Review articleThe circadian machinery links metabolic disorders and depression: A review of pathways, proteins and potential pharmacological interventions
Graphical abstract
Introduction
Circadian rhythms are endogenous timing systems that are found in most organisms [1]. They are regulated by internal biological clocks and environmental stimuli including the light-dark cycle, nutrition, sleep, stress, physical activity and temperature [[2], [3], [4], [5], [6], [7]]. These external factors are referred to as zeitgebers and they are able to reset the circadian clock in a process called entrainment (Fig. 1) [8]. In general, circadian rhythms can be represented as graphs and are depicted as sinusoidal waves [1]. The key characteristics are the period (~24 h), amplitude, peak, trough and phase [1].
The central pacemaker or ‘master clock’ is located in the brain, specifically within the suprachiasmatic nucleus (SCN) of the hypothalamus [1,9,10]. The SCN consists of a network of neurons that exhibit peptidergic heterogeneity [11]. The retinohypothalamic tract (RHT) relays information about the environmental light-dark cycle from photoreceptor cells in the retina to the SCN and facilitates synchronisation [12]. The central oscillator within the SCN generates rhythmic outputs and coordinates physiological processes [1,13].
N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are involved in the circadian entrainment pathway [14]. They are ionotropic receptors that are also located in the SCN and are activated by glutamate, which is an excitatory neurotransmitter that is released in response to light stimulation [15,16]. This results in the activation of signal transduction cascades and the phosphorylation of cyclic AMP response binding element protein (CREB) [17]. This process is also regulated by the release of neuropeptides, including pituitary adenylate cyclase-activating peptide (PACAP), as well as melatonin [18,19]. In addition to NMDA and AMPA receptors, it's known that melatonin receptors (MT1 and MT2), the pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1), voltage-gated calcium channels (VGCCs) and inwardly-rectifying potassium channels (Kir3) play a role in circadian entrainment [[20], [21], [22]].
Aside from the SCN, there are cells, tissues or organs that produce daily rhythms and contain peripheral clocks [10,23]. These peripheral circadian oscillators are synchronised by the SCN however, emerging evidence suggests that external factors can control peripheral rhythmicity independently of the SCN [24]. When assessing the expression of the Period (Per) gene under light-dark conditions in the head, thorax and abdomen tissues from Drosophila, it was reported that the segments exhibited rhythmic bioluminescence [25]. Interestingly, the proboscis, antennae, legs and wings were also able to maintain oscillations in these conditions [25]. Similar findings were obtained in an experiment using a transgenic rat model [26]. These rats were raised in light-dark cycles (12 h light, 12 h dark) and circadian rhythms were detected in the liver, lungs and skeletal muscle [26]. Most notably, the rhythms were delayed by 7 to 11 h compared to the SCN [26]. Zylka et al. also demonstrated that the expression of the Per genes were widespread and that circadian oscillations were occurring in non-neuronal tissues of mice [27]. These initial results provided the foundation for future research into circadian rhythms and their biological significance.
Section snippets
Mammalian transcription-translation feedback loops
The core molecular clock is composed of transcription-translation feedback loops (TTFLs) and several circadian clock proteins are involved in these pathways (Fig. 2) [28]. In mammals, the transcription factors aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL/BMAL1) and circadian locomotor output cycles kaput (CLOCK) accumulate and heterodimerise in the cytoplasm [29]. Neuronal PAS domain-containing protein 2 (NPAS2) is a paralog of the CLOCK protein [30,31]. The CLOCK:BMAL1
Post-translational modifications and interactions with chromatin-modifying complexes
Components of the circadian clock can also be modulated by post-translational modifications including phosphorylation and ubiquitination [47,54]. In regards to the PER proteins, there is evidence to suggest that they interact with kinases including casein kinase 1δ/ε (CK1δ/ε) [55]. These kinases phosphorylate PER proteins and affect their stability, degradation, interaction with other clock proteins and translocation into the nucleus [56]. A number of mutational studies have been conducted on
Disruption of circadian rhythms
In 1988, a mutation was found to occur at the tau locus encoded by CK1ε in hamsters [102]. This was the first mammalian single gene mutation identified that affected the circadian rhythm, as it created a shortened period [102]. Soon after, the Clock gene in mice was discovered via N-ethyl-N-nitrosourea (ENU) mutagenesis and the Northern blot analysis indicated that it was widely expressed [[103], [104], [105]]. Interestingly, the CLOCK-Δ19 mutation acted in a dominant-negative manner and had
The circadian rhythm, metabolic disorders and major depressive disorder
Type 2 diabetes mellitus, cardiovascular diseases and obesity have emerged as major causes of death over the years and contribute greatly to the global burden of disease [121,122]. Terms such as ‘diabesity’ have even been used to describe the current epidemic of obesity and type 2 diabetes [123]. According to the ‘Harmonising the Metabolic Syndrome’ statement that was developed by a consortium in 2009, there are a number of risk factors that constitute the metabolic syndrome and can contribute
Potential modulation of the circadian rhythm by pharmacological and dietary compounds
Over the years, scientists have gained further insight into chronobiology and have developed a deeper understanding on the rhythms of biological processes in physiological and pathological states [188]. This has also given rise to the field of chronotherapy and behavioural approaches can be used to reset the circadian clock [188,189]. This can be used in the management of sleep disorders and bright light therapy is an example [189]. In terms of chronopharmacology, this method of treatment is
Conclusion and future directions
Overall, many studies investigating pharmacological and dietary compounds have been conducted using comprehensive in vitro and preclinical in vivo models however, the precise molecular mechanisms of action on the circadian rhythm require further clarification. This is of particular importance for the management of metabolic disorders and MDD, as health professionals recommend that patients make modifications to aspects of their lifestyle including diet [325,326]. Therefore, research into the
CRediT authorship contribution statement
EP and JL contributed to visualization and writing the original draft. TCK and AH were involved in supervision. All authors contributed to editing and reviewing the manuscript.
Declaration of competing interest
Epigenomic Medicine Program (TCK) is supported financially by McCord Research (Iowa, USA), which may have financial interests in dietary compounds and interventions described in this work.
Acknowledgements
We would like to acknowledge intellectual and financial support by McCord Research (Iowa, USA). JL is supported by an Australian Government Research Training Program Scholarship. Several of the figures were created with BioRender.com.
References (326)
- et al.
Short-term feeding at the wrong time is sufficient to desynchronize peripheral clocks and induce obesity with hyperphagia, physical inactivity and metabolic disorders in mice
Metab. Clin. Exp.
(2016) - et al.
In situ hybridization of antisense mRNA oligonucleotides for AMPA, NMDA and metabotropic glutamate receptor subtypes in the rat suprachiasmatic nucleus at different phases of the circadian cycle
Mol. Brain Res.
(1994) - et al.
Time-fixed feeding prevents obesity induced by chronic advances of light/dark cycles in mouse models of jet-lag/shift work
Biochem. Biophys. Res. Commun.
(2015) - et al.
Three period homologs in mammals: differential light responses in the suprachisamtic circadian clock and oscillating transcripts outside of brain
Neuron
(1998) - et al.
Circadian rhythms and autoregulatory transcription loops—going round in circles?
Mol. Cell. Endocrinol.
(1996) - et al.
Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei
Neuron
(1997) - et al.
RIGUI, a putative mammalian ortholog of the Drosophila period gene
Cell
(1997) - et al.
mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop
Cell
(1999) - et al.
Human casein kinase Iδ phosphorylation of human circadian clock proteins period 1 and 2
FEBS Lett.
(2001) - et al.
The orphan nuclear receptor REV-ERBalpha; controls circadian transcription within the positive limb of the mammalian circadian oscillator
Cell
(2002)
Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase
Mol. Cell
SCFβ-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian Period-1 (Per1) protein
J. Biol. Chem.
FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes
Cell
A bivalent chromatin structure marks key developmental genes in embryonic stem cells
Cell
Circadian regulator CLOCK is a histone acetyltransferase
Cell
Histone demethylation mediated by the nuclear amine oxidase homolog LSD1
Cell
Phosphorylation of LSD1 by PKCa1; is crucial for circadian rhythmicity and phase resetting
Mol. Cell
Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features
Genet Med
Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with kabuki syndrome
Am. J. Hum. Genet.
Identification of KMT2D and KDM6A variants by targeted sequencing from patients with kabuki syndrome and other congenital disorders
Gene
SIRT1 regulates circadian clocl gene expression through PER2 acetylation
Cell
The polycomb group protein EZH2 is required for mammalian circadian clock function
J. Biol. Chem.
Structural basis of LSD1-CoREST selectivity in histone H3 recognition
J. Biol. Chem.
Distinct roles of HDAC3 in the core circadian negative feedback loop are critical for clock function
Cell Rep.
Circadian oscillator proteins across the kingdoms of life: structural aspects
BMC Biol.
Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus
Genes Dev.
Diurnal hypothalamic-pituitary-adrenal axis measures and inflammatory marker correlates in major depressive disorder
Int. J. Mol. Sci.
Light as a central modulator of circadian rhythms, sleep and affect
Nat. Rev. Neurosci.
Phase shifts in circadian peripheral clocks caused by exercise are dependent on the feeding schedule in PER2::LUC mice
Chronobiol. Int.
Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production
Proc. Natl. Acad. Sci. U. S. A.
New insights into the circadian rhythm and its related diseases
Front. Physiol.
Circadian rhythms: will it revolutionise the management of diseases?
J Lifestyle Med
Off the clock: from circadian disruption to metabolic disease
Int. J. Mol. Sci.
Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs
Nature
Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions
Proc. Natl. Acad. Sci. U. S. A.
Modulation of NMDA-mediated clock resetting in the suprachiasmatic nuclei of mPer2Luc mouse by endocannabinoids
Front. Physiol.
Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO
Science
Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock
Science
Pituitary adenylate cyclase activating peptide phase shifts circadian rhythms in a manner similar to light
J. Neurosci.
Melatonin receptors as therapeutic targets in the suprachiasmatic nucleus
Expert Opin. Ther. Targets
Pituitary adenylate cyclase-activating peptide (PACAP)-glutamate co-transmission drives circadian phase-advancing responses to intrinsically photosensitive retinal ganglion cell projections by suprachiasmatic nucleus
Front. Neurosci.
Circadian regulation and function of voltage-dependent calcium channels in the suprachiasmatic nucleus
J. Neurosci.
Melatonin receptors activate heteromeric G-protein coupled Kir3 channels
NeuroReport
The light-dark cycle controls peripheral rhythmicity in mice with a genetically ablated suprachiasmatic nucleus clock
FASEB J.
Independent photoreceptive circadian clocks throughout Drosophila
Science
Resetting central and peripheral circadian oscillators in transgenic rats
Science
Role of the CLOCK protein in the mammalian circadian mechanism
Science
CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock
Nat. Neurosci.
NPAS2 compensates for loss of CLOCK in peripheral circadian oscillators
PLoS Genet.
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