Impact of nutrients on circadian rhythmicity

Abstract

The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock.

Keywords: clock genes; glucose; hypothalamus; metabolism; nutrient sensors; saturated fatty acid.

Fig. 1.

Suprachiasmatic nucleus (SCN) and its output to non-SCN brain clocks and peripheral clocks. The SCN generates an approximate 24-h rhythm, which is adjusted to exact 24 h by the light-dark cycle. SCN receives photic information through the retinohypothalamic tract and transmits its information to other hypothalamic nuclei, mostly to the paraventricular nucleus of the hypothalamus (PVN). From here, information is translated into hormonal and autonomic signals, which will reach peripheral organs. Non-SCN brain areas and peripheral organs contain endogenous clocks as well, and these clocks are synchronized by the SCN, but also by external signals, including the feeding/fasting cycle.

Fig. 2.

Effects of saturated fatty acids on the expression profile Bmal1, Per2, and Rev-erbα in mHypoE-37 neuronal cells. Relative mRNA transcript levels of Bmal1, Per2, and Rev-erbα, respectively, are shown. Bmal1 transcript levels are upregulated in the palmitate-treated cells compared with controls. *P < 0.05 between palmitate and control group at the indicated time point as determined by two-way ANOVA with post hoc t-test. Values are plotted as mean values ± SE. From Greco JA et al. (32).

Fig. 3.

Temporal relationship between plasma glucose concentrations and glucose disappearance rate. Both plasma glucose concentrations and glucose disappearance rate rise before the onset of the activity period, independently from food intake. From la Fleur SE (64).

Fig. 4.

Overview of the molecular circadian clock mechanism in relation to metabolism. The clock regulates many clock output genes involved in metabolism. Conversely, the clock receives input from transcription factors and nutrient sensors with important roles in metabolic processes. Feeding and fasting can influence the core clock in a number of ways, and glucose and fat intake can also directly or indirectly influence the clock, as depicted in this figure. It becomes clear that energy status is important in regulating the clock, whereas there is a paucity of studies showing the specific effects of fat and sugar. O, O-glcNAcylation; P, phosphorylation; A, poly-ADP-ribosylation.