All life on Earth is subject to predictable changes in the environment, as the rotation of the planet results in alternating day and night. There is a major survival advantage in anticipating these changes, rather than reacting to them, and this has supported the acquisition of circadian timing mechanisms in all kingdoms of life. Although the design principles remain constant, the genes involved vary, suggesting discrete evolutionary development.
A constant feature of all circadian timing systems is a positive arm. This activates transcription of genes, which result in the synthesis of proteins, which then act to repress the positive arm. The serial time delays involved in transcription, translation, modification of proteins and subsequent achievement of critical concentrations to repress the active arm gives the period of the oscillation: approximately 24 hours.
The core cellular circadian mechanism is relatively resistant to the external environment, but does retain a resetting response to changes in external cues such as light or feeding. It is this resistance to change that we perceive as jet lag.
A CENTRAL CLOCK
In mammals, the development of a solid cranium prevented detection of sunlight by deep brain photoreceptors. Therefore, light sensing for circadian entrainment takes place through the retina, with a specific neural projection to the central brain clock, the suprachiasmatic nucleus (SCN).
Interestingly, light entrainment of the central clock can be dissociated from image formation in the primary visual cortex. A major photoreceptor in the retina, melanopsin, which is expressed on a subset of retinal ganglion cells, has evolved to detect short wavelength, blue, light, and to transmit this daylight signal to the SCN.
In addition to the central brain clock in the SCN, it has emerged that virtually all cells have their own circadian machinery, and are capable of sustained circadian oscillations, even when cultured ex vivo. Therefore, the SCN serves as a synchronising centre, ensuring that the diverse clocks through the body ‘tick in time’. It is thought that neural and humoral signals act on peripheral cells to correct drift in timing, rather like the actions of the Greenwich time signal used to set clocks and watches in our homes.
Amongst the most important humoral signals are glucocorticoids (GCs). Indeed, in early studies, cultured cells were synchronised by application of a short pulse of high dose GC.
THE CLOCK AND GLUCOCORTICOIDS
Discovery that the clock was regulated by the stress hormone GC was followed by further work showing that the GC receptor was itself regulated by the clock. Both the availability of ligand, cortisol, and also the function of the GC receptor, were found to vary across time, with profound effects on organ function.
We, and others, have characterised major impacts on inflammation, and its GC regulation, and also energy metabolism, and its regulation by GC. Therefore, the long recognised circadian variation in serum cortisol that we all recognise is only part of the picture. There is also a marked variation of GC sensitivity across the circadian period.
The role of the clock is very strong in energy metabolism. The move from activity and feeding during the day to rest and fasting by night requires a major rewiring of hepatic, adipose and muscle energy metabolism.
More than 90% of the liver genes involved in lipid synthesis lie under strong circadian control. Consequently, the impact of feeding at different times of the day has attracted attention. Striking studies in mice suggest that restricting feeding times is an effective means to prohibit development of obesity, even in the presence of a high fat diet and excess calorie intake. Furthermore, even people on standard activity and feeding schedules show a marked change in insulin sensitivity across the circadian day, with implications for clinical trials, biomarkers and, in time, clinical management.
Sleep and its disorders are highly prevalent, and the most frequently reported co-morbidity in long term disease. Most doctors feel underequipped to manage sleep disorders, and there is a lack of effective pharmacological options. Psychological approaches can be effective, but are slow, expensive and not widely available.
The major drives to sleep are a homeostatic drive, which increases from the time of waking, and a circadian input. These two inputs explain the drowsiness that arrives in the afternoon, and the difficulties in sleeping well when jet-lagged.
Sleep deprivation is common in modern societies, with implications for mental and physical health. Sleep deprivation and sleep disruption, such as in shift-working, result in changes in energy metabolism, and in changes in behaviour. There is evidence for altered food selection in tired people, which may explain the excess risks of obesity and type II diabetes in long term shift-workers. Acute sleep deprivation exerts a profound effect on the serum metabolome and proteome, and affects the adaptive immune system, as determined by variation in vaccination efficacy. Human sleep studies are now benefiting from advances in genetics, brain imaging and experimental medicine, and have widespread implications for social policy and medicine.
Chronotype refers to the timing preference of a person. Early chronotypes favour mornings, and late chronotypes the evenings ‒ or ‘larks’ vs ‘owls’. Recent large scale genetic studies have identified a number of genes affecting human chronotype, supporting the existence of hard-wired traits. In addition, rare individuals have marked changes in chronotype, manifest by persisting and intractable sleep phase disorder, due to mutations in core circadian clock genes.
There are also changes in chronotype with age and gender. In particular, the teenage years are characterised by a marked late chronotype, with boys more affected than girls. The can affect school attendance and academic achievement, leading some schools to alter start times. It is unclear why adolescents would gain from having a distinctly delayed period of preferred activity compared with their parents and younger siblings.
A CHALLENGE FOR ENDOCRINOLOGISTS
Taken together, circadian mechanisms underpin many of the systems that we, as endocrinologists, study and treat. There remains much to understand, and the challenges of translating the fascinating scientific advances in the field to the clinic remain. However, the time for the circadian clock is now, as recognised by the award of last year’s Nobel Prize, and the challenge is laid down for us to accept.
David Ray, Professor of Endocrinology, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford