A sense of time: how molecular clocks organize metabolism

doi:10.1016/j.tem.2006.11.005

Trends in Endocrinology & Metabolism

Volume 18, Issue 1, January–February 2007, Pages 4-11

https://doi.org/10.1016/j.tem.2006.11.005 Get rights and content

The discovery of an internal temporal clockwork that coordinates behavior and metabolism according to the rising and setting of the sun was first revealed in flies and plants. However, in the past decade, a molecular transcription–translation feedback loop with similar properties has also been identified in mammals. In mammals, this transcriptional oscillator programs 24-hour cycles in sleep, activity and feeding within the master pacemaker neurons of the suprachiasmatic nucleus of the hypothalamus. More recent studies have shown that the core transcription mechanism is also present in other locations within the brain, in addition to many peripheral tissues. Processes ranging from glucose transport to gluconeogenesis, lipolysis, adipogenesis and mitochondrial oxidative phosphorylation are controlled through overlapping transcription networks that are tied to the clock and are thus time sensitive. Because disruption of tissue timing occurs when food intake, activity and sleep are altered, understanding how these many tissue clocks are synchronized to tick at the same time each day, and determining how each tissue ‘senses time’ set by these molecular clocks might open new insight into human disease, including disorders of sleep, circadian disruption, diabetes and obesity.

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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Trends in Endocrinology & Metabolism

ReviewA sense of time: how molecular clocks organize metabolism

Section snippets

Introduction: why time and metabolism?

A window in time: our temporal world uncovered, from plants to animals

Organization and central nervous system wiring of the mammalian clock

Molecular machinery of the clock within all cells

Post-translational regulation and outputs of the clock

Integration of circadian and metabolic systems

Insight from experimental genetics into links between circadian and metabolic systems

Future questions

Acknowledgements

Glossary

Semin. Perinatol.

Trends Neurosci.

Horm. Behav.

Trends Neurosci.

Neuron

Cell Metab.

Neurosci. Biobehav. Rev.

Cell

Cell

Neuron

Curr. Opin. Cell Biol.

Cell

Trends Neurosci.

Cell

Neuron

Cell

Cell

Curr. Biol.

Cell

J. Biol. Chem.

Neuron

J. Biol. Chem.

Cell

Cell

J. Thromb. Haemost.

FEBS Lett.

The Origin of Species

The rhythm of rest and excess

Nat. Rev. Neurosci.

Sleepless in America: a pathway to obesity and the metabolic syndrome?

Arch. Intern. Med.

When the Clock stops ticking, metabolic syndrome explodes

Nat. Med.

The Power of Movement in Plants

Timeline: circadian clocks – the fall and rise of physiology

Nat. Rev. Mol. Cell Biol.

A clockwork web: circadian timing in brain and periphery, in health and disease

Nat. Rev. Neurosci.

Transplanted suprachiasmatic nucleus determines circadian period

Science

Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling

Science

A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms

Nature

Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus

Nature

Effects of suprachiasmatic transplants on circadian rhythms of neuroendocrine function in golden hamsters

Endocrinology

Output pathways of the mammalian suprachiasmatic nucleus: coding circadian time by transmitter selection and specific targeting

Cell Tissue Res.

Interacting appetite-regulating pathways in the hypothalamic regulation of body weight

Endocr. Rev.

The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems

Neuroreport

SCN efferents to peripheral tissues: implications for biological rhythms

J. Biol. Rhythms

Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake

J. Comp. Neurol.

Review
A sense of time: how molecular clocks organize metabolism