Dapagliflozin and aerobic exercise synergistically attenuate hepatic steatosis via complementary regulation of lipogenesis and fatty acid oxidation in type 2 diabetic rats

Abstract Background Dapagliflozin (Dapa) and aerobic exercise (AE) are widely used interventions for type 2 diabetes mellitus (T2DM) and may influence hepatic lipid metabolism. However, whether combining Dapa with AE confers additional benefit on hepatic lipid accumulation and related metabolic pathways remains unclear. Methods A T2DM rat model was established using a high-fat diet (HFD) combined with streptozotocin (STZ). After model establishment, rats were assigned to a diabetic control group, a dapagliflozin group, or a dapagliflozin plus aerobic exercise group, while normal-diet rats served as non-diabetic controls. Hepatic lipid accumulation was assessed by Oil Red O staining and triglyceride measurements, and the expression of key proteins related to de novo lipogenesis, fatty acid oxidation, and fatty acid uptake/export was analyzed by Western blot. Results Both dapagliflozin monotherapy and the combined intervention reduced hepatic lipid accumulation and improved metabolic parameters. Dapagliflozin was mainly associated with suppression of de novo lipogenesis-related proteins, whereas the addition of AE was associated with higher expression of lipolysis- and fatty-acid-oxidation-related proteins. Conclusion Dapagliflozin ameliorated hepatic steatosis in T2DM rats and was associated with suppression of de novo lipogenesis. The addition of AE was associated with a greater reduction in hepatic lipid accumulation together with enhanced expression of lipolysis and fatty-acid-oxidation-related proteins.