Combined effect of canagliflozin and exercise training on high-fat diet-fed mice

Area of Science:

• Metabolic diseases
• Pharmacology
• Exercise physiology

Background:

• Sodium-glucose cotransporter 2 inhibitors (SGLT2is) show promise for obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD).
• The combined effects of SGLT2 inhibitors and exercise training require further investigation.

Purpose of the Study:

• To investigate the combined effects of the SGLT2 inhibitor canagliflozin (CAN) and exercise training on obesity, glucose metabolism, and hepatic steatosis in mice.
• To explore the molecular mechanisms underlying the combined therapy's effects in skeletal muscle.

Main Methods:

• High-fat diet-induced obese mice were divided into four groups: sedentary control, exercise control, sedentary CAN, and exercise CAN.
• Mice underwent 4 weeks of treatment with or without canagliflozin (0.03% of diet) and with or without voluntary wheel running.
• Evaluations included body weight, body fat mass, glucose metabolism, insulin resistance, hepatic steatosis, and gastrocnemius muscle gene expression via microarray analysis.

Main Results:

• The combination group (CAN/WCR) showed additive improvements in body weight, body fat mass, blood glucose, glucose intolerance, insulin resistance, and fatty liver.
• Canagliflozin increased food intake and reduced running distance, but neither CAN nor exercise altered skeletal muscle weight.
• Microarray analysis revealed distinct gene expression changes in skeletal muscle, with the CAN/WCR group showing accelerated angiogenesis and suppressed adipogenesis pathways.

Conclusions:

• The combination of SGLT2 inhibitors and exercise training provides additive benefits for obesity, insulin resistance, and NAFLD.
• Gene expression modifications in skeletal muscle appear to play a role in the observed improvements in obesity and insulin sensitivity.