Journal of Circadian Rhythms - Latest Articles

Differential roles of breakfast only (one meal per day) and a bigger breakfast with a small dinner (two meals per day) in mice fed a high-fat diet with regard to induced obesity and lipid metabolism

Yuta Fuse — 2012-05-15T00:00:00Z

Background: Recent studies on humans and rodents have suggested that the timing of food intake plays an important role in circadian regulation and metabolic health. Consumption of high-fat foods during the inactive period or at the end of the awake period results in weight gain and metabolic syndrome in rodents. However, the distinct effects of breakfast size and the breakfast/dinner size ratio on metabolic health have not yet been fully examined in mice. Methods: We examined whether the parameters of metabolic syndrome were differentially affected in mice that consumed a large meal at the beginning of the awake period (breakfast; one meal group) and a relatively smaller meal at end of the awake period (dinner; two meals group).The mice of each group were provided equal food volume per day. Results: Mice on one meal exhibited an increase in body weight gain, hyperinsulinemia, hyperleptinemia, and a decrease of gene expression associated with beta-oxidation in adiposetissue and liver compared with those on two meals. The circadian expression pattern of the Clock gene in mice on one meal was disturbed compared with those on two meals. Conclusions: In conclusion, a bigger breakfast with a smaller dinner (two meals per day) but not breakfast only (one meal per day) helps control body weight and fat accumulation in mice on a high-fat meals schedule. The findings of this study suggest that dietary recommendations for weight reduction and/or maintenance should include information on the timing and quantity of dietary intake.

Chronotolerance study of the antiepileptic drug valproic acid in mice

Wafa Ben-Cherif — 2012-05-10T00:00:00Z

Background: Valproic acid (VPA) is an antiepileptic drug widely used for the treatment of absence seizures and generalized tonic-clonic seizures. The present work aims to study whether VPA-induced toxicity varies according to the dosing-time in the 24hour-scale. Methods: The influence of dosing-time on tolerance to VPA was investigated in 120 male Swiss mice synchronized under a light-dark cycle (12:12). The mean VPA lethal dose was determined in a preliminary study in mice (850 +/- 0.2 mg/kg, i.p.). Such a dose was administered by i.p. route to a total of 90 mice divided in six circadian stages [1, 5, 9, 13, 17 and 21Hours After Light Onset (HALO)] (15 mice/circadian time); 30 mice were used as control (5 mice / circadian time). Results: The surviving treated mice exhibited a significant circadian variation in rectal temperature and body weight loss (p < 0.001). The least rectal temperature change and body weight loss occurred when VPA was injected at 9 HALO. Drug dosing at 9 HALO resulted in -9% weight loss whereas drug dosing at 17 HALO was -15% (O = 20.3 HALO +/- 1.1 h, p [less than or equal to] 0.0001). Lethal toxicity also varied according to circadian dosing-time (chi2= 42.1, p < 0.0001). The highest (60%) and the lowest (6.67%) survival rates were observed at 9 HALO and 17 HALO respectively. Cosinor analyses validated a significant circadian rhythm in survival duration with an acrophase at 8.4 HALO +/- 0.75 h (p < 0.001). Conclusions: With regards to these data the optimal tolerance to VPA occurred when the drug was administered in the second half of the light-rest span of mice which is physiologically analogous to the second half of the night for the human patients.

Summer activity patterns among teenage girls: harmonic shape invariant modeling to estimate circadian cycles

Semhar Ogbagaber — 2012-05-06T00:00:00Z

Background: Physical activity as measured by activity counts over short time intervals across a 24 h periodare often used to assess circadian variation. We are interested in characterizing circadianpatterns in activity among adolescents and examining how these patterns vary by obesitystatus. New statistical approaches are needed to examine how factors affect different featuresof the circadian pattern and to make appropriate covariate adjustments when the outcomes arelongitudinal count data. Methods: We develop a statistical model for longitudinal or repeated activity count data that is used toexamine differences in the overall activity level, amplitude (defined as the difference betweenthe lowest and highest activity level over a 24 hour period), and phase shift. Using seven daysof continuous activity monitoring, we characterize the circadian patterns and compare thembetween obese and non-obese adolescent girls. Results: We find a statistically significant phase delay in adolescent girls who were obese comparedwith their non-obese counterparts. After the appropriate adjustment for measured potentialconfounders, we did not find differences in mean activity level between the two groups. Conclusion: New statistical methodology was developed to identify a phase delay in obese compared withnon-obese adolescents. This new approach for analyzing longitudinal circadian rhythm countdata provides a useful statistical technique to add to the repertoire for those analyzingcircadian rhythm data.

A dynamic model of circadian rhythms in rodent tail skin temperature for comparison of drug effects

Dorothee Girbig — 2012-01-05T00:00:00Z

Menopause-associated thermoregulatory dysfunction can lead to symptoms such as hot flushes severely impairing quality of life of affected women. Treatment effects are often assessed by the ovariectomized rat model providing time series of tail skin temperature measurements in which circadian rhythms are a fundamental ingredient. In this work, a new statistical strategy is presented for analyzing such stochastic-dynamic data with the aim of detecting successful drugs in hot flush treatment. The circadian component is represented by a nonlinear dynamical system which is defined by the van der Pol equation and provides well-interpretable model parameters. Results regarding the statistical evaluation of these parameters are presented.

Magel2, a Prader-Willi Syndrome candidate gene, modulates the activities of circadian rhythm proteins in cultured cells.

Julia Devos — 2011-12-30T00:00:00Z

Background: The Magel2 gene is most highly expressed in the suprachiasmatic nucleus of the hypothalamus, where its expression cycles in a circadian pattern comparable to that of clock-controlled genes. Mice lacking the Magel2 gene have hypothalamic dysfunction, including circadian defects that include reduced and fragmented total activity, excessive activity during the subjective day, but they have a normal circadian period. Magel2 is a member of the MAGE family of proteins that have various roles in cellular function, but the specific function of Magel2 is unknown. Methods: We used a variety of cell-based assays to determine whether Magel2 modifies the properties of core circadian rhythm proteins. Results: Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. Conclusion: Consistent with the blunted circadian rhythm observed in Magel2-null mice, these data suggest that Magel2 normally promotes negative feedback regulation of the cellular circadian cycle, through interactions with key core circadian rhythm proteins.

Measuring the Impact of Apnea and Obesity on Circadian Activity Patterns Using Functional Linear Modeling of Actigraphy Data

Jia Wang — 2011-10-13T00:00:00Z

Background: Actigraphy provides a way to objectively measure activity in human subjects. This paper describes a novel family of statistical methods that can be used to analyze this data in a more comprehensive way. Methods: A statistical method for testing differences in activity patterns measured by actigraphy across subgroups using functional data analysis is described. For illustration this method is used to statistically assess the impact of apnea-hypopnea index (apnea) and body mass index (BMI) on circadian activity patterns measured using actigraphy in 395 participants from 18 to 80 years old, referred to the Washington University Sleep Medicine Center for general sleep medicine care. Mathematical descriptions of the methods and results from their application to real data are presented. Results: Activity patterns were recorded by an Actical device (Philips Respironics Inc.) every minute for at least seven days. Functional linear modeling was used to detect the association between circadian activity patterns and apnea and BMI. Results indicate that participants in high apnea group have statistically lower activity during the day, and that BMI in our study population does not significantly impact circadian patterns. Conclusions: Compared with analysis using summary measures (e.g., average activity over 24 hours, total sleep time), Functional Data Analysis (FDA) is a novel statistical framework that more efficiently analyzes information from actigraphy data. FDA has the potential to reposition the focus of actigraphy data from general sleep assessment to rigorous analyses of circadian activity rhythms.

Relationship between daylength and suicide in Finland

Laura Hiltunen — 2011-09-23T00:00:00Z

Background: Many previous studies have documented seasonal variation in suicides globally. We re-assessed the seasonal variation of suicides in Finland and tried to relate it to the seasonal variation in daylength and ambient temperature and in the discrepancy between local time and solar time. Methods: The daily data of all suicides from 1969 to 2003 in Finland (N = 43,393) were available. The calendar year was divided into twelve periods according to the length of daylight and the routinely changing time difference between sun time and official time. The daily mean of suicide mortality was calculated for each of these periods and the 95% confidence intervals of the daily means were used to evaluate the statistical significance of the means. In addition, daily changes in sunshine hours and mean temperature were compared to the daily means of suicide mortality in two locations during these afore mentioned periods. Results: A significant peak of the daily mean value of suicide mortality occurred in Finland between May 15th and July 25th, a period that lies symmetrically around the solstice. Concerning the suicide mortality among men in the northern location (Oulu), the peak was postponed as compared with the southern location (Helsinki). The daily variation in temperature or in sunshine did not have significant association with suicide mortality in these two locations. Conclusions: The period with the longest length of the day associated with the increased suicide mortality. Furthermore, since the peak of suicide mortality seems to manifest later during the year in the north, some other physical or biological signals, besides the variation in daylight, may be involved. In order to have novel means for suicide prevention, the assessment of susceptibility to the circadian misalignment might help.

Relationship between psychosomatic complaints and circadian rhythm irregularity assessed by salivary levels of melatonin and growth hormone

Mitsuo Nagane — 2011-09-14T00:00:00Z

Background: In university health care settings, students with psychosomatic complaints often have chronotypic problems. For this reason, we investigated a potential connection between psychosomatic complaints and circadian rhythm irregularity assessed by salivary levels of melatonin and growth hormone. Methods: Fifteen healthy students between 21 and 22 years of age were examined for physiological parameters of chronotypes based on melatonin and growth hormone secretion patterns, using a fluorescence enzyme immunoassay. Salivary samples were collected from subjects at home five times each day (20:00, 24:00, 04:00, 08:00, and 12:00 h). In addition, the subjects rated their psychosomatic symptoms twice (at 08:00 and 20:00 h). Results: A group with irregular circadian rhythm of melatonin (ICR) showed more psychosomatic complaints than a group with the regular circadian rhythm (RCR), especially for anxiety. Conclusion: Psychosomatic symptoms, particularly anxiety, may be associated with irregularity in melatonin and growth hormone rhythms, which can be altered by basic lifestyle habits even in healthy students.

Polymorphisms in melatonin synthesis pathways: possible influences on depression

Daniel Kripke — 2011-08-09T00:00:00Z

Background: It has been reported that rs4446909, a single nucleotide polymorphism (SNP) in the promoter of acetylserotonin methyltransferase (ASMT), influences the expression of the ASMT enzyme. The common G allele is associated with lower ASMT activity, and therefore, diminishes conversion of N-acetylserotonin to melatonin. The G allele was associated with recurrent depressive disorder in a Polish group. ASMT might also affect bipolar relapse, given evidence that N-acetylserotonin might stimulate TRKB receptors, and TRKB may influence mood relapse in bipolar disorder. Additionally, arylalkylamine N-acetyltransferase (AANAT) polymorphisms have been reported associated with depression, perhaps through their influence upon N-acetylserotonin or melatonin synthesis. Results: To replicate and further explore these ideas, rs4446909 was genotyped in four research groups, as part of a panel of 610 SNPs surveyed by an Illumina Golden Gate assay. In 768 cases with delayed sleep phase disorder or matched controls, rs4446909 was indeed associated with the depressive symptoms on a self-report scale (P = 0.01, R2 = 0.007). However, there was no significant association of rs4446909 with self-reported depression in a sleep clinic patient group or with two groups of elderly men and women from multicenter studies, nor was the response to lithium treatment associated with rs4446909 in bipolar patients. No associations of two AANAT SNPs with depression were found. Conclusions: The evidence did not support a strong influence of rs4446909 upon mood, but the partial replication may be consistent with a modest effect. It is possible that larger or younger subject groups with improved phenotype ascertainment might demonstrate more persuasive replication.

Effects of restraint stress on the daily rhythm of hydrolysis of adenine nucleotides in rat serum

Andressa Souza — 2011-07-28T00:00:00Z

Background: Adenosine 5-triphosphate (ATP) and its breakdown products ADP and adenosine can act as extracellular messengers in a range of biological processes. Extracellular adenine nucleotides are metabolized by a number of enzymes including NTPDases and 5'-nucleotidase, which are considered to be the major regulators of purinergic signaling in the blood. Previous work by our group demonstrated that ATPase and ADPase activities in rat serum exhibit a 24-h temporal pattern, with higher enzyme activity during the dark (activity) phase. It was found that stress can cause disruptions in biological circadian rhythms and in the cardiovascular system. Therefore, the aim of the present study was to examine the influence of acute stress exposure upon temporal patterns of NTPDase and 5-nucleotidase enzyme activities in rat blood serum. Methods: Adult male Wistar rats were divided into 4 groups: ZT0, ZT6, ZT12 and ZT18. Each group was subdivided in 4 groups: control, immediately, 6 h and 24 h after one hour of restraint stress. ATP, ADP and AMP hydrolysis were assayed in the serum. Results: All stressed groups showed significant decreases in all enzyme activities at ZT 12 and ZT 18 when compared with control. Conclusion: Acute stress provokes a decrease in nucleotidase activities dependent on the time that this stress occurs and this effect appears to persist for at least 24 hours. Stress can change levels of nucleotides, related to increased frequency of cardiovascular events during the activity phase. Altered levels of nucleotides in serum may be involved in cardiovascular events more frequent during the activity phase in mammals, and with their etiology linked to stress.