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 . 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. endothelial cells, and macrophages. 9 RAGE is initially identified as the receptor for advanced glycation end products (AGEs), 10 but, in addition to AGEs, RAGE also interacts with multiple members of the proinflammatory S100/calgranulin family and high motility group box 1 protein. Conclusions-RAGE-mediated9,11 Binding of these ligands to RAGE leads to activation of signaling cascade and induction of nuclear factor-κB, which can subsequently lead to the production of inflammatory mediators.9,12 Therefore, the potential role of RAGE in the regulation of inflammation suggests that RAGE might be an important mechanism contributing to obesity-associated dysregulation of adipokines and development of insulin resistance. N ε -(carboxymethyl)lysine (CML) is a major AGE and is an important ligand for RAGE.10 CML is formed on proteins by nonenzymatic glycation and oxidation reactions. 13Alternative routes for CML formation have been described, including lipid peroxidation of polyunsaturated fatty acids.14,15 In fact, lipid peroxidation is a more important source for CML formation than glycoxidation reactions.14 Because of the reaction mechanism, CML formation is increased under hyperglycemic and hyperlipidemic conditions. The adipose tissue in obese conditions is characterized by increased levels of fatty acids, lipid peroxidation, and oxidative stress. Therefore, we can deduce that obesity is also a condition in which CML formation is increased and where CML can interact with RAGE. However, the role of CML-RAGE in obesity, obesity-associated inflammation, and insulin resistance has to date not been investigated.The aim of this study was to investigate the role of CML-RAGE axis in obesity-associated inflammation and insulin resistance. In the present study, we showed in huma...

Serum carboxymethyl-lysine, a dominant advanced glycation end product, is increased in women with gestational diabetes mellitus

“…Other studies found the same relationship and specifically confirmed the presence of CML in adipose tissue 17,18 . Taken together, it appears that CML is preferentially deposited in fat tissue and acts as an important mechanism involved in the dysregulation of adipokines in obesity, thereby contributing to the development of obesity-associated insulin resistance.…”

Dietary Sugars and Endogenous Formation of Advanced Glycation Endproducts: Emerging Mechanisms of Disease

“…First, the high-temperature and long-time cooking of foods can generate AGEs that are exogenously introduced with the diet [46]. Second, emerging evidence indicates that high dietary simple sugars consumption can represent a substantial source of endogenous AGEs [47]. In this regards, it is a long time that studies started to investigate the glycative potential of different monosaccharides by in vitro incubations with physiologically relevant proteins such as haemoglobin and serum albumin [48,49].…”

The analysis of advanced glycation endproducts

“…This was in reasonable agreement with data described in literature [36][37][38][39][40][41] . The described method is suitable for studying AGEs in several different human and animal studies [42][43][44][45][46][47][48][49] and is a strong tool to investigate the putative effects of AGEs in the pathophysiology of different diseases.…”

“…Possible lifestyle interventions, such as glucose-, blood-pressure-and lipid-lowering treatments 50,53,54 and changes in dietary AGEs (due to diet interventions), may potentially influence circulating AGEs. Moreover, CML has been found to be trapped in adipose tissues 42,55 and consequently, plasma CML levels are lower in individuals with overweight compared to lean individuals 55 . Given the high prevalence of overweight and obesity in patients with T2DM, this phenomenon manifests more often in T2DM as compared to T1DM or lean individuals.…”

“…MGO is detoxified by the glyoxalase pathway by two dependent thiol-enzymes; glyoxalase-1 and -2 (GLO-I and GLO-II) and reduced glutathione (GSH) into D-lactate (Figure 1.3) 40,41 . Glyoxal is formed by the degradation of glucose by retro-aldol condensation reactions 42 activated by deprotonation of the 2-and 3-hydroxy groups 43 . Glyoxal reacts further with lysine to form N -(carboxymethyl)lysine (CML), a well-known ligand for the receptor for AGEs (RAGE) 44 .…”