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.