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Glucocorticoids (GCs) are essential drivers of mammalian tissue growth and maturation during one of the most critical developmental windows, the perinatal period. The developing circadian clock is shaped by maternal GCs. GC deficits, excess, or exposure at the wrong time of day leads to persisting effects later in life. During adulthood, GCs are one of the main hormonal outputs of the circadian system, peaking at the beginning of the active phase (i.e., the morning in humans and the evening in nocturnal rodents) and contributing to the coordination of complex functions such as energy metabolism and behavior, across the day. Our article discusses the current knowledge on the development of the circadian system with a focus on the role of GC rhythm. We explore the bidirectional interaction between GCs and clocks at the molecular and systemic levels, discuss the evidence of GC influence on the master clock in the suprachiasmatic nuclei (SCN) of the hypothalamus during development and in the adult system.

Members of the protein kinase C (PKC) family of serine/threonine kinases play key regulatory roles in numerous cellular processes, including differentiation and proliferation. Of the 11 mammalian PKC isoforms known, several have been implicated in tumor development and progression. However, in most cases, isotype specificity is poorly defined, and even contrary functions for a single PKC have been reported mostly because appropriate molecular and genetic tools were missing to specifically assess the contribution of single PKC isoforms in vivo. In this report, we therefore used PKC genetic targeting to study the role of PKCα and PKCζ in colorectal cancer. Both isoforms were found to be strongly down-regulated in intestinal tumors of ApcMin/+ mice. A deletion of PKCζ did not affect tumorigenesis in this animal model. In contrast, PKCα-deficient ApcMin/+ mice developed more aggressive tumors and died significantly earlier than their PKCα-proficient littermates. Even without an additional Apc mutation, PKCα knockout mice showed an elevated tendency to develop spontaneous intestinal tumors. Transcriptional profiling revealed a role for this kinase in regulating epidermal growth factor receptor (EGFR) signaling and proposed a synergistic mechanism for EGFR/activator protein and WNT/APC pathways in mediating intestinal tumor development. (Cancer Res 2006; 66(14): 6955-63)

Supplementary Figure 1 from Protein Kinase C α but not PKCζ Suppresses Intestinal Tumor Formation in ApcMin/+ Mice

Background & AimsThe liver ensures organismal homeostasis through modulation of physiological functions over the course of the day. How liver diseases such as non-alcoholic steatohepatitis (NASH) affects daily transcriptome rhythms in the liver remains elusive. To start closing this gap, we evaluated the impact of NASH on the diurnal regulation of the liver transcriptome in mice. Along this, we investigated how stringent consideration of circadian rhythmicity affects the outcomes of NASH transcriptome analyses.Approach & ResultsComparative rhythm analysis of the liver transcriptome from diet-induced NASH and control mice revealed an almost 3h phase advance in global gene expression rhythms. Rhythmically expressed genes associated with DNA repair and cell cycle regulation showed increased overall expression and circadian amplitude. In contrast, lipid and glucose metabolism associated genes showed loss of circadian amplitude, reduced overall expression, and phase advances in NASH livers. Comparison of NASH-induced liver transcriptome responses between published studies revealed little overlap (12%) in differentially expressed genes (DEGs). However, by controlling for sampling time and using circadian analytical tools, a 7-fold increase in DEG detection was achieved compared to methods without time control.ConclusionsNASH had a strong effect on circadian liver transcriptome rhythms with phase- and amplitude-specific effects for key metabolic and cell repair pathways, respectively. Accounting for circadian rhythms in NASH transcriptome studies markedly improves DEGs detection and enhances reproducibility.

Circadian rhythms are imprinted in all organisms and influence virtually all aspects of physiology and behaviour in adaptation to the 24-hour day-night cycle. This recognition of a circadian timekeeping system permeating essentially all healthy functioning of body and mind quickly leads to the realisation that, in turn, human ailments should be probed for the degree to which they are rooted in or marked by disruptions and dysregulations of circadian clock functions in the human body. In this review, we will focus on psychosis as a key mental illness and foremost one of its cardinal symptoms: auditory hallucinations. We will discuss recent empirical evidence and conceptual advances probing the potential role of circadian disruption in auditory hallucinations. Moreover, a dysbalance in excitation and inhibition within cortical networks, which in turn drive a disinhibition of dopaminergic signalling will be highlighted as central physiological mechanism. Finally, we will propose two avenues for experimentally intervening on the circadian influences to potentially alleviate hallucinations in psychotic disorders.

The circadian clock comprises a cellular endogenous timing system coordinating the alignment of physiological processes with geophysical time. Disruption of circadian rhythms has been associated with several metabolic diseases. In this review we focus on liver as a major metabolic tissue and one of the most well-studied organs with regard to circadian regulation. We summarize current knowledge about the role of local and systemic clocks and rhythms in regulating biological functions of the liver. We discuss how the disruption of circadian rhythms influences the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). We also critically evaluate whether NAFLD/NASH may in turn result in chronodisruption. The last chapter focuses on potential roles of the clock system in prevention and treatment of NAFLD/NASH and the interaction of current NASH drug candidates with liver circadian rhythms and clocks. It becomes increasingly clear that paying attention to circadian timing may open new avenues for the optimization of NAFLD/NASH therapies and provide interesting targets for prevention and treatment of these increasingly prevalent disorders.

Adrenal glucocorticoid (GC) hormones are important regulators of energy metabolism, brain functions, and the immune system. Their release follows robust diurnal rhythms and GCs themselves serve as entrainment signals for circadian clocks in various tissues. In the clinics, synthetic GC analogues are widely used as immunosuppressive drugs. GC inhibitory effects on the immune system are well documented and include suppression of cytokines and increased immune cell death. However, the circadian dynamics of GC action are often neglected. Synthetic GC medications fail to mimic complex GC natural rhythms. Several recent publications have shown that endogenous GCs and their daily concentration rhythms prepare the immune system to face anticipated environmental threats. That includes migration patterns that direct specific cell population to organs and tissues best exemplified by the rhythmic expression of chemoattractants and their receptors. On the other hand, chronotherapeutic approaches may benefit the treatment of immunological diseases such as asthma. In this review, we summarise our current knowledge on the circadian regulation of GCs, their role in innate and adaptive immune functions and the implications for the clinics.

Bariatric surgery is still the most effective long-term weight-loss therapy. Recent data indicate that surgical outcomes may be affected by diurnal food intake patterns. In this study, we aimed to investigate how surgery-induced metabolic adaptations (i.e. weight loss) interact with circadian clock function. For that reason, vertical sleeve gastrectomy (VSG) was performed in obese mice and rhythms in behavior, tissue rhythmicity, and white adipose tissue transcriptome were evaluated. VSG under constant darkness conditions led to a maximum weight loss of 18% compared to a loss of 3% after sham surgery. Post-surgical weight development was characterized by two distinct intervals of catabolic and subsequent anabolic metabolic state. Locomotor activity was not affected. However, VSG significantly increased active phase meal frequency in the anabolic state. No significant effects on clock gene rhythmicity were detected in adrenal and white adipose tissue (WAT) explant cultures. Transcriptome rhythm analyses of subcutaneous WAT revealed a reduction of cycling genes after VSG (sham: 2493 vs VSG: 1013) independent of sustained rhythms in core clock gene expression. This may be a consequence of weight loss-induced morphological reconstruction of WAT that overwrites the direct influence of the local clock machinery on the transcriptome. However, VSG altered rhythmic transcriptional regulation of WAT lipid metabolism pathways. Thus, our data suggest a reorganization of diurnal metabolic rhythms after VSG downstream of the molecular clock machinery.

Diurnal (i.e., 24 hr) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day-dependent manner. A 24-hr transcriptome profiling of liver tissue identified 37 robustly and time independently T3-associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10–15% of the liver transcriptome as rhythmic in control and T3 groups, but only 4% of the liver transcriptome (1033 genes) were rhythmic across both conditions – amongst these, several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state-dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In summary, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

Snacking of small quantities of palatable food items throughout the day is common in modern societies and is promoted by 24/7 lifestyles. Long-term mistimed high-caloric food intake disrupts endogenous circadian rhythms and supports the development of obesity and other metabolic disorders. However, less is known about the time-of-day dependent effects of snacking. We hypothesized that already a single snacking episode may affect the circadian regulation of metabolic parameters, in particular when the snack is consumed during the daily rest phase. We performed an acute snack experiment in mice by providing access to chow or chocolate either at day- or nighttime and assessed snack effects on core body temperature, locomotor activity, and gene expression in metabolic tissues. Our results show that daytime chocolate snacking leads to a higher body temperature and locomotor activity increase compared to chow and nighttime intake. This goes along with altered clock and metabolic gene expression in peripheral tissues. Changes in nutrient uptake transporter gene expression in the small intestine suggest increased glucose resorption after daytime snacking. Our results indicate an early mechanism for the adipogenic effect of mistimed high-calorie snacking.

ObjectiveInternal clocks time behavior and physiology, including the gut microbiome in a circadian (∼24 h) manner. Mismatch between internal and external time, e.g. during shift work, disrupts circadian system coordination promoting the development of obesity and type 2 diabetes (T2D). Conversely, body weight changes induce microbiota dysbiosis. The relationship between circadian disruption and microbiota dysbiosis in metabolic diseases, however, remains largely unknown.MethodsCore and accessory clock gene expression in different gastrointestinal (GI) tissues were determined by qPCR in two different models of circadian disruption - mice with Bmal1 deficiency in the circadian pacemaker, the suprachiasmatic nucleus (Bmal1SCNfl/-), and wild-type mice exposed to simulated shift work (SSW). Body composition and energy balance were evaluated by nuclear magnetic resonance (NMR), bomb calorimetry, food intake and running-wheel activity. Intestinal permeability was measured in an Ussing chamber. Microbiota composition and functionality were evaluated by 16S rRNA gene amplicon sequencing, PICRUST2.0 analysis and targeted metabolomics. Finally, microbiota transfer was conducted to evaluate the functional impact of SSW-associated microbiota on the host’s physiology.ResultsBoth chronodisruption models show desynchronization within and between peripheral clocks in GI tissues and reduced microbial rhythmicity, in particular in taxa involved in short-chain fatty acid (SCFA) fermentation and lipid metabolism. In Bmal1SCNfl/- mice, loss of rhythmicity in microbial functioning associates with previously shown increased body weight, dysfunctional glucose homeostasis and adiposity. Similarly, we observe an increase in body weight in SSW mice. Germ-free colonization experiments with SSW- associated microbiota mechanistically link body weight gain to microbial changes. Moreover, alterations in expression of peripheral clock genes as well as clock-controlled genes (CCGs) relevant for metabolic functioning of the host were observed in recipients, indicating a bidirectional relationship between microbiota rhythmicity and peripheral clock regulation.ConclusionsCollectively, our data suggest that loss of rhythmicity in bacteria taxa and their products, which likely originates in desynchronization of intestinal clocks, promotes metabolic abnormalities during shift work.

Metabolic syndrome (MS) and its related diseases, including obesity and non-alcoholic fatty liver disease (NAFLD), have become a public health issue due to their increasing prevalence. Polyphenols, such as grape seed proanthocyanidin extract (GSPE), are bioactive compounds present in fruits and vegetables that show promise for MS treatment. We have previously demonstrated that the efficacy of this phenolic extract in the modulation of liver circadian clocks was affected by the time of the day at which it was ingested. Thus, we wondered if the beneficial effects of GSPE consumption in NAFLD could be mediated by diurnal modulation of hepatic lipid and glucose metabolism and whether GSPE effects on liver metabolism are impacted by the timing of administration. Results from hepatic lipid profiling, expression rhythm analysis of metabolic genes together with liver metabolomics in rats revealed that the CAF diet impaired glucose homeostasis and enhanced lipogenesis in the liver, leading to the generation of hepatosteatosis. Chronic consumption of GSPE at the onset of the active phase was able to restore the daily oscillation of liver mass and of key lipogenic and glycogenic genes, along with the reestablishment of liver metabolite rhythms, demonstrating hepatoprotective properties by decreasing triglyceride accumulation and lipid droplet formation in the liver, thus mitigating the development of CAF-induced NAFLD. Furthermore, in vitro data suggest that catechin, one of the main phenolic compounds found in the GSPE extract, may be involved in the ameliorating effects of GSPE against NAFLD.

Internal clocks time behavior and physiology, including the gut microbiome, in a circadian (∼24 h) manner. Mismatch between internal and external time, e.g. during shift work, disrupts circadian system coordination promoting the development of obesity and type 2 diabetes (T2D). Conversely, body weight changes induce microbiota dysbiosis. The relationship between circadian disruption and microbiota dysbiosis in metabolic diseases, however, remains largely unknown.Core and accessory clock gene expression in different gastrointestinal (GI) tissues were determined by qPCR in two different models of circadian disruption - mice with Bmal1 deficiency in the circadian pacemaker, the suprachiasmatic nucleus (Bmal1Both chronodisruption models show desynchronization within and between peripheral clocks in GI tissues and reduced microbial rhythmicity, in particular in taxa involved in short-chain fatty acid (SCFA) fermentation and lipid metabolism. In Bmal1SCNfl/- mice, loss of rhythmicity in microbial functioning associates with previously shown increased body weight, dysfunctional glucose homeostasis and adiposity. Similarly, we observe an increase in body weight in SSW mice. Germ-free colonization experiments with SSW-associated microbiota mechanistically link body weight gain to microbial changes. Moreover, alterations in expression of peripheral clock genes as well as clock-controlled genes (CCGs) relevant for metabolic functioning of the host were observed in recipients, indicating a bidirectional relationship between microbiota rhythmicity and peripheral clock regulation.Collectively, our data suggest that loss of rhythmicity in bacteria taxa and their products, which likely originates in desynchronization of intestinal clocks, promotes metabolic abnormalities during shift work.

In mammals, molecular circadian clocks not only exist in the suprachiasmatic nucleus (SCN) but in almost all organ systems. Intriguingly, tissue clocks can operate in both isolated tissues and cell lines with endocrine signals mediating the circadian expression of local transcriptomes. This can be demonstrated by treating tissue explants with endocrine cues in a phase- and dose-dependent manner. In this chapter we provide an overview of methods to study the effects of candidate hormonal time cues on tissue clock resetting. We propose an experimental procedure based on an in vitro setup consisting of several consecutive steps in which organotypic tissue cultures or cells can be used. Our approach targets the potential resetting mechanism at three levels: the hormone, the direct clock gene target, and the tissue clock response.

Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 – 15 % of the liver transcriptome as rhythmic in control and T3groups, but only 4 % of the liver transcriptome (1,033 genes) were rhythmic across both conditions – amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

Diurnal (i.e., 24 hr) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (TMany environmental conditions, including light and temperature, vary with a daily rhythm that affects how animals interact with their surroundings. Indeed, most species have developed so-called circadian clocks: internal molecular timers that cycle approximately every 24 hours and regulate many bodily functions, including digestion, energy metabolism and sleep. The energy metabolism of the liver – the chemical reactions that occur in the organ to produce energy from nutrients – is controlled both by the circadian clock system, and by the hormones produced by a gland in the neck called the thyroid. However, the interaction between these two regulators is poorly understood. To address this question, de Assis, Harder et al. elevated the levels of thyroid hormones in mice by adding these hormones to their drinking water. Studying these mice showed that, although thyroid hormone levels were good indicators of how much energy mice burn in a day, they do not reflect daily fluctuations in metabolic rate faithfully. Additionally, de Assis, Harder et al. showed that elevating T

BackgroundMost mammalian cells harbor molecular circadian clocks that synchronize physiological functions with the 24-h day-night cycle. Disruption of circadian rhythms, through genetic or environmental changes, promotes the development of disorders like obesity, cardiovascular diseases, and cancer. At the cellular level, circadian, mitotic, and redox cycles are functionally coupled. Evernic (EA) and usnic acid (UA), two lichen secondary metabolites, show various pharmacological activities including anti-oxidative, anti-inflammatory, and neuroprotective action. All these effects have likewise been associated with a functional circadian clock.Hypothesis/PurposeTo test, if the lichen compounds EA and UA modulate circadian clock function at the cellular level.MethodsWe used three different cell lines and two circadian luminescence reporter systems for evaluating dose- and time-dependent effects of EA/UA treatment on cellular clock regulation at high temporal resolution. Output parameters studied were circadian luminescence rhythm period, amplitude, phase, and dampening rate.ResultsBoth compounds had marked effects on clock rhythm amplitudes and dampening independent of cell type, with UA generally showing a higher efficiency than EA. Only in fibroblast cells, significant effects on clock period were observed for UA treated cells showing shorter and EA treated cells showing longer period lengths. Transient treatment of mouse embryonic fibroblasts at different phases had only minor clock resetting effects for both compounds.ConclusionSecondary metabolites of lichen alter cellular circadian clocks through amplitude reduction and increased rhythm dampening.

Innere, sog. zirkadiane Uhren regulieren zahlreiche Korperfunktionen – darunter unseren Schlaf-Wach-Rhythmus – im 24-h-Takt. Wahrend die Funktion des zirkadianen Systems in der Regulation der Phasenlage des Schlafs (Prozess C) lange bekannt war, zeigen neuere Studien eine weit engere Verknupfung von Uhrensystem und Schlaffunktion auf mehreren Ebenen. Genetische Defekte im molekularen Uhrwerk haben Auswirkungen auf den Schlafhomoostat (Prozess S). Umgekehrt wirken Anderungen im naturlichen Schlafzyklus zuruck auf die Funktion der zirkadianen Uhr – und das nicht nur im zentralen Nervensystem (ZNS), sondern insbesondere auch in peripheren Organen. Dieser Schlaf-Uhr-Crosstalk konnte viele der negativen Effekte von Rhythmus- und Schlafstorungen auf den Energiestoffwechsel erklaren. Gleichzeitig bietet er neue Ansatzpunkte fur die Pravention und Behandlung von schlafassoziierten pathologischen Effekten, z. B. bei Schichtarbeitern. Dieser Ubersichtsartikel beschreibt die Interaktion von Uhrensystem und Schlaf-Regelkreisen im ZNS und deren Effekte auf periphere physiologische Prozesse, insbesondere den Energiestoffwechsel. Er skizziert ein Modell der engen Kopplung von Schlaf und Uhrenfunktion und deren Bedeutung als Angriffspunkt fur die Behandlung von durch Schlafstorungen bedingte Erkrankungen.

Meal timing and composition are frequently reported in the literature as zeitgebers (that is, time cues) for the circadian system of humans and animal models, albeit secondary to light. Although widely assumed to be true, evidence for food zeitgeber effects specific to humans is notably scarce. Fostering zeitgeber hygiene in the general population as the development and practice of healthy use of zeitgebers could potentially reduce chronobiological strain, which is defined as disruption or misalignment within the circadian system. Such chronobiological strain is associated with modern 24/7 lifestyles (for example, shift work) and several negative health outcomes. Adjustments to meal timing and composition are an attractive strategy to synchronize circadian rhythms and develop zeitgeber hygiene. Thus, clarifying the actual effect of meal timing and composition on the human circadian system is a crucial piece of the human chronobiology puzzle. This Review weighs the evidence from human studies pertaining to the hypothesis that food is a circadian zeitgeber by comparing findings against formal zeitgeber criteria put forward by Jurgen Aschoff in the 1950s.

The circadian clock is an evolutionarily highly conserved endogenous timing program that structures physiology and behavior according to the time of day. Disruption of circadian rhythms is associated with many common pathologies. The emerging field of circadian medicine aims to exploit the mechanisms of circadian physiology and clock–disease interaction for clinical diagnosis, treatment, and prevention. In this Essay, we outline the principle approaches of circadian medicine, highlight the development of the field in selected areas, and point out open questions and challenges. Circadian medicine has unambiguous health benefits over standard care but is rarely utilized. It is time for clock biology to become an integrated part of translational research.

24-h rhythms in physiology and behaviour are orchestrated by an endogenous circadian clock system. In mammals, these clocks are hierarchically organized with a master pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN). External time signals—so-called zeitgebers—align internal with geophysical time. During shift work, zeitgeber input conflicting with internal time induces circadian desynchrony which, in turn, promotes metabolic and psychiatric disorders. However, little is known about how internal desynchrony is expressed at the molecular level under chronodisruptive environmental conditions. We here investigated the effects of zeitgeber misalignment on circadian molecular organisation by combining 28-h light–dark (LD-28) cycles with either 24-h (FF-24) or 28-h feeding-fasting (FF-28) regimes in mice. We found that FF cycles showed strong effects on peripheral clocks, while having little effect on centrally coordinated activity rhythms. Systemic, i.e., across-tissue internal circadian desynchrony was profoundly induced within four days in LD-28/FF-24, while phase coherence between tissue clocks was maintained to a higher degree under LD-28/FF-28 conditions. In contrast, temporal coordination of clock gene activity across tissues was reduced under LD-28/FF-28 conditions compared to LD-28/FF-24. These results indicate that timed food intake may improve internal synchrony under disruptive zeitgeber conditions but may, at the same time, weaken clock function at the tissue level.

Most lifeforms on earth use endogenous, so-called circadian clocks to adapt to 24-h cycles in environmental demands driven by the planet’s rotation around its axis. Interactions with the environment change over the course of a lifetime, and so does regulation of the circadian clock system. In this review, we summarize how circadian clocks develop in humans and experimental rodents during embryonic development, how they mature after birth and what changes occur during puberty, adolescence and with increasing age. Special emphasis is laid on the circadian regulation of reproductive systems as major organizers of life segments and life span. We discuss differences in sexes and outline potential areas for future research. Finally, potential options for medical applications of lifespan chronobiology are discussed.

A network of cellular timers ensures the maintenance of homeostasis by temporal modulation of physiological processes across the day. These so-called circadian clocks are synchronized to geophysical time by external time cues (or zeitgebers). In modern societies, natural environmental cycles are disrupted by artificial lighting, around-the-clock availability of food or shift work. Such contradictory zeitgeber input promotes chronodisruption, i.e., the perturbation of internal circadian rhythms, resulting in adverse health outcomes. While this phenomenon is well described, it is still poorly understood at which level of organization perturbed rhythms impact on health and wellbeing. In this review, we discuss different levels of chronodisruption and what is known about their health effects. We summarize the results of disrupted phase coherence between external and internal time vs. misalignment of tissue clocks amongst each other, i.e., internal desynchrony. Last, phase incoherence can also occur at the tissue level itself. Here, alterations in phase coordination can emerge between cellular clocks of the same tissue or between different clock genes within the single cell. A better understanding of the mechanisms of circadian misalignment and its effects on physiology will help to find effective tools to prevent or treat disorders arising from modern-day chronodisruptive environments.

Hormonal signalling is a central component of the regulation of sleep, behaviour, and multiple other physiological processes aligned with external time cues through endogenous circadian clocks. Endocrine feedback to the circadian clock is exerted via key systems and supports the robustness of endogenous rhythmicity. It is challenged by multiple modern lifestyle factors such as shift work, light pollution, or high-calorie diets which may alter this delicate balance and shift physiological set points. The following chapter summarizes current knowledge on the underlying mechanisms controlling this interregulation of circadian timing, sleep, and the endocrine system, and what disorders may be caused by its imbalance.

Motivation A fundamental interest in chronobiology is to compare patterns between groups of rhythmic data. However, many existing methods are ill-equipped to derive statements concerning the statistical significance of differences between rhythms that may be visually apparent. This is attributed to both the form of data used (longitudinal versus cross-sectional) and the limitations of the statistical tests used to draw conclusions. Results To address this problem, we propose that a cosinusoidal curve with a particular parametrization be used to model and compare data of two sets of observations collected over a 24-h period. The novelty of our test is in the parametrization, which allows the explicit estimation of rhythmic parameters [mesor (the rhythm-adjusted mean level of a response variable around which a wave function oscillates), amplitude and phase], and simultaneously testing for statistical significance in all three parameters between two or more groups of datasets. A statistically significant difference between two groups, regarding each of these rhythmic parameters, is indicated by a P-value. The method is evaluated by applying the model to publicly available datasets, and is further exemplified by comparison to the currently recommended method, DODR. The results suggest that the method proposed may be highly sensitive to detect rhythmic differences between groups in phase, amplitude and mesor. Availability and implementation https://github.com/RWParsons/circacompare/

Was ist neu? Chronodisruption und Metabolismus Die zunehmende Aufweichung von festen Tagesrhythmen in der modernen Gesellschaft stört die zeitliche Koordination physiologischer Prozesse im Körper. Die resultierende interne Desynchronisation begünstigt die Entwicklung zahlreicher Krankheiten, insbesondere im metabolischen Bereich – von Verdauungsstörungen über Adipositas bis hin zu Typ-2-Diabetes. Chronodisruption und Immunsystem Die Kombination aus Chronodisruption und Schlafmangel beeinträchtigt zudem die Sensitivität und Effektivität der Immunabwehr. Umgekehrt kann eine Stabilisierung des zirkadianen Systems die Resilienz gegen viele Krankheiten erhöhen. Chronomedizin Das Feld der Chronobiologie hat sich in den letzten Jahren von einer Grundlagendisziplin zu einer klinisch angewandten Wissenschaft entwickelt. Neben der klassischen Chronotherapie, der tageszeitlich optimierten Gabe von Medikamenten, bietet insbesondere die Stabilisierung des zirkadianen Systems – durch Verhaltensinterventionen oder Chronobiologicals – eine Reihe neuer Ansätze für die Prävention und Therapie vieler Volkskrankheiten.

Die zirkadiane Uhr ist ein hoch spezialisierter Taktgeber des menschlichen Organismus und stellt einen essenziellen Bestandteil eines gesunden Stoffwechsels dar. Der intrinsische zirkadiane Rhythmus kann unter anderem durch exogene Faktoren wie Licht/Dunkelheit, Verhaltensmuster, korperliche Aktivitat, Essgewohnheiten und Schlafmangel bzw. Schlafstorungen moduliert werden. Zudem kann eine veranderte Expression von Uhrengenen, beispielsweise von PERIOD 1 und 2, die innere Rhythmik beeinflussen. Veranderungen der zirkadianen Rhythmik werden mit einer Vielzahl an psychischen und physischen Erkrankungen in Verbindung gebracht. Aktuelle Studien belegen, dass vor allem quantitative und qualitative Veranderungen des Schlafrhythmus signifikant mit einer erhohten Pravalenz von Adipositas einhergehen. Zudem konnen eine eingeschrankte Schlafdauer und -qualitat eine verminderte Glukosetoleranz und Insulinsensitivitat bewirken und damit ein erhohtes Diabetesrisiko mit sich bringen. Neben den Kernkomponenten des metabolischen Syndroms zeigen sich Veranderungen hormoneller und neuronaler Signalwege, die erheblich unseren Energiestoffwechsel beeinflussen. Diese Ubersichtsarbeit bietet einen Uberblick uber die aktuelle Studienlage und beschreibt den Zusammenhang zwischen zirkadianen Rhythmen, Schlaf und menschlichem Stoffwechsel.

Hormones are major systemic regulators of homeostatic functions. Not surprisingly, most endocrine signals show some extent of variation across the day. This holds true for the three major hormonal axes of the body originating from the hypothalamus, relayed by the pituitary and terminating in the adrenal (HPA axis), the thyroid (HPT axis), and the gonads (HPG axis), respectively. The rhythmicity of endocrine axis formation has important functions for the maintenance of homeostasis and stabilizes physiological functions against external perturbations. In some cases, such as cortisol, hormonal signals are themselves implicated in circadian regulation and, thus, endocrine disruption may affect the function of the circadian clock network to alter further downstream processes.

Attention deficit hyperactivity disorder (ADHD) is a very common disorder in children and adults. A connection with sleep disorders, and above all, disorders of the circadian rhythm are the subject of research and debate. The circadian system can be represented on different levels. There have been a variety of studies examining 24-h rhythms at the behavioral and endocrine level. At the molecular level, these rhythms are based on a series of feedback loops of core clock genes and proteins. In this paper, we compared the circadian rhythms at the behavioral, endocrine, and molecular levels between children with ADHD and age- and BMI-matched controls, complementing the previous data in adults. In a minimally invasive setting, sleep was assessed via a questionnaire, actigraphy was used to determine the motor activity and light exposure, saliva samples were taken to assess the 24-h profiles of cortisol and melatonin, and buccal mucosa swaps were taken to assess the expression of the clock genes BMAL1 and PER2. We found significant group differences in sleep onset and sleep duration, cortisol secretion profiles, and in the expression of both clock genes. Our data suggest that the analysis of circadian molecular rhythms may provide a new approach for diagnosing ADHD in children and adults.

The adaptation of organisms to a rhythmic environment is mediated by an internal timing system termed the circadian clock. In mammals, molecular clocks are found in all tissues and organs. This circadian clock network regulates the release of many hormones, which in turn influence some of the most vital behavioural functions. Sleep-wake cycles are under strict circadian control with strong influence of rhythmic hormones such as melatonin, cortisol and others. Food intake, in contrast, receives circadian modulation through hormones such as leptin, ghrelin, insulin and orexin. A third behavioural output covered in this review is mating and bonding behaviours, regulated through circadian rhythms in steroid hormones and oxytocin. Together, these data emphasize the pervasive influence of the circadian clock system on behavioural outputs and its mediation through endocrine networks.

The term energy metabolism comprises the entirety of chemical processes associated with uptake, conversion, storage, and breakdown of nutrients. All these must be tightly regulated in time and space to ensure metabolic homeostasis in an environment characterized by cycles such as the succession of day and night. Most organisms evolved endogenous circadian clocks to achieve this goal. In mammals, a ubiquitous network of cellular clocks is coordinated by a pacemaker residing in the hypothalamic suprachiasmatic nucleus. Adipocytes harbor their own circadian clocks, and large aspects of adipose physiology are regulated in a circadian manner through transcriptional regulation of clock-controlled genes. White adipose tissue (WAT) stores energy in the form of triglycerides at times of high energy levels that then serve as fuel in times of need. It also functions as an endocrine organ, releasing factors in a circadian manner to regulate food intake and energy turnover in other tissues. Brown adipose tissue (BAT) produces heat through nonshivering thermogenesis, a process also controlled by the circadian clock. We here review how WAT and BAT contribute to the circadian regulation of energy metabolism. We describe how adipose rhythms are regulated by the interplay of systemic signals and local clocks and summarize how adipose-originating circadian factors feed-back on metabolic homeostasis. The role of adipose tissue in the circadian control of metabolism becomes increasingly clear as circadian disruption leads to alterations in adipose tissue regulation, promoting obesity and its sequelae. Stabilizing adipose tissue rhythms, in turn, may help to combat disrupted energy homeostasis and obesity.

An endogenous circadian clock system enables organisms to adapt to time-of-day dependent environmental changes. In consequence, most physiological processes exhibit daily rhythms of, e.g., energy metabolism, immune function, sleep, or hormone production. Hypothalamic circadian clocks have been identified to play a particular role in coordinating many of these processes. Primary neuronal cultures are widely used as a physiologically relevant model to study molecular events within neurons. However, as circadian rhythms include dynamic molecular changes over longer timescales that vary between individual cells, longitudinal measurement methods are essential to investigate the regulation of circadian clocks of hypothalamic neurons. Here we provide a protocol for generating primary hypothalamic neuronal cultures expressing a circadian luciferase reporter. Such reporter cells can be used to longitudinally monitor cellular circadian rhythms at high temporal resolution by performing bioluminescence measurements.

The circadian clock exerts an important role in systemic homeostasis as it acts a keeper of time for the organism. The synchrony between the daily challenges imposed by the environment needs to be aligned with biological processes and with the internal circadian clock. In this review, it is provided an in-depth view of the molecular functioning of the circadian molecular clock, how this system is organized, and how central and peripheral clocks communicate with each other. In this sense, we provide an overview of the neuro-hormonal factors controlled by the central clock and how they affect peripheral tissues. We also evaluate signals released by peripheral organs and their effects in the central clock and other brain areas. Additionally, we evaluate a possible communication between peripheral tissues as a novel layer of circadian organization by reviewing recent studies in the literature. In the last section, we analyze how the circadian clock can modulate intracellular and tissue-dependent processes of metabolic organs. Taken altogether, the goal of this review is to provide a systemic and integrative view of the molecular clock function and organization with an emphasis in metabolic tissues.

A gradual adaptation to a shifted light-dark (LD) cycle is a key element of the circadian clock system and believed to be controlled by the central circadian pacemaker, the suprachiasmatic nucleus (SCN). Endocrine factors have a strong influence on the regulation of the circadian clock network and alter acute photic responses of the SCN clock. In females, endocrine function depends on the stage of the ovarian cycle. So far, however, little is known about the effect of the estrous cycle on behavioral and molecular responses to shifts in the LD rhythm. Based on this, we investigated whether estrous state affects the kinetics of phase shift during jetlag in behavior, physiology, and molecular clock rhythms in the SCN and in peripheral tissues. Female mice exposed to an advanced LD phase at proestrous or metestrous showed different phase-shift kinetics, with proestrous females displaying accelerated adaptation in behavior and physiology. Constant darkness release experiments suggest that these fast phase shifts do not reflect resetting of the SCN pacemaker. Explant experiments on SCN, adrenal gland, and uterus confirmed this finding with proestrous females showing significantly faster clock phase shifts in peripheral tissues compared with the SCN. Together, these findings provide strong evidence for an accelerated adaptation of proestrous compared with metestrous females to new LD conditions that is accompanied by rapid behavioral, physiological, and molecular rhythm resetting. Not only do these findings open up a new avenue to understand the effect of estrous cycle on the clock network under changing environmental conditions but also imply a greater susceptibility in proestrous females.

In mammals, 24-h rhythms of physiology and behavior are organized by a body-wide network of clock genes and proteins. Despite the well-known function of the adult circadian system, the roles of maternal, fetal and placental clocks during pregnancy are poorly defined. In the mature mouse placenta, the labyrinth zone (LZ) is of fetal origin and key for selective nutrient and waste exchange. Recently, clock gene expression has been detected in LZ and other fetal tissues; however, there is no evidence of a placental function controlled by the LZ clock. Here, we demonstrate that specifically the trophoblast layer of the LZ harbors an already functional clock by late gestation, able to regulate in a circadian manner the expression and activity of the xenobiotic efflux pump, ATP-binding cassette sub-family B member 1 (ABCB1), likely gating the fetal exposure to drugs from the maternal circulation to certain times of the day. As more than 300 endogenous and exogenous compounds are substrates of ABCB1, our results might have implications in choosing the maternal treatment time when aiming either maximal/minimal drug availability to the fetus/mother., Instituto de Investigaciones Bioquímicas de La Plata

Endogenous circadian clocks adapt an organism’s physiology and behavior to predictable changes in the environment as a consequence of the Earth’s rotation around its axis. In mammals, circadian rhythms are the output of a ubiquitous network of cellular timers coordinated by a hypothalamic master pacemaker. Circadian clock function is closely connected to the stress response system which has evolved to ensure survival under less predictable situations of danger. Disruptions in both of these functions are highly prevalent in modern society and have been linked to pathologic alterations in metabolic setpoints, promoting overeating, obesity, and type-2 diabetes. This paper describes the different levels of interaction between the circadian clock and acute and chronic stress responses. It summarizes studies assessing clock-stress crosstalk in the context of metabolic homeostasis and outlines options to use this interaction for diagnostic and therapeutic measures targeting metabolic health and well-being in the highly chronodisruptive environment of modern 24-h globalized societies.