Nutrition and the circadian system

Abstract

The human circadian system anticipates and adapts to daily environmental changes to optimise behaviour according to time of day and temporally partitions incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24-h day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation, and thereby contributes to adverse metabolic consequences and chronic disease development. 'High-fat diets' (HFD) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFD in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases.

Keywords: CLOCK circadian locomotor output cycles kaput; Chrononutrition; FAA food anticipatory activity; HFD high-fat diet; Metabolism; Obesity; SCN suprachiasmatic nuclei; SIRT SIRTUIN; TRF time-of-day-restricted feeding; Time-restricted feeding.

Figure 1. The mammalian circadian clock

The molecular clock consists of ‘clock’ genes that form negative feedback loops. The transcription factors circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) heterodimerise and activate clock-controlled genes (CCGs). On activation by CLOCK-BMAL1, cryptochrome (CRY) 1-2 and period (PER) 1-3 proteins accumulate in the cytosol, multimerise, translocate into the nucleus and form inhibitory complexes, repressing CLOCK-BMAL1 and ending CRY1-2 and PER1-3 transcription during the rest phase. As the rest phase progresses, PER-CRY complexes are degraded by F-box/LRR-repeat protein 3 (FBXL3), casein kinase 1 (CK1) ε and CK1δ. Inhibition of CLOCK-BMAL1 activity ends, completing the negative feedback loop. Auxiliary feedback loops are antiphasic to the core loop and regulate BMAL1 transcription. The nuclear receptors reverse-erythroblastosis (REV–ERB) α and β repress BMAL1 transcription, whereas RAR-related orphan receptor (ROR) α activates BMAL1 transcription. Auxiliary feedback loops add robustness, among other roles.