Pharmacological antagonism of receptor for advanced glycation end products signaling promotes thermogenesis, healthful body mass and composition, and metabolism in mice

Abstract

Objective Optimal body mass and composition as well as metabolic fitness require tightly regulated and interconnected mechanisms across tissues. Disturbances in these regulatory networks tip the balance between metabolic health versus overweight and obesity and their complications. The authors previously demonstrated roles for the receptor for advanced glycation end products (RAGE) in obesity, as global‐ or adipocyte‐specific deletion of Ager (the gene encoding RAGE) protected mice from high‐fat diet‐induced obesity and metabolic dysfunction. Methods To explore translational strategies evoked by these observations, a small molecule antagonist of RAGE signaling, RAGE229, was administered to lean mice and mice with obesity undergoing diet‐induced weight loss. Body mass and composition and whole body and adipose tissue metabolism were examined. Results This study demonstrates that antagonism of RAGE signaling reduced body mass and adiposity and improved glucose, insulin, and lipid metabolism in lean male and female mice and in male mice with obesity undergoing weight loss. In adipose tissue and in human and mouse adipocytes, RAGE229 enhanced phosphorylation of protein kinase A substrates, which augmented lipolysis, mitochondrial function, and thermogenic programs. Conclusions Pharmacological antagonism of RAGE signaling is a potent strategy to optimize healthful body mass and composition and metabolic fitness.

Development of Receptor for Advanced Glycation End Products (RAGE) ligands through target directed dynamic combinatorial chemistry: a novel class of possible antagonists

“…[25] Therefore, the discovery of an efficient ligand which can inhibit RAGE has been pursued as a pathway to control the effects from over-stimulated RAGE-mediated inflammation observed in these disorders. [26] Starting from the hypothesis that blocking RAGE via antagonistic molecules will prevent inflammation and aging, RAGE serves as a very attractive therapeutic target. Several small molecules have been tested for their efficacy to inhibit RAGE, among which Azeliragon (TTP488) [27] is the first RAGE antagonist which reached phase III clinical trials (STEADFAST) as treatment for patients with mild Alzheimer's disease (NCT02080364, NCT02916056, etc) (Figure 1b).…”