Trends in Endocrinology & Metabolism
ReviewA sense of time: how molecular clocks organize metabolism
Section snippets
Introduction: why time and metabolism?
Opening quote
It is interesting to contemplate an entangled bank, clothed with many plants of many kinds, with birds singing on the bushes, with various insects flitting about, and with worms crawling through the damp earth, and to reflect that these elaborately constructed forms, so different from each other, and dependent on each other in so complex a manner, have all been produced by laws acting around us…as a consequence (sic leading) to Natural Selection…There is grandeur in this view of
A window in time: our temporal world uncovered, from plants to animals
In the 20 years following his travels to the Galapagos Islands, Darwin himself came to recognize that one of the most immutable pressures to have shaped life on our planet is its ‘continuous cycling…according to the fixed laws of gravity’. His interest in internal timing led to the publication of a treatise later in life, on the daily pattern of leaf movements in plants [6]. The daily rotation of the Earth leads to dramatic changes on its surface, many of which involve the transition from light
Organization and central nervous system wiring of the mammalian clock
The observation that circadian rhythms are endogenous, and even present in unicellular organisms, emerged before identification of the location of the clock in mammals 8, 9. Classic lesioning studies localized the site of the master pacemaker neurons to two paired nuclei located in the hypothalamus, just dorsal to the optic chiasm. Mechanical and electrolytic ablation of these cell clusters resulted in a loss of rhythms, not only in locomotor activity and drinking, but also in adrenal
Molecular machinery of the clock within all cells
Insight into the molecular underpinnings of the circadian system was provided initially by the seemingly simple observation of Konopka and Benzer [31] that locomotor activity rhythms in Drosophila melanogaster were heritable and could be altered through deliberate mutagenesis. By screening for flies with varying activity cycle lengths, they identified the first circadian clock mutant D. melanogaster in 1971, which they termed ‘Period’ [31]. Eventually, three Period (Per) genes were cloned 32, 33
Post-translational regulation and outputs of the clock
In addition to regulation at the level of transcription, nucleocytoplasmic transport and post-translational phosphorylation of the PER and CRY proteins by CKIɛ add further levels of regulation to the clock oscillator 52, 53, 54, 55. Interestingly, recent in vitro studies have suggested that circadian oscillations can be reconstituted in the absence of transcription, implying that 24-hour oscillations can be produced with protein and ATP only [56]. The rapid unraveling of the core clock
Integration of circadian and metabolic systems
The observation that neuroendocrine and metabolic systems are subject to strong circadian control, together with the discovery of extensive 24-hour variation in the RNAs that induce key factors involved in metabolism, has led to the hypothesis that metabolic and circadian gene networks might be coregulated. Interestingly, several pathways have been identified that might link circadian networks with both gluconeogenic and lipogenic pathways. For example, the transcription factors
Insight from experimental genetics into links between circadian and metabolic systems
While in vitro studies continue to yield new insight into the transcription networks linking the circadian clock and metabolism, experiments in Clock mutant and Bmal1−/− animals have demonstrated a role of the circadian networks in mammalian energy balance, metabolism and adipogenesis 81, 82. Clock mutant mice develop behavioral abnormalities as they age, including deficits in nonrapid eye movement sleep and, when monitored under free-running conditions, an abnormality in activity. The
Future questions
Studies of the clock and the relationship between circadian and metabolic systems are highly interdisciplinary, and a wide range of approaches will be needed to address how molecules of the clock function within individual cell and tissue contexts. A related question is whether the effects of Clock mutation on metabolism are dependent or independent of their role in controlling circadian rhythmicity. A further implication of such studies is the possibility that they will elucidate interactions
Acknowledgements
This work was supported by National Institutes of Health grants to J. Bass. We acknowledge the support of the Steven and Arlene Lazarus Foundation. We are also grateful to Drs R. Allada, A. Laposky, J. Takahashi and F. Turek for helpful discussions.
Glossary
- Circadian rhythm
- A biological rhythm with a ∼24-hour period that persists in constant conditions.
- Clock
- A central mechanism controlling circadian rhythms.
- Entrainment
- The phenomenon of synchronization of internal biological rhythms by external cues.
- Oscillator
- A system of components that produces a rhythm. Circadian oscillators express periods of 24 hours and constitute the biological clock that can be entrained by external cues, such as light.
- Free run
- Constant conditions under which an organism is
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