Journal
JOURNAL OF BIOLOGICAL RHYTHMS
Volume 21, Issue 6, Pages 494-506Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/0748730406293889
Keywords
mammalian circadian timing system; peripheral clocks; phase entrainment; self-sustained oscillators; PAR basic leucine zipper proteins; circadian metabolism; SCN; detoxification
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In mammals, the circadian timing system is composed of multiple oscillators that are organized in a hierarchical manner. The central pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, is believed to orchestrate countless subsidiary clocks in the periphery. These peripheral oscillators are cell-autonomous, self-sustained, resilient to cell division, and virtually insensitive to large fluctuations in general transcription rates. However, they are probably not coupled within an organ, and daily zeitgeber signals emanating from the SCN appear to be required to ensure phase coherence within and between tissues. Peripheral clocks are implicated in a variety of biochemical pathways, and recent results tightly link circadian rhythms to several aspects of metabolism. Thus, the expression of many key enzymes conducting rate-limiting steps in various metabolic pathways is regulated in a circadian fashion by core clock components or clock-controlled transcription factors. Genetic loss-of-function studies have now established a role for mammalian circadian clock components in energy homeostasis and xenobiotic detoxification, and the latter manifests itself in the daytime-dependent modulation of drug efficacy and toxicity.
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