ReviewSignalling entrains the peripheral circadian clock
Introduction
In mammals, biorhythms are essential for maintaining whole-body homeostasis, while disruption of biorhythms may lead to deregulation of homeostasis and development of diseases [1,2]. An internal timing system has evolved to measure time, anticipate environmental daily changes, and tune physiology and behaviour to these variations. This anticipatory internal timing system was named the “circadian clock”, providing a good example of how changes in the environment influence behaviour and physiology [3].
Circadian clocks are composed of central and peripheral clocks, which are both coordinated to produce daily rhythms in physiology and behaviour [4]. In mammals, circadian clocks are found in nearly all cells and tissues. The central clock is located in the superchiasmatic nucleus (SCN) of the hypothalamus, which is a dominant circadian pacemaker [5]. It can receive direct photic input from the retina via the intrinsically photoreceptive retinal ganglion cell (ipRGC), a type of photoreceptive cell, and produces robust biorhythms [6]. In turn, the central clock uses diverse and not entirely known pathways to reset the phase of peripheral clocks. SCN transmits signals to the periphery of the body by directly interacting with other brain regions, through the production of signalling molecules, or by indirectly determining rest-activity periods that in turn regulate feeding-fasting rhythms [7,8].
Mammalian SCN is resistant to most non-photic zeitgebers, while the peripheral clocks respond to ambient influences such as temperature, which allows the maintenance of SCN circadian properties despite external changes [9]. The synchronization mechanisms are different among different tissues. Circadian rhythms in peripheral organs are controlled by the interaction of local tissue clocks and SCN-generated rhythms in physiology and behaviours. Nevertheless, under some conditions, the peripheral clock could be independent of the central clock. In response to advances and delays of the environmental light cycle, when isolated in cell culture, the central clock maintains its own rhythmicity, while the peripheral clock loses its rhythm in a few days, as seen in a transgenic rat line in which luciferase is rhythmically expressed under the control of the mouse Period (Per1) promoter [10].
Most mammalian cell types seem to contain all the molecular ingredients required to achieve circadian gene expression. Analysis of clock gene expression in mammals revealed that most of their corresponding mRNA products accumulated in a circadian manner not only in the SCN but also in a variety of peripheral tissues, including liver, muscle, kidney and lung [[11], [12], [13], [14]]. The expression of circadian clock genes was also found in other cells, such as mononuclear leukocytes and vascular smooth muscle cells [[15], [16], [17]]. However, the phase of the rhythmic expression of clock genes in the periphery is opposite or phase-delayed to the rhythm of the same clock genes expressed in the SCN.
Many reviews have focused on the function of the central circadian clock. Accumulating evidence has revealed that peripheral clocks are different from SCN clocks and can regulate synchronization independent of SCN. In this review, we discuss the signals that control peripheral clocks in individual organs and tissues, such as the liver, gastrointestinal tract (GIT), pancreas, lung, breast, skin, skeletal muscle, adipose tissues and cardiovascular system (See Table 1). Furthermore, we review work on how peripheral clocks in different organs communicate.
Section snippets
Peripheral clock in the liver
The liver is one of the most important organs involved in glucose and lipid metabolism and is finely regulated by coordination between the central clock and the peripheral clock in the liver. The circadian clock plays key roles in liver function in both health and disease [[18], [19], [20], [21]]. Accumulating data reveal that the peripheral clock in the liver is entrained by many factors, including feeding cues, insulin, glucocorticoid, ghrelin, mammalian/mechanistic target of rapamycin (mTOR)
Peripheral clock in the GIT
The GIT is subject to various 24-h rhythmic processes, which are under circadian clock gene control. The GIT exhibits diurnal rhythms in many physiologic functions, such as colonic motor activity, gastric acid secretion, mucosal transporters, mucosal enzyme activities, proliferation rates, etc. Clock genes, which are present within colonic epithelial cells and neurons of the myenteric plexus, coordinate rhythmic physiological functions such as motility, cell proliferation, and migration [42,43].
Peripheral clock in the pancreas
Circadian clock is critical for maintaining glucose homeostasis. The pancreas is one of the most important endocrine and exocrine organs and plays an essential role in body metabolism. The peripheral clock in the pancreas is required for achieving its function, such as insulin release. Peripheral circadian clocks in the pancreas have been identified in rats [54] and mice [55]. The expression of the major clock genes Per1, Per2, Bmal1, Cry1, timeless (Tim) and Clock, as well as of the output
Peripheral clock in the lung
Chronic lung diseases are often characterized by disrupted daily or circadian rhythms of lung function and inflammatory responses [60]. The molecular clock and redox signalling in the lung play a critical role in regulating inflammation, oxidative stress, and DNA damage responses in the pathophysiology of chronic airway diseases and their exacerbations, providing a potential for the molecular clock genes to be used as novel biomarkers for lung disease severity and as therapeutic targets for
Peripheral clock in the breast
Circadian clocks and breast biology are tightly connected, and the rhythmic expression of numerous genes is regulated by the circadian clock in the breast [65,66]. The disruption of circadian genes can change breast biology and may further contribute to breast cancer. Studies have shown that breast cancer is associated with the upregulation of TIMELESS and the downregulation of PER, CRY, and CLOCK, which might be related to the methylation of those genes in the tumour tissue [67,68]. In
Peripheral clock in the cardiovascular system
The circadian rhythms and the molecular clock have important functions in cardiovascular physiology and disease [71]. The clock machinery is found in the cells in the vascular system, such as endothelial cells, smooth muscle cells, fibroblasts, and stem cells. Daily vascular function and its disturbance are modulated by this machinery, which plays a critical role in the dysfunction of the vascular system [72]. The link between the peripheral circadian clock and hypoxia signalling in the
Peripheral clock in skeletal muscle
The functions of skeletal muscle are under the control of a circadian clock, especially myogenesis and skeletal muscle metabolism, which have been summarized in many reviews [[77], [78], [79]]. Therefore, we will only review the signalling involved in the entrainment of the peripheral circadian clock in skeletal muscle (Fig. 3).
Exercise plays an important role in regulating core clock gene expression in skeletal muscle. Dyar et al. examined circadian gene expression in fast- and slow-twitch
Peripheral clock in the skin
The skin is the largest organ in the human body and the interface between the organism and the external environment. Therefore, the peripheral circadian clock in the skin is entrained by multiple ambient and endogenous stimuli, such as UV and infrared radiation, visible light, temperature, hormones, reactive oxygen species, etc. These stimuli can affect the molecular clock in the skin, contributing to skin-related biological processes. Skin is widely used as a model to study the regulation of
Peripheral clock in the adipose tissues
Adipose tissues (white, brown and beige adipose) play important roles in the regulation of whole-body metabolism, thermogenesis and energy homeostasis. The interaction between circadian clocks and diet or exercise might have an impact on adipose tissue physiology and metabolism and therefore impact the whole-body phenotype and energy homeostasis, especially in brown adipose tissue, which plays more important roles in whole-body metabolic homeostasis [[92], [93], [94]]. The clock proteins and
Organ-to-organ communications entrain peripheral circadian clocks
Interestingly, an increasing number of studies have revealed that different tissues that achieve circadian rhythm have to interact with each other in a way that is not independent of environmental signals. Known organ-organ communications in the peripheral circadian clock are shown in Fig. 4. The loss or disruption of the clock in one peripheral tissue can affect the clock in another tissue. Paschos et al. demonstrated that the specific deletion of Bmal1, which encodes a core molecular clock
Perspectives
Here, we reviewed the peripheral clock in different organs. Every organ has its own circadian rhythm, which is synchronized by the integration of multiple signals. One signal molecule, such as insulin, could also affect the peripheral clock in multiple organs. It would be interesting to understand how one signal molecule acts on different peripheral circadian clocks and coordinates their functions. Although there are increasing data on the regulation of peripheral circadian clocks, the
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgements
This study was supported by the National Natural Science Foundation of China (No. 81672358, No. 81701945, No. 81802890), the Natural Science Foundation of Shanghai (No. 18ZR1436900), and Shanghai Municipal Health Bureau (No. 2018BR32) and the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20181708).
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These authors contributed equally to this work.