INTERMITTENT FASTING IN MICE PROMOTES HISTONE ACETYLATION IN THE PROMOTER REGIONS OF MITOCHONDRIAL ACTIVATING GENES IN THE MUSCLE AND IMPROVES EXERCISE ENDURANCE

Abstract

Objective: Intermittent fasting (IF) has benefits in increasing insulin sensitivity and lowering body weight. However, the underlining mechanism for the beneficial effects has not been elucidated so far. Design and method: Mice were subjected to a severe IF regimen, in which they were fasted for 72 hours and refed ad libitum for subsequent 96 hours. This cycle was consecutively repeated 4 times to enforce the effects. After 4 cycles of the IF regimen, mice were fed a high-fat diet (HFD) ad-libitum for subsequent 4 weeks of observational period. The body weight (BW) was monitored throughout the study in the IF and ad-libitum feeding groups. At the 2 different time points: just after 4 cycles of the IF regimen and after subsequent 4 weeks of observational ad-libitum feeding period, the glucose tolerance was examined. Results: There was no significant difference in the BW between the adlib eating and the IF groups just after 4 cycles of the IF regimen. Glucose tolerance tests showed a significant decrease in the glucose level of IF group. In PCR analysis, expressions of genes responsible for fat oxidation and thermogenesis (ACO and UCP1 et al.) were significantly increased in the harvested tissues (the skeletal muscle, white and brown adipose tissues). The histone acetylation in the promoter region of these mitochondria activating genes was augmented and suggested the significance for the enhanced expression of genes. In addition, we found that exercise endurance was improved in the IF group, without a change in the grip power. After subsequent 4 weeks of observational feeding period, the BW in IF group was significantly lower than ad-libitum feeding group. At the time-point, the exercise endurance, glucose tolerance, histone acetylation and expression of genes maintained the similar changes observed just after 4 cycles of the IF regimen. Conclusions: The 72 hours fasting IF regimen augmented histone acetylation in the promoter regions of mitochondrial activating genes in the muscle that would accounts for the prolonged enhancement of the expression. We found that not only glucose tolerance and body weight but also exercise endurance was improved through the IF procedure.