Original Abstract

BACKGROUND: Adipose lipolysis, a process involving the degradation of triglycerides and the release of fatty acids and glycerol, is an important biological event in lipid metabolism. Canagliflozin (Cana), an oral antidiabetic drug, regulates blood glucose by inhibiting sodium-glucose cotransporter 2 (SGLT2) in renal tubules and has also been shown to improve lipid metabolism in adipocytes. This study aims to determine whether Cana directly affects adipose lipolysis and to explore the underlying mechanistic pathways. METHOD: Primary mature adipocytes and differentiated preadipocytes isolated from the epididymal fat pads of Sprague-Dawley rats were used as in vitro models. The effects of Cana on glycerol release and lipase activity were evaluated using ELISA and Western blot analyses. RESULTS: Cana treatment directly inhibited basal glycerol release and lipase activity in both primary adipocytes and topically administered adipose tissue, achieving a dose-dependent 35% to 65% suppression of lipolysis. This was associated with a 2.3-fold decrease in the level of HSL phosphorylated at the Ser660 site. Using differentiated adipocytes derived from the human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell line, we found that Cana significantly attenuated glycerol release (~32% to 53% reductions) induced by lipolysis. Moreover, Cana exerted antilipolytic effects in models of both acute (isoprenaline-induced) and chronic (tumor necrosis factor-α-induced) lipolysis. Mechanistically, the antilipolytic effect of Cana was mediated through activation of the PI3K/AKT pathway and reduction of cAMP production. CONCLUSION: In conclusion, Cana regulates adipocyte lipolysis via an SGLT2-independent signaling pathway, which enhances our understanding of its role in modulating lipid metabolism.