Abstract 11561: Pharmacological Inhibition of Rage/diaph1 Axis Enhances Weight Loss in Diet Induced Obese Mice and Improves Glucose Homeostasis

Abstract

Introduction: The incidence of obesity and its comorbidities has soared at an alarming rate in US and around the world. Our previous studies have shown that the receptor for advanced glycation end products (RAGE) and its ligands contribute to the pathogenesis of obesity and insulin resistance. Both global and adipocyte-specific Ager (gene encoding RAGE) deleted mice fed a high fat diet (HFD) showed protection from weight gain and insulin resistance. However, if RAGE deletion/inhibition affects weight loss in mice with established obesity is under investigation. We have discovered novel small molecule antagonists of the interaction between the cytoplasmic domain of RAGE with its intracellular effector Diaphanous 1(DIAPH1). We tested the hypothesis that these chow containing small molecule antagonists vs. vehicle might enhance weight loss and improve metabolic function in obese mice undergoing weight loss. Methods: Male mice (C57BL/6, N=78) were fed HFD (60% kcal/fat) for 20 weeks starting at 8 weeks of age to establish obesity; mice were then switched to either low fat RAGE/DIAPH1 inhibitor diet (N=40) or vehicle diet (N=38). Body mass was serially monitored and after six weeks of medicated chow vs. vehicle, glucose and insulin tolerance, body composition, plasma insulin and lipids were measured. Adipocyte size was monitored by histology. Results: Six weeks administration of RAGE/DIAPH1 antagonist in mice with established obesity resulted in significantly greater weight loss and fat mass vs. vehicle treatment. Further, metabolic recovery was enhanced, as evidenced by greater improvement in glucose tolerance and reduced plasma insulin and cholesterol levels. Histology revealed that epididymal and subcutaneous adipose tissues displayed smaller mean adipocyte size in mice receiving the RAGE/DIAPH1 antagonists vs. vehicle. Conclusion: Pharmacological inhibition of RAGE/DIAPH1 axis in mice with established obesity enhances weight loss, and improves metabolic recovery.