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

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.