Multi-Modal Regulation by Biological Clocks: Comparison
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The circadian clock is a fundamental biological timing mechanism that generates nearly 24 h rhythms of physiology and behaviors, including sleep/wake cycles, hormone secretion, and metabolism. Evolutionarily, the endogenous clock is thought to confer living organisms, including humans, with survival benefits by adapting internal rhythms to the day and night cycles of the local environment. Mirroring the evolutionary fitness bestowed by the circadian clock, daily mismatches between the internal body clock and environmental cycles, such as irregular work (e.g., night shift work) and life schedules (e.g., jet lag, mistimed eating), have been recognized to increase the risk of cardiac, metabolic, and neurological diseases. Moreover, increasing numbers of studies with cellular and animal models have detected the presence of functional circadian oscillators at multiple levels, ranging from individual neurons and fibroblasts to brain and peripheral organs. These oscillators are tightly coupled to timely modulate cellular and bodily responses to physiological and metabolic cues. 

  • circadian clock
  • circadian disruption
  • SCN
  • brain clocks
  • peripheral clocks
  • redox metabolism

1. Introduction

Since the formation and settlement of our solar system roughly 4.5 billion years ago, the Earth has been rotating on its axis and revolving around the Sun, bringing about continuous light and dark cycles on this planet. In accordance with these cycles, nearly all living unicellular and multicellular organisms have evolved rhythmic life processes controlled by the circadian clock (from the Latin phrase circa diem meaning “about a day”), which have about 24 h periods and constantly predict and adapt to daily environmental changes [1]. This internal timing system is believed to help organisms survive by increasing their ability to timely anticipate the cyclic changes of light and food availability as well as predation risk. At the unicellular level, the timely compartmentalization of the organism’s biochemical, metabolic, and redox processes, coordinated by the intrinsic clockwork, ensures the temporal fitness of cell physiology and functions across species [2]. In lower eukaryotic species, biological timers may help single-celled organisms escape the DNA-damaging effects of ionizing radiation from sunlight as well as oxidative stress during cell division [3]. In higher, complex organisms, including humans, common cellular oscillators constitute the brain and peripheral tissue clocks that interconnect to form a circadian network at the whole-body level. Interestingly, human or cross-species studies reveal differences in behavioral chronotype not only between species but also within and between different individuals of each species, suggesting the extent of intra- and inter-subject variability of circadian timing systems [4,5,6,7,8][4][5][6][7][8]. With periodic anticipation and synchronization to day–night cycles, these internal timing systems, in concert, coordinate rhythmic physiology and behaviors such as the sleep–wake cycle, body temperature, blood pressure, hormone production, neural and immune system processes, and cell proliferation [9,10][9][10].
In contrast to the adaptive benefits of circadian rhythms, modern lifestyles result in misalignment of the working, eating, and sleeping cycles, relative to natural 24 h light/dark cycles, that historically defined human existence. Such misalignment has been found to increase our susceptibility to the onset and development of cardiometabolic, digestive, immune, and neuropsychiatric disorders, as well as cancers [11,12,13,14][11][12][13][14]. Several studies in animal models containing genetic mutations of clock genes or those exposed to forced circadian desynchrony regimens have also reinforced the causal relationship between circadian disturbances and disease pathologies [15,16,17,18,19,20][15][16][17][18][19][20]. Furthermore, increasing numbers of studies in cellular and animal models have reported that cellular and bodily rhythms are highly influenced by physiological and metabolic stimuli, such as diet, exercise, metabolites, ions, and gaseous molecules [21,22,23][21][22][23]. In this review, we will describe recent advances in chronobiology as well as the roles of central and peripheral clocks in physiology and diseases, with a particular focus on the dynamic interactions between biological timing systems and metabolic factors.

2. Multi-Modal Mechanisms of Circadian Physiology

The basic circadian rhythm mechanism, conserved across living species on earth, is typically characterized by a cell-autonomous autoregulatory feedback loop [3,24][3][24]. In eukaryotes, a subset of dedicated positive and negative clock regulators forms the interlocked transcriptional translational feedback loop (TTFL), which constitutes a cell-intrinsic oscillator that drives the rhythmic expression of output genes involved in metabolic, biosynthetic, and signal transduction pathways [9]. In mammals, the BMAL1 and CLOCK transcriptional activator complex cyclically drives the transcription of its own repressors, period (PER) and cryptochrome (CRY). The core oscillator is complemented by a second loop in which periodic expression of BMAL1 is maintained by the REV-ERBα/β repressor and RORα/β activator proteins [25] (Figure 1).
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Figure 1. Coupled-cellular oscillators. Bidirectional regulation between transcriptional and metabolic rhythms. The auto-regulatory feedback cycles between the CLOCK/BMAL1 transcriptional activator complex and its transcriptional repressors (PER/CRY, REV-ERBα) and activators (RORα/β), constituting the molecular clock oscillator. This oscillator drives the expression of multiple clock-controlled genes (CCGs), such as metabolic enzymes, ion channels, and transporters. The transcriptional rhythms (TR) mediate metabolic rhythms (MR) involving the cyclic synthesis, degradation, and transport (e.g., influx/efflux) of redox factors, gases, and ions, which, in turn, provide feedback that regulates the TR, constituting coupled-cellular oscillators.
Besides the core regulatory loops, multiple levels of epigenetic, posttranscriptional, and posttranslational regulation involving various kinases and phosphatases, ubiquitin–proteasome pathway components, nuclear–cytoplasmic transporters, non-coding RNAs, and chromatin remodelers contribute to the molecular clockwork, thus coordinating temporal programs via multiple clock–output genes involved in cellular physiology and metabolism [26,27,28,29,30,31,32,33][26][27][28][29][30][31][32][33]. Notably, recent large-scale genomic studies reveal that ~50% of mammalian genes exhibit circadian regulation in at least one tissue, although the identity of genes expressed rhythmically varies from tissue to tissue [34,35,36][34][35][36]. In addition, multi-scale omics studies demonstrated circadian regulation of the epigenome, the metabolome, the proteome/phosphoproteome, and the microbiome [34,35,37,38,39,40,41,42,43,44,45][34][35][37][38][39][40][41][42][43][44][45]. These studies reveal that proteins or metabolites display different patterns of oscillations relative to transcript rhythms in a given tissue (e.g., hippocampus, liver), and oscillations at all levels can be reprogramed by circadian disturbances, such as sleep deprivation, jet lag, high-fat diet, and aging.
In mammalian species, the circadian clock machinery is shared across the brain and peripheral organ systems, constituting a body-wide circadian network (Figure 2).
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Figure 2. Coupled-tissue oscillators. Reciprocal crosstalk between the brain and peripheral clocks. The coupled TR and MR oscillators are thought to be commonly present across all body cells. Neurons and glial cells (e.g., astrocytes, microglia) interact to form the SCN central clock and non-SCN clocks in the brain. These autonomous brain clocks communicate with each other via neurotransmitters or neuropeptides, and with multiple peripheral tissue clocks via systemic innervations (ANS/SNS) or hormonal signals (e.g., cortisol, melatonin) in response to light–dark cycles. On the other hand, peripheral organs possess tissue autonomous clocks that can respond to non-photic physiological and environmental cues (e.g., temperature, food intake, exercise, stress) and provide feedback that influences the brain clocks via immune, metabolic, and endocrine signals. TR—transcriptional rhythms; MR—metabolic rhythms; ANS—autonomic nervous system; SNS—sympathetic nervous system.
The intracellular oscillators, in approximately 20,000 neurons, comprise the hypothalamic suprachiasmatic nucleus (SCN), a central clock in the rodent brain. The SCN in humans has been found to contain a total number of neurons close to 100,000, though these numbers decline with age [46,47,48][46][47][48]. The SCN consists of different subtypes of neurons that express the neurotransmitter c-aminobutyric acid (GABA), an inhibitory neurotransmitter in the brain, alongside a range of neuropeptides such as vasoactive intestinal peptide (VIP), arginine vasopressin (AVP), and their cognate receptors (VPAC2 and AVPR1A/B) [49,50,51,52][49][50][51][52]. These GABAergic/peptidergic SCN neurons interact among themselves or with the other neurons in extra-SCN brain regions, constituting the main output pathway of the clock. Notably, a recent study has demonstrated that the VIP-VPAC2 neuropeptidergic axis plays a central role in mediating the endogenous pacemaking function of the SCN circadian circuit [53]. In line with this, the suprachiasmatic VIP neurons (SCNVIP) have been shown to be required for normal circadian behaviors via functional connectivity between SCNVIP neurons and dorsomedial hypothalamic neurons [54]. Interestingly, recent single-cell RNA sequencing (scRNASeq) studies with mouse SCN slice revealed novel neuronal phenotypes and interaction networks involved in the central clock, including the identification of five SCN neuronal subtypes, with cluster-specific marker genes of VIP, AVP, gastrin-releasing peptide (GRP), cholecystokinin (CCK), and the cell adhesion regulator C1ql3 [55,56][55][56]. Additional scRNASeq study has also identified a subgroup of cells expressing Prokineticin2 (Prok2) and its cognate receptor (ProkR2) found to be topologically and functionally distinct pacemaking element of the central clock [57]. Thus, these studies highlight diverse cellular sub-populations within the neuropeptidergic topology of the SCN, which may differently contribute to the central pacemaker function. Notably, recent studies have shown that astrocytes harbor distinct rhythmic properties, such as anti-phasic Ca2+ rhythms, that direct the circadian rhythmicity of SCN neurons and behavior [58,59,60][58][59][60]. This work suggests the importance of bipartite intercellular communication between astrocytes and neurons in modulating SCN pacemaker functions, beyond neuronal regulation of the central clock.
Along with endogenous circadian pacemaking activity, the SCN central clock also mediates the periodic synchronization of internal body rhythms with external day and night cycles by communicating retinal light information received from the retinohypothalamic tract (RHT) to peripheral clock systems [26]. In a hierarchical organization model, the SCN master clock coordinates the circadian phases of individual subordinate clocks in other brain regions via rhythmic release of neurotransmitters and neuropeptides as well as in peripheral tissues via systemic hormonal secretion and neural innervations, thus generating rhythmic output physiology and behaviors that are in keeping with the daily changes in environment and needs [61,62,63,64][61][62][63][64]. For example, the SCN coordinates the rhythmic anti-phasic secretion of the night sleep hormone melatonin in the pineal gland and the morning stress hormone glucocorticoid in the adrenal glands via the sympathetic nervous system, ensuring daily rhythms in sleep/wake, as well as neural, metabolic, and immune functions [65,66,67][65][66][67]. In addition, the brain master clock controls peripheral clock functions in the heart, kidney, pancreas, lung, intestine, and thyroid glands by circadian regulation of the autonomic nervous system [68,69,70,71,72,73][68][69][70][71][72][73].
Besides SCN-driven clock entrainment, a growing number of studies have reported that non-SCN brain regions and peripheral tissues possess their own autonomous, entrainable oscillators that influence not only circadian functions in the SCN and neighboring local clocks, but also whole body rhythms via neural, hormonal, and metabolic feedback mechanisms [13,74,75,76,77,78,79,80][13][74][75][76][77][78][79][80]. The SCN receives a myriad of nonphotic input, arousal, feeding behavior, locomotor activity, immune function, blood pressure, and melatonin, which are all able to adjust and synchronize the SCN [81,82,83,84][81][82][83][84]. The SCN can receive this feedback through its large array of reciprocal neuronal connections with different hypothalamic regions, such as the arcuate nucleus (ARC), intergeniculate leaflet (IGL), nucleus tractus solitarius (NTS), dorsal raphe, and dorsomedial hypothalamus, allowing these nuclei to convey nonphotic feedback to the SCN and thus adjusting circadian rhythmicity [85,86,87,88,89][85][86][87][88][89].
Beyond photic entrainment, multiple physiological and environmental cues (e.g., food intake, gut microbial products, redox cofactors, metal ions, metabolic gases) control non-SCN and peripheral clock functions, which, in turn, impact the entire host clock system via neural and immune–metabolic circuits [12,22,72,90,91,92,93,94,95][12][22][72][90][91][92][93][94][95]. These findings suggest that systemic circadian rhythms are achieved through multi-modal regulation of tightly coupled body clocks according to daily changes that occur in the internal and external environments.

3. Conclusions

In recent decades, extensive chronobiological research has expanded our understanding of the functional roles and mechanisms of the circadian clockwork in human health and diseases. Thus, research trends in chronobiology have undergone a paradigm shift in many ways, particularly changing from hierarchical models to more integrated ones for understanding the circadian clock mechanism. In this regard, the overall evidence points to bidirectional crosstalk between transcriptional and metabolic rhythms, neuronal and glial clocks, SCN and non-SCN clocks, as well as brain and peripheral clocks (Figure 1, Figure 2). Our growing knowledge of the interactive nature of clock regulatory systems is expected to not only diversify our understanding of circadian physiology and pathophysiology but also increase our capacity to harness chronobiological knowledge to improve the prevention and treatment of multiple circadian-related disorders.

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