AIM: Exposure to light at night and meal time misaligned with the light/dark (LD) cycle-typical features of daily life in modern 24/7 society-are associated with negative effects on health. To understand the mechanism, we developed a novel protocol of complex chronodisruption (CD) in which we exposed female rats to four weekly cycles consisting of 5-day intervals of constant light and 2-day intervals of food access restricted to the light phase of the 12:12 LD cycle. METHODS: We examined the effects of CD on behavior, estrous cycle, sleep patterns, glucose homeostasis and profiles of clock- and metabolism-related gene expression (using RT qPCR) and liver metabolome and lipidome (using untargeted metabolomic and lipidomic profiling). RESULTS: CD attenuated the rhythmic output of the central clock in the suprachiasmatic nucleus via Prok2 signaling, thereby disrupting locomotor activity, the estrous cycle, sleep patterns, and mutual phase relationship between the central and peripheral clocks. In the periphery, CD abolished Per1,2 expression rhythms in peripheral tissues (liver, pancreas, colon) and worsened glucose homeostasis. In the liver, it impaired the expression of NAD+, lipid, and cholesterol metabolism genes and abolished most of the high-amplitude rhythms of lipids and polar metabolites. Interestingly, CD abolished the circadian rhythm of Cpt1a expression and increased the levels of long-chain acylcarnitines (ACar 18:2, ACar 16:0), indicating enhanced fatty acid oxidation in mitochondria. CONCLUSION: Our data show the widespread effects of CD on metabolism and point to ACars as biomarkers for CD due to misaligned sleep and feeding patterns.

• Klíčová slova
• acylcarnitine, chronodisruption, clock, female, glucose homeostasis, liver, metabolome, pancreas, rat, sleep, suprachiasmatic nucleus,
• MeSH
• cirkadiánní hodiny fyziologie   MeSH
• cirkadiánní rytmus * fyziologie   MeSH
• fotoperioda MeSH
• játra * metabolismus   MeSH
• karnitin * analogy a deriváty   metabolismus   MeSH
• krysa rodu Rattus MeSH
• metabolom * MeSH
• nucleus suprachiasmaticus metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acylcarnitine MeSH Prohlížeč
• karnitin * MeSH

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, mPer2Luc, 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.

• Klíčová slova
• mPer2 Luc mouse, Choroid plexus, Circadian clock, Circadian transcriptome, Glucocorticoid, Mouse, Suprachiasmatic nuclei,
• MeSH
• cirkadiánní hodiny * fyziologie   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• nucleus suprachiasmaticus * metabolismus   fyziologie   MeSH
• plexus chorioideus * metabolismus   fyziologie   MeSH
• transkripční faktory ARNTL metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Bmal1 protein, mouse MeSH Prohlížeč
• transkripční faktory ARNTL MeSH

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.

• Klíčová slova
• cardiovascular disease risk, circadian clock, circadian rhythm disruption, glucose tolerance, insulin sensitivity, time restricted eating, type 2 diabetes mellitus,
• MeSH
• chronobiologické poruchy patofyziologie   komplikace   MeSH
• cirkadiánní rytmus * fyziologie   MeSH
• diabetes mellitus 2. typu patofyziologie   metabolismus   MeSH
• kardiovaskulární nemoci * etiologie   patofyziologie   MeSH
• lidé MeSH
• metabolické nemoci * patofyziologie   metabolismus   etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The choroid plexus (ChP) in the brain ventricles has a major influence on brain homeostasis. In this study, we aimed to determine whether the circadian clock located in ChP is affected by chronodisruption caused by misalignment with the external light/dark cycle and/or inflammation. Adult mPer2Luc mice were maintained in the LD12:12 cycle or exposed to one of two models of chronic chronodisruption - constant light for 22-25 weeks (cLL) or 6-hour phase advances of the LD12:12 cycle repeated weekly for 12 weeks (cLD-shifts). Locomotor activity was monitored before the 4th ventricle ChP and suprachiasmatic nuclei (SCN) explants were recorded in real time for PER2-driven population and single-cell bioluminescence rhythms. In addition, plasma immune marker concentrations and gene expression in ChP, prefrontal cortex, hippocampus and cerebellum were analyzed. cLL dampened the SCN clock but did not shorten the inactivity interval (sleep). cLD-shifts had no effect on the SCN clock, but transiently affected sleep duration and fragmentation. Both chronodisruption protocols dampened the ChP clock. Although immune markers were elevated in plasma and hippocampus, levels in ChP were unaffected, and unlike the liver clock, the ChP clock was resistant to lipopolysaccharide treatment. Importantly, both chronodisruption protocols reduced glucocorticoid signaling in ChP. The data demonstrate the high resistance of the ChP clock to inflammation, highlighting its role in protecting the brain from neuroinflammation, and on the other hand its high sensitivity to chronodisruption. Our results provide a novel link between human lifestyle-induced chronodisruption and the impairment of ChP-dependent brain homeostasis.

• Klíčová slova
• Bioluminescence rhythm, Choroid plexus, Chronodisruption, Circadian clock, Constant light, Neuroinflammation, Sleep disruption, mPer2Luc mouse,
• MeSH
• chronická lymfatická leukemie * MeSH
• cirkadiánní hodiny * MeSH
• cirkadiánní proteiny Period genetika   metabolismus   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• lidé MeSH
• myši MeSH
• plexus chorioideus metabolismus   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cirkadiánní proteiny Period MeSH

STUDY OBJECTIVES: Social jetlag manifests as a difference in sleep timing on workdays and free days. Social jetlag is often associated with shorter, lower-quality sleep, so it is unclear how much the chronic circadian misalignment contributes to observed negative health outcomes. We aimed to (1) investigate associations between social jetlag, chronotype (one of its determinants), and the levels of health markers, (2) describe factors associated with social jetlag, and (3) examine whether working from home can reduce social jetlag. METHODS: Adult respondents participated in a nationally representative longitudinal survey of Czech households (individuals in each wave: n2018/19/20 = 5132/1957/1533), which included Munich ChronoType Questionnaire to evaluate chronotype and social jetlag. A subset provided blood samples (n2019 = 1957) for detection of nine biomarkers and was surveyed in three successive years (social jetlag calculated for n2018/19/20 = 3930/1601/1237). Data were analyzed by nonparametric univariate tests and mixed effects multivariate regression with social jetlag, chronotype, sex, age, body-mass index, and reported diseases as predictors and biomarker levels as outcomes. RESULTS: Higher social jetlag (≥0.65 h) was significantly associated with increased levels of total cholesterol and low-density lipoprotein cholesterol, particularly in participants older than 50 years (Mann-Whitney, men: pCHL = 0.0005, pLDL = 0.0009; women: pCHL = 0.0079, pLDL = 0.0068). Extreme chronotypes were associated with cardiovascular disease risk markers regardless of social jetlag (Kruskal-Wallis, p < 0.0001). Commuting to work and time stress were identified as important contributors to social jetlag. Individual longitudinal data showed that working from home decreased social jetlag and prolonged sleep. CONCLUSIONS: We report significant associations between sleep phase preference, social jetlag, and cardio-metabolic biomarkers.

• Klíčová slova
• Biomarkers, Cholesterol, Chronotype, Circadian Rhythm, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Models, Statistical, Social jetlag,
• MeSH
• biologické markery MeSH
• cholesterol MeSH
• cirkadiánní rytmus * MeSH
• dospělí MeSH
• jet lag syndrom MeSH
• lidé MeSH
• metabolické nemoci * komplikace   MeSH
• průzkumy a dotazníky MeSH
• spánek MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• cholesterol MeSH

Lithium is an effective mood stabilizer, but the mechanism of its therapeutic action is not well understood. We investigated the effect of lithium on the circadian clock located in the ventricle barrier complex containing the choroid plexus (CP), a part of the glymphatic system that influences gross brain function via the production of cerebrospinal fluid. The mPer2Luc mice were injected with lithium chloride (LiCl) or vehicle, and their effects on the clock gene Nr1d1 in CP were detected by RT qPCR. CP organotypic explants were prepared to monitor bioluminescence rhythms in real time and examine the responses of the CP clock to LiCl and inhibitors of glycogen synthase kinase-3 (CHIR-99021) and protein kinase C (chelerythrine). LiCl affected Nr1d1 expression levels in CP in vivo and dose-dependently delayed the phase and prolonged the period of the CP clock in vitro. LiCl and CHIR-99021 had different effects on 1] CP clock parameters (amplitude, period, phase), 2] dexamethasone-induced phase shifts of the CP clock, and 3] dynamics of PER2 degradation and de novo accumulation. LiCl-induced phase delays were significantly reduced by chelerythrine, suggesting the involvement of PKC activity. The effects on the CP clock may be involved in the therapeutic effects of lithium and hypothetically improve brain function in psychiatric patients by aligning the function of the CP clock-related glymphatic system with the sleep-wake cycle. Importantly, our data argue for personalized timing of lithium treatment in BD patients.

• Klíčová slova
• Bipolar disorder, Choroid plexus, Circadian clock, GSK3, Lithium chloride, MPer2Luc mice,
• MeSH
• cirkadiánní hodiny * MeSH
• cirkadiánní proteiny Period genetika   MeSH
• cirkadiánní rytmus genetika   MeSH
• lithium farmakologie   MeSH
• myši MeSH
• plexus chorioideus metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cirkadiánní proteiny Period MeSH
• lithium MeSH

AIMS: Circadian clocks in the hippocampus (HPC) align memory processing with appropriate time of day. Our study was aimed at ascertaining the specificity of glycogen synthase kinase 3-beta (GSK3β)- and glucocorticoid (GC)-dependent pathways in the entrainment of clocks in individual HPC regions, CA1-3, and dentate gyrus (DG). METHODS: The role of GCs was addressed in vivo by comparing the effects of adrenalectomy (ADX) and subsequent dexamethasone (DEX) supplementation on clock gene expression profiles (Per1, Per2, Nr1d1, and Bmal1). In vitro the effects of DEX and the GSK3β inhibitor, CHIR-99021, were assessed from recordings of bioluminescence rhythms in HPC organotypic explants of mPER2Luc mice. RESULTS: Circadian rhythms of clock gene expression in all HPC regions were abolished by ADX, and DEX injections to the rats rescued those rhythms in DG. The DEX treatment of the HPC explants significantly lengthened periods of the bioluminescence rhythms in all HPC regions with the most significant effect in DG. In contrast to DEX, CHIR-99021 significantly shortened the period of bioluminescence rhythm. Again, the effect was most significant in DG which lacks the endogenously inactivated (phosphorylated) form of GSK3β. Co-treatment of the explants with CHIR-99021 and DEX produced the CHIR-99021 response. Therefore, the GSK3β-mediated pathway had dominant effect on the clocks. CONCLUSION: GSK3β- and GC-dependent pathways entrain the clock in individual HPC regions by modulating their periods in an opposite manner. The results provide novel insights into the mechanisms connecting the arousal state-relevant signals with temporal control of HPC-dependent memory and cognitive functions.

• Klíčová slova
• Adrenalectomy, Circadian clock, Dexamethasone, GSK3-beta, Glucocorticoids, Hippocampus,
• MeSH
• cirkadiánní hodiny * genetika   MeSH
• cirkadiánní proteiny Period genetika   metabolismus   MeSH
• cirkadiánní rytmus MeSH
• glukokortikoidy metabolismus   farmakologie   MeSH
• gyrus dentatus metabolismus   MeSH
• hipokampus metabolismus   MeSH
• kinasa 3 glykogensynthasy metabolismus   farmakologie   MeSH
• kinasa glykogensynthasy 3beta metabolismus   MeSH
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cirkadiánní proteiny Period MeSH
• glukokortikoidy MeSH
• kinasa 3 glykogensynthasy MeSH
• kinasa glykogensynthasy 3beta MeSH

BACKGROUND: The MTNR1B gene encodes a receptor for melatonin, a hormone regulating biorhythms. Disruptions in biorhythms contribute to the development of type 2 diabetes mellitus (T2DM). Genetic studies suggest that variability in the MTNR1B gene affects T2DM development. Our aim was to compare the distribution of the genetic variant rs10830963 between persons differing in glucose tolerance in a sample of the Czech population (N=1206). We also evaluated possible associations of the polymorphism with insulin sensitivity, beta cell function, with the shape of glucose, insulin and C-peptide trajectories measured 7 times during a 3-hour oral glucose tolerance test (OGTT) and with glucagon response. In a subgroup of 268 volunteers we also evaluated sleep patterns and biorhythm. RESULTS: 13 persons were diagnosed with T2DM, 119 had impaired fasting blood glucose (IFG) and/or impaired glucose tolerance (IGT). 1074 participants showed normal results and formed a control group. A higher frequency of minor allele G was found in the IFG/IGT group in comparison with controls. The GG constellation was present in 23% of diabetics, in 17% of IFG/IGT probands and in 11% of controls. Compared to CC and CG genotypes, GG homozygotes showed higher stimulated glycemia levels during the OGTT. Homozygous as well as heterozygous carriers of the G allele showed lower very early phase of insulin and C-peptide secretion with unchanged insulin sensitivity. These differences remained significant after excluding diabetics and the IFG/IGT group from the analysis. No associations of the genotype with the shape of OGTT-based trajectories, with glucagon or with chronobiological patterns were observed. However, the shape of the trajectories differed significantly between men and women. CONCLUSION: In a representative sample of the Czech population, the G allele of the rs10830963 polymorphism is associated with impaired early phase of beta cell function, and this is evident even in healthy individuals.

• Klíčová slova
• MTNR1B gene, OGTT trajectories, beta cell function, glucose tolerance, insulin sensitivity, rs10830963, type 2 daibetes mellitus,
• MeSH
• C-peptid MeSH
• diabetes mellitus 2. typu * epidemiologie   genetika   MeSH
• glukagon MeSH
• glukosa MeSH
• inzulin MeSH
• inzulinová rezistence * genetika   MeSH
• kinetika MeSH
• krevní glukóza MeSH
• lidé MeSH
• porucha glukózové tolerance * epidemiologie   genetika   MeSH
• prediabetes * MeSH
• receptor melatoninový MT2 * genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• C-peptid MeSH
• glukagon MeSH
• glukosa MeSH
• inzulin MeSH
• krevní glukóza MeSH
• MTNR1B protein, human MeSH Prohlížeč
• receptor melatoninový MT2 * MeSH

Misaligned feeding may lead to pancreatic insufficiency, however, whether and how it affects circadian clock in the exocrine pancreas is not known. We exposed rats to a reversed restricted feeding regimen (rRF) for 10 or 20 days and analyzed locomotor activity, daily profiles of hormone levels (insulin, glucagon, and corticosterone) in plasma, and clock gene expression in the liver and endocrine and exocrine pancreas. In addition, we monitored responses of the exocrine pancreatic clock in organotypic explants of mPer2Luc mice in real time to acetylcholine, insulin, and glucocorticoids. rRF phase-reversed the clock in the endocrine pancreas, similar to the clock in the liver, but completely abolished clock gene rhythmicity and significantly downregulated the expression of Cpb1 and Cel in the exocrine pancreas. rRF desynchronized the rhythms of plasma insulin and corticosterone. Daily profiles of their receptor expression differed in the two parts of the pancreas and responded differently to rRF. Additionally, the pancreatic exocrine clock responded differently to treatments with insulin and the glucocorticoid analog dexamethasone in vitro. Mathematical simulation confirmed that the long-term misalignment between these two hormonal signals, as occurred under rRF, may lead to dampening of the exocrine pancreatic clock. In summary, our data suggest that misaligned meals impair the clock in the exocrine part of the pancreas by uncoupling insulin and corticosterone rhythms. These findings suggest a new mechanism by which adverse dietary habits, often associated with shift work in humans, may impair the clock in the exocrine pancreas and potentially contribute to exocrine pancreatic insufficiency.

• Klíčová slova
• Circadian clock, Dexamethasone, Insulin, Misaligned feeding, Pancreas, mPer2Luc mouse,
• MeSH
• cirkadiánní hodiny * fyziologie   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• glukokortikoidy MeSH
• inzulin metabolismus   MeSH
• kortikosteron metabolismus   farmakologie   MeSH
• krysa rodu Rattus MeSH
• myši MeSH
• pankreas exokrinní * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• glukokortikoidy MeSH
• inzulin MeSH
• kortikosteron MeSH

The suprachiasmatic nuclei (SCN) of the hypothalamus harbor the central clock of the circadian system, which gradually matures during the perinatal period. In this study, time-resolved transcriptomic and proteomic approaches were used to describe fetal SCN tissue-level rhythms before rhythms in clock gene expression develop. Pregnant rats were maintained in constant darkness and had intact SCN, or their SCN were lesioned and behavioral rhythm was imposed by temporal restriction of food availability. Model-selecting tools dryR and CompareRhythms identified sets of genes in the fetal SCN that were rhythmic in the absence of the fetal canonical clock. Subsets of rhythmically expressed genes were assigned to groups of fetuses from mothers with either intact or lesioned SCN, or both groups. Enrichment analysis for GO terms and signaling pathways revealed that neurodevelopment and cell-to-cell signaling were significantly enriched within the subsets of genes that were rhythmic in response to distinct maternal signals. The findings discovered a previously unexpected breadth of rhythmicity in the fetal SCN at a developmental stage when the canonical clock has not yet developed at the tissue level and thus likely represents responses to rhythmic maternal signals.

• MeSH
• cirkadiánní rytmus * genetika   MeSH
• hypothalamus MeSH
• krysa rodu Rattus MeSH
• nucleus suprachiasmaticus metabolismus   MeSH
• plod fyziologie   MeSH
• proteomika * MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH