Nε-(Carboxymethyl)lysine-Receptor for Advanced Glycation End Product Axis Is a Key Modulator of Obesity-Induced Dysregulation of Adipokine Expression and Insulin Resistance

K.H. Gaens, G.H. Goossens, P.M. Niessen, M.M. van Greevenbroek, C.J. van der Kallen, H.W. Niessen, S.S. Rensen, W.A. Buurman, J.W. Greve, E.E. Blaak, M.A. van Zandvoort, A. Bierhaus, C.D. Stehouwer, C.G. Schalkwijk*

*Corresponding author for this work

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Abstract

OBJECTIVE: Dysregulation of inflammatory adipokines by the adipose an important role in obesity-associated insulin resistance. Pathways this dysregulation remain largely unknown. We hypothesized that the advanced glycation end products (RAGEs) and the ligand Nepsilon-(carboxymethyl)lysine (CML) are increased in adipose tissue moreover, that activation of the CML-RAGE axis plays an important role obesity-associated inflammation and insulin resistance. APPROACH AND this study, we observed a strong CML accumulation and increased RAGE in adipose tissue in obesity. We confirmed in cultured human that adipogenesis is associated with increased levels of CML and RAGE Moreover, CML induced a dysregulation of inflammatory adipokines in via a RAGE-dependent pathway. To test the role of RAGE in obesity- inflammation further, we constructed an obese mouse model that is RAGE (ie, RAGE-/-/LeptrDb-/- mice). RAGE-/-/LeptrDb-/- mice displayed an inflammatory profile and glucose homeostasis when compared with RAGE+/+/LeptrDb-/- mice. In addition, CML was trapped in adipose tissue RAGE+/+/LeptrDb-/- mice but not in RAGE-/-/LeptrDb-/-. RAGE-mediated adipose tissue provides a mechanism underlying CML accumulation in and explaining decreased CML plasma levels in obese subjects. Decreased plasma levels in obese individuals were strongly associated with insulin resistance. CONCLUSIONS: RAGE-mediated CML accumulation in adipose activation of the CML-RAGE axis are an important mechanism involved in dysregulation of adipokines in obesity, thereby contributing to the of obesity-associated insulin resistance.
Original languageEnglish
Pages (from-to)1199-1208
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume34
Issue number6
DOIs
Publication statusPublished - 1 Jan 2014

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