The Suprachiasmatic Nucleus, Circadian Clocks, and the Liver

Abstract

The circadian clock system adapts phasic physiological activities, such as sleeping and eating, to environmental cycles. The “master clock” is in the suprachiasmatic nucleus (SCN) and the principal cue (Zeitgeber) is the light–dark cycle, around which most mammalian (and those of all living organisms) functions have evolved. In our society, with activity 24 h per day, the clock is frequently overridden or does not match the activity schedule, with increased susceptibility to disease (obesity, type 2 diabetes, and their cardiovascular sequelae) resulting. In the SCN and in other cells, the core molecular clock mechanism consists of specific genes (“clock” genes). These include Clock (and Npas2) , Bmal , the period homologs, Per1 and Per2 , and cryptochrome 1 ( Cry1 ) and Cry2 . The circadian clock mechanism revolves around transcription–translation feedback loops, in which repression and activation of transcriptional activity are dependent on dimerization, posttranslational modification, and degradation rate constants that define the reactions. Kinetically (in conjunction with a secondary feedback loop comprising nuclear receptor genes, Reverbs and Rors ), this system defines an oscillator with a period that is near 24 h (1,2). Photic cues channeled via the SCN fine-tune the period to correspond to that of the environment. Information on this period is then transmitted to the periphery. The same molecular clocks are also found in peripheral cells (e.g., kidney, liver, pancreas). They can function autonomously. However, the master clock in the SCN generally coordinates these peripheral clocks by way of the autonomic or humoral (e.g., corticosteroids, melatonin) routes to generate a synchronized signal that aligns metabolic and other activities with environmental conditions (1,3). Sleep–waking cycles are clearly set by the light–dark cycle. Disrupted sleep patterns impose alterations in this cycle. As, for example, with jet lag, the circadian clock adapts to these changes (4 …