Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences, and Countermeasures

Abstract

Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.

Figure 1.

Temporal control of physiology. Light exposure provides the primary time cue for the central clock in the suprachiasmatic nuclei (SCN) of the hypothalamus and suppresses melatonin synthesis by the pineal gland. Artificial light exposure at night can therefore disrupt the SCN clock and melatonin rhythm. As a diurnal species, melatonin is hypnogenic in humans, although a recent prospective study of pinealectomy demonstrated that endogenous melatonin may not have a strong regulatory role in sleep (42). The sleep/wake cycle has been effectively simulated by a two-process model in which a circadian process (C) influences wakefulness and interacts with a sleep-promoting process (S) that accumulates during wakefulness. Within the hypothalamus—a nodal point of body temperature regulation—the SCN influences the circadian rhythm of body temperature, a key synchronizer of clocks in peripheral tissues. The use of thermostats can obviate daily oscillations in temperature, which could perhaps influence some circadian rhythms. In addition to temperature mechanisms, the SCN influences clocks in peripheral tissues through neural signals communicated via the autonomic nervous system (ANS), as well as the timely secretion of signaling factors such as prokineticin 2. Hypothalamic-pituitary-peripheral organ axes are important to hormonal regulation of the circadian system. For example, corticotropin-releasing hormone (CRH) enters the portal system through the median eminence (ME) of the hypothalamus and stimulates the secretion of adrenocorticotropic hormone (ACTH) by the anterior pituitary gland. ACTH then regulates adrenal cortex production of cortisol, a hormone with a robust circadian oscillation and important synchronizing effects in many peripheral clocks. The timing of metabolic processes in peripheral clocks is also modified by nutritional status, and peripheral clocks relay metabolic information back to the hypothalamus through the ME. Today, around-the-clock access to food can distort the clear feeding/fasting cycles that typified much of our history.

Figure 2.

Mechanisms linking circadian system and sleep disruption to hyperglycemia, insulin resistance, and obesity. With further research, mechanisms that are currently listed as distinct may prove to be common.