Body rhythms/biological clocks

The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronize them with daily cycles. While the central clock in the suprachiasmatic nucleus (SCN) is mainly synchronized by the light/dark cycles, the peripheral clocks react to other stimuli, including the feeding/fasting state, nutrients, sleep-wake cycles, and physical activity. During the disruption of circadian rhythms due to genetic mutations or social and occupational obligations, incorrect arrangement between the internal clock system and environmental rhythms leads to the development of obesity. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition leads to uncoupling of the peripheral clocks from the central pacemaker and to the development of metabolic disorders. The strong coupling of the SCN to the light-dark cycle creates a situation of misalignment when food is ingested during the "wrong" time of day. Food-anticipatory activity is mediated by a self-sustained circadian timing, and its principal component is a food-entrainable oscillator. Modifying the time of feeding alone greatly affects body weight, whereas ketogenic diet (KD) influences circadian biology, through the modulation of clock gene expression. Night-eating behavior is one of the causes of circadian disruption, and night eaters have compulsive and uncontrolled eating with severe obesity. By contrast, time-restricted eating (TRE) restores circadian rhythms through maintaining an appropriate daily rhythm of the eating-fasting cycle. The hypothalamus has a crucial role in the regulation of energy balance rather than food intake. While circadian locomotor output cycles kaput (CLOCK) expression levels increase with high-fat diet-induced obesity, peroxisome proliferator-activated receptor-alpha (PPARα) increases the transcriptional level of brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1) in obese subjects. In this context, effective timing of chronotherapies aiming to correct SCN-driven rhythms depends on an accurate assessment of the SCN phase. In fact, in a multi-oscillator system, local rhythmicity and its disruption reflects the disruption of either local clocks or central clocks, thus imposing rhythmicity on those local tissues, whereas misalignment of peripheral oscillators is due to exosome-based intercellular communication.Consequently, disruption of clock genes results in dyslipidemia, insulin resistance, and obesity, while light exposure during the daytime, food intake during the daytime, and sleeping during the biological night promote circadian alignment between the central and peripheral clocks. Thus, shift work is associated with an increased risk of obesity, diabetes, and cardiovascular diseases because of unusual eating times as well as unusual light exposure and disruption of the circadian rhythm.

ABSTRACTIn mammals, the central clock (the suprachiasmatic nuclei, SCN) is entrained mainly by the light-dark cycle, whereas peripheral clocks in the peripheral tissues are entrained/synchronized by multiple factors, including feeding patterns and endocrine hormones such as glucocorticoids. Clock-mutant mice (Clock/Clock), which have a mutation in a core clock gene, show potent phase resetting in response to light pulses compared with wild-type (WT) mice, owing to the damped and flexible oscillator in the SCN. However, the phase resetting of the peripheral clocks in Clock/Clock mice has not been elucidated. Here, we characterized the peripheral clock gene synchronization in Clock/Clock mice by daily injections of a synthetic glucocorticoid (dexamethasone, DEX) by monitoring in vivo PER2::LUCIFERASE bioluminescence. Compared with WT mice, the Clock/Clock mice showed significantly decreased bioluminescence and peripheral clock rhythms with decreased amplitudes and delayed phases. In addition, the DEX injections increased the amplitudes and advanced the phases. In order to examine the robustness of the internal oscillator, T-cycle experiments involving DEX stimulations with 24- or 30-h intervals were performed. The Clock/Clock mice synchronized to the 30-h T-cycle stimulation, which suggested that the peripheral clocks in the Clock/Clock mice had increased synchronizing ability upon DEX stimulation, to that of circadian and hour-glass type oscillations, because of weak internal clock oscillators.

In the past decade, it has become increasingly evident that the circadian clock system plays an important role in many physiological processes. The circadian clock can be divided into 2 parts: the central clock, residing in the suprachiasmatic nucleus of the hypothalamus, which receives light cues, and the peripheral clocks that reside in various tissues throughout the body. The peripheral clocks play an integral and unique role in each of their respective tissues, driving the circadian expression of specific genes involved in a variety of physiological functions. The goal of this review is to provide an introduction to and overview of the peripheral clocks, including potential mechanisms, targets, and implications for disease states. The peripheral clocks include the cardiovascular, metabolic, endocrine, immune, and reproductive systems.

Biological functions of living things are regulated by the circadian rhythm, a 24-hour cycle. Master clock in the hypothalamus is dependent on light-dark signals, while peripheral clock (present in organs) is cell-independent being synchronized with central clock. Mammals’ circadian clocks control various catabolic and anabolic processes in their peripheral tissues. Peripheral organs display tissue-specific differences in the circadian period and phase and exhibit a circadian oscillator. Various diets will affect the peripheral clock in different organ systems. Ketogenic and high-fat diets can alter clock gene expression, while intermittent fasting shows improved circadian rhythm desynchronization. High-sugar diets can cause circadian rhythm-dependent gene amplification involved in hepatic carbohydrate and fat metabolism, leading to dyslipidemia and disturbed metabolism. High-salt diets can increase peripheral clock gene expression. Different diets can affect the peripheral clock rhythm, causing phase shifts, leading to the desynchronization of the central and peripheral clocks subsequently leading to various metabolic diseases.

Biological rhythms are an integral component of essentially all aspects of life. These rhythms are controlled in part by circadian clocks, transcriptionally based mechanisms that synchronize the organism to its changing environment. The central circadian clock is located within the suprachiasmatic nucleus of the brain, while peripheral clocks are located within virtually all cells outside of the suprachiasmatic nucleus. Although our understanding of central clock structure and function is well advanced, the role of peripheral clocks in whole body energy metabolism is just beginning to be elucidated. Both central and peripheral circadian clocks likely regulate many physiological functions, including insulin sensitivity, endocrine regulation, energy homeostasis, satiety signalling, cellular proliferation and cardiovascular function. Widely varying phenotypes have been reported following global genetic disruption of the clock mechanism in mice, with phenotype dependent on both the clock component targeted and genetic background. The inconsistency in phenotypes associated with clock disruption may be due, in part, to cell-specific effects of the circadian clocks. To address this question, many laboratories have begun generating animal models of cell type-specific clock disruption. In this review, we summarize the existing literature on tissue-specific models of circadian clock disruption and provide a focus for future research in this area.

Daily rhythms regulate everiday life and sleep/wake alternation is the best expression of this. Disruptions in biological rhythms is strongly associated with mood disorders, often being the major feature of this, major depressive disorder first of all. Although stabilization of rhythms produced by treatments have important outcome on therapeutic efficacy, insomnia often remains an unresolved symptom when major depression has otherwise been successfully treated with antidepressant. We review scientific literature in order to better clarify how to better approach insomnia as a clinical aspect to investigate and to early treat while treating other psychiatric conditions, major depression in particular. Insomnia is associated with impaired quality of life. It can be resolved with adequate diagnosis and treatment: it should be considered a comorbid condition and should be early identificated and treated in a multidisciplinary way, so that the ideal of treatment for patients with treatment resistant insomnia in major depression is an integration of non-pharmacologic measures, along with judicious use of medication, often used as an adjunctive therapy.

SummaryCircadian clocks are characterized by three properties: they run in constant conditions with a period of ∼24 h, synchronize to the environmental cycles of light and temperature, and are temperature compensated, meaning they do not speed up with temperature. Central brain clocks regulate daily activity rhythms, whereas peripheral clocks are dispersed throughout the body of insects and vertebrates. Using a set of luciferase reporter genes, we show that Drosophila peripheral clocks are self-sustained but over-compensated, i.e., they slow down with increasing temperature. In contrast, central clock neurons in the fly brain, both in intact flies and in cultured brains, show accurate temperature compensation. Although this suggests that neural network properties contribute to temperature compensation, the circadian neuropeptide Pigment Dispersing Factor (PDF) is not required for temperature-compensated oscillations in brain clock neurons. Our findings reveal a fundamental difference between central and peripheral clocks, which likely also applies for vertebrate clocks.

The central biological clock of the brain, contained within the suprachiasmatic nuclei (SCN) of mammals, orchestrates an orderly "internal day" of physiology and behavior. The developing biological clock begins to respond to light at an early stage and a particular concern in humans is whether light exposure has disruptive effects on the developing biological clock of infants exposed to constant lighting conditions in neonatal intensive care units (NICUs). Worldwide, eighteen million, or 14%, of newborns estimated to be of low birth weight, are exposed to artificial lighting environments in hospital nurseries annually. Here, we have tested whether constant light (LL) exposure disrupts the developing biological clock of mice, using a circadian reporter transgenic mouse model in which the organization of the central biological clock can be assayed by real-time gene expression imaging. We now find that LL has both acute and long-term disruptive effects on developing biological clocks and that cyclic lighting conditions are critical for developing circadian clocks to coordinate their molecular circadian mechanisms. This suggests that, from the perspective of developing circadian organization in humans, cyclic light conditions in NICUs are likely to be most appropriate for infants.

Aims/hypothesisThe central pacemaker of the mammalian biological timing system is located within the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. Together with the peripheral clocks, this central brain clock ensures a timely, up-to-date and proper behaviour for an individual throughout the day–night cycle. A mismatch between the central and peripheral clocks results in a disturbance of daily rhythms in physiology and behaviour. It is known that the number of rhythmically expressed genes is reduced in peripheral tissue of individuals with type 2 diabetes mellitus. However, it is not known whether the central SCN clock is also affected in the pathogenesis of type 2 diabetes. In the current study, we compared the profiles of the SCN neurons and glial cells between type 2 diabetic and control individuals.MethodsWe collected post-mortem hypothalamic tissues from 28 type 2 diabetic individuals and 12 non-diabetic control individuals. We performed immunohistochemical analysis for three SCN neuropeptides, arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP) and neurotensin (NT), and for two proteins expressed in glial cells, ionised calcium-binding adapter molecule 1 (IBA1, a marker of microglia) and glial fibrillary acidic protein (GFAP, a marker of astroglial cells).ResultsThe numbers of AVP immunoreactive (AVP-ir) and VIP-ir neurons and GFAP-ir astroglial cells in the SCN of type 2 diabetic individuals were significantly decreased compared with the numbers in the SCN of the control individuals. In addition, the relative intensity of AVP immunoreactivity was reduced in the individuals with type 2 diabetes. The number of NT-ir neurons and IBA1-ir microglial cells in the SCN was similar in the two groups.Conclusions/interpretationOur data show that type 2 diabetes differentially affects the numbers of AVP- and VIP-expressing neurons and GFAP-ir astroglial cells in the SCN, each of which could affect the daily rhythmicity of the SCN biological clock machinery. Therefore, for effectively treating type 2 diabetes, lifestyle changes and/or medication to normalise central biological clock functioning might be helpful.

The Institute of Physiology of the Czech Academy of Sciences (CAS) has been involved in the field of chronobiology, i.e., in research on temporal regulation of physiological processes, since 1970. The review describes the first 35 years of the research mostly on the effect of light and daylength, i.e., photoperiod, on entrainment or resetting of the pineal rhythm in melatonin production and of intrinsic rhythms in the central biological clock. This clock controls pineal and other circadian rhythms and is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. During the early chronobiological research, many original findings have been reported, e.g. on mechanisms of resetting of the pineal rhythm in melatonin production by short light pulses or by long exposures of animals to light at night, on modulation of the nocturnal melatonin production by the photoperiod or on the presence of high affinity melatonin binding sites in the SCN. The first evidence was given that the photoperiod modulates functional properties of the SCN and hence the SCN not only controls the daily programme of the organism but it may serve also as a calendar measuring the time of a year. During all the years, the chronobiological community has started to talk about "the Czech school of chronobiology". At present, the today´s Laboratory of Biological Rhythms of the Institute of Physiology CAS continues in the chronobiological research and the studies have been extended to the entire circadian timekeeping system in mammals with focus on its ontogenesis, entrainment mechanisms and circadian regulation of physiological functions. Key words: Pineal, Melatonin, AA-NAT rhythm, Light entrainment, Photoperiod, SCN clock.

SummaryBackgroundCircadian (24-h) rhythms are important regulators in physiology and disease, but systemic disease may disrupt circadian rhythmicity. Heart failure (HF) is a systemic disease affecting hormonal regulation. We investigate whether HF affects the rhythmic expression of melatonin and cortisol, main endocrine products of the central clock, and cardiac-specific troponin in patients. We corroborate the functionality of the peripheral clock directly in the organs of translational models, inaccessible in human participants.MethodsWe included 46 HF patients (71.7% male, median age of 60 years, NYHA class II (32.6%) or III (67.4%), ischemic cardiomyopathy (43.5%), comorbidities: diabetes 21.7%, atrial fibrillation 30.4%), and 24 matched controls. Blood was collected at seven time-points during a 24-h period (totalling 320 HF and 167 control samples) for melatonin, cortisol, and cardiac troponin T (cTnT) measurements after which circadian rhythms were assessed through cosinor analyses, both on the individual and the group level. Next, we analysed peripheral circadian clock functionality using cosinor analysis in male animal HF models: nocturnal mice and diurnal zebrafish, based on expression of core clock genes in heart, kidneys, and liver, every 4 h during a 24-h period in a light/darkness synchronised environment.FindingsMelatonin and cortisol concentrations followed a physiological 24-h pattern in both patients and controls. For melatonin, acrophase occurred during the night for both groups, with significantly decreased amplitude (median 5.2 vs 8.8, P = 0.0001) and circadian variation ([maximum]/[minimum]) in heart failure patients. For cortisol, mesor showed a significant increase for HF patients (mean 331.9 vs 275.1, P = 0.017) with a difference of 56.8 (95% CI 10.3–103.3) again resulting in a relatively lower variation: median 3.9 vs 6.3 (P = 0.0058). A nocturnal blood pressure dip was absent in 77.8% of HF patients.Clock gene expression profiles (Bmal, Clock, Per, Cry) were similar and with expected phase relations in animal HF models and controls, demonstrating preserved peripheral clock functionality in HF. Furthermore, oscillations in diurnal zebrafish were expectedly in opposite phases to those of nocturnal mice. Concordantly, cTnT concentrations in HF patients revealed significant circadian oscillations.InterpretationCentral clock output is dampened in HF patients while the molecular peripheral clock, as confirmed in animal models, remains intact. This emphasises the importance of taking timing into account in research and therapy for HF, setting the stage for another dimension of diagnostic, prognostic and therapeutic approaches.Funding10.13039/501100002996Hartstichting.

Circadian rhythms are ubiquitous phenomena that recur daily in a self-sustaining, entrainable, and oscillatory manner, and orchestrate a wide range of molecular, physiological, and behavioral processes. Circadian clocks are comprised of a hierarchical network of central and peripheral clocks that generate, sustain, and synchronize the circadian rhythms. The functioning of the peripheral clock is regulated by signals from autonomic innervation (from the central clock), endocrine networks, feeding, and other external cues. The critical role played by circadian rhythms in maintaining both systemic and tissue-level homeostasis is well established, and disruption of the rhythm has direct consequence for human health, disorders, and diseases. Circadian oscillations in both pharmacokinetics and pharmacodynamic processes are known to affect efficacy and toxicity of several therapeutic agents. A variety of modeling approaches ranging from empirical to more complex systems modeling approaches have been applied to characterize circadian biology and its influence on drug actions, optimize time of dosing, and identify opportunities for pharmacological modulation of the clock mechanisms and their downstream effects. In this review, we summarize current understanding of circadian rhythms and its influence on physiology, pharmacology, and therapeutic interventions, and discuss the role of chronopharmacometrics in gaining new insights into circadian rhythms and its applications in chronopharmacology.

PurposeThis study is designed to investigate a critical association between social media addiction and employee sleep while considering its implications for employee well-being and performance in the hospitality industry.Design/methodology/approachBased on adapted measures for the study variables, an electronic questionnaire was designed and used for the survey administered in the chain-restaurants of Pakistan. Through a non-probability convenient sampling survey, a total of 347 usable responses were obtained and analyzed for testing the hypothesized research model.FindingsResults reveal negative associations between social media addiction, sleep quality, employee performance and well-being. The results have further shown sleep quality as an underlying mediating reason that explains the associations between social media addiction, employee performance and well-being.Originality/valueThe study addresses a gap in the literature by examining rarely explored factors such as social media addiction and sleep quality at the same time investigating its impact on performance and well-being of service employees. Significant implications for scholars and practitioners of the hospitality industry have been discussed while highlighting limitations and directions for future research.

Chapter 10 - Interaction of central and peripheral clocks in physiological regulation

Background: Although clock genes generate oscillations in about 10 % of all gene expressions as a 24-hour cycle in the cellular level cooperating with the central clock, little is known about the role of clock genes in angiogenesis. Objective: The aim of this study was to determine if a peripheral clock would modulate angiogenesis in a hind limb ischemia (HLI) model. Methods and Results: First, we surgically induced the HLI model in C57BL/6J (wild type; WT) mice (N=6 for each time point) and checked mRNA expressions of clock genes in a local ischemic tissue by PCR array in the setting of blood perfusion recovery. In vitro study, we next investigated those gene expressions in human umbilical vein endothelial cells (HUVECs) with or without stimulation by growth factors. Those data demonstrated that the peripheral clock genes were modulated in ECs and tissues in the presence of growth factors and tissue ischemia. Then, we examined whether inhibition of clock gene expressions had any effects on angiogenesis. For this study, we focused on Cryptochrome (Cry), which is well known as one of the core-loop forming clock genes producing circadian rhythm in mammals. Our loss-of-function study revealed that the abilities of proliferation, migration and tube formation were significantly inhibited by Cry1 and Cry2 double knockdown in HUVECs. Interestingly, although the knockdown of Cry1 and Cry2 changed the mRNA expression of Period2, it did not affect those of BMAL1 and Clock in HUVECs. Finally, we tested if Cry1 and Cry2 double hetero knockout mice of HLI models displayed worse blood perfusion recoveries with deterioration of angiogenesis. As results, compared with control WT mice, Cry1 and Cry2 double knockout mice showed the low capillary density detected by CD31-immunohistochemistry and low tissue blood perfusion demonstrated by laser Doppler perfusion imaging (LDPI) in a HLI. Conclusion: Our data indicated that Cryptochrome as a peripheral clock plays an important role in angiogenesis of the reparative tissue ischemia model.