Calorie restriction reprograms diurnal rhythms in protein translation to regulate metabolism

Abstract

Calorie restriction (CR) delays aging and affects the circadian clocks by reprogramming circadian rhythms in gene expression. To expand on the circadian mechanisms in CR, we assayed rhythms in the protein translation by analyzing polysome‐associated mRNAs in the liver of mice fed ad libitum (AL) and CR diets. Global comparison of the diets revealed that <1% of transcripts were differentially abundant in the polysomes. In contrast, the large differential, up to 10%, was detected when CR and AL diets were compared at individual times throughout the day. Most transcripts that were rhythmic under AL lost their rhythms, and many new transcripts gained rhythms under CR. Only a small fraction of transcripts, including the circadian clock genes, were rhythmic under both diets. Thus, CR strongly reprograms translation. CR affected translation of enzymes regulating long‐chain acetyl‐coenzyme A (Acyl‐CoA) metabolism. The expression of the Acyl‐CoA thioesterase (ACOT) family was induced upon CR, leading to the increased transcriptional activity of peroxisome proliferator‐activated receptor α, the transcriptional factor regulated by the ACOT products. We propose that the differential translation induced by CR leads to a temporal partition and reprogramming of metabolic processes and provides a link between CR, lipid metabolism, and the circadian clock.—Makwana, K., Gosai, N., Poe, A., Kondratov, R. V. Calorie restriction reprograms diurnal rhythms in protein translation to regulate metabolism. FASEB J. 33, 4473–4489 (2019). http://www.fasebj.org

CR reprograms acetyl‐CoA metabolism and induces long‐chain acyl‐CoA dehydrogenase and CrAT expression

“…The expression of Acadvl (encodes VLCAD), Acadl (encodes LCAD), and peroxisomal Acot3 and Acot4 was significantly induced by CR in a time of the day‐dependent manner (Figure 2d). mRNA expression was in agreement with protein expression and with published data on polysome association (Makwana et al, 2019). Thus, the changes in mRNA expression might provide a mechanistic explanation for increased protein expression.…”

“…Discrepancy of results from different reports may be due to different times of feeding for the experiment and analysis of RNA. The feeding/oxidation cycle has 24-h periodicity, which implies a possible interaction with circadian rhythms, and this is supported by evidence of a crosstalk between aging, CR, and the circadian clock (Makwana et al, 2019;Patel et al, 2016;Sato et al, 2017). Therefore, the circadian rhythms must be taken into consideration to understand CR-induced reprogramming of fat metabolism.…”

Endogenous circadian time genes expressions in the liver of mice under constant darkness

“…The peak (nadir) of those oscillation genes under L-DD occurred at CT9 or CT13. The circadian rhythm of Acot3 and Acot4 are evidently induced by calorie restriction and are transcriptional targets of PPARa [55]. Compared to LD, the circadian rhythm of Acot3, 4, 8 and 13 were also induced by L-DD with increased amplitude.…”

Reduced caloric intake and periodic fasting independently contribute to metabolic effects of caloric restriction

“…Dietary interventions such as CR, HF, or ketogenic diet affect the circadian clock and rhythms. CR increases the amplitude of clock gene expression and reprograms circadian rhythms in transcription, translation, hormone secretion, and mTOR signaling (Makwana, Gosai, Poe, & Kondratov, 2018; Patel, Velingkaar, Velingkaar, Makwana, Chaudhari, & Kondratov, 2016; Sato et al, 2017; Tulsian, Velingkaar, & Kondratov, 2018). In turn, many metabolic benefits of caloric restriction, including effects on lifespan, are impaired in circadian clock mutants indicating an interaction between CR and the circadian clock (Katewa et al, 2016; Patel, Chaudhari, et al, 2016).…”