Dapagliflozin attenuates hepatic steatosis and induces a fasting-mimicking metabolic state in C57BL/6 mice

Metabolic steatotic liver disease (MASLD) lacks effective pharmacological therapies targeting mitochondrial dysfunction, a central driver of disease progression. We hypothesized that dapagliflozin attenuates MASLD progression by promoting an indirect systemic fasting-mimicking state, thereby proposing the hypothesis of mitochondrial restoring mitochondrial bioenergetics restoration via modulation of the SIRT1-PGC-1α signaling pathway. C57BL/6 mice were fed either a control diet or a high-fat diet, associated, respectively, with drinking water or water with 15% fructose. From the 10th to the 16th week, the animals received, by orogastric gavage, saline solution or dapagliflozin (10 mg/kg). Biochemical analyses, magnetic resonance imaging, oral glucose tolerance tests, stereology, and ultrastructural analysis of the liver, as well as Western blotting using mitochondrial markers, were performed. The study showed that exposure to the high-fat diet associated with fructose effectively mimicked the main aspects of obesity and MASLD. Intervention resulted in a reduction in adiposity without compromising muscle mass, preservation of mitochondrial integrity, improvement in mitochondrial bioenergetics, and attenuation of steatosis and hepatic cellular stress. These results suggest an association with the NT-PGC-1α-NRF1 axis; our study hypothesizes that this acts as a compensatory mechanism. These findings support further investigation of dapagliflozin as a potential therapeutic strategy for MASLD.