Empagliflozin Ameliorates Obesity-Related Cardiac Dysfunction by Regulating Sestrin2-Mediated AMPK-mTOR Signaling and Redox Homeostasis in High-Fat Diet–Induced Obese Mice

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have favorable cardiovascular outcomes in patients with diabetes. However, whether SGLT2i can improve obesity-related cardiac dysfunction is unknown. Sestrin2 is a novel stress-inducible protein that regulates AMPK–mammalian target of rapamycin (mTOR) and suppresses oxidative damage. The aim of this study was to determine whether empagliflozin (EMPA) improves obesity-related cardiac dysfunction via regulating Sestrin2-mediated pathways in diet-induced obesity. C57BL/6J mice and Sestrin2 knockout mice were fed a high-fat diet (HFD) for 12 weeks and then treated with or without EMPA (10 mg/kg) for 8 weeks. Treating HFD-fed C57BL/6J mice with EMPA reduced body weight and whole-body fat and improved metabolic disorders. Furthermore, EMPA improved myocardial hypertrophy/fibrosis and cardiac function and reduced cardiac fat accumulation and mitochondrial injury. Additionally, EMPA significantly augmented Sestrin2 levels and increased AMPK and endothelial nitric oxide synthase phosphorylation, but inhibited Akt and mTOR phosphorylation. These beneficial effects were partially attenuated in HFD-fed Sestrin2 knockout mice. Intriguingly, EMPA treatment enhanced the Nrf2/HO-1–mediated oxidative stress response, suggesting antioxidant and anti-inflammatory activity. Thus, EMPA improved obesity-related cardiac dysfunction via regulating Sestrin2-mediated AMPK-mTOR signaling and maintaining redox homeostasis. These findings provide a novel mechanism for the cardiovascular protection of SGLT2i in obesity.