Elsevier

Life Sciences

Volume 265, 15 January 2021, 118809
Life Sciences

Review article
The circadian machinery links metabolic disorders and depression: A review of pathways, proteins and potential pharmacological interventions

https://doi.org/10.1016/j.lfs.2020.118809Get rights and content

Highlights

  • Metabolic disorders are often accompanied by comorbidities, including depression.

  • The shared pathophysiological and aetiological mechanisms require further research.

  • An underlying pathway may be disruption of circadian rhythms.

  • The links between circadian rhythms, metabolism and depression are highlighted.

  • The modulation of key circadian clock proteins by small molecules is discussed.

Abstract

Circadian rhythms are responsible for regulating a number of physiological processes. The central oscillator is located within the suprachiasmatic nucleus (SCN) of the hypothalamus and the SCN synchronises the circadian clocks that are found in our peripheral organs through neural and humoral signalling. At the molecular level, biological clocks consist of transcription-translation feedback loops (TTFLs) and these pathways are influenced by transcription factors, post-translational modifications, signalling pathways and epigenetic modifiers. When disruptions occur in the circadian machinery, the activities of the proteins implicated in this network and the expression of core clock or clock-controlled genes (CCGs) can be altered. Circadian misalignment can also arise when there is desychronisation between our internal clocks and environmental stimuli.

There is evidence in the literature demonstrating that disturbances in the circadian rhythm contribute to the pathophysiology of several diseases and disorders. This includes the metabolic syndrome and recently, it has been suggested that the ‘circadian syndrome’ may be a more appropriate term to use to not only describe the cardio-metabolic risk factors but also the associated comorbidities. Here we overview the molecular architecture of circadian clocks in mammals and provide insight into the effects of shift work, exposure to artificial light, food intake and stress on the circadian rhythm. The relationship between circadian rhythms, metabolic disorders and depression is reviewed and this is a topic that requires further investigation. We also describe how particular proteins involved in the TTFLs can be potentially modulated by small molecules, including pharmacological interventions and dietary compounds.

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.

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