Table 1.
Possible connecting components between the circadian oscillators and metabolic processes
| Candidates | Plausible roles/ involvement in cross‐talks | References |
|---|---|---|
| CLOCK/NPAS2 | Circadian transcription factor CLOCK/NPAS2 controls NAD+ biosynthesis through regulation of NAMPT expression | 62 |
| NAD(P)+/NAD(P)H ratio regulates the binding of CLOCK/NPAS2‐BMAL1 heterodimers to their E box cognate sequence | ||
| PER proteins | PER proteins regulate expression of the core clock gene Bmal1 | 59, 115 |
| Binding of SIRT1 to CLOCK‐BMAL1 complexes promotes PER2 deacetylation and degradation | ||
| PER proteins regulates lipid and glycogen metabolism through their interactions with diverse nuclear receptors | ||
| CRY proteins | CRY proteins (along with the PER proteins) function as the negative regulators for maintenance of circadian rhythms | 69, 116 |
| They regulate circadian rhythmicity of cAMP signaling and hepatic gluconeogenesis | ||
| AMPK directly phosphorylates CRY proteins and reduces their half‐life | ||
| NAD+ | NAD(P)+ and NAD(P)H reflect the metabolic and redox status of the cell | 58, 62 |
| NAD+ serves as a metabolic oscillator and controls the core clock machinery primly through SIRT1 | ||
| SIRT1 | NAD+‐dependent SIRT1 controls expression the circadian clock genes (Bmal1, Per2, and Cry1) through PER2 deacetylation | 58, 59, 60 |
| CLOCK‐SIRT1 regulates circadian control of the NAD+ salvage pathway | ||
| It regulates circadian transcription also by the deacetylation of histone H3 tails | ||
| SIRT3 | SIRT3 maintains rhythms in the acetylation and activity of oxidative enzymes and respiration | 64 |
| Core clock components regulate its activity through control of concentrations of NAD+ | ||
| NAMPT | NAMPT is the rate‐limiting enzyme in mammalian NAD+ biosynthesis | 62 |
| Its expression is regulated by the core clock genes | ||
| Its inhibition leads to the oscillation of Per2 by releasing CLOCK: BMAL1 | ||
| PARP1 | PARP1 modifies clock components in response to feeding‐fasting cycles | 63, 117 |
| It regulates the binding of CLOCK‐BMAL1 to DNA and interaction of CLOCK‐BMAL1 with PER and CRY repressor proteins | ||
| SP1, a nuclear target protein of PARP‐1, regulate its expression | ||
| PRXs | PRX proteins exhibit self‐sustained oscillation in their oxidation–reduction cycles | 34, 40 |
| PRX cycle provides feedback to regulate the core clock transcriptional network probably through the oscillation of ROS | ||
| Perturbation of their functions causes a long‐period phenotype or leads to a depression in the amplitude of circadian oscillations | ||
| AceCS1 | Circadian control of intracellular levels of acetyl‐CoA and thereby fatty acid elongation is regulated through the enzymatic activity of AceCS1 | 118 |
| AceCS1 activity is controlled by acetylation, and its rhythmic acetylation is regulated by SIRT1 | ||
| AMPK | AMPK serves as the major sensor of the AMP/ATP ratio, activates stress‐promoted transcription and regulates clock gene expression | 119 |
| It regulates stability (promotes degradation) of core clock proteins (CRY and PER) | ||
| PPARα and PGC‐1α | Transcriptional coactivator PGC‐1α stimulates expressions of clock genes (Bmal1 and Rev‐erbα) | 120, 121 |
| It has association with the SirT1 histone deacetylase complex, can serve as a sensor for the metabolic state of the cell, and also induces the expression of gluconeogenic genes | ||
| PPARα regulates fatty acid oxidation and apolipoprotein synthesis | ||
| ALAS1 | ALAS1, the rate limiting enzyme in haem biosynthesis, is a target gene for the NPAS2/BMAL1 heterodimer | 122 |
| Circadian rhythmicity in the cellular haem levels in maintained through the regulation of the expression of ALAS1 by the core clock genes | ||
| Reciprocally, haem regulates activity of the BMAL1‐NPAS2 transcription complex | ||
| HSF1 | HSF1 plays an important role in transporting nutrient signals to the circadian circuitry | 123 |
| Phosphorylation by diverse protein kinases regulates its activity | ||
| It also functions as a key regulator of temperature‐dependent expression of heat shock protein/ chaperone genes associated with circadian oscillators | ||
| CREB | cAMP signaling via CREB and other transcriptional oscillator is imperative for the molecular circadian oscillators | 124, 125 |
| CREB‐dependent transcription supports steady cycling of the core clock transcriptional loop | ||
| FOXO | Nutrient and stress sensor FOXO regulates sensitivity of the circadian clock to stress conditions; its effects on circadian rhythms are non‐cell‐autonomous | 126, 127 |
| SIRT1 regulates FOXO transcription factors in a stress‐dependent manner | ||
| Expression of several gluconeogenic genes is directly regulated by FOXO1 | ||
| RORs | RORs are components of the master oscillator in mammalian circadian system that regulate Bmal1 transcription through formation of a feedback loop involving RORα and REV‐ERBα | 128, 129 |
| RORs can alter PER2 activity by direct physical interactions |
AceCS1, Acetyl‐CoA Synthetase 1; ALAS1, aminolevulinate synthase 1; AMPK, AMP‐dependent protein kinase; CREB, cAMP response element‐binding protein; Cry, cryptochrome; FOXO, Forkhead homeobox type O; HSF1, heat shock transcription factor 1; NAD, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyl‐transferase; NPAS2, neuronal PAS domain protein 2; PARP1, poly (ADP‐ribose) polymerase 1; Per, period; PPAR, peroxisome proliferators–activated receptor; PGC‐1α, PPAR gamma coactivator‐1 alpha; PRX, peroxiredoxin; ROR, retinoic acid orphan receptors; ROS, reactive oxygen species; SIRT, sirtuin.