TY - JOUR
T1 - Nε-(Carboxymethyl)lysine-Receptor for Advanced Glycation End Product Axis Is a Key Modulator of Obesity-Induced Dysregulation of Adipokine Expression and Insulin Resistance
AU - Gaens, K.H.
AU - Goossens, G.H.
AU - Niessen, P.M.
AU - van Greevenbroek, M.M.
AU - van der Kallen, C.J.
AU - Niessen, H.W.
AU - Rensen, S.S.
AU - Buurman, W.A.
AU - Greve, J.W.
AU - Blaak, E.E.
AU - van Zandvoort, M.A.
AU - Bierhaus, A.
AU - Stehouwer, C.D.
AU - Schalkwijk, C.G.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
U2 - 10.1161/ATVBAHA.113.302281
DO - 10.1161/ATVBAHA.113.302281
M3 - Article
SN - 1079-5642
VL - 34
SP - 1199
EP - 1208
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 6
ER -