AMPK/Autophagy‐Dependent Pro‐Adipogenic Effect Coupled With Enhanced Lipid Mobilization and Thermogenesis Underlies the Dual Action of Canagliflozin Against Obesity

Abstract

Canagliflozin (CANA) exhibits prominent anti‐obesity effects in clinical practice, yet its direct adipocyte‐intrinsic functions remain poorly understood. Here, we investigated the regulatory mechanism of CANA in adipogenesis and adipose tissue remodeling. We found that CANA promoted 3 T3‐L1 preadipocyte differentiation and lipid accumulation. Mechanistically, CANA facilitated this pro‐adipogenic effect via AMPK‐dependent autophagy activation. In high‐fat diet (HFD)‐fed mice, CANA exerted both preventive and therapeutic benefits, reducing body weight gain and fat mass, alleviating hepatic steatosis and dyslipidemia, and improving hyperglycemia despite increased food intake. To resolve the in vitro pro‐adipogenic vs. in vivo anti‐obesity paradox, we identified stage‐specific lipolysis. During differentiation, CANA increased triglycerides (TG) and glycerol release without net lipid loss. In post‐differentiated adipocytes, CANA also enhanced glycerol release but markedly reduced intracellular TG, reflecting a switch from lipid‐building to lipid‐mobilizing. Notably, this lipolytic effect is autophagy‐independent. Additionally, CANA enhanced adipocyte thermogenesis and browning, with Seahorse assays confirming elevated mitochondrial proton leak and uncoupled respiration. Importantly, SGLT2 expression was undetectable in 3 T3‐L1 adipocytes and white adipose tissues. Collectively, CANA exerts anti‐obesity effects by reprogramming adipocytes in an SGLT2‐independent manner through AMPK/autophagy‐dependent differentiation, coupled with enhanced lipolysis and thermogenesis, synergistically driving healthy lipid turnover.