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Frontiers in Genetics 2024Circadian rhythms, essential 24-hour cycles guiding biological functions, synchronize organisms with daily environmental changes. These rhythms, which are evolutionarily... (Review)
Review
Circadian rhythms, essential 24-hour cycles guiding biological functions, synchronize organisms with daily environmental changes. These rhythms, which are evolutionarily conserved, govern key processes like feeding, sleep, metabolism, body temperature, and endocrine secretion. The central clock, located in the suprachiasmatic nucleus (SCN), orchestrates a hierarchical network, synchronizing subsidiary peripheral clocks. At the cellular level, circadian expression involves transcription factors and epigenetic remodelers, with environmental signals contributing flexibility. Circadian disruption links to diverse diseases, emphasizing the urgency to comprehend the underlying mechanisms. This review explores the communication between the environment and chromatin, focusing on histone post-translational modifications. Special attention is given to the significance of histone methylation in circadian rhythms and metabolic control, highlighting its potential role as a crucial link between metabolism and circadian rhythms. Understanding these molecular intricacies holds promise for preventing and treating complex diseases associated with circadian disruption.
PubMed: 38818037
DOI: 10.3389/fgene.2024.1343030 -
Frontiers in Endocrinology 2024This article discusses data showing that mammals, including humans, have two sources of melatonin that exhibit different functions. The best-known source of melatonin,... (Review)
Review
This article discusses data showing that mammals, including humans, have two sources of melatonin that exhibit different functions. The best-known source of melatonin, herein referred to as Source #1, is the pineal gland. In this organ, melatonin production is circadian with maximal synthesis and release into the blood and cerebrospinal fluid occurring during the night. Of the total amount of melatonin produced in mammals, we speculate that less than 5% is synthesized by the pineal gland. The melatonin rhythm has the primary function of influencing the circadian clock at the level of the suprachiasmatic nucleus (the CSF melatonin) and the clockwork in all peripheral organs (the blood melatonin) via receptor-mediated actions. A second source of melatonin (Source # 2) is from multiple tissues throughout the body, probably being synthesized in the mitochondria of these cells. This constitutes the bulk of the melatonin produced in mammals and is concerned with metabolic regulation. This review emphasizes the action of melatonin from peripheral sources in determining re-dox homeostasis, but it has other critical metabolic effects as well. Extrapineal melatonin synthesis does not exhibit a circadian rhythm and it is not released into the blood but acts locally in its cell of origin and possibly in a paracrine matter on adjacent cells. The factors that control/influence melatonin synthesis at extrapineal sites are unknown. We propose that the concentration of melatonin in these cells is determined by the subcellular redox state and that melatonin synthesis may be inducible under stressful conditions as in plant cells.
Topics: Melatonin; Humans; Animals; Circadian Rhythm; Pineal Gland; Suprachiasmatic Nucleus
PubMed: 38808108
DOI: 10.3389/fendo.2024.1414463 -
Fluids and Barriers of the CNS May 2024Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be...
Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be elucidated. The aim of our study was to [1] identify rhythmically controlled cellular processes in the mouse ChP and [2] assess the role and nature of signals derived from the master clock in the suprachiasmatic nuclei (SCN) that control ChP rhythms. To accomplish this goal, we used various mouse models (WT, mPer2, ChP-specific Bmal1 knockout) and combined multiple experimental approaches, including surgical lesion of the SCN (SCNx), time-resolved transcriptomics, and single cell luminescence microscopy. In ChP of control (Ctrl) mice collected every 4 h over 2 circadian cycles in darkness, we found that the ChP clock regulates many processes, including the cerebrospinal fluid circadian secretome, precisely times endoplasmic reticulum stress response, and controls genes involved in neurodegenerative diseases (Alzheimer's disease, Huntington's disease, and frontotemporal dementia). In ChP of SCNx mice, the rhythmicity detected in vivo and ex vivo was severely dampened to a comparable extent as in mice with ChP-specific Bmal1 knockout, and the dampened cellular rhythms were restored by daily injections of dexamethasone in mice. Our data demonstrate that the ChP clock controls tissue-specific gene expression and is strongly dependent on the presence of a functional connection with the SCN. The results may contribute to the search for a novel link between ChP clock disruption and impaired brain health.
Topics: Animals; Suprachiasmatic Nucleus; Choroid Plexus; Circadian Clocks; Mice; Mice, Inbred C57BL; Circadian Rhythm; Male; Mice, Knockout; ARNTL Transcription Factors
PubMed: 38802875
DOI: 10.1186/s12987-024-00547-3 -
Neuropharmacology Sep 2024Feeding, like many other biological functions, displays a daily rhythm. This daily rhythmicity is controlled by the circadian timing system of which the central master... (Review)
Review
Feeding, like many other biological functions, displays a daily rhythm. This daily rhythmicity is controlled by the circadian timing system of which the central master clock is located in the hypothalamic suprachiasmatic nucleus (SCN). Other brain areas and tissues throughout the body also display rhythmic functions and contain the molecular clock mechanism known as peripheral oscillators. To generate the daily feeding rhythm, the SCN signals to different hypothalamic areas with the lateral hypothalamus, paraventricular nucleus and arcuate nucleus being the most prominent. With respect to the rewarding aspects of feeding behavior, the dopaminergic system is also under circadian influence. However the SCN projects only indirectly to the different reward regions, such as the ventral tegmental area where dopamine neurons are located. In addition, high palatable, high caloric diets have the potential to disturb the normal daily rhythms of physiology and have been shown to alter for example meal patterns. Around a meal several hormones and peptides are released that are also under circadian influence. For example, the release of postprandial insulin and glucagon-like peptide following a meal depend on the time of the day. Finally, we review the effect of deletion of different clock genes on feeding behavior. The most prominent effect on feeding behavior has been observed in Clock mutants, whereas deletion of Bmal1 and Per1/2 only disrupts the day-night rhythm, but not overall intake. Data presented here focus on the rodent literature as only limited data are available on the mechanisms underlying daily rhythms in human eating behavior.
Topics: Animals; Feeding Behavior; Circadian Rhythm; Humans; Suprachiasmatic Nucleus
PubMed: 38795953
DOI: 10.1016/j.neuropharm.2024.110007 -
Chrono-Endocrinology in Clinical Practice: A Journey from Pathophysiological to Therapeutic Aspects.Life (Basel, Switzerland) Apr 2024This review was aimed at collecting the knowledge on the pathophysiological and clinical aspects of endocrine rhythms and their implications in clinical practice,... (Review)
Review
This review was aimed at collecting the knowledge on the pathophysiological and clinical aspects of endocrine rhythms and their implications in clinical practice, derived from the published literature and from some personal experiences on this topic. We chose to review, according to the PRISMA guidelines, the results of original and observational studies, reviews, meta-analyses and case reports published up to March 2024. Thus, after summarizing the general aspects of biological rhythms, we will describe the characteristics of several endocrine rhythms and the consequences of their disruption, paying particular attention to the implications in clinical practice. Rhythmic endocrine secretions, like other physiological rhythms, are genetically determined and regulated by a central hypothalamic CLOCK located in the suprachiasmatic nucleus, which links the timing of the rhythms to independent clocks, in a hierarchical organization for the regulation of physiology and behavior. However, some environmental factors, such as daily cycles of light/darkness, sleep/wake, and timing of food intake, may influence the rhythm characteristics. Endocrine rhythms are involved in important physiological processes and their disruption may cause several disorders and also cancer. Thus, it is very important to prevent disruptions of endocrine rhythms and to restore a previously altered rhythm by an early corrective chronotherapy.
PubMed: 38792568
DOI: 10.3390/life14050546 -
Clinical and Experimental Hepatology Mar 2024The biological rhythm is a fundamental aspect of an organism, regulating many physiological processes. This study focuses on the analysis of the molecular basis of... (Review)
Review
The biological rhythm is a fundamental aspect of an organism, regulating many physiological processes. This study focuses on the analysis of the molecular basis of circadian rhythms and its impact on the functioning of the liver. The regulation of biological rhythms is carried out by the clock system, which consists of the central clock and peripheral clocks. The central clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and is regulated by signals received from the retinal pathway. The SCN regulates the circadian rhythm of the entire body through its indirect influence on the peripheral clocks. In turn, the peripheral clocks can maintain their own rhythm, independent of the SCN, by creating special feedback loops between transcriptional and translational factors. The main protein families involved in these processes are CLOCK, BMAL, PER and CRY. Disorders in the expression of these factors have a significant impact on the functioning of the liver. In such cases lipid metabolism, cholesterol metabolism, bile acid metabolism, alcohol metabolism, and xenobiotic detoxification can be significantly affected. Clock dysfunctions contribute to the pathogenesis of various disorders, including fatty liver disease, liver cirrhosis and different types of cancer. Therefore understanding circadian rhythm can have significant implications for the therapy of many liver diseases, as well as the development of new preventive and treatment strategies.
PubMed: 38765904
DOI: 10.5114/ceh.2024.136220 -
Frontiers in Endocrinology 2024The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The... (Review)
Review
The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.
Topics: Humans; Circadian Rhythm; Cardiovascular Diseases; Metabolic Diseases; Diabetes Mellitus, Type 2; Chronobiology Disorders
PubMed: 38742195
DOI: 10.3389/fendo.2024.1328139 -
Cell Reports May 2024The suprachiasmatic nucleus (SCN) encodes time of day through changes in daily firing; however, the molecular mechanisms by which the SCN times behavior are not fully...
The suprachiasmatic nucleus (SCN) encodes time of day through changes in daily firing; however, the molecular mechanisms by which the SCN times behavior are not fully understood. To identify factors that could encode day/night differences in activity, we combine patch-clamp recordings and single-cell sequencing of individual SCN neurons in mice. We identify PiT2, a phosphate transporter, as being upregulated in a population of VipNms SCN neurons at night. Although nocturnal and typically showing a peak of activity at lights off, mice lacking PiT2 (PiT2) do not reach the activity level seen in wild-type mice during the light/dark transition. PiT2 loss leads to increased SCN neuronal firing and broad changes in SCN protein phosphorylation. PiT2 mice display a deficit in seasonal entrainment when moving from a simulated short summer to longer winter nights. This suggests that PiT2 is responsible for timing activity and is a driver of SCN plasticity allowing seasonal entrainment.
Topics: Animals; Suprachiasmatic Nucleus; Mice; Neurons; Locomotion; Mice, Inbred C57BL; Vasoactive Intestinal Peptide; Male; Circadian Rhythm; Photoperiod; Mice, Knockout; Sodium-Phosphate Cotransporter Proteins, Type III; Phosphate Transport Proteins
PubMed: 38735047
DOI: 10.1016/j.celrep.2024.114220 -
International Journal of Molecular... Apr 2024Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the...
Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats' SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption.
Topics: Animals; Mitophagy; Rats; Circadian Rhythm; Male; ARNTL Transcription Factors; Nuclear Receptor Subfamily 1, Group D, Member 1; Weightlessness Simulation; Suprachiasmatic Nucleus; Microtubule-Associated Proteins; Body Temperature; Heart Rate; Rats, Sprague-Dawley; Proteolysis
PubMed: 38732079
DOI: 10.3390/ijms25094853 -
Frontiers in Neuroscience 2024
PubMed: 38707592
DOI: 10.3389/fnins.2024.1371195