The classic view of circadian timing in mammals emphasizes a light-responsive 'master clock' within the hypothalamus which imparts temporal information to the organism. Recent work indicates that such a unicentric model of the clock is inadequate. Autonomous circadian timers have now been demonstrated in numerous brain regions and peripheral tissues in which molecular-clock machinery drives rhythmic transcriptional cascades in a tissue-specific manner. Clock genes also participate in reciprocal regulatory feedback with key signalling pathways (including many nuclear hormone receptors), thereby rendering the clock responsive to the internal environment of the body. This implies that circadian-clock genes can directly affect previously unforeseen physiological processes, and that amid such a network of body clocks, internal desynchronisation may be a key aspect to circadian dysfunction in humans. Here we consider the implications of decentralised and internally responsive clockwork to disease, with a focus on energy metabolism and the immune response.
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