Dapagliflozin and Aerobic Exercise Synergistically Attenuate Hepatic Steatosis via Complementary Regulation of Lipogenesis and Fatty Acid Oxidation in Type 2 Diabetic Rats

Background Pharmacological interventions and regular exercise are widely regarded as core strategies for improving type 2 diabetes mellitus (T2DM) accompanied by non-alcoholic fatty liver disease (NAFLD), as supported by previous metabolic and clinical research. Nevertheless, the potential synergistic impact of combination therapy involving dapagliflozin (Dapa) and physical exercise on hepatic lipid metabolism—particularly its mechanism in regulating the balance between lipogenesis and lipolysis—remains incompletely understood and a definitive consensus has not yet been established. Therefore, the present study was designed to elucidate the effects of Dapa, administered either as monotherapy or in combination with aerobic exercise, on hepatic lipid deposition and its potential underlying mechanisms. Methods A total of 24 four-week-old male Sprague-Dawley (SD) rats were randomly assigned to four groups (n = 6 per group) following successfully model establishment. T2DM was induced in using a high-fat diet combined with streptozotocin administration (30 mg/kg, intraperitoneally), a protocol commonly employed in metabolic disease research. Dapagliflozin was administered daily by gavage to the treatment group. The combination group received both dapagliflozin treatment and a progressive treadmill running program designed to represent aerobic exercise intervention. Hepatic lipid deposition was quantified using Oil Red O staining, whereas Western blot analysis was conducted to determine the expression of key proteins involved in lipid metabolic regulation. Results Both dapagliflozin monotherapy and the combined intervention with aerobic exercise significantly attenuated hepatic steatosis and were associated with improvement in insulin resistance, as reflected by HOMA-IR. Although no additive improvement in HOMA-IR was observed with the combined therapy, a more pronounced reduction in hepatic lipid accumulation was detected. Moreover, the findings suggest that dapagliflozin monotherapy primarily acted through inhibition of hepatic de novo lipogenesis. In contrast, the combined intervention appeared to exert additional effects through enhanced fatty-acid catabolism, thereby contributing to a greater reduction in hepatic lipid content. Conclusion (1) Dapagliflozin suppresses hepatic de novo lipogenesis; (2) Aerobic exercise preferentially enhances lipolysis, thereby producing a complementary therapeutic effect when combined with Dapa; and (3) The combined intervention, through a dual mechanism characterized by suppressing of lipid synthesis and promotion of lipid breakdown, results in an additive metabolic benefit.