BACKGROUND: the metabolic effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i), such as lipolysis and ectopic fat reduction, seem related to the synthesis of fibroblast growth factor-21 (FGF-21), and FGF-21 analogs are now under investigation for the treatment of obesity complications such as metabolic dysfunction-associated steatotic liver disease. However, FGF-21 levels are paradoxically higher in obesity, indicating a hormone-resistant state that may hinder the benefits of SGLT2i. METHODS: To define if a different energy status influences the response to SGLT2i, we evaluated the effects of dapagliflozin administration on nine-week-old C57BL/6J wild-type and B6.V-LEP ob/ob mice as a model of genetic obesity. Blood glucose, body weight and food intake were evaluated, and the FGF-21 expression was determined in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and brown adipose tissue (BAT). In the liver, FGF-21 gene expression, protein concentration and triglyceride content were evaluated. RESULTS: glucose plasma levels and body weight were higher in ob/ob than in lean mice. After four weeks of treatment, dapagliflozin reduced blood glucose levels and body weight in both animal models, but weight loss was more significant in lean mice. The baseline expression of FGF-21 was higher in both SAT, VAT and the liver of ob/ob mice, whereas it was almost undetectable in BAT in both animal groups. After the treatment period, dapagliflozin was shown to increase FGF-21 expression in VAT only in lean animals, while the expression was unaffected in ob/ob mice. Similar effects were observed in the liver analyses, along with no variation in triglyceride content. CONCLUSIONS: SGLT2i administration results in less pronounced metabolic effects in ob/ob mice than in lean mice. This data suggests a less sensitive response in obesity, probably due to a chronic stimulation leading to abnormalities of the SGLT2i-FGF-21 axis which should be considered in managing patients affected by genetic obesity.