Circadian clock-coordinated 12 Hr period rhythmic activation of the IRE1alpha pathway controls lipid metabolism in mouse liver.

The mammalian circadian clock plays a fundamental role in the liver by regulating fatty acid, glucose, and xenobiotic metabolism. Impairment of this rhythm has been shown to lead to diverse pathologies, including metabolic syndrome. Currently, it is supposed that the circadian clock regulates metabolism mostly by regulating expression of liver enzymes at the transcriptional level. Here, we show that the circadian clock also controls hepatic metabolism by synchronizing a secondary 12 hr period rhythm characterized by rhythmic activation of the IRE1alpha pathway in the endoplasmic reticulum. The absence of circadian clock perturbs this secondary clock and provokes deregulation of endoplasmic reticulum-localized enzymes. This leads to impaired lipid metabolism, resulting in aberrant activation of the sterol-regulated SREBP transcription factors. The resulting aberrant circadian lipid metabolism in mice devoid of the circadian clock could be involved in the appearance of the associated metabolic syndrome.

The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification.

The PAR-domain basic leucine zipper (PAR bZip) transcription factors DBP, TEF, and HLF accumulate in a highly circadian manner in several peripheral tissues, including liver and kidney. Mice devoid of all three of these proteins are born at expected Mendelian ratios, but are epilepsy prone, age at an accelerated rate, and die prematurely. In the hope of identifying PAR bZip target genes whose altered expression might contribute to the high morbidity and mortality of PAR bZip triple knockout mice, we compared the liver and kidney transcriptomes of these animals to those of wild-type or heterozygous mutant mice. These experiments revealed that PAR bZip proteins control the expression of many enzymes and regulators involved in detoxification and drug metabolism, such as cytochrome P450 enzymes, carboxylesterases, and constitutive androstane receptor (CAR). Indeed, PAR bZip triple knockout mice are hypersensitive to xenobiotic compounds, and the deficiency in detoxification may contribute to their early aging.

Circadian Variations of Ischemic Burden Among Patients with Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Introduction Le rythmes circadiens influencent différents paramètres de la physiologie et de la physiopathologie cardiovasculaire. Récemment, une relation entre la taille d'un infarctus et l'heure du jour à laquelle il se produit a été suggérée dans des modèles expérimentaux d'infarctus du myocarde. Le but de cette étude a été de déterminer si les rythmes circadiens pouvaient influencer la gravité d'un infarctus en terme de taille et de mortalité chez les patients hospitalisés pour un infarctus du myocarde avec sus-décalage du segment ST (STEMI) ayant bénéficié d'une intervention coronarienne percutanée primaire (ICPP). Méthode Chez 353 patients consécutifs admis avec un STEMI et traités par ICPP, l'heure à la survenue des symptômes, le pic de créatine kinase (reflet de la taille d'un infarctus) et le suivi à 30 jours ont été collectés. Les patients ont été répartis en 4 groupes en fonction de l'heure de survenue de leurs symptômes (00 :00 - 05h59, 06:00 - 11 59 12 00-17h59 et 18h00-23h59). Résultats Aucune différence statistiquement significative n'a été retrouvée entre les différents groupes en ce qui concerne les caractéristiques des patients ou de leur prise en charge. Après analyse multivariée, nous avons mis en évidence une différence statistiquement significative entre les pics de créatine kinase chez les patients avec survenue des symptômes entre 00 :00 et 05:59, qui étaient plus élevés que les pics de créatine kinase chez les patients avec survenue des symptômes à tout autre moment de la journée (augmentation moyenne de 38,4%, ρ <0.05). A 30 jours, la mortalité des patients avec survenue des symptômes entre 00 :00 et 05:59 était également significativement plus élevé que celle des patients avec survenue à tout autre moment de la journée (p <0.05). Conclusion Notre étude démontre une corrélation indépendante entre la taille d'un infarctus STEMI traité par ICPP et le moment de la journée où les symptômes apparaissent. Ces résultats suggèrent que ce moment devrait être un paramètre important à prendre en compte pour évaluer le pronostic des patients.

Circadian control of tissue homeostasis and adult stem cells.

The circadian timekeeping mechanism adapts physiology to the 24-hour light/dark cycle. However, how the outputs of the circadian clock in different peripheral tissues communicate and synchronize each other is still not fully understood. The circadian clock has been implicated in the regulation of numerous processes, including metabolism, the cell cycle, cell differentiation, immune responses, redox homeostasis, and tissue repair. Accordingly, perturbation of the machinery that generates circadian rhythms is associated with metabolic disorders, premature ageing, and various diseases including cancer. Importantly, it is now possible to target circadian rhythms through systemic or local delivery of time cues or compounds. Here, we summarize recent findings in peripheral tissues that link the circadian clock machinery to tissue-specific functions and diseases.

Sex of College Students Moderates Associations among Bedtime, Time in Bed, and Circadian Phase Angle.

Sex differences in circadian rhythms have been reported with some conflicting results. The timing of sleep and length of time in bed have not been considered, however, in previous such studies. The current study has 3 major aims: (1) replicate previous studies in a large sample of young adults for sex differences in sleep patterns and dim light melatonin onset (DLMO) phase; (2) in a subsample constrained by matching across sex for bedtime and time in bed, confirm sex differences in DLMO and phase angle of DLMO to bedtime; (3) explore sex differences in the influence of sleep timing and length of time in bed on phase angle. A total of 356 first-year Brown University students (207 women) aged 17.7 to 21.4 years (mean = 18.8 years, SD = 0.4 years) were included in these analyses. Wake time was the only sleep variable that showed a sex difference. DLMO phase was earlier in women than men and phase angle wider in women than men. Shorter time in bed was associated with wider phase angle in women and men. In men, however, a 3-way interaction indicated that phase angles were influenced by both bedtime and time in bed; a complex interaction was not found for women. These analyses in a large sample of young adults on self-selected schedules confirm a sex difference in wake time, circadian phase, and the association between circadian phase and reported bedtime. A complex interaction with length of time in bed occurred for men but not women. We propose that these sex differences likely indicate fundamental differences in the biology of the sleep and circadian timing systems as well as in behavioral choices.

Role of the renal circadian timing system in maintaining water and electrolytes homeostasis.

Many basic physiological functions exhibit circadian rhythmicity. These functional rhythms are driven, in part, by the circadian clock, an ubiquitous molecular mechanism allowing cells and tissues to anticipate regular environmental events and to prepare for them. This mechanism has been shown to play a particularly important role in maintaining stability (homeostasis) of internal conditions. Because the homeostatic equilibrium is continuously challenged by environmental changes, the role of the circadian clock is thought to consist in the anticipative adjustment of homeostatic pathways in relation with the 24h environmental cycle. The kidney is the principal organ responsible for the regulation of the composition and volume of extracellular fluids (ECF). Several major parameters of kidney function, including renal plasma flow (RPF), glomerular filtration rate (GFR) and tubular reabsorption and secretion have been shown to exhibit strong circadian oscillations. Recent evidence suggest that the circadian clock can be involved in generation of these rhythms through external circadian time cues (e.g. humoral factors, activity and body temperature rhythms) or, trough the intrinsic renal circadian clock. Here, we discuss the role of renal circadian mechanisms in maintaining homeostasis of water and three major ions, namely, Na(+), K(+) and Cl(-).

Circadian clock-coordinated hepatic lipid metabolism: only transcriptional regulation?

By regulating the metabolism of fatty acids, carbohydrates, and xenobiotic, the mammalian circadian clock plays a fundamental role on the liver physiology. At present, it is supposed that the circadian clock regulates metabolism mostly by regulating the expression of liver enzymes at the transcriptional level. However, recent evidences suggest that some signaling pathways synchronized by the circadian clock can also influence metabolism at a post-transcriptional level. In this context, we have recently shown that the circadian clock synchronizes the rhythmic activation of the IRE1alpha pathway in the endoplasmic reticulum. The absence of circadian clock perturbs this secondary clock, provokes deregulation of endoplasmic reticulum-localized enzymes, and leads to impaired lipid metabolism. We will describe here the additional pathways synchronized by the clock and discussed the influence of the circadian clock-controlled feeding rhythm on them.

Molecular clock is involved in predictive circadian adjustment of renal function.

Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e., distal convoluted tubule (DCT) and connecting tubule (CNT) and the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf, and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, alphaENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms, and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function.

The mammalian circadian timing system: from gene expression to physiology.

Many physiological processes in organisms from bacteria to man are rhythmic, and some of these are controlled by self-sustained oscillators that persist in the absence of external time cues. Circadian clocks are perhaps the best characterized biological oscillators and they exist in virtually all light-sensitive organisms. In mammals, they influence nearly all aspects of physiology and behavior, including sleep-wake cycles, cardiovascular activity, endocrinology, body temperature, renal activity, physiology of the gastro-intestinal tract, and hepatic metabolism. The master pacemaker is located in the suprachiasmatic nuclei, two small groups of neurons in the ventral part of the hypothalamus. However, most peripheral body cells contain self-sustained circadian oscillators with a molecular makeup similar to that of SCN (suprachiasmatic nucleus) neurons. This organization implies that the SCN must synchronize countless subsidiary oscillators in peripheral tissues, in order to coordinate cyclic physiology. In this review, we will discuss some recent studies on the structure and putative functions of the mammalian circadian timing system, but we will also point out some apparent inconsistencies in the currently publicized model for rhythm generation.

The circadian rhythm of the perinatal mortality rate in Switzerland.

The authors examine the relation between the perinatal mortality rate (PMR), birth weight in four categories, and hour of birth throughout the week in Switzerland, using data on 672,013 births and 5,764 perinatal deaths recorded between 1979 and 1987. From Monday to Friday, the PMR follows a circadian rhythm with a regular increase from early morning to evening, with a peak for babies born between 7 and 8 p.m. This pattern of variation has two main components: The circadian rhythms for the proportion of births in the four weight categories and the PMR circadian rhythm for babies weighing more than 2.5 kg. According to a cosinor model, which describes about 40% of the total variation in the PMR, the most important determinants are changes in the proportions of births: Low birth weight increases toward the afternoon and night. Mechanisms underlying the weight-specific timing of birth are discussed, including time selection of birth according to obstetric risks, the direct effect of neonatal and obstetric care, and chronobiologic behavior.

Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer.

BACKGROUND: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS: Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (nâeuro0/00=âeuro0/00543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS: The proportions of patients in the 4 subgroups were comparable in both treatment arms (Pâeuro0/00=âeuro0/00.77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (Pâeuro0/00=âeuro0/00.45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (Pâeuro0/00<âeuro0/00.0001) and OS (Pâeuro0/00=âeuro0/00.001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively. CONCLUSIONS: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.

Circadian regulation of renal function and potential role in hypertension.

PURPOSE OF REVIEW: Previous studies have shown that a variety of specific renal functions exhibit circadian oscillations. This review aims to provide an update on the molecular mechanisms underlying circadian rhythms in the kidney, and to discuss how dysregulation of circadian rhythms can interfere with kidney function. RECENT FINDINGS: The molecular mechanism responsible for generating and maintaining circadian rhythms has been unraveled in great detail. This mechanism, known as the circadian clock, drives circadian oscillation in expression levels of a large number of renal mRNA transcripts. Several proteins critically involved in renal homeostatic functions have been shown to exhibit significant circadian oscillation in their expression levels or in their posttranslational modifications. In transgenic mouse models, disruption of circadian clock activity results in dramatic changes in the circadian pattern of urinary sodium and potassium excretion and causes significant changes in arterial blood pressure. A growing amount of evidence suggests that dysregulation of circadian rhythms is associated with the development of hypertension and accelerated progression of chronic kidney disease and cardiovascular disease in humans. Chronotherapy studies have shown that the efficacy of antihypertensive medication is greatly dependent on the circadian time of drug administration. SUMMARY: Recent research points to the major role of circadian rhythms in renal function and in control of blood pressure.

Molecular bases of circadian rhythmicity in renal physiology and pathology.

The physiological processes that maintain body homeostasis oscillate during the day. Diurnal changes characterize kidney functions, comprising regulation of hydro-electrolytic and acid-base balance, reabsorption of small solutes and hormone production. Renal physiology is characterized by 24-h periodicity and contributes to circadian variability of blood pressure levels, related as well to nychthemeral changes of sodium sensitivity, physical activity, vascular tone, autonomic function and neurotransmitter release from sympathetic innervations. The circadian rhythmicity of body physiology is driven by central and peripheral biological clockworks and entrained by the geophysical light/dark cycle. Chronodisruption, defined as the mismatch between environmental-social cues and physiological-behavioral patterns, causes internal desynchronization of periodic functions, leading to pathophysiological mechanisms underlying degenerative, immune related, metabolic and neoplastic diseases. In this review we will address the genetic, molecular and anatomical elements that hardwire circadian rhythmicity in renal physiology and subtend disarray of time-dependent changes in renal pathology.

Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver.

Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological light-dark conditions using stable isotope labeling by amino acids quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one-half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors.

Differentially phased leaf growth and movements in Arabidopsis depend on coordinated circadian and light regulation.

In contrast to vastly studied hypocotyl growth, little is known about diel regulation of leaf growth and its coordination with movements such as changes in leaf elevation angle (hyponasty). We developed a 3D live-leaf growth analysis system enabling simultaneous monitoring of growth and movements. Leaf growth is maximal several hours after dawn, requires light, and is regulated by daylength, suggesting coupling between growth and metabolism. We identify both blade and petiole positioning as important components of leaf movements in Arabidopsis thaliana and reveal a temporal delay between growth and movements. In hypocotyls, the combination of circadian expression of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and PIF5 and their light-regulated protein stability drives rhythmic hypocotyl elongation with peak growth at dawn. We find that PIF4 and PIF5 are not essential to sustain rhythmic leaf growth but influence their amplitude. Furthermore, EARLY FLOWERING3, a member of the evening complex (EC), is required to maintain the correct phase between growth and movement. Our study shows that the mechanisms underlying rhythmic hypocotyl and leaf growth differ. Moreover, we reveal the temporal relationship between leaf elongation and movements and demonstrate the importance of the EC for the coordination of these phenotypic traits.