Night shift work and the risk of metabolic syndrome: Findings from an 8-year hospital cohort.

OBJECTIVES: Studies concerning the risk of metabolic syndrome associated with night work have shown inconsistent findings, due to imprecise working time data and cross-sectional design. We used register-based daily working time data to examine the risk of incident metabolic syndrome associated with night shift work. METHODS: Working time data collected between 2010 and 2018 of 5775 Taiwanese hospital workers were used to identify night shift workers and to calculate the number of night shifts. Metabolic syndrome was identified by annual occupational health examination results, which were linked to the working time data. Logistic regression models and generalized estimating equations were used to examine the association between night shift work and metabolic syndrome and the 5 components of metabolic syndrome. RESULTS: Night shift work is associated with a higher risk of developing metabolic syndrome (adjusted OR = 1.36, 95% CI = 1.04 to 1.78) and high waist circumference (adjusted OR = 1.27, 95% CI = 1.07 to 1.78) compared to day work. Among night shift workers, increased number of night shifts was associated with high blood pressure (adjusted OR = 1.15, 95% CI = 1.01 to 1.31). CONCLUSIONS: Night shift work is associated with metabolic risk factors. Long-term effects of circadian rhythm disruption on metabolic disturbances needs to be further studied.

Social Jetlag and Related Risks for Human Health: A Timely Review.

The term social jetlag is used to describe the discrepancy between biological time, determined by our internal body clock, and social times, mainly dictated by social obligations such as school or work. In industrialized countries, two-thirds of the studying/working population experiences social jetlag, often for several years. Described for the first time in 2006, a considerable effort has been put into understanding the effects of social jetlag on human physiopathology, yet our understanding of this phenomenon is still very limited. Due to its high prevalence, social jetlag is becoming a primary concern for public health. This review summarizes current knowledge regarding social jetlag, social jetlag associated behavior (e.g., unhealthy eating patterns) and related risks for human health.

The Effects of Shift Work on Cardio-Metabolic Diseases and Eating Patterns.

Energy metabolism is tightly linked with circadian rhythms, exposure to ambient light, sleep/wake, fasting/eating, and rest/activity cycles. External factors, such as shift work, lead to a disruption of these rhythms, often called circadian misalignment. Circadian misalignment has an impact on some physiological markers. However, these proxy measurements do not immediately translate into major clinical health outcomes, as shown by later detrimental health effects of shift work and cardio-metabolic disorders. This review focuses on the effects of shift work on circadian rhythms and its implications in cardio-metabolic disorders and eating patterns. Shift work appears to be a risk factor of overweight, obesity, type 2 diabetes, elevated blood pressure, and the metabolic syndrome. However, past studies showed discordant findings regarding the changes of lipid profile and eating patterns. Most studies were either small and short lab studies, or bigger and longer cohort studies, which could not measure health outcomes in a detailed manner. These two designs explain the heterogeneity of shift schedules, occupations, sample size, and methods across studies. Given the burden of non-communicable diseases and the growing concerns about shift workers' health, novel approaches to study shift work in real contexts are needed and would allow a better understanding of the interlocked risk factors and potential mechanisms involved in the onset of metabolic disorders.

Circadian Rhythm Disruption Influenced Hepatic Lipid Metabolism, Gut Microbiota and Promoted Cholesterol Gallstone Formation in Mice.

Background: Hepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1, which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation. Methods: Adult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed. Results: TRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice. Conclusion: Disordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation.

Defining circadian disruption in neurodegenerative disorders.

Neurodegenerative diseases encompass a large group of conditions that are clinically and pathologically diverse yet are linked by a shared pathology of misfolded proteins. The accumulation of insoluble aggregates is accompanied by a progressive loss of vulnerable neurons. For some patients, the symptoms are motor focused (ataxias), while others experience cognitive and psychiatric symptoms (dementias). Among the shared symptoms of neurodegenerative diseases is a disruption of the sleep/wake cycle that occurs early in the trajectory of the disease and may be a risk factor for disease development. In many cases, the disruption in the timing of sleep and other rhythmic physiological markers immediately raises the possibility of neurodegeneration-driven disruption of the circadian timing system. The aim of this Review is to summarize the evidence supporting the hypothesis that circadian disruption is a core symptom within neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, and Parkinson's disease, and to discuss the latest progress in this field. The Review discusses evidence that neurodegenerative processes may disrupt the structure and function of the circadian system and describes circadian-based interventions as well as timed drug treatments that may improve a wide range of symptoms associated with neurodegenerative disorders. It also identifies key gaps in our knowledge.

Adiponectin improves amyloid-ß 31-35-induced circadian rhythm disorder in mice.

Adiponectin is an adipocyte-derived hormone, which is closely associated with the development of Alzheimer's disease (AD) and has potential preventive and therapeutic significance. In the present study, we explored the relationship between adiponectin and circadian rhythm disorder in AD, the effect of adiponectin on the abnormal expression of Bmal1 mRNA/protein induced by amyloid-ß protein 31-35 (Aß31-35), and the underlying mechanism of action. We found that adiponectin-knockout mice exhibited amyloid-ß deposition, circadian rhythm disorders and abnormal expression of Bmal1. Adiponectin ameliorated the abnormal expression of the Bmal1 mRNA/protein caused by Aß31-35 by inhibiting the activity of glycogen synthase kinase 3ß (GSK3ß). These results suggest that adiponectin deficiency could induce circadian rhythm disorders and abnormal expression of the Bmal1 mRNA/protein, whilst exogenous administration of adiponectin may improve Aß31-35-induced abnormal expression of Bmal1 by inhibiting the activity of GSK3ß, thus providing a novel idea for the treatment of AD.

Microbial Reconstitution Improves Aging-Driven Lacrimal Gland Circadian Dysfunction.

Lacrimal glands are highly susceptible to aging and exhibit age-related structural and functional alterations. However, the mechanisms by which aging affects the lacrimal glands are not well-established. The current study explores the crosstalk between the aging process, gut microbiota, and circadian rhythm in age-associated lacrimal gland dysfunction. C57BL/6J mice were divided into young, old, and fecal microbiota transplant (FMT)-treated old groups. The gut bacterial community diversity was analyzed by 16S rRNA sequencing. Exorbital lacrimal glands (ELGs) were collected at 3-hour intervals over a 24-hour circadian cycle, and total RNA was subjected to high-throughput sequencing. Rhythmic transcriptional data were analyzed using the Jonckheere-Terpstra-Kendall algorithm and bioinformatics analysis technology. Immunostaining was used to identify lymphocytic infiltration, lipid deposition, and nerve innervation in the ELGs. Compared with young mice, old mice underwent a significant gut microbial community shift. The rhythmically transcriptomic profile was significantly reprogrammed over a 24-hour cycle in the old ELG group. Intervention with serial FMT from young donors for 1 month rejuvinated the gut microbial community of the old mice. Most alterations in rhythmic transcriptomic profiling were improved. Furthermore, chronic inflammation, lipid deposition, and aberrant neural response of the aging lacrimal glands were significantly reduced. Thus, the study shows that reconstitution of age-associated gut dysbiosis with FMTs from young donors improves aging-driven lacrimal gland circadian dysfunction.

Sleep and Metabolic Syndrome.

Metabolic syndrome (MetS) refers to the clustering of risk factors for cardiovascular disease and diabetes, including central adiposity, hypertension, dyslipidemia, and hyperglycemia. During the past 20 years, there have been parallel and epidemic increases in MetS and impaired sleep. This article describes evidence on the association between MetS and short sleep duration, circadian misalignment, insomnia, and sleep apnea. Potential mechanisms where impaired sleep desynchronizes and worsens metabolic control and interventions to improve sleep and potentially improve MetS are presented.

Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.

Adenosine integrates light and sleep signalling for the regulation of circadian timing in mice.

The accumulation of adenosine is strongly correlated with the need for sleep and the detection of sleep pressure is antagonised by caffeine. Caffeine also affects the circadian timing system directly and independently of sleep physiology, but how caffeine mediates these effects upon the circadian clock is unclear. Here we identify an adenosine-based regulatory mechanism that allows sleep and circadian processes to interact for the optimisation of sleep/wake timing in mice. Adenosine encodes sleep history and this signal modulates circadian entrainment by light. Pharmacological and genetic approaches demonstrate that adenosine acts upon the circadian clockwork via adenosine A1/A2A receptor signalling through the activation of the Ca2+ -ERK-AP-1 and CREB/CRTC1-CRE pathways to regulate the clock genes Per1 and Per2. We show that these signalling pathways converge upon and inhibit the same pathways activated by light. Thus, circadian entrainment by light is systematically modulated on a daily basis by sleep history. These findings contribute to our understanding of how adenosine integrates signalling from both light and sleep to regulate circadian timing in mice.

Removal of melatonin receptor type 1 signalling induces dyslipidaemia and hormonal changes in mice subjected to environmental circadian disruption.

Background: Melatonin is a hormone secreted by the pineal gland in a circadian rhythmic manner with peak synthesis at night. Melatonin signalling was suggested to play a critical role in metabolism during the circadian disruption. Methods: Melatonin-proficient (C3H-f+/+ or WT) and melatonin receptor type 1 knockout (MT1 KO) male and female mice were phase-advanced (6 hours) once a week for 6 weeks. Every week, we measured weight, food intake and basal glucose levels. At the end of the experiment, we sacrificed the animals and measured the blood's plasma for lipids profile (total lipids, phospholipids, triglycerides and total cholesterol), metabolic hormones profiles (ghrelin, leptin, insulin, glucagon, glucagon-like-peptide and resistin) and the body composition. Results: Environmental circadian disruption (ECD) did not produce any significant effects in C3H-f+/+, while it increased lipids profile in MT1 KO with the significant increase observed in total lipids and triglycerides. For metabolic hormones profile, ECD decreased plasma ghrelin and increased plasma insulin in MT1 KO females. Under control condition, MT1 KO females have significantly different body weight, fat mass, total lipids and total cholesterol than the control C3H-f+/+ females. Conclusion: Our data show that melatonin-proficient mice are not affected by ECD. When the MT1 receptors are removed, ECD induced dyslipidaemia in males and females with females experiencing the most adverse effect. Overall, our data demonstrate that MT1 signalling is an essential modulator of lipid and metabolic homeostasis during ECD.

Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans.

Circadian disruption has been identified as a risk factor for health disorders such as obesity, cardiovascular disease, and cancer. Although epidemiological studies suggest an increased risk of various cancers associated with circadian misalignment due to night shift work, the underlying mechanisms have yet to be elucidated. We sought to investigate the potential mechanistic role that circadian disruption of cancer hallmark pathway genes may play in the increased cancer risk in shift workers. In a controlled laboratory study, we investigated the circadian transcriptome of cancer hallmark pathway genes and associated biological pathways in circulating leukocytes obtained from healthy young adults during a 24-hour constant routine protocol following 3 days of simulated day shift or night shift. The simulated night shift schedule significantly altered the normal circadian rhythmicity of genes involved in cancer hallmark pathways. A DNA repair pathway showed significant enrichment of rhythmic genes following the simulated day shift schedule, but not following the simulated night shift schedule. In functional assessments, we demonstrated that there was an increased sensitivity to both endogenous and exogenous sources of DNA damage after exposure to simulated night shift. Our results suggest that circadian dysregulation of DNA repair may increase DNA damage and potentiate elevated cancer risk in night shift workers.

Melanopsin Cell Dysfunction is Involved in Sleep Disruption in Parkinson's Disease.

BACKGROUND: Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) signal the environmental light to mediate circadian photoentrainment and sleep-wake cycles. There is high prevalence of circadian and sleep disruption in people with Parkinson's disease, however the underlying mechanisms of these symptoms are not clear. OBJECTIVE: Based on recent evidence of anatomical and functional loss of melanopsin ganglion cells in Parkinson's disease, we evaluate the link between melanopsin function, circadian, and sleep behavior. METHODS: The pupil light reflex and melanopsin-mediated post-illumination pupil response were measured using chromatic pupillometry in 30 optimally medicated people with Parkinson's disease and 29 age-matched healthy controls. Circadian health was determined using dim light melatonin onset, sleep questionnaires, and actigraphy. Ophthalmic examination quantified eye health and optical coherence tomography measured retinal thickness. RESULTS: The melanopsin-mediated post-illumination pupil response amplitudes were significantly reduced in Parkinson's disease (p < 0.0001) and correlated with poor sleep quality (r2 = 33; p < 0.001) and nerve fiber layer thinning (r2 = 0.40; p < 0.001). People with Parkinson's disease had significantly poorer sleep quality with higher subjective sleep scores (p < 0.05) and earlier melatonin onset (p = 0.01). Pupil light (outer retinal) response metrics, daily light exposure and outer retinal thickness were similar between the groups (p > 0.05). CONCLUSION: Our evidence-based data identify a mechanism through which inner retinal ipRGC dysfunction contributes to sleep disruption in Parkinson's disease in the presence of normal outer retinal (rod-cone photoreceptor) function. Our findings provide a rationale for designing new treatment approaches in Parkinson's disease through melanopsin photoreceptor-targeted light therapies for improving sleep-wake cycles.

Late Eating Is Associated with Obesity, Inflammatory Markers and Circadian-Related Disturbances in School-Aged Children.

Late eating has been shown to promote metabolic dysregulation and to be associated with obesity in adults. However, few studies have explored this association in children. We compared the presence of obesity, metabolic alterations and circadian-related disturbances between school-aged children who were early dinner eaters (EDE) or late dinner eaters (LDE). School-age children (n = 397; 8-12 years; mean BMI (range): 19.4 kg/m2 (11.6-35.1); 30.5% overweight/obesity) from Spain were classified into EDE and LDE, according to dinner timing (Median: 21:07). Seven-day-dietary-records were used to assess food-timing and composition. Non-invasive tools were used to collect metabolic biomarkers (saliva), sleep and circadian-related variables (body-temperature and actigraphy). Compared to EDE, LDE were more likely to be overweight/obese [OR: 2.1 (CI: 1.33, 3.31); p = 0.002], and had higher waist-circumference and inflammatory markers, such as IL-6 (1.6-fold) (p = 0.036)) and CRP (1.4-fold) than EDE (p = 0.009). LDE had alterations in the daily patterns of: (a) body-temperature, with a phase delay of 26 min (p = 0.002), and a reduced amplitude (LDE = 0.028 (0.001) and EDE = 0.030 (0.001) (Mean (SEM); p = 0.039); (b) cortisol, with a reduced amplitude (LDE = 0.94 (0.02) and EDE = 1.00 (0.02); p = 0.035). This study represents a significant step towards the understanding of novel aspects in the timing of food intake in children.

Suvorexant ameliorates cognitive impairments and pathology in APP/PS1 transgenic mice.

Cognitive impairments and circadian rhythm disorders are the main clinical manifestations of Alzheimer's disease (AD). Orexin has been reported as abnormally elevated in the cerebrospinal fluid of AD patients, accompanied with cognitive impairments. Our recent research revealed that suvorexant, a dual orexin receptor antagonist, could improve behavioral circadian rhythm disorders in 9-month-old APP/PS1 mice. Here we further observed whether suvorexant could ameliorate the cognitive decline in APP/PS1 mice by using behavioral tests, and investigated the possible mechanisms by in vivo electrophysiological recording, western blot, and immunochemistry. The results showed that suvorexant treatment effectively ameliorated the cognitive impairments, alleviated in vivo hippocampal long-term potentiation suppression, restored the circadian phosphorylated CREB expression in the hippocampus, and reduced amyloid-ß protein deposition in the hippocampus and cortex in APP/PS1 mice. These results indicate that the neuroprotective effects of suvorexant against AD are involved in the reduction of amyloid-ß plaques, improvement of synaptic plasticity, and circadian expression of phosphorylated CREB, suggesting that suvorexant could be beneficial to the prevention and treatment of AD.

RNA Splicing Factor Mutations That Cause Retinitis Pigmentosa Result in Circadian Dysregulation.

Circadian clocks regulate multiple physiological processes in the eye, but their requirement for retinal health remains unclear. We previously showed that Drosophila homologs of spliceosome proteins implicated in human retinitis pigmentosa (RP), the most common genetically inherited cause of blindness, have a role in the brain circadian clock. In this study, we report circadian phenotypes in murine models of RP. We found that mice carrying a homozygous H2309P mutation in Pre-mRNA splicing factor 8 (Prpf8) display a lengthened period of the circadian wheel-running activity rhythm. We show also that the daily cycling of circadian gene expression is dampened in the retina of Prpf8-H2309P mice. Surprisingly, molecular rhythms are intact in the eye cup, which includes the retinal pigment epithelium (RPE), even though the RPE is thought to be the primary tissue affected in this form of RP. Downregulation of Prp31, another RNA splicing factor implicated in RP, leads to period lengthening in a human cell culture model. The period of circadian bioluminescence in primary fibroblasts of human RP patients is not significantly altered. Together, these studies link a prominent retinal disorder to circadian deficits, which could contribute to disease pathology.

Night shift work and cardiovascular disease biomarkers in female nurses.

BACKGROUND: Night shift work is associated with cardiovascular disease, but its associations with cardiovascular disease biomarkers are unclear. We investigated these associations in a study of female nurses. METHODS: We used data from the Nurses' Health Study II for total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, C-reactive protein (CRP), and fibrinogen. The sample sizes for our analysis ranged from 458 (fibrinogen) to 3574 (total cholesterol). From questionnaires, we determined the number of night shifts worked in the 2 weeks before blood collection and total years of rotating night shift work. We used quantile regression to estimate differences in biomarker levels by shift work history, adjusting for potential confounders. RESULTS: Nurses working 1 to 4 recent night shifts had median HDL cholesterol levels 4.4 mg/dL (95% confidence interval [CI]: 0.3, 7.5) lower than nurses without recent night shifts. However, working ≥5 recent night shifts and years of rotating night shift work were not associated with HDL cholesterol. There was no association between recent night shifts and CRP, but median CRP levels were 0.1 (95% CI: 0.0, 0.2), 0.2 (95% CI: 0.1, 0.4), and 0.2 (95% CI: 0.0, 0.4) mg/L higher among nurses working rotating night shifts for 1 to 5, 6 to 9, and ≥10 years compared with nurses never working rotating night shifts. These associations were attenuated when excluding postmenopausal women and women taking statins. We observed no associations between night shift work and other biomarkers. CONCLUSIONS: We found suggestive evidence of adverse short-term and long-term effects of night shift work on select cardiovascular disease biomarkers.

Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults.

BACKGROUND: Circadian disturbances are commonly seen in people with Alzheimer's disease and have been reported in individuals without symptoms of dementia but with Alzheimer's pathology. We aimed to assess the temporal relationship between circadian disturbances and Alzheimer's progression. METHODS: We did a prospective cohort study of 1401 healthy older adults (aged >59 years) enrolled in the Rush Memory and Aging Project (Rush University Medical Center, Chicago, IL, USA) who had been followed up for up to 15 years. Participants underwent annual assessments of cognition (with a battery of 21 cognitive performance tests) and motor activities (with actigraphy). Four measures were extracted from actigraphy to quantify daily and circadian rhythmicity, which were amplitude of 24-h activity rhythm, acrophase (representing peak activity time), interdaily stability of 24-h activity rhythm, and intradaily variability for hourly fragmentation of activity rhythm. We used Cox proportional hazards models and logistic regressions to assess whether circadian disturbances predict an increased risk of incident Alzheimer's dementia and conversion of mild cognitive impairment to Alzheimer's dementia. We used linear mixed-effects models to investigate how circadian rhythms changed longitudinally and how the change integrated to Alzheimer's progression. FINDINGS: Participants had a median age of 81·8 (IQR 76·3-85·7) years. Risk of developing Alzheimer's dementia was increased with lower amplitude (1 SD decrease, hazard ratio [HR] 1·39, 95% CI 1·19-1·62) and higher intradaily variability (1 SD increase, 1·22, 1·04-1·43). In participants with mild cognitive impairment, increased risk of Alzheimer's dementia was predicted by lower amplitude (1 SD decrease, HR 1·46, 95% CI 1·24-1·72), higher intradaily variability (1 SD increase, 1·36, 1·15-1·60), and lower interdaily stability (1 SD decrease, 1·21, 1·02-1·44). A faster transition to Alzheimer's dementia in participants with mild cognitive impairment was predicted by lower amplitude (1 SD decrease, odds ratio [OR] 2·08, 95% CI 1·53-2·93), increased intradaily variability (1 SD increase, 1·97, 1·43-2·79), and decreased interdaily stability (1 SD decrease, 1·35, 1·01-1·84). Circadian amplitude, acrophase, and interdaily stability progressively decreased over time, and intradaily variability progressively increased over time. Alzheimer's progression accelerated these aging effects by doubling or more than doubling the annual changes in these measures after the diagnosis of mild cognitive impairment, and further doubled them after the diagnosis of Alzheimer's dementia. The longitudinal change of global cognition positively correlated with the longitudinal changes in amplitude and interdaily stability and negatively correlated with the longitudinal change in intradaily variability. INTERPRETATION: Our results indicate a link between circadian dysregulation and Alzheimer's progression, implying either a bidirectional relation or shared common underlying pathophysiological mechanisms. FUNDING: National Institutes of Health, and the BrightFocus Foundation.