Effects of canagliflozin on weight loss in highfat diet-induced obese mice

Canagliflozin, an inhibitor of sodium glucose co-transporter (SGLT) 2, has been shown to reduce body weight during the treatment of type 2 diabetes mellitus (T2DM). In this study, we sought to determine the role of canagliflozin in body weight loss and liver injury in obesity. C57BL/6J mice were fed a high-fat diet to simulate diet-induced obesity (DIO). Canagliflozin (15 and 60 mg/kg) was administered to DIO mice for 4 weeks. Orlistat (10 mg/kg) was used as a positive control. The body weight, liver weight, liver morphology, total cholesterol (TC) and triglyceride (TG) levels were examined. Signaling molecules, including diacylgycero1 acyltransferase-2 (DGAT2), peroxisome proliferation receptor alpha-1 (PPAR alpha 1), PPAR gamma 1, PPAR gamma 2 mRNA levels and the protein expression of SGLT2 were evaluated. Canagliflozin reduced body weight, especially the high-dose canagliflozin, and resulted in increased body weight loss compared with orlistat. Moreover, canagliflozin reduced the liver weight and the ratio of liver weight to body weight, lowered the serum levels of TC and TG, and ameliorated liver steatosis. During the canagliflozin treatment, SGLT2, DGAT2, PPAR gamma 1 and PPAR gamma 2 were inhibited, and PPARa1 was elevated in the liver tissues. This finding may explain why body weight was reduced and secondary liver injury was ameliorated in response to canagliflozin. Together, the results suggest that canagliflozin may be a potential anti-obesity strategy.