The circadian rhythm, controlled by a complex network of cellular transcription factors, orchestrates behavior and physiology in the vast majority of animals. The circadian system is comprised of a master clock located in central nervous system with 24-hour rotation and periphery clocks to ensure optimal timing of physiology in peripheral tissues. Circadian expression of peroxisome proliferator-activated receptors (PPARs), members of the nuclear receptor superfamily and key mediators of energy homeostasis and metabolism, is regulated by clock genes. PPARs serve as sensors of nutrient and energy/metabolism status to temporally entrain peripheral clock. Metabolism and circadian clocks are tightly intertwined: clock genes drive metabolism, and various metabolic parameters affect clock genes, producing a reciprocal feedback relationship. Due to PPARs' robust relationship with energy status and metabolism, the aberration of PPARs in the biological clock system leads to abnormal expression of genes in metabolic pathways, thus, contributing to etiology of metabolic syndrome. Studying PPARs' functions under the context of the mammalian circadian system could advance our understanding of how energy and metabolic status are maintained in the body, which may ultimately lead to rhythmic medical treatment against metabolic syndrome.
Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs) including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer.
Circadian rhythms regulate a vast array of biological processes and play a fundamental role in mammalian physiology. As a result, considerable diurnal variation in the pharmacokinetics, efficacy, and side effect profiles of many therapeutics has been described. This variation has subsequently been tied to diurnal rhythms in absorption, distribution, metabolism, and excretion, as well as in pharmacodynamic variables, such as target expression. More recently, the molecular basis of circadian rhythmicity has been elucidated with the identification of clock genes, which oscillate in a circadian manner in most cells and tissues and regulate transcription of large sets of genes. Ongoing research efforts are beginning to reveal the critical role of circadian clock genes in the regulation of pharmacologic parameters, as well as the reciprocal impact of drugs on circadian clock function. This chapter will review the role of circadian clocks in the pharmacokinetics and pharmacodynamics of drug response, and provide several examples of the complex regulation of pharmacologic systems by components of the molecular circadian clock.
circadian clock; pharmacology; pharmacokinetics; pharmacodynamics; CLOCK; Bmal1
Many aspects of cellular physiology display circadian (approximately 24-h) rhythms. Dysfunction of the circadian clock molecular circuitry is associated with human health derangements, including neurodegeneration, increased risk of cancer, cardiovascular diseases and the metabolic syndrome. Viruses triggering hepatitis depend tightly on the host cell synthesis machinery for their own replication, survival and spreading. Recent evidences support a link between the circadian clock circuitry and viruses’ biological cycle within host cells. Currently, in vitro models for chronobiological studies of cells infected with viruses need to be implemented. The establishment of such in vitro models would be helpful to better understand the link between the clock gene machinery and viral replication/viral persistence in order to develop specifically targeted therapeutic regimens. Here we review the recent literature dealing with the interplay between hepatitis B and C viruses and clock genes.
Hepatitis C virus; Hepatitis B virus; Anti-hepatitis therapy; Clock genes; Chronobiology
Drosophila clock neurons are self-sustaining cellular oscillators that rely on negative transcriptional feedback to keep circadian time. Proper regulation of organismal rhythms of physiology and behavior requires coordination of the oscillations of individual clock neurons within the circadian control network. Over the last decade, it has become clear that a key mechanism for intercellular communication in the circadian network is signaling between a subset of clock neurons that secrete the neuropeptide pigment dispersing factor (PDF) and clock neurons that possess its G protein-coupled receptor (PDFR). Furthermore, the specific hypothesis has been proposed that PDF-secreting clock neurons entrain the phase of organismal rhythms, and the cellular oscillations of other clock neurons, via the temporal patterning of secreted PDF signals. In order to test this hypothesis, we have devised a novel technique for altering the phase relationship between circadian transcriptional feedback oscillation and PDF secretion by using an ion channel–directed spider toxin to modify voltage-gated Na+ channel inactivation in vivo. This technique relies on the previously reported “tethered-toxin” technology for cell-autonomous modulation of ionic conductances via heterologous expression of subtype-specific peptide ion channel toxins as chimeric fusion proteins tethered to the plasma membrane with a glycosylphosphatidylinositol (GPI) anchor. We demonstrate for the first time, to our knowledge, the utility of the tethered-toxin technology in a transgenic animal, validating four different tethered spider toxin ion channel modifiers for use in Drosophila. Focusing on one of these toxins, we show that GPI-tethered Australian funnel-web spider toxin δ-ACTX-Hv1a inhibits Drosophila para voltage-gated Na+ channel inactivation when coexpressed in Xenopus oocytes. Transgenic expression of membrane-tethered δ-ACTX-Hv1a in vivo in the PDF-secreting subset of clock neurons induces rhythmic action potential bursts and depolarized plateau potentials. These in vitro and in vivo electrophysiological effects of membrane-tethered δ-ACTX-Hv1a are consistent with the effects of soluble δ-ACTX-Hv1a purified from venom on Na+ channel physiological and biophysical properties in cockroach neurons. Membrane-tethered δ-ACTX-Hv1a expression in the PDF-secreting subset of clock neurons induces an approximately 4-h phase advance of the rhythm of PDF accumulation in their terminals relative to both the phase of the day:night cycle and the phase of the circadian transcriptional feedback loops. As a consequence, the morning anticipatory peak of locomotor activity preceding dawn, which has been shown to be driven by the clocks of the PDF-secreting subset of clock neurons, phase advances coordinately with the phase of the PDF rhythm of the PDF-secreting clock neurons, rather than maintaining its phase relationship with the day:night cycle and circadian transcriptional feedback loops. These results (1) validate the tethered-toxin technology for cell-autonomous modulation of ion channel biophysical properties in vivo in transgenic Drosophila, (2) demonstrate that the kinetics of para Na+ channel inactivation is a key parameter for determining the phase relationship between circadian transcriptional feedback oscillation and PDF secretion, and (3) provide experimental support for the hypothesis that PDF-secreting clock neurons entrain the phase of organismal rhythms via the temporal patterning of secreted PDF signals.
The regulation of the daily fluctuations that characterize an organism's physiology and behavior requires coordination of the cellular oscillations of individual “clock” neurons within the circadian control network. Clock neurons that secrete a neuropeptide called pigment dispersing factor (PDF) calibrate, or entrain, both the phase of organismal rhythms and the cellular oscillations of other clock neurons. In this study, we tested the hypothesis that phase of PDF secretion rhythms entrains phase of non-PDF neurons and locomotor rhythms using the tethered- toxin technique (which affixes toxins to the cell membrane) to express ion channel–specific peptide toxins in PDF neurons. A particular toxin inhibits inactivation of the Drosophila para sodium (Na+) channel. Inhibition of Na+ channel inactivation in PDF neurons of transgenic flies induces phase advance of PDF rhythm, and correlated phase advance of lights-on anticipatory locomotor activity, suggesting that phase of morning activity is determined by phase of PDF oscillation. Therefore, voltage-gated Na+ channels of Drosophila clock neurons play a key role in determining the phase relationship between circadian transcriptional feedback oscillation and PDF secretion, and PDF-secreting clock neurons entrain the phase of organismal rhythms via the temporal patterning of secreted PDF signals.
Cell-autonomous inhibition ofDrosophila para Na+ channel inactivation using a membrane-tethered spider toxin phase shifts circadian neuropeptide output from cellular oscillation, and the phase of morning anticipatory activity is determined by this phase-shifted neuropeptide output.
The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue and systems levels. A common molecular mechanism underlies the cell autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.
Clock Genes; Suprachiasmatic Nucleus; Oscillator Coupling; Metabolism; Temperature
Circadian pacemaker neurons in the Drosophila brain gather network information through the highly conserved BMP signaling pathway to establish the daily period of locomotor behavior.
Living organisms use biological clocks to maintain their internal temporal order and anticipate daily environmental changes. In Drosophila, circadian regulation of locomotor behavior is controlled by ∼150 neurons; among them, neurons expressing the PIGMENT DISPERSING FACTOR (PDF) set the period of locomotor behavior under free-running conditions. To date, it remains unclear how individual circadian clusters integrate their activity to assemble a distinctive behavioral output. Here we show that the BONE MORPHOGENETIC PROTEIN (BMP) signaling pathway plays a crucial role in setting the circadian period in PDF neurons in the adult brain. Acute deregulation of BMP signaling causes period lengthening through regulation of dClock transcription, providing evidence for a novel function of this pathway in the adult brain. We propose that coherence in the circadian network arises from integration in PDF neurons of both the pace of the cell-autonomous molecular clock and information derived from circadian-relevant neurons through release of BMP ligands.
The circadian clock controls rhythms in behavior, physiology, and metabolism in all living organisms. The molecular components as well as the neuronal network required to keep this clock running have been identified in several species. In the Drosophila brain this neuronal network is represented by an ensemble of 150 neurons, and among them, those expressing the Pigment Dispersing Factor (PDF) neuropeptide encompass the “central oscillator”—also called master clock as it ensures 24-hour periods—of the fly brain. In this study we show that the widely conserved Bone Morphogenetic Protein (BMP) signaling pathway is present in PDF neurons, and upon adult-specific activation it lengthens the endogenous period of locomotor behavior. We find that period lengthening correlates with delayed accumulation of nuclear PERIOD, a core component of the molecular clock. We also identified a putative DNA binding motif for the BMP pathway nuclear components within the regulatory region of the Clock (Clk) promoter, another core component of the circadian machinery. Interestingly, upon BMP pathway activation endogenous CLK levels are downregulated, thus accounting for the lengthening of the endogenous period. We propose that the endogenous period is a network property commanded by PDF neurons that results from integration of information from both the autonomous molecular clock and the nonautonomous BMP signaling pathway.
Dividing cells, including human cancers, organize processes necessary for their duplication according to circadian time. Recent evidence has shown that disruption of central regulation of circadian rhythms can increase the rate at which a variety of cancers develop in rodents. In order to study circadian rhythms in liver tumors, we have chemically induced hepatocellular carcinoma in transgenic rats bearing a luciferase reporter gene attached to the promoter of a core circadian clock gene (Period 1). We explanted normal liver cells and hepatomas, placed them into short-term culture, and precisely measured their molecular clock function by recording light output. Results show that isolated hepatocellular carcinoma is capable of generating circadian rhythms in vitro. Temporally restricting food availability to either day or night altered the phase of the rhythms in both healthy and malignant tissue. However the hepatomas were much less sensitive to this signal resulting in dramatically different phase relationships between host and tumor tissue as a function of mealtime. These data support the conclusion that hepatoma is differentially sensitive to circadian timing signals, although it maintains the circadian organization of the non-malignant cells from which it arose. Because circadian clocks are known to modulate the sensitivity of many therapeutic cytotoxic targets, controlling mealtiming might be used to increase the efficacy of treatment. Specifically, meal and treatment schedules could be designed that take advantage of coincident times of greatest tumor sensitivity and lowest sensitivity of host tissue to damage.
Cancer; circadian rhythm; peripheral oscillator
Circadian clocks are intracellular molecular mechanisms designed to allow the cell, organ, and organism to prepare for an anticipated stimulus prior to its onset. In order for circadian clocks to maintain their selective advantage, they must be entrained to the environment. Light, sound, temperature, physical activity (including sleep/wake transitions), and food intake are among the strongest environmental factors influencing mammalian circadian clocks. Normal circadian rhythmicities in these environmental factors have become severely disrupted in our modern day society, concomitant with increased incidence of type 2 diabetes mellitus, obesity, and cardiovascular disease. Here, we review our current knowledge regarding the roles of peripheral circadian clocks, concentrating on those found within tissues directly involved in metabolic homeostasis and cardiovascular function. We propose that both inter- and intra- organ dyssynchronization, through alteration/impairment of peripheral circadian clocks, accelerates the development of cardiovascular disease risk factors associated with cardiometabolic syndrome.
The circadian clock is driven by transcriptional oscillation of clock genes in almost all body cells. To investigate the effect of cell type-specific intracellular environment on the circadian machinery, we examined gene expression profiles in five peripheral tissues. As expected, the phase relationship between expression rhythms of nine clock genes was similar in all tissues examined. We also compared relative expression levels of clock genes among tissues, and unexpectedly found that quantitative variation remained within an approximately three-fold range, which was substantially smaller than that of metabolic housekeeping genes. Interestingly, circadian gene expression was little affected even when fibroblasts were cultured with different concentrations of serum. Together, these findings support a hypothesis that expression levels of clock genes are quantitatively compensated for the intracellular environment, such as redox potential and metabolite composition. However, more comprehensive studies are required to reach definitive conclusions.
During the past decade, the molecular mechanisms underlying the mammalian circadian clock have been defined. A core set of circadian clock genes common to most cells throughout the body code for proteins that feed back to regulate not only their own expression, but also that of clock output genes and pathways throughout the genome. The circadian system represents a complex multioscillatory temporal network in which an ensemble of coupled neurons comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus is entrained to the daily light/dark cycle and subsequently transmits synchronizing signals to local circadian oscillators in peripheral tissues. Only recently has the importance of this system to the regulation of such fundamental biological processes as the cell cycle and metabolism become apparent. A convergence of data from microarray studies, quantitative trait locus analysis, and mutagenesis screens demonstrates the pervasiveness of circadian regulation in biological systems. The importance of maintaining the internal temporal homeostasis conferred by the circadian system is revealed by animal models in which mutations in genes coding for core components of the clock result in disease, including cancer and disturbances to the sleep/wake cycle.
circadian clock genes; suprachiasmatic nucleus; complex traits; ENU mutagenesis; sleep-wake cycle
Daily rhythms are a ubiquitous feature of living systems. Generally, these rhythms are not just passive consequences of cyclic fluctuations in the environment, but instead originate within the organism. In mammals, including humans, the master pacemaker controlling 24-hour rhythms is localized in the suprachiasmatic nuclei of the hypothalamus. This circadian clock is responsible for the temporal organization of a wide variety of functions, ranging from sleep and food intake, to physiological measures such as body temperature, heart rate and hormone release. The retinal circadian clock was the first extra-SCN circadian oscillator to be discovered in mammals and several studies have now demonstrated that many of the physiological, cellular, and molecular rhythms that are present within the retina are under the control of a retinal circadian clock, or more likely a network of hierarchically organized circadian clocks that are present within this tissue.
After approximately 50 years of circadian research, especially in selected circadian model systems (Drosophila, Neurospora, Gonyaulax and, more recently, cyanobacteria and mammals), we appreciate the enormous complexity of the circadian programme in organisms and cells, as well as in physiological and molecular circuits. Many of our insights into this complexity stem from experimental reductionism that goes as far as testing the interaction of molecular clock components in heterologous systems or in vitro. The results of this enormous endeavour show circadian systems that involve several oscillators, multiple input pathways and feedback loops that contribute to specific circadian qualities but not necessarily to the generation of circadian rhythmicity. For a full appreciation of the circadian programme, the results from different levels of the system eventually have to be put into the context of the organism as a whole and its specific temporal environment. This review summarizes some of the complexities found at the level of organisms, cells and molecules, and highlights similar strategies that apparently solve similar problems at the different levels of the circadian system.
Jet lag encompasses a range of psycho- and physiopathological symptoms that arise from temporal misalignment of the endogenous circadian clock with external time. Repeated jet lag exposure, encountered by business travelers and airline personnel as well as shift workers, has been correlated with immune deficiency, mood disorders, elevated cancer risk, and anatomical anomalies of the forebrain. Here, we have characterized the molecular response of the mouse circadian system in an established experimental paradigm for jet lag whereby mice entrained to a 12-hour light/12-hour dark cycle undergo light phase advancement by 6 hours. Unexpectedly, strong heterogeneity of entrainment kinetics was found not only between different organs, but also within the molecular clockwork of each tissue. Manipulation of the adrenal circadian clock, in particular phase-shifting of adrenal glucocorticoid rhythms, regulated the speed of behavioral reentrainment. Blocking adrenal corticosterone either prolonged or shortened jet lag, depending on the time of administration. This key role of adrenal glucocorticoid phasing for resetting of the circadian system provides what we believe to be a novel mechanism-based approach for possible therapies for jet lag and jet lag–associated diseases.
Circadian regulation of gene expression plays a major role in health and disease. The precise role of the circadian system remains to be clarified, but it is known that circadian proteins generate physiological rhythms in organisms by regulating clock-controlled target genes. The estrogen receptor beta (ERβ) is, together with ERα, a member of the nuclear receptor superfamily and a key mediator of estrogen action. Interestingly, recent studies show that disturbed circadian rhythmicity in humans can increase the risk of reproductive malfunctions, suggesting a link between the circadian system and ER-mediated transcription pathways. Here, we identify a novel level of regulation of estrogen signaling where ERβ, but not ERα, is controlled by circadian clock proteins. We show that ERβ mRNA levels fluctuate in different peripheral tissues following a robust circadian pattern, with a peak at the light-dark transition, which is maintained under free-running conditions. Interestingly, this oscillation is abolished in clock-deficient BMAL1 knockout mice. Circadian control of ERβ expression is exerted through a conserved E-box element in the ERβ promoter region that recruits circadian regulatory factors. Furthermore, using small interfering RNA-mediated knockdown assays, we show that the expression levels of the circadian regulatory factors directly influence estrogen signaling by regulating the intracellular levels of endogenous ERβ.
Clock output pathways play a pivotal role by relaying timing information from the circadian clock to a diversity of physiological systems. Both cell-autonomous and systemic mechanisms have been implicated as clock outputs; however, the relative importance and interplay between these mechanisms are poorly understood. The cell cycle represents a highly conserved regulatory target of the circadian timing system. Previously, we have demonstrated that in zebrafish, the circadian clock has the capacity to generate daily rhythms of S phase by a cell-autonomous mechanism in vitro. Here, by studying a panel of zebrafish mutants, we reveal that the pituitary–adrenal axis also plays an essential role in establishing these rhythms in the whole animal. Mutants with a reduction or a complete absence of corticotrope pituitary cells show attenuated cell-proliferation rhythms, whereas expression of circadian clock genes is not affected. We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity. Strikingly, high-amplitude rhythms can be rescued by exposing mutant larvae to a tonic concentration of a glucocorticoid agonist. Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level. Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part.
To guarantee normal growth and to avoid tumor formation, the timing of cell division must be under strict control. Remarkably, cells, from bacteria to man, often divide only at certain times of day, suggesting the influence of internal biological clocks. A central pacemaker structure in the brain controls diurnal rhythms of behavior and hormone release. However, biological clocks are also encountered in almost every cell type (so-called “peripheral” clocks), in which they regulate daily changes in cell biology, including cell division. Very little is known to date about how the two clock systems interact. Here, by examining zebrafish strains with defects in hormone production, we find that peripheral clocks require the steroid hormone cortisol to generate daily rhythms of cell proliferation. Interestingly, the daily changes in cortisol levels observed in normal zebrafish are not required to achieve this control; treating the cortisol-deficient strains with constant levels of a drug that mimics the effects of cortisol restores normal cell-division rhythms. Thus, it appears that internal cell timers cooperate with hormonal signals to regulate the timing of cell division.
To establish circadian cell cycle rhythms, cell-autonomous clock mechanisms act in concert with a systemic signaling environment of which glucocorticoids are an essential part.
Purpose of Review
Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of BP has been shown to be associated with greater target organ damage and to be associated with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP
The time-keeper of the mammals resides centrally in the suprachiasmatic nucleus. Besides this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice to the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon 3 major factors: physical activity, autonomic function, and sodium sensitivity.
The integrated consideration of physical activity, autonomic function, and sodium sensitivity appear to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.
blood pressure; circadian rhythms; molecular clocks; cosinor modeling; chronic kidney disease; pathophysiology
The biochemical activity of a stunning diversity of cell types and organ systems is shaped by a 24-hour (circadian) clock. This rhythmic drive to a good deal of the transcriptome (up to 15% of all coding genes) imparts circadian modulation over a wide range of physiological and behavioral processes (from cell division to cognition). Further, dysregulation of the clock has been implicated in the pathogenesis of a large and diverse array of disorders, such as hypertension, cancer and depression. Indeed, the possibility of utilizing therapeutic approaches that target clock physiology (that is, chronotherapy) has gained broad interest. However, a deeper understanding of the underlying molecular mechanisms that modulate the clock, and give rise to organ-specific clock transcriptomes, will be required to fully realize the power of chronotherapies. Recently, microRNAs have emerged as significant players in circadian clock timing, thus raising the possibility that clock-controlled microRNAs could contribute to disorders of the human circadian timing system. Here, we highlight recent work revealing a key role for microRNAs in clock physiology, and discuss potential approaches to unlocking their utility as effectors of circadian physiology and pathophysiology.
Circadian rhythms occur with a periodicity of about 24 hours and regulate a wide array of metabolic and physiologic functions. Accumulating epidemiological and genetic evidence indicates that disruption of circadian rhythms can be directly linked to many pathological conditions, including sleep disorders, depression, metabolic syndrome and cancer. Intriguingly, a number of molecular gears constituting the clock machinery have been found to establish functional interplays with regulators of cellular metabolism. While the circadian clock regulates multiple metabolic pathways, metabolite availability and feeding behavior can in turn regulate the circadian clock. An in-depth understanding of this reciprocal regulation of circadian rhythms and cellular metabolism may provide insights in the development of therapeutic intervention against specific metabolic disorders.
Circadian rhythms (24 h cycles) are observed in virtually all aspects of mammalian function from expression of genes to complex physiological processes. The master clock is present in the suprachiasmatic nucleus (SCN) in the anterior part of the hypothalamus and controls peripheral clocks present in other parts of the body. Components of this core clock mechanism regulate the circadian rhythms in genome-wide mRNA expression, which in turn regulate various biological processes. Disruption of circadian rhythms can be either the cause or the effect of various disorders including metabolic syndrome, inflammatory diseases and cancer. Furthermore, circadian rhythms in gene expression regulate both the action and disposition of various drugs and affect therapeutic efficacy and toxicity based on dosing time. Understanding the regulation of circadian rhythms in gene expression plays an important role in both optimizing the dosing time for existing drugs and in development of new therapeutics targeting the molecular clock.
molecular clocks; metabolic disease; inflammation; cancer; drug targets; pharmacokinetics
A long-term high-fat diet may result in a fatty liver. However, whether or not high-fat diets affect the hepatic circadian clock is controversial. The objective of this study is to investigate the effects of timed high-fat diet on the hepatic circadian clock and clock-controlled peroxisome proliferator-activated receptor (PPAR) α-mediated lipogenic gene expressions. Mice were orally administered high-fat milk in the evening for 4 weeks. The results showed that some hepatic clock genes, such as Clock, brain-muscle-Arnt-like 1 (Bmal1), Period 2 (Per2), and Cryptochrome 2 (Cry2) exhibited obvious changes in rhythms and/or amplitudes. Alterations in the expression of clock genes, in turn, further altered the circadian rhythm of PPARα expression. Among the PPARα target genes, cholesterol 7α-hydroxylase (CYP7A1), 3-hydroxy-3-methylglutaryl-coenzyme A reductase, low-density lipoprotein receptor, lipoprotein lipase, and diacylglycerol acyltransferase (DGAT) showed marked changes in rhythms and/or amplitudes. In particular, significant changes in the expressions of DGAT and CYP7A1 were observed. The effects of a high-fat diet on the expression of lipogenic genes in the liver were accompanied by increased hepatic cholesterol and triglyceride levels. These results suggest that timed high-fat diets at night could change the hepatic circadian expressions of clock genes Clock, Bmal1, Per2, and Cry2 and subsequently alter the circadian expression of PPARα-mediated lipogenic genes, resulting in hepatic lipid accumulation.
High-fat diet; Clock genes; Peroxisome proliferator-activated receptor α; Lipid metabolism; Mice
Circadian clocks organize behavior and physiology to adapt to daily environmental cycles. Genetic approaches in the fruit fly, Drosophila melanogaster, have revealed widely conserved molecular gears of these 24-h timers. Yet much less is known about how these cell-autonomous clocks confer temporal information to modulate cellular functions. Here we discuss our current knowledge of circadian clock function in Drosophila, providing an overview of the molecular underpinnings of circadian clocks. We then describe the neural network important for circadian rhythms of locomotor activity, including how these molecular clocks might influence neuronal function. Finally, we address a range of behaviors and physiological systems regulated by circadian clocks, including discussion of specific peripheral oscillators and key molecular effectors where they have been described. These studies reveal a remarkable complexity to circadian pathways in this “simple” model organism.
peripheral clocks; pacemaker neurons; locomotor activity; feeding; mating
Rheumatoid arthritis exhibits diurnal variation in symptoms, with patients suffering with increased painful joint stiffness in the early morning. This correlates with an early morning rise in circulating levels of pro-inflammatory cytokines, such as interleukin-6. This temporal variation in disease pathology is directed by the circadian clock, both at a systemic level, through signalling pathways derived in the central clock, and at a local level by autonomous clocks found within inflammatory organs and cells. Indeed, many cellular components of the immune system, which are involved in the pathogenesis of rheumatoid arthritis, possess independent clocks that facilitate temporal gating of their functions. Furthermore, the circadian clock regulates the expression and activity of several genes and proteins that have demonstrated roles in progression of this autoimmune disease. These include a number of nuclear receptors and also fat-derived adipokines. Employing the knowledge we have about how the inflammatory response is regulated by the clock will facilitate the development of chronotherapy regimens to improve the efficacy of current treatment strategies. Furthermore, a full understanding of the mechanisms by which the clock couples to the immune system may provide novel therapeutic targets for the treatment of this debilitating disease.
Daily scheduled feeding is a potent time cue that elicits anticipatory
activity in rodents. This food-anticipatory activity (FAA) is controlled by a
food-entrainable oscillator (FEO) that is distinct from light-entrained
oscillators of the suprachiasmatic nucleus (SCN). Circadian rhythms within the
SCN depend on transcription-translation feedback loops in which CLOCK protein is
a key positive regulator. The Clock gene is expressed in
rhythmic tissues throughout the brain and periphery, implicating its widespread
involvement in the functioning of circadian oscillators. To examine whether
CLOCK protein is also necessary for the FEO, the effect of daily food
restriction was studied in homozygous Clock mutant
(Clk/Clk) mice. The results show that
Clk/Clk mutant mice exhibit FAA, even when their circadian
wheel-running behavior is arrhythmic. As in wild-type controls, FAA in
Clk/Clk mutants persists after temporal feeding cues are
removed for several cycles, indicating that the FEO is a circadian timer. This
is the first demonstration that the Clock gene is not necessary
for the expression of a circadian, food-entrained behavior and suggests that the
FEO is mediated by a molecular mechanism distinct from that of the SCN.
food-anticipatory activity; feeding; entrainment; clock genes; suprachiasmatic nucleus
The circadian rhythm is an endogenous time keeping system shared by most organisms. The circadian clock is comprised of both peripheral oscillators in most organ tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN) of the central nervous system. The circadian rhythm is crucial in maintaining the normal physiology of the organism including, but not limited to, cell proliferation, cell cycle progression, and cellular metabolism; whereas disruption of the circadian rhythm is closely related to multi-tumorigenesis. In the past several years, studies from different fields have revealed that the genetic or functional disruption of the molecular circadian rhythm has been found in various cancers, such as breast, prostate, and ovarian. In this review, we will investigate and present an overview of the current research on the influence of circadian rhythm regulating proteins on breast cancer.
Circadian rhythm; breast cancer; circadian proteins; chronotherapy