Anticipatory metabolic regulation drives the distinct and improved metabolic state of caloric restriction compared to Fasting-Refeeding cycles

Interest in fasting-based diets to improve metabolic health is growing. Caloric restriction (CR) with one meal per day includes an extended fasting component that contributes to its metabolic and longevity benefits, yet the role of fasting within CR remains unclear. Here, we compare CR with a fasting-refeeding-fasting (FRF) regimen while controlling food intake and fasting duration. Changes in plasma insulin and free fatty acids, hepatic mTOR signaling and ketogenesis, metabolic rhythms, and food digestion kinetics suggest that gastric emptying serves as a primary metabolic trigger in acute fasting. In contrast, CR fasting responses are regulated, suggesting anticipatory mechanisms. CR enhances circadian rhythmicity and metabolic gene coordination, whereas FRF disrupts it. CR improves glucose and fatty acid metabolism, while fasting leads to glucose intolerance and liver fat accumulation. These findings reveal that CR engages clock-aligned, anticipatory metabolic control, while fasting-refeeding cycles rely on direct nutrient cues.