The circadian clock controls fluctuations of colonic cell proliferation during the light/dark cycle via feeding behavior in mice

Abstract

The mammalian circadian system is controlled not only by the suprachiasmatic nucleus (SCN), but also by the peripheral clocks located in tissues such as liver, kidney, small intestine, and colon, mediated through signals such as hormones. Peripheral clocks, but not the SCN, can be entrained by food intake schedules. While it is known that cell proliferation exhibits a circadian rhythm in the colon epithelium, it is unclear how this rhythm is influenced by food intake schedules. Here, we aimed to determine the relationships between feeding schedules and cell proliferation in the colon epithelium by means of immunochemical analysis, using 5-bromo-2'-deoxyuridine (BrdU), as well as to elucidate how feeding schedules influence the colonic expression of clock and cell cycle genes, using real-time reverse-transcription PCR (qRT-PCR). Cell proliferation in the colonic epithelium of normal mice exhibited a daily fluctuation, which was abrogated in Clock mutant mice. The day/night pattern of cellular proliferation and clock gene expression under daytime and nighttime restricted feeding (RF) schedules showed opposite tendencies. While daytime RF for every 4 h attenuated the day/night pattern of cell proliferation, this was restored to normal in the Clock mutant mice under the nighttime RF schedule. These results suggest that feeding schedules contribute to the establishment of a daily fluctuation of cell proliferation and RF can recover it in Clock mutant mice. Thus, this study demonstrates that the daily fluctuation of cell proliferation in the murine colon is controlled by a circadian feeding rhythm, suggesting that feeding schedules are important for rhythmicity in the proliferation of colon cells.

The Circadian Clock Gene BMAL1 Coordinates Intestinal Regeneration

“…Consistent with previous reports,13, 14, 15, 16, 31 the undamaged intestine of BMAL1 +/+ mice exhibits a diurnal expression pattern of PER2 , BMAL1 , and REV-ERBα (Figure 4 A ). The sinusoidal, rhythmic expression profiles are consistent with rhythms seen in other mouse tissues, with BMAL1 expression peaking at ZT20, approximately antiphase to the time of peaks of PER2 (ZT8-12) and REV-ERBα (ZT8) 32 .…”

Age-Induced Differential Changes in the Central and Colonic Human Circadian Oscillators

“…A limitation of our study is that the feeding schedule of the subjects was not controlled. Given that meal time has been shown to synchronize epithelial proliferation in the mice colon [26], it could be argued that the effects of aging on the colon rhythms are due to differences in the feeding pattern of elderly individuals. However, to be certain it would be necessary that aging produces the same modification of the meal pattern in all the individuals in free living conditions, which is an unlikely condition.…”

Day-Night Oscillation of Atrogin1 and Timing-Dependent Preventive Effect of Weight-Bearing on Muscle Atrophy

“…Locomotor activity of mice was monitored with an area sensor (F5B; Omron) and analyzed with ClockLab software (Actimetrics) as previously described [33]. Locomotor activity was continuously monitored during experimental periods.…”