Post-restriction hyperphagia and metabolic responses to short-term calorie restriction in C57BL/6 mice

Abstract

Aims: To evaluate post-restriction hyperphagia (PRH) responses to short-term calorie restriction (CR) and the potential drivers of this behaviour. Methods: Adult male C57BL/6J mice underwent 30% CR for 5 to 30 days, then refed for 12 days. Energy intake, body mass, fat mass, fat-free mass, body temperature, and physical activity were measured continuously throughout the CR and re-feeding phases and daily energy expenditure was measured over final 2 days of CR and the first 5 days of re-feeding. Results: Following restriction, energy intake, body mass, fat free mass, body temperature and daily energy expenditure were reduced in all groups compared to controls (P<0.05). Only the 20d and 25d groups had significantly lower fat mass than controls (P=0.004). Total physical activity and dark-phase physical activity did not differ between control and CR groups (P=0.446 and 0.380 respectively); but light-phase physical activity of groups 20d, 25d and 30d increased significantly (P<0.001) due to food anticipatory activity. All CR groups displayed peak PRH on day1 of refeeding. Total energy intake over the following 2-5 days of refeeding was also greater than the controls (P=0.002). The magnitude of PRH increased with CR duration and body mass loss at the individual level (P<0.001). In a multiple regression analysis fat free mass loss was the main factor that was correlated with the level of PRH (Multiple regression R2=32.7%, fat mass P=0.036, fat free mass P=0.003). Conclusion: Hunger (reflected by PRH) was mostly related to body mass and fat free mass loss. The effect of fat free mass loss was the opposite of that expected if fat free mass is a key driver of food intake as recently postulated. Developing restriction protocols that minimize loss of fat free mass may reduce the level of hunger that emerges when individuals are under restriction.