The N^ε-(carboxymethyl)lysine–RAGE axis: putative implications for the pathogenesis of obesity-related complications

Abstract

Obesity is an important contributor to the burden of insulin resistance, Type 2 diabetes and cardiovascular disease. An important mechanism by which excess adiposity causes obesity-associated complications is the dysregulated production and secretion of biologically active molecules derived from adipocytes. These adipokines affect the vascular wall and contribute to the development of insulin resistance and Type 2 diabetes. However, factors that cause an increased production of pro-inflammatory adipokines, while decreasing anti-inflammatory adipokines, have not been fully clarified. Owing to local conditions in adipose tissue, that is, increased fatty acids, hypoxia and oxidative stress, we speculate that an increased formation of the major advanced lipoxidation end product, N^ε-(carboxymethyl)lysine (CML), may play a role. CML-adducts in proteins are major ligands for the receptor for advanced glycation end products (RAGE). The consequence of RAGE activation by CML is the activation of important signaling inflammatory pathways. The putative role of CML-modified proteins in obesity is addressed in this article. The identification of this pathway may provide an important strategy for novel therapeutic approaches against obesity-associated complications.

Keywords::

• adipokines
• advanced lipoxidation end products
• N^ε-(carboxymethyl)lysine
• obesity
• RAGE
• receptor for advanced glycation end product

Financial & competing interests disclosure

This research is founded by the Dutch Diabetes Research Foundation (grant 2005.00.035). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.