanced glycation end product axis is a key modulator of obesity-induced dysregulation of adipokine expression and 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.


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.
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.).
Katrien H J
KH
Gaens
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.).
Gijs H
GH
Goossens
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.).
Petra M
PM
Niessen
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.).
Marleen M
MM
van Greevenbroek
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.).
Carla J H
CJ
van der Kallen
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.).
Hans W
HW
Niessen
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.).
Sander S
SS
Rensen
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.).
Wim A
WA
Buurman
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.).
Jan Willem M
JW
Greve
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.).
Ellen E
EE
Blaak
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.).
Marc A
MA
van Zandvoort
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.).
Angelika
A
Bierhaus
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.).
Coen D A
CD
Stehouwer
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.
Casper G
CG
Schalkwijk
D054392:Adipokines / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*
D054392:Adipokines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C048496:N(6)-carboxymethyllysine; D008239:Lysine
Nε-(carboxymethyl)lysine; advanced glycation end product; inflammation; obesity; receptor for advanced glycation end products