Chronodisruption
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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.
- 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
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.
- 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
Cirkadiánne rytmy sú externým vyjadrením vnútorného časového mechanizmu merajúceho denný čas. Cirkadiánne hodiny sú nastavené primárnym endogénnym generátorom časových rytmov (tzv. pacemakerom) lokalizovaným v hypotalamickom párovom jadre nucleus suprachiasmaticus a modulované periodickými vstupmi z vonkajšieho prostredia (tzv. synchronizátormi), z ktorých najsilnejšie sú striedanie svetla a tmy. Objav lokálnych cirkadiánnych oscilátorov v periférnych tkanivách (napr. pankrease) viedol k zmene pohľadu na cirkadiánnu biológiu a podnietil záujem o štúdium úlohy periférnych oscilátorov v etiopatogenéze niektorých ochorení vrátane diabetu mellitu 2. typu.
Circadian rhythms are external expression of the internal timing mechanism that measures daily time. Circadian clock is under direct control of the master cirkadian pacemaker located in the suprachiasmatic nucleus in the hypothalamus and is modulated by periodic inputs from the external environment (synchronisators), from which light/dark cycle is the most important. Local circadian oscillators have been proven in the peripheral tissues (e. g. pancreas) recently and it has caused change in the look at circadian biology and role of the circadian disruption or chronodisruption in the etiopathogenensis of some diseases including type 2 diabetes mellitus.
The lifestyle of human society is drifting apart from the natural environmental cycles that have influenced it since its inception. These cycles were fundamental in structuring the daily lives of people in the pre-industrial era, whether they were seasonal or daily. Factors that disrupt the regularity of human behaviour and its alignment with solar cycles, such as late night activities accompanied with food intake, greatly disturb the internal temporal organization in the body. This is believed to contribute to the rise of the so-called diseases of civilization. In this review, we discuss the connection between misalignment in daily (circadian) regulation and its impact on health, with a focus on cardiovascular and metabolic disorders. Our aim is to review selected relevant research findings from laboratory and human studies to assess the extent of evidence for causality between circadian clock disruption and pathology. Keywords: Circadian clock, Chronodisruption, Metabolism, Cardiovascular disorders, Spontaneously hypertensive rat, Human, Social jetlag, Chronotype.
- MeSH
- chronobiologické poruchy patofyziologie metabolismus komplikace MeSH
- cirkadiánní hodiny fyziologie MeSH
- cirkadiánní rytmus * fyziologie MeSH
- kardiovaskulární nemoci * metabolismus etiologie epidemiologie patofyziologie MeSH
- lidé MeSH
- metabolické nemoci * metabolismus epidemiologie patofyziologie etiologie MeSH
- modely nemocí na zvířatech MeSH
- rizikové faktory MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Disturbed circadian activity of the sympathetic system may be involved in negative consequences of chronodisruption on the cardiovascular system. We studied daily changes in pressure response to adrenergic stimulation in rats exposed to repeated phase advance shifts (PAS) of light/dark (LD) regimen. Blood pressure (BP), heart rate (HR) and locomotor activity was measured by radiotelemetry in normotensive Wistar rats exposed to repeated PAS (three 8-h shifts per week) lasting for 12 weeks. Norepinephrine was administered subcutaneously in the middle of L and D during week 12 of PAS exposure. In the control LD cycle, cardiovascular parameters exhibited significant daily rhythms with expected higher values during D than L phase. Rats exposed to PAS showed disturbed rhythms without a BP and HR increase. Administration of norepinephrine to control rats revealed daily variability in the cardiovascular response with higher stimulation of BP during L than D. This daily pattern of BP response to norepinephrine was diminished in the PAS group. The damped daily variability in pressure response to norepinephrine and augmented response during the light phase of the day suggest that the increased and desynchronized activity of the sympathetic system may worsen responses of the cardiovascular system to load in individuals exposed to irregular LD conditions.
- MeSH
- časové faktory MeSH
- cirkadiánní rytmus * MeSH
- fotoperioda * MeSH
- injekce subkutánní MeSH
- krevní tlak účinky léků MeSH
- noradrenalin aplikace a dávkování farmakologie MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar MeSH
- srdeční frekvence účinky léků MeSH
- světlo * MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Circadian rhythms are such an innate part of our lives that we rarely pause to speculate why they even exist. Recently, some studies have suggested that the disruption of the circadian system may be causal for the manifestations of metabolic syndrome (MetS). This review summarizes the latest evidence of the existing interaction among chronobiology, genetics and MetS. RECENT FINDINGS: Shift work, sleep deprivation and bright light exposure at night are related to increased adiposity and prevalence of MetS. Animal models have revealed that mice with circadian locomotor output cycles kaput (clock) gene disruption are prone to develop a phenotype resembling MetS. Moreover, studies in humans have shown that clock genes are expressed in adipose tissue, and that both their levels of expression and their genetic variants correlate with different components of the MetS. Current studies are illustrating the particular role of different clock gene variants and their predicted haplotypes in MetS. SUMMARY: The circadian system has an important impact on metabolic disturbances and vice versa. Although the precise mechanism linking the MetS to chronodisruption is not well known, hypotheses point to the internal desynchronization between different circadian rhythms. The novelty of this area of research is contributing to the development of new and intriguing studies, particularly those focused on the association between different clock genes polymorphisms and MetS traits.
