Abstract
Feeding behavior, metabolism and circadian clocks are interlinked. Calorie restriction (CR) is a feeding paradigm known to extend longevity. We found that CR significantly affected the rhythms in the expression of circadian clock genes in mice on the mRNA and protein levels, suggesting that CR reprograms the clocks both transcriptionally and post-transcriptionally. The effect of CR on gene expression was distinct from the effects of time-restricted feeding or fasting. Furthermore, CR affected the circadian output through up- or down-regulation of the expression of several clock-controlled transcriptional factors and the longevity candidate genes. CR-dependent effects on some clock gene expression were impaired in the liver of mice deficient for BMAL1, suggesting importance of this transcriptional factor for the transcriptional reprogramming of the clock, however, BMAL1- independent mechanisms also exist. We propose that CR recruits biological clocks as a natural mechanism of metabolic optimization under conditions of limited energy resources.
Highlights
The clock and clock-controlled transcriptional factors generate transcriptional output of the circadian clock in metabolism and cellular biochemical processes[20]
Time restricted (TR) feeding group, animals were provided with the 100% of their average daily Ad libitum (AL) food intake at ZT14 for two weeks; this time period is sufficient to reset circadian clocks in peripheral tissues[23,24]
We noticed that animals in both Calorie restriction (CR) and time restricted (TR) groups consumed all the food within the first 3–5 hours, in agreement with our previous report on TR feeding[25]; the TR group represents an appropriate control for the CR group
Summary
The clock and clock-controlled transcriptional factors generate transcriptional output of the circadian clock in metabolism and cellular biochemical processes[20]. In this study we have assayed the effects of 30% CR on the expression of circadian clock and clock-controlled genes at the mRNA and protein level in the liver. We found that CR significantly affected circadian clockworks in a manner distinct from time-restricted feeding and fasting. We analyzed the effects of 30% CR on clock genes expression in the liver of mice deficient for the clock transcriptional factor BMAL1. The longevity candidate genes, reported to be regulated by CR, analyzed in the circadian manner showed that the effects were gene- and time of the day-dependent
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