Endocrine Abstracts

Circadian rhythms are cycles of behaviour and physiology that persist with a period of approximately (circa-) one day (-dian) when an individual is held in temporal isolation. They permeate all levels of biological activity, from gene expression and hormone secretion to cognitive ability. These daily rhythms are co-ordinated by a hypothalamic pacemaker, the suprachiasmatic nuclei (SCN). Individual SCN neurons are competent circadian pacemakers, synchronised to solar time by retinal innervation. Their intrinsic oscillator consists of a series of inter-linked, autoregulatory transcriptional/post-translational feedback loops incorporating Per and Cry genes. Mutations that alter the rate of transcription of these genes or the stability of Per and Cry proteins affect clock speed, shortening or lengthening the period of dependent behavioural, metabolic and molecular circadian cycles. Molecular time-keeping in SCN neurons is synchronised and sustained by inter-neuronal signals mediated by the neuropeptide vasoactive intestinal peptide and its Vpac2 receptor. A molecular clock mechanism comparable to that of the SCN is present in most major organ systems. These tissue clocks are synchronised by endocrine, autonomic and behavioural cues that are dependent on the SCN. In turn they drive the circadian expression of local transcriptomes and proteomes, thereby co-ordinating circadian metabolism and physiology. Rhythmic glucocorticoid signalling is a potent internal synchroniser of local clocks. The role of local, SCN-synchronised clocks in controlling vital processes (including xenobiotic detoxification, cell division and nutrient metabolism) is essential to health. Disturbances to circadian timing arising from modern working schedules are becoming recognised as an increasingly relevant factor in major systemic illness. In neurodegenerative conditions, such as Alzheimer’s disease and Huntington’s disease, breakdown of the circadian regulation over sleep and wakefulness is a major determinant of institutionalisation. Moreover, the newly identified molecular components of circadian control systems provide novel avenues for therapeutic intervention in systemic disease.