The Crosstalk Between Physiology and Circadian Clock Proteins

In mammals, many physiological processes present diurnal variations, and most of these rhythms persist even in absence of environmental timing cues. These endogenous circadian rhythms are generated by intracellular timing mechanisms termed circadian clocks. In mammals, the master clock is located in the suprachiasmatic nuclei (SCN), but other brain regions and most peripheral tissues contain circadian clocks. These clocks are responsive to environmental cues, in particular light/dark and feeding/fasting cycles. In the last few years, tissue-specific knock-out and transgenic mouse models have helped to define the physiological roles of specific clocks. Recent reports indicate that the clock-physiology connection is bi-directional, and physiological cues, in particular the energetic status of the cell, can feed into the clockwork. This effect was discovered unexpectedly in molecular analyses of clock protein modifications. Beyond the positive and negative transcription/translation feedback loops of the molecular oscillator lies another level of complexity. Post-translational modifications of clock proteins are both critical for the timing of the clock feedback mechanism and to provide regulatory fine-tuning. This review summarizes recent advances in our understanding of the roles of peripheral clocks and of post-translational modifications occurring on clock proteins. These two matters are at the intersection of physiology, metabolism, and the circadian system.