Integration of 12-Hour Time-Restricted Feeding with Exercise Training Potentiates Weight Loss and Attenuates MASLD in Diet-Induced Obese Mice

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease worldwide, particularly among individuals with overweight and obesity. Non-pharmacological strategies such as time-restricted feeding (TRF) and exercise training can effectively mitigate obesity and metabolic disorders associated with MASLD. However, the specific effects of TRF combined with aerobic training (AT), resistance training (RT), or combined training (CT) on weight loss and MASLD remain unclear. This study investigated the effects of 12h-TRF and exercise training (AT, RT, and CT), applied alone or in combination with TRF, for 10 weeks in diet-induced obese male Swiss mice. Individually, TRF and all exercise protocols reduced weight gain and adiposity, improved glycemic homeostasis, and decreased hepatic fat accumulation. Combining TRF with exercise resulted in more pronounced improvements, suggesting complementary mechanisms. Among the interventions, TRF+AT was the most effective in reducing body weight, fat mass, and hepatic saturated fatty acid accumulation. TRF+CT induced similar effects but with a less marked reduction in hepatic steatosis. Moreover, TRF+AT downregulated lipogenic and inflammatory genes while upregulating genes related to hepatic fatty acid oxidation. TRF+RT was particularly effective in improving glucose homeostasis and insulin sensitivity. In conclusion, combining TRF with AT, RT, or CT significantly improved metabolic and hepatic parameters compared to TRF or training alone in obese mice. These findings highlight the synergistic potential of TRF and exercise and emphasize their specific outcomes, providing new perspectives for personalized interventions against obesity and MASLD.