Mechanism of the circadian clock in physiology (original) (raw)
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Molecular regulations of circadian rhythm and implications for physiology and diseases
Signal Transduction and Targeted Therapy, 2022
The term “circadian rhythms” describes endogenous oscillations with ca. 24-h period associated with the earth’s daily rotation and light/dark cycle. Such rhythms reflect the existence of an intrinsic circadian clock that temporally orchestrates physiological processes to adapt the internal environment with the external cues. At the molecular level, the circadian clock consists of multiple sets of transcription factors resulting in autoregulatory transcription-translation feedback loops. Notably, in addition to their primary role as generator of circadian rhythm, the biological clock plays a key role in controlling physiological functions of almost all tissues and organs. It regulates several intracellular signaling pathways, ranging from cell proliferation, DNA damage repair and response, angiogenesis, metabolic and redox homeostasis, to inflammatory and immune response. In this review, we summarize findings showing the crosstalk between the circadian molecular clock and some key in...
Circadian Rhythms and Hormonal Homeostasis: Pathophysiological Implications
Biology, 2017
Over recent years, a deeper comprehension of the molecular mechanisms that control biological clocks and circadian rhythms has been achieved. In fact, many studies have contributed to unravelling the importance of the molecular clock for the regulation of our physiology, including hormonal and metabolic homeostasis. Here we will review the structure, organisation and molecular machinery that make our circadian clock work, and its relevance for the proper functioning of physiological processes. We will also describe the interconnections between circadian rhythms and endocrine homeostasis, as well as the underlying consequences that circadian dysregulations might have in the development of several pathologic affections. Finally, we will discuss how a better knowledge of such relationships might prove helpful in designing new therapeutic approaches for endocrine and metabolic diseases.
No time to lose: workshop on circadian rhythms and metabolic disease
Genes & Development, 2010
The objective of the workshop was to gain a better understanding of the link between circadian rhythms and human health and disease. The impacts of circadian rhythms on metabolic gene regulation, as well as the effect of nutrient uptake and balance on the molecular components of the clock, were discussed. Topics included the neural circuitry underlying the central clock; the effect of the environment and diet on the central clock as well as peripheral, tissue-specific clocks; and the transcriptional, post-transcriptional, and post-translational (e.g., epigenomic) mechanisms through which these signals are transduced. Evidence presented during the meeting demonstrated that circadian rhythms and metabolism are intricately linked, and that disruption in these rhythms have profound consequences-many times leading to metabolic disease. The mechanisms by which circadian rhythms are maintained and the cross-talk with metabolic signaling are just beginning to be elucidated. However, the interactions between these fields and the knowledge learned will clearly have a profound impact on our understanding of metabolic disease and lead to novel therapeutic approaches in the future In the past decade, it has become clear that the signaling cascades contributing to metabolic regulation respond to both central and cellular timing signals. Disruptions in the normal circadian rhythms of an animal result in changes in sleep, activity, and eating patterns. Change in patterns can lead to the dysfunction of metabolic pathways, and may ultimately lead to a number of diseases, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease, and cancer. The environmental cue of light and dark is well described to entrain the central clock. However, it is becoming better appreciated that cues such as nutrient uptake (feeding) and temperature also can impinge on the central clock. Many of the genes responsible for the regulation of the ''core'' clock have been identified, and their role in peripheral (tissue-specific) clocks is becoming apparent. Evidence from studies on these peripheral clocks, especially as they affect metabolism, is beginning to elucidate the integral role of these clocks in normal physiology as well as disease. Studies demonstrate that the mechanisms by which this dysregulation occurs include signaling at the transcriptional, post-transcriptional, posttranslational, and epigenomic levels. One specific point of intersection lies at the level of nuclear receptors (NRs)-hormones, vitamins, and xenobiotic and nutrientdependent transcription factors involved in reproduction, feeding, and homeostasis. It has now been shown that a number of these NRs are also key components of the clock, providing a direct link between the workings of the clock, gene regulation, and metabolism. Epigenetic mechanisms-specifically the role of clock genes in the modification of chromatin to influence gene regulationalso represent an exciting new overlay to regulation of the clock. A workshop on Circadian Rhythms and Metabolic Disease sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in Bethesda, MD, on April 12 and 13, 2010, brought together scientists in the fields of circadian rhythms and metabolism in order to gain a better understanding of the complex interrelationship between clock genes and genes involved in metabolism, and their potential roles in metabolic disease. The workshop brought together investigators from different disciplines to (1) enhance the exchange of information and (2) increase the collaboration between and among investigators from different disciplines with the goal to develop a better understanding of the role(s) of circadian rhythmicity in the regulation and/or modulation of signaling pathways responsible for metabolic regulation.
Circadian disruption in the pathogenesis of metabolic syndrome
Diabetes & Metabolism, 2014
Metabolic syndrome is a multifactorial process induced by a combination of genetic and environmental factors and recent evidence has highlighted that circadian disruption and sleep loss contribute to disease pathogenesis. Emerging work in experimental genetic models has provided insight into the mechanistic basis for clock disruption in disease. Indeed, disruption of the clock system perturbs both neuroendocrine pathways within the hypothalamus important in feeding and energetics, in addition to peripheral tissues involved in glucose and lipid metabolism. This review illustrates the impact of molecular clock disruptions at the level of both brain and behavior and peripheral tissues, with a focus on how such dysregulation in turn impacts lipid and glucose homeostasis, inflammation and cardiovascular function. New insight into circadian biology may ultimately lead to improved therapeutics for metabolic syndrome and cardiovascular disease in humans.
The role of the circadian clock system in physiology
Pflügers Archiv - European Journal of Physiology, 2018
Life on earth is shaped by the 24-h rotation of our planet around its axes. To adapt behavior and physiology to the concurring profound but highly predictable changes, endogenous circadian clocks have evolved that drive 24-h rhythms in invertebrate and vertebrate species. At the molecular level, circadian clocks comprised a set of clock genes organized in a system of interlocked transcriptional-translational feedback loops. A ubiquitous network of cellular central and peripheral tissue clocks coordinates physiological functions along the day through activation of tissue-specific transcriptional programs. Circadian rhythms impact on diverse physiological processes including the cardiovascular system, energy metabolism, immunity, hormone secretion, and reproduction. This review summarizes our current understanding of the mechanisms of circadian timekeeping in different species, its adaptation by external timing signals and the pathophysiological consequences of circadian disruption.
Advanced Drug Delivery Reviews, 2010
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.
Circadian regulation of metabolism
Journal of Endocrinology, 2014
In association with sleep–wake and fasting–feeding cycles, organisms experience dramatic oscillations in energetic demands and nutrient supply. It is therefore not surprising that various metabolic parameters, ranging from the activity status of molecular energy sensors to circulating nutrient levels, oscillate in time-of-day-dependent manners. It has become increasingly clear that rhythms in metabolic processes are not simply in response to daily environmental/behavioral influences, but are driven in part by cell autonomous circadian clocks. By synchronizing the cell with its environment, clocks modulate a host of metabolic processes in a temporally appropriate manner. The purpose of this article is to review current understanding of the interplay between circadian clocks and metabolism, in addition to the pathophysiologic consequences of disruption of this molecular mechanism, in terms of cardiometabolic disease development.
Circadian Rhythms: Attributes, Disruption, and Implementation in Cardiometabolic Health
Hypertension Journal, 2017
It is a well-known fact, proved by evidence, that all the organisms consist of an internal biological clock, right from the singlecelled organisms to humans. In the hierarchy of classification of vertebrate, these rhythms have shown to play an important role concerning the physiological aspects of all organisms. Not only are these rhythms related to sleep, seasonal migration, reproduction, etc., in animals, but also, in humans, circadian rhythms control various vegetative functions including regulation of temperature, cardiac activity, endocrine secretion, blood pressure (BP), oxygen utilization, metabolic rate, menstrual and ovarian cycles, and other body functions. The change in the normal pattern of the circadian clock because of genetic, behavioral, and various environmental factors can produce cardiovascular, metabolic, and endocrinal disorders including hypertension and diabetes. The concentration of glucose in plasma displays circadian variation; in the morning hours, it is the highest. Since the level of insulin depends on the feeding behavior, the glucose concentration follows the daily rhythm of intake of food. On the contrary, BP and other cardiovascular reflexes have characteristic and diurnal circadian rhythms. Circadian trends are exhibited in many cardiovascular pathophysiological conditions like stroke, myocardial infarction, rhythm disorders, and bed death syndrome. There is enough evidence to show that disruption of circadian rhythms can act as a risk factor for the development of cardiovascular diseases. Recent research also suggests that the circadian clock and associated central as well as peripheral genes are responsible for glucose and lipid metabolic rhythms.
Recent advances in modulators of circadian rhythms: an update and perspective
Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Circadian rhythm is a universal life phenomenon that plays an important role in maintaining the multiple physiological functions and regulating the adaptability to internal and external environments of flora and fauna. Circadian alignment in humans has the greatest effect on human health, and circadian misalignment is closely associated with increased risk for metabolic syndrome, cardiovascular diseases, neurological diseases, immune diseases, cancer, sleep disorders, and ophthalmic diseases. The recent description of clock proteins and related post-modification targets was involved in several diseases, and numerous lines of evidence are emerging that small molecule modulators of circadian rhythms can be used to rectify circadian disorder. Herein, we attempt to update the disclosures about the modulators targeting core clock proteins and related post-modification targets, as well as the relationship between circadian rhythm disorders and human health as well as the therapeutic role and prospect of these small molecule modulators in circadian rhythm related disease.
Metabolic implications of circadian disruption
Pflügers Archiv - European Journal of Physiology
Circadian rhythms are generated by the circadian clock, a self-sustained internal timing system that exhibits 24-h rhythms in the body. In mammals, circadian rhythms are driven by a central clock located in suprachiasmatic nucleus and various peripheral clocks located in different tissues and organs of the body. Many cellular, behavioral, and physiological processes are regulated by the circadian clock in coordination with environmental cues. The process of metabolism is also under circadian regulation. Loss of synchronization between the internal clock and environmental zeitgebers results in disruption of the circadian rhythms that seriously impacts metabolic homeostasis leading to changed eating behavior, altered glucose and lipid metabolism, and weight gain. This in turn augments the risk of having various cardio-metabolic disorders such as obesity, diabetes, metabolic syndrome, and cardiovascular disease. This review sheds light on circadian rhythms and their role in metabolism with the identification of gaps in the current knowledge that remain to be explored in these fields. In this review, the molecular mechanisms underlying circadian rhythms have been elaborated first. Then, the focus has been kept on explaining the physiological significance of circadian rhythms in regulating metabolism. Finally, the implications for metabolism when these rhythms are disrupted due to genetic mutations or social and occupational needs enforced by modern lifestyle have been discussed.