Crosstalk between metabolism and circadian clocks

Abstract

Humans, like all mammals, partition their daily behaviour into activity (wakefulness) and rest (sleep) phases that differ largely in their metabolic requirements. The circadian clock evolved as an autonomous timekeeping system that aligns behavioural patterns with the solar day and supports the body functions by anticipating and coordinating the required metabolic programmes. The key component of this synchronization is a master clock in the brain, which responds to light–darkness cues from the environment. However, to achieve circadian control of the entire organism, each cell of the body is equipped with its own circadian oscillator that is controlled by the master clock and confers rhythmicity to individual cells and organs through the control of rate-limiting steps of metabolic programmes. Importantly, metabolic regulation is not a mere output function of the circadian system, but nutrient, energy and redox levels signal back to cellular clocks in order to reinforce circadian rhythmicity and to adapt physiology to temporal tissue-specific needs. Thus, multiple systemic and molecular mechanisms exist that connect the circadian clock with metabolism at all levels, from cellular organelles to the whole organism, and deregulation of this circadian–metabolic crosstalk can lead to various pathologies.

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Fig. 1: Transcriptional and metabolic circadian oscillators.
Fig. 2: Entrainment of the clock by light and food.
Fig. 3: Circadian control of mitochondria.
Fig. 4: Cellular circadian metabolism of glucose and feedback of metabolism on the cellular clock.

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Acknowledgements

The authors are grateful to R. Aviram and G. Manella for their valuable comments on the manuscript and for their assistance in the figure preparation. G.A. is supported by the European Research Council (ERC-2017 CIRCOMMUNICATION 770869). G.A. is recipient of the European Molecular Biology Organization (EMBO) young investigator award.

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Nature Reviews Molecular Cell Biology thanks A. Weljie, F. Gachon and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Glossary

Phase

The relative position of the internal circadian clock time to the external time.

E-box elements

DNA elements (consensus sequence CANNTG) bound by transcription factors, most commonly basic helix–loop–helix domain-containing proteins.

Photic responses

Light-induced molecular changes in cells that contribute to photoentrainment in the suprachiasmatic nucleus.

Arcuate nucleus

A hypothalamic nucleus that contains neuroendocrine and centrally projecting neurons and that has pre-eminent roles in central homeostatic processes, such as energy metabolism.

Ketogenic diet

A high-fat, low-carbohydrate diet that results in elevated levels of ketone bodies in the circulation by promoting the metabolism of lipids over the use of carbohydrates for energy generation.

RORE binding sites

DNA elements (consensus sequence AGGTCA preceded by a 5 bp AT-rich sequence) bound by transcription factors from the RAR-related orphan receptor (ROR) and nuclear receptor subfamily 1 group D (REV-ERBA) nuclear receptor families.

Peroxiredoxins

Ubiquitous, small (20–30 kDa) antioxidant enzymes that catalyse the reduction of hydroperoxides, toxic by-products of aerobic respiration, to alcohols.

Melanopsin

Opsin of intrinsically photoactive retinal ganglion cells involved in non-image-forming visual functions including light-entrainment of the suprachiasmatic nucleus.

Retinal ganglion cells

Neurons in the ganglion cell layer of the retina; their axons form the optic nerve and the retinohypothalamic tract.

Melatonin

A pineal hormone that regulates circadian rhythms and wakefulness; its synthesis is suppressed by light.

Heterotrimeric G proteins

Membrane-associated GTP-binding and/or GDP-binding signalling proteins consisting of three subunits α, β and γ.

RevDR2 elements

DNA elements (direct repeats of two AGGTCA motifs separated by 2 bp) bound by transcription factors from the RAR-related orphan receptor (ROR) and nuclear receptor subfamily 1 group D (REV-ERBA) nuclear receptor families.

Haem

A porphyrin complex with a central iron atom that can bind and transport diatomic gases and can be used as a redox partner in electron transfer reactions.

Oxysterols

Oxidized derivatives of cholesterol with biological activity, for example, as binding partners for nuclear receptors.

Toll-like receptors

Transmembrane receptors with homology to the Drosophila melanogaster Toll protein that recognize microbial pathogen structures.

Operational taxonomic units

Classifiers for clusters of closely related organisms, in particular used for prokaryotes owing to the lack of a traditional system of biological classification.

O-GlcNAcylation

Post-translational modification of proteins, whereby N-acetylglucosamine is covalently attached via an O-glycosidic linkage to serine or threonine residues.

Metabolic flux

Substrate use in a biochemical pathway determined as the turnover rate of a metabolite as opposed to its steady-state levels, which can be constant in different conditions despite widely varying flux rates.

NAD cofactors

NAD molecules that can serve in their reduced form, NADH, as an electron donor and in their oxidized form, NAD+, as an electron acceptor in biochemical reactions.

Prosthetic group

A small molecule that is covalently bound to a protein and is essential for its function. An example of a prosthetic group is haem bound to haemoglobin.

Ischaemia–reperfusion injury

The tissue damage caused by oxidative stress when cells are resupplied with oxygen and nutrients after a period of anoxia, for example, after a stroke.

Poly-ADP-ribosylation

The post-translational modification by transfer of multiple ADP-ribose units to target proteins.

Leptin

An adipocyte-derived hormone that can cross the blood–brain barrier and inhibit hunger by regulating the production of other satiety-controlling hormones in the hypothalamus. The name comes from a Greek word meaning thin.

Ghrelin

(Growth hormone release inducing). A gastrointestinal peptide hormone that stimulates growth hormone secretion from the anterior pituitary and can cross the blood–brain barrier to increase hunger in the hypothalamus antagonistically to leptin.

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Reinke, H., Asher, G. Crosstalk between metabolism and circadian clocks. Nat Rev Mol Cell Biol 20, 227–241 (2019). https://doi.org/10.1038/s41580-018-0096-9

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