Hepatic, Duodenal, and Colonic Circadian Clocks Differ in their Persistence under Conditions of Constant Light and in their Entrainment by Restricted Feeding

Abstract

Physiological functions of the gastrointestinal tract (GIT) are temporally controlled such that they exhibit circadian rhythms. The circadian rhythms are synchronized with the environmental light-dark cycle via signaling from the central circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and by food intake. The aim of the study was to determine the extent to which disturbance in the SCN signaling via prolonged exposure to constant light affects circadian rhythms in the liver, duodenum, and colon, as well as to determine whether and to what extent food intake can restore rhythmicity in individual parts of the GIT. Adult male rats were maintained in constant light (LL) for 30 days and fed ad libitum throughout the entire interval or exposed to a restricted feeding (RF) regime for the last 14 days in LL. Locomotor and feeding behaviors were recorded throughout the experiment. On the 30th day, daily expression profiles of clock genes (Per1, Per2, Rev-erbα, and Bmal1) and of clock-controlled genes (Wee1 and Dbp) were measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in the duodenum, colon, and liver. By the end of the LL exposure, rats fed ad libitum had completely lost their circadian rhythms in activity and food intake. Daily expression profiles of clock genes and clock-controlled genes in the GIT were impaired to an extent depending on the tissue and gene studied, but not completely abolished. In the liver and colon, exposure to LL abolished circadian rhythms in expression of Per1, Per2, Bmal1, and Wee1, whereas it impaired, but preserved, rhythms in expression of Rev-erbα and Dbp. In the duodenum, all but Wee1 expression rhythms were preserved. Restricted feeding restored the rhythms to a degree that varied with the tissue and gene studied. Whereas in the liver and duodenum the profiles of all clock genes and clock-controlled genes became rhythmic, in the colon only Per1, Bmal1, and Rev-erbα-but not Per2, Wee1, and Dbp-were expressed rhythmically. The data demonstrate a greater persistence of the rhythmicity of the circadian clocks in the duodenum compared with that in the liver and colon under conditions when signaling from the SCN is disrupted. Moreover, disrupted rhythmicity may be restored more effectively by a feeding regime in the duodenum and liver compared to the colon.

Development and entrainment of the colonic circadian clock during ontogenesis

“…Approximately 24 h after the activation of clock gene transcription, the inhibitory PER-CRY complex is degraded, and the cycle starts again as CLOCK-BMAL1 begins to activate gene expression. The colonic clock is entrained by signals emanating from the central circadian clock in the suprachiasmatic nuclei (SCN) in the hypothalamus and by the feeding regime per se (16,17,23). The SCN signal is modulated according to the external light-dark (LD) regime, whereas the signals from the feeding regime are modulated by the SCN and according to the actual food availability.…”

“…These data indicate that intestinal development continues into the postnatal period and is completed during weaning, i.e., the period when profound alterations in the animal's alimentation occur. Whereas the morphology and function of developing colon have been extensively studied, no data are available on the ontogenetic development of the mechanisms that ensure temporal daily regulation of these colonic processes.In adult rats, similar to other species, the individual parts of the intestine, including the colon, harbor functional daily clocks (17, 23), which drive daily rhythms in various colonic functions, including motility (7), permeability (28), as well as expression of genes coding electrolyte transporters (23, 25) and cell cycle regulators (16,17). It is supposed that the principal role of the colonic clock is to ensure that its optimal functional state is achieved in anticipation of the chyme supply, which rhythmically varies during the day and night, according to feeding regime.…”

“…In adult rats, similar to other species, the individual parts of the intestine, including the colon, harbor functional daily clocks (17, 23), which drive daily rhythms in various colonic functions, including motility (7), permeability (28), as well as expression of genes coding electrolyte transporters (23, 25) and cell cycle regulators (16,17). It is supposed that the principal role of the colonic clock is to ensure that its optimal functional state is achieved in anticipation of the chyme supply, which rhythmically varies during the day and night, according to feeding regime.…”

Effects of Circadian Disruption on Physiology and Pathology: From Bench to Clinic (and Back)

“…Furthermore, rhythmic clock gene expression has been found in peripheral oscillators throughout the GT, which can be shifted, or entrained, by timed meals (Hoogerwerf et al 2007;Mazzoccoli et al 2012;Polidarova et al 2011). The correct phaserelationship between feeding time and the activity-rest cycle led to normal entrainment of the GT, by a myriad of neural and humoral signals related with the interplay between SCN activity, food-entrainable oscillators, and metabolism (Stenvers et al 2012).…”

Chrono-biology, Chrono-pharmacology, and Chrono-nutrition

“…First, wee1, a negative regulator of the G2/M transition, is likely a clockcontrolled gene in colonic epithelial cells because its promoter contains an E-box (46), and wee1 gene expression exhibits circadian changes (77,95). Second, the proliferation level is controlled by extrinsic luminal signals, neural output signals (glucocorticoids), gastric hormones (gastrin and neurotensin), and growth factors (EGF) because all show a circadian pattern (96).…”