Abstract 14007: Sodium-Dependent Glucose Transporters 2 Inhibition Ameliorates Obesity-Induced Metabolic Changes and Cardiomyopathy

Abstract

Introduction: Inhibition of renal sodium-glucose cotransporter-2 (SGLT2) reduces urinary glucose reabsorption to decrease glycemia. Recent large-scale trials have shown that SGLT2 inhibitors provide cardio protection beyond lowering glucose. Hypothesis: Treating SGLT2 inhibitor (SGLT2i) reduces the cardiovascular risk in type 2 diabetes that indicates the potential correlation of SGLT2i in cardiomyopathy mediating metabolic effects. Methods: Male 8 weeks old C57/BL6 mice were fed high fat diet (> 60% of fat) for 4 months, and treated SGLT2i, canagliflozin (CANA) in the third and the fourth month. Measured its blood glucose, body weight and echocardiology every month. Moreover, analyzed the lipid contents in its plasma, the adipose tissue, liver and heart, and also examine the cardiomyopathy markers and its potential signaling pathways. Furthermore, palmitate acid (PA) was treated to H9c2 cells to mimic a high lipid environment, and validate its potential signaling pathways. Results: Treatments of high fat diet-induced obese mice with the CANA reduced blood glucose, body weight and adiposity. Moreover, CANA reversed the obesity-induced cardiomyopathy including heart weight ratio, echocardiology and cardiomyopathy markers ( Col1 , Col4 , Icam1 and Myh7 ). Furthermore, CANA increased AKT phosphorylation which is the one of the key pathways, and reduces apoptosis in cardiomyopathy. To investigate the potential mechanisms of metabolic changes in cardiomyopathy by CANA, we searched the hepatic RNA expression from high fat diet induced obesity mice by GEO profiles online. FGF21, a hepatokine increased in CANA action by hepatic and adipose tissue lipolysis, next circulated to the heart, and induced AKT phosphorylation to reduce apoptosis. CANA increased plasma and hepatic FGF21 in obese mice. Further treating recombinant FGF21 in H9c2 differentiated cardiomyocyte like cells with palmitic acid, FGF21 reduced cardiomyocyte apoptosis via AKT phosphorylation. Conclusions: These data demonstrated that SGLT2 inhibition ameliorates metabolic changes and apoptosis via FGF21-AKT pathway in cardiomyopathy.