Alternate‐day fasting enhanced weight loss and metabolic benefits over pair‐fed calorie restriction in obese mice

Abstract Objective Both alternate‐day fasting (ADF) and calorie restriction (CR) are effective weight loss strategies. However, most individuals find it difficult to adhere to CR. Furthermore, CR can induce an excessive loss of not only fat but also muscle mass. This study aimed to compare the effects of ADF and pair‐feeding (PF) CR on metabolic pathways underlying obesity in mice with high‐fat diet (HFD)‐induced obesity. Methods Male C57BL/6N Tac mice ( n = 10 per group) were fed an HFD for 8 weeks to establish a diet‐induced obesity model. Mice were then continued on the HFD with either alternate‐day access to food or PF for the next 8 weeks. We measured body weight, adiposity, plasma biomarkers, and molecular mechanisms involving lipolysis and autophagy. Results Both ADF and PF resulted in comparable weight and fat loss. Compared with PF, ADF showed a significant reduction in liver weight and hepatic triglyceride levels. ADF significantly increased plasma ketone body levels and white adipose tissue lipolysis. Compared with PF, ADF tended to activate autophagy elongation and autophagosome formation, which were insignificant. Conclusions These findings indicated that ADF is a promising intervention for metabolic diseases, potentially due to its superior efficacy in promoting ketogenesis and lipolysis compared with PF.