Circadian disruption and metabolic disease: findings from animal models

Abstract

Social opportunities and work demands have caused humans to become increasingly active during the late evening hours, leading to a shift from the predominantly diurnal lifestyle of our ancestors to a more nocturnal one. This voluntarily decision to stay awake long into the evening hours leads to circadian disruption at the system, tissue, and cellular levels. These derangements are in turn associated with clinical impairments in metabolic processes and physiology. The use of animal models for circadian disruption provides an important opportunity to determine mechanisms by which disorganization in the circadian system can lead to metabolic dysfunction in response to genetic, environmental, and behavioral perturbations. Here we review recent key animal studies involving circadian disruption and discuss the possible translational implications of these studies for human health and particularly for the development of metabolic disease.

Figure 1

Light entering the retina stimulates specialized photoreceptors and send signals to the suprachiasmatic nuclei (SCN) via the retinohypothalamic tract. The SCN then orchestrates the timing of other brain regions. These brain regions can then influence one other, cause behavior changes and send timing cues to peripheral tissues using hormones and neural signals through, for example, the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS). Behaviors such as feeding can also directly influence the expression of circadian clock and clock controlled genes within peripheral tissues. Hormones and neural signals originating from the periphery can then feedback to the SCN and other brain regions to influence circadian rhythms and genes.

Figure 2

The effect of circadian feeding on body weight, caloric intake, and activity. (a) The effect of light or dark phase feeding on body weight. Body weight (mean ± s.e.m.) of C5BL/6J mice fed 60% high fat only during the 12-h light phase (dashed line) or only during the 12-h dark phase (solid line). Body weights were taken at the end of the 12-h feeding phase in all animals. Within 2 weeks of maintenance on the high fat diet, the light-fed animals weighed significantly more than the dark-fed animals (*p < 0.05 light-fed vs. dark-fed) and remained significantly heavier over the next 4 weeks. (b) Weekly activity counts and caloric intake. Total weekly activity counts (squares) and calories (kcal, triangles) are depicted for both light-fed (dashed line) and dark-fed (solid line) groups (mean ± s.e.m.). Note that while over the 6-week period neither activity nor caloric intake differed significantly (p > 0.10), the light-fed group appears to be consuming more calories and moving less than the dark-fed group. This raised the possibility that the additive effect of a small increase in caloric intake and a small decrease in activity can together contribute to specific differences in body weight.

Figure 3

Sleep During Phase Restricted Feeding. Male, 6-week old C5BL/6J mice were fed a standard diet either ad libitum (Ad libitum), only during the 12 hour light phase (Light-fed), or only during the 12 hour dark phase (Dark-fed). Sleep recording from week 5 of restricted feeding indicates no differences among the groups in NREM (white bars), REM (gray bars), or total sleep time over the 24 hour day.

Figure 4

Clock and metabolic genes interact with each other and can independently influence the metabolic phenotype seen in rodent models. Circadian rhythms, such as the feeding rhythm, and environment (e.g. diet), may also feedback and influence gene expression and metabolism characteristics.