Species sensitivities to artificial light at night: A phylogenetically controlled multilevel meta-analysis on melatonin suppression.

The rapid urbanization of our world has led to a surge in artificial lighting at night (ALAN), with profound effects on wildlife. Previous research on wildlife's melatonin, a crucial mechanistic indicator and mediator, has yielded inconclusive evidence due to a lack of comparative analysis. We compiled and analysed an evidence base including 127 experiments with 437 observations across 31 wild vertebrates using phylogenetically controlled multilevel meta-analytic models. The evidence comes mainly from the effects of white light on melatonin suppression in birds and mammals. We show a 36% average decrease in melatonin secretion in response to ALAN across a diverse range of species. This effect was observed for central and peripheral melatonin, diurnal and nocturnal species, and captive and free-living populations. We also reveal intensity-, wavelength-, and timing-dependent patterns of ALAN effects. Exposure to ALAN led to a 23% rise in inter-individual variability in melatonin suppression, with important implications for natural selection in wild vertebrates, as some individuals may display higher tolerance to ALAN. The cross-species evidence has strong implications for conservation of wild populations that are subject to natural selection of ALAN. We recommend measures to mitigate harmful impacts of ALAN, such as using 'smart' lighting systems to tune the spectra to less harmful compositions.

PERfect Day: reversible and dose-dependent control of circadian time-keeping in the mouse suprachiasmatic nucleus by translational switching of PERIOD2 protein expression.

The biological clock of the suprachiasmatic nucleus (SCN) orchestrates circadian (approximately daily) rhythms of behaviour and physiology that underpin health. SCN cell-autonomous time-keeping revolves around a transcriptional/translational feedback loop (TTFL) within which PERIOD (PER1,2) and CRYPTOCHROME (CRY1,2) proteins heterodimerise and suppress trans-activation of their encoding genes (Per1,2; Cry1,2). To explore its contribution to SCN time-keeping, we used adeno-associated virus-mediated translational switching to express PER2 (tsPER2) in organotypic SCN slices carrying bioluminescent TTFL circadian reporters. Translational switching requires provision of the non-canonical amino acid, alkyne lysine (AlkK), for protein expression. Correspondingly, AlkK, but not vehicle, induced constitutive expression of tsPER2 in SCN neurons and reversibly and dose-dependently suppressed pPer1-driven transcription in PER-deficient (Per1,2-null) SCN, illustrating the potency of PER2 in negative regulation within the TTFL. Constitutive expression of tsPER2, however, failed to initiate circadian oscillations in arrhythmic PER-deficient SCN. In rhythmic, PER-competent SCN, AlkK dose-dependently reduced the amplitude of PER2-reported oscillations as inhibition by tsPER2 progressively damped the TTFL. tsPER2 also dose-dependently lengthened the period of the SCN TTFL and neuronal calcium rhythms. Following wash-out of AlkK to remove tsPER2, the SCN regained TTFL amplitude and period. Furthermore, SCN retained their pre-washout phase: the removal of tsPER2 did not phase-shift the TTFL. Given that constitutive tsCRY1 can regulate TTFL amplitude and period, but also reset TTFL phase and initiate rhythms in CRY-deficient SCN, these results reveal overlapping and distinct properties of PER2 and CRY1 within the SCN, and emphasise the utility of translational switching to explore the functions of circadian proteins.

Circadian patterns of growth factor receptor-dependent signaling and implications for carcinogenesis.

Several different signaling pathways that regulate cell proliferation and differentiation are initiated by binding of ligands to cell-surface and membrane-bound enzyme-linked receptors, such as receptor tyrosine kinases and serine-threonine kinases. They prompt phosphorylation of tyrosine and serine-threonine residues and initiate downstream signaling pathways and priming of intracellular molecules that convey the signal in the cytoplasm and nucleus, with transcriptional activation of specific genes enriching cell growth and survival-related cascades. These cell processes are rhythmically driven by molecular clockworks endowed in every cell type and when deregulated play a crucial role in cancer onset and progression. Growth factors and their matching receptor-dependent signaling are frequently overexpressed and/or dysregulated in many cancer types. In this review we focus on the interplay between biological clocks and Growth Factor Receptor-dependent signaling in the context of carcinogenesis.

Circadian coupling of mitochondria in a deep-diving mammal.

Regulation of mitochondrial oxidative phosphorylation is essential to match energy supply to changing cellular energy demands, and to cope with periods of hypoxia. Recent work implicates the circadian molecular clock in control of mitochondrial function and hypoxia sensing. Because diving mammals experience intermittent episodes of severe hypoxia, with diel patterning in dive depth and duration, it is interesting to consider circadian-mitochondrial interaction in this group. Here, we demonstrate that the hooded seal (Cystophora cristata), a deep-diving Arctic pinniped, shows strong daily patterning of diving behaviour in the wild. Cultures of hooded seal skin fibroblasts exhibit robust circadian oscillation of the core clock genes per2 and arntl. In liver tissue collected from captive hooded seals, expression of arntl was some 4-fold higher in the middle of the night than in the middle of the day. To explore the clock-mitochondria relationship, we measured the mitochondrial oxygen consumption in synchronized hooded seal skin fibroblasts and found a circadian variation in mitochondrial activity, with higher coupling efficiency of complex I coinciding with the trough of arntl expression. These results open the way for further studies of circadian-hypoxia interactions in pinnipeds during diving.

The neuropeptide allatostatin C from clock-associated DN1p neurons generates the circadian rhythm for oogenesis.

The link between the biological clock and reproduction is evident in most metazoans. The fruit fly Drosophila melanogaster, a key model organism in the field of chronobiology because of its well-defined networks of molecular clock genes and pacemaker neurons in the brain, shows a pronounced diurnal rhythmicity in oogenesis. Still, it is unclear how the circadian clock generates this reproductive rhythm. A subset of the group of neurons designated "posterior dorsal neuron 1" (DN1p), which are among the ∼150 pacemaker neurons in the fly brain, produces the neuropeptide allatostatin C (AstC-DN1p). Here, we report that six pairs of AstC-DN1p send inhibitory inputs to the brain insulin-producing cells, which express two AstC receptors, star1 and AICR2. Consistent with the roles of insulin/insulin-like signaling in oogenesis, activation of AstC-DN1p suppresses oogenesis through the insulin-producing cells. We show evidence that AstC-DN1p activity plays a role in generating an oogenesis rhythm by regulating juvenile hormone and vitellogenesis indirectly via insulin/insulin-like signaling. AstC is orthologous to the vertebrate neuropeptide somatostatin (SST). Like AstC, SST inhibits gonadotrophin secretion indirectly through gonadotropin-releasing hormone neurons in the hypothalamus. The functional and structural conservation linking the AstC and SST systems suggest an ancient origin for the neural substrates that generate reproductive rhythms.

Ontogeny of daily rhythms in the expression of metabolic factors in Nile tilapia (Oreochromis niloticus) kept at two different temperature regimes: Thermocycle and constant temperature.

The daily variations of temperature are one of the main synchronizers of the circadian rhythms. In addition, water temperature influences the embryonic and larval development of fish and directly affects their metabolic processes. The application of thermocycles to fish larvae has been reported to improve growth and the maturation of the digestive system, but their effects on metabolism are poorly understood. The aim of the present study was to evaluate the effect of two different temperature regimes, cycling versus constant, on the daily rhythms of metabolic factors of Nile tilapia (Oreochromis niloticus) larvae. For this purpose, fertilized eggs were divided into two groups: one reared in a 31 °C:25 °C day:night thermocycle (TCY) and another group maintained in a constant 28 °C temperature (CTE). The photoperiod was set to a 12:12 h light/dark cycle. Samples were collected every 4 h during a 24-h cycle on days 4, 8 and 13 post fertilization (dpf). The expression levels of alanine aminotransferase (alt), aspartate aminotransferase (ast), malic enzyme, glucose-6-phosphate dehydrogenase (g6pd), phosphofructokinase (pfk) and pyruvate kinase (pk) were analyzed by qPCR. Results showed that, in 13 dpf animals, most of the genes analyzed (alt, ast, malic, g6pd and pfk) showed daily rhythms in TCY, but not in the group kept at constant temperature, with most acrophases detected during the feeding period. An increase in nutrient metabolism around feeding time can improve food utilization and thus increase larval performance. Therefore, the use of thermocycles is recommended for tilapia larviculture.

Maternal dietary and environmental factors associated with infant circadian rhythm, growth, and temperament: Research protocol for a prospective cohort study.

Introduction: Emerging evidence has been explored to determine the factors affecting the development of infant circadian rhythm. While fetal programming happens during the pregnancy period, external environmental cues and infant nutritional programming can have substantial effects on the infant circadian rhythm. Understanding prenatal and postnatal factors determining infant circadian rhythm can improve future interventions in optimizing maternal and infant health. Methods: This is a prospective observational cohort study, targeting 216 pregnant women from government maternity clinics in Kuala Lumpur, Malaysia. Pregnant women will be recruited at third trimester (baseline), and follow up at 3 months, and 6 months. A subsample will be collected for salivary cortisol analysis to determine circadian rhythm of the mother and infant at third trimester and 3 months. Data of eating misalignment, light exposure, chronotype, infant temperament, sleep quality, and mood will be collected via validated questionnaires. Anthropometric data and birth outcomes will be collected from antenatal and postnatal health records. Summary: Studies on infant circadian rhythm development have yet to be explored and established, hence this study presents a novel approach to identify the factors from prenatal to postnatal periods on infant circadian rhythm and its influence on growth and temperament. Findings from this study will provide insights in the critical timing which has larger effects on infant circadian rhythm development for future interventions to be conducted.

[Effects of Total Intravenous Anesthesia on Circadian Rhythms in Patients Undergoing Cardiac Transcatheter Closure].

Objective To evaluate the effects of total intravenous anesthesia on the circadian rhythms in the patients undergoing cardiac transcatheter closure. Methods Thirty patients undergoing cardiac transcatheter closure under elective intravenous anesthesia were included in this study.Paired t-tests were performed to compare the mRNA levels of the genes encoding circadian locomotor output cycles kaput(CLOCK),brain and muscle ARNT-1 like protein-1(BMAL1),cryptochrome 1(CRY1),and period circadian clock 2(PER2),the Munich Chronotype Questionnaire(MCTQ)score,and the Pittsburgh Sleep Quality Index(PSQI)score before and after anesthesia.Multiple stepwise regression analysis was performed to screen the factors influencing sleep chronotype and PSQI total score one week after surgery. Results The postoperative mRNA level of CLOCK was higher [1.38±1.23 vs.1.90±1.47;MD(95%CI):0.52(0.20-0.84),t=3.327,P=0.002] and the postoperative mRNA levels of CRY1 [1.56±1.50 vs.1.13±0.98;MD(95%CI):-0.43(-0.81--0.05),t=-2.319,P=0.028] and PER2 [0.82±0.63 vs.0.50±0.31;MD(95%CI):-0.33(-0.53--0.12),t=-3.202,P=0.003] were lower than the preoperative levels.One week after surgery,the patients presented advanced sleep chronotype [3:03±0:59 vs.2:42±0:37;MD(95%CI):-21(-40--1),t=-2.172,P=0.038],shortened sleep latency [(67±64)min vs.(37±21)min;MD(95%CI):-30.33(-55.28--5.39),t=-2.487,P=0.019],lengthened sleep duration [(436±83)min vs.(499±83)min;MD(95%CI):62.80(26.93-98.67),t=3.581,P=0.001],increased sleep efficiency [(87.59±10.35)% vs.(92.98±4.27)%;MD(95%CI):5.39(1.21-9.58),t=2.636,P=0.013],decreased sleep quality score [1.13±0.78 vs.0.80±0.71;MD(95%CI):-0.33(-0.62--0.05),t=-2.408,P=0.023],and declined PSQI total score [6.60±3.17 vs.4.03±2.58;MD(95%CI):-2.57(-3.87--1.27),t=-4.039,P<0.001].Body mass index(BMI)(B=-227.460,SE=95.475,t=-2.382,P=0.025),anesthesia duration(B=-47.079,SE=18.506,t=-2.544,P=0.017),and mRNA level of PER2(B=2815.804,SE=1080.183,t=2.607,P=0.015)collectively influenced the sleep chronotype,and the amount of anesthesia medicine(B=0.067,SE=0.028,t=2.385,P=0.024)independently influenced the PSQI one week after surgery. Conclusion Total intravenous anesthesia can improve sleep habits by advancing sleep chronotype.BMI,anesthesia duration,and mRNA level of PER2 collectively influence sleep chronotype one week after surgery.The amount of anesthesia medicine independently influences the PSQI total score one week after surgery.

Circadian rhythm of cutaneous pruritus. / 皮肤瘙痒的昼夜节律.

One of the most common and significant symptoms for skin disorders is pruritus. Additionally, it serves as a significant catalyst for the exacerbation or reoccurrence of skin diseases. Pruritus seriously affects patients' physical and mental health, and even the quality of life. It brings a heavy burden to the patients, the families, even the whole society. The pathogenesis and regulation mechanisms for pruritus are complicated and have not yet been elucidated. Previous clinical studies have shown that itch worsens at night in scabies, chronic pruritus, atopic dermatitis, and psoriasis, suggesting that skin pruritus may change with circadian rhythm. Cortisol, melatonin, core temperature, cytokines, and prostaglandins are the main regulatory factors of the circadian rhythm of pruritus. Recent studies have shown that some CLOCK genes, such as BMAL1, CLOCK, PER, and CRY, play an important role in the regulation of the circadian rhythm of pruritus by regulating the Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor kappa-B (NF-κB) signaling pathways. However, the mechanisms for circadian clock genes in regulation of circadian rhythm of pruritus have not been fully elucidated. Further studies on the mechanism of circadian clock genes in the regulation of circadian rhythm of pruritus will lay a foundation for elucidating the regulatory mechanisms for pruritus, and also provide new ideas for the control of pruritus and the alleviation of skin diseases.

The pace of biological aging helps explain the association between insomnia and chronic low back pain.

Chronic low back pain (cLBP) is associated with insomnia and advanced age. Emerging evidence suggests that the severity of both sleep disorders (like insomnia) and chronic pain are associated with a faster pace of biological aging. We aimed to determine whether the pace of biological age mediates the relationship between insomnia and the impact of cLBP in a sample of community-dwelling adults ages 19 to 85 years. Participants (49 with no pain, 32 with low-impact pain, and 37 with high-impact pain) completed sociodemographic, pain, insomnia, and short physical performance battery assessments. We calculated the pace of biological aging using DunedinPACE from blood leukocyte DNA. On average, individuals with high-impact cLBP had significantly faster biological aging than those with low-impact and no chronic pain (p < .001). Bivariate associations of DunedinPACE scores with insomnia severity and functional performance were significant at p < .01 (rs = 0.324 and -0.502, respectively). After adjusting for race and sex, the association of insomnia severity and the impact of cLBP was partially mediated by the pace of biological aging (ß = 0.070, p < .001). Also, the association of insomnia severity with functional performance was partially mediated by the pace of biological aging (ß = -0.105, p < .001). Thus, insomnia remains strongly predictive of cLBP outcomes, and the pace of biological aging helps explain this association. Future prospective studies with repeated assessments are needed to uncover the directionality of these complex relationships and ultimately develop interventions to manage cLBP.

Circadian rhythm entrainment of the jewel wasp, Nasonia vitripennis, by antagonistic interactions of multiple spectral inputs.

Circadian light entrainment in some insects is regulated by blue-light-sensitive cryptochrome (CRY) protein that is expressed in the clock neurons, but this is not the case in hymenopterans. The hymenopteran clock does contain CRY, but it appears to be light-insensitive. Therefore, we investigated the role of retinal photoreceptors in the photic entrainment of the jewel wasp Nasonia vitripennis. Application of monochromatic light stimuli at different light intensities caused phase shifts in the wasp's circadian activity from which an action spectrum with three distinct peaks was derived. Electrophysiological recordings from the compound eyes and ocelli revealed the presence of three photoreceptor classes, with peak sensitivities at 340 nm (ultraviolet), 450 nm (blue) and 530 nm (green). An additional photoreceptor class in the ocelli with sensitivity maximum at 560-580 nm (red) was found. Whereas a simple sum of photoreceptor spectral sensitivities could not explain the action spectrum of the circadian phase shifts, modelling of the action spectrum indicates antagonistic interactions between pairs of spectral photoreceptors, residing in the compound eyes and the ocelli. Our findings imply that the photic entrainment mechanism in N. vitripennis encompasses the neural pathways for measuring the absolute luminance as well as the circuits mediating colour opponency.

Blind fish have cells that see light.

Most animals on earth have evolved under daily light-dark cycles and consequently possess a circadian clock which regulates much of their biology, from cellular processes to behaviour. There are however some animals that have invaded dark ecosystems and have adapted to an apparently arrhythmic environment. One such example is the Mexican blind cavefish Astyanax mexicanus, a species complex with over 30 different isolated cave types, including the founding surface river fish. These cavefish have evolved numerous fascinating adaptations to the dark, such as loss of eyes, reduced sleep phenotype and alterations in their clock and light biology. While cavefish are an excellent model for studying circadian adaptations to the dark, their rarity and long generational time makes many studies challenging. To overcome these limitations, we established embryonic cell cultures from cavefish strains and assessed their potential as tools for circadian and light experiments. Here, we show that despite originating from animals with no eyes, cavefish cells in culture are directly light responsive and show an endogenous circadian rhythm, albeit that light sensitivity is relatively reduced in cave strain cells. Expression patterns are similar to adult fish, making these cavefish cell lines a useful tool for further circadian and molecular studies.

Histopathologic brain age estimation via multiple instance learning.

Understanding age acceleration, the discordance between biological and chronological age, in the brain can reveal mechanistic insights into normal physiology as well as elucidate pathological determinants of age-related functional decline and identify early disease changes in the context of Alzheimer's and other disorders. Histopathological whole slide images provide a wealth of pathologic data on the cellular level that can be leveraged to build deep learning models to assess age acceleration. Here, we used a collection of digitized human post-mortem hippocampal sections to develop a histological brain age estimation model. Our model predicted brain age within a mean absolute error of 5.45 ± 0.22 years, with attention weights corresponding to neuroanatomical regions vulnerable to age-related changes. We found that histopathologic brain age acceleration had significant associations with clinical and pathologic outcomes that were not found with epigenetic based measures. Our results indicate that histopathologic brain age is a powerful, independent metric for understanding factors that contribute to brain aging.

Resveratrol as a circadian clock modulator: mechanisms of action and therapeutic applications.

In the past decades, resveratrol has gained increasing attention due to its versatile and beneficial properties. This natural polyphenol, commonly present in the human diet, has been shown to induce SIRT1 and to modulate the circadian rhythm at the cellular and organismal levels. The circadian clock is a system regulating behavior and function of the human body, thus playing a crucial role in health maintenance. It is primarily entrained by light-dark cycles; however, other factors such as feeding-fasting, oxygen and temperature cycles play a significant role in its regulation. Chronic circadian misalignment can lead to numerous pathologies, including metabolic disorders, age-related diseases or cancer. Therefore, the use of resveratrol may be a valuable preventive and/or therapeutic strategy for these pathologies. This review summarizes studies that evaluated the modulatory effect of resveratrol on circadian oscillators by focusing on the potential and limitations of resveratrol in biological clock-related disorders.

Effects of circadian rhythm on anaerobic performance and blood lactate level: a systematic review.

PURPOSE: Circadian rhythm affects maximal short-term performance, and it is an important determinant of the training component. This review aimed to summarise the influence of circadian rhythm on peak and mean power output of muscle, fatigue index, and blood lactate levels. METHODS: English language articles were searched through the following databases: PubMed, Web of Science, Science Direct, and Google Scholar, and pertinent randomized control trials were scrutinized. RESULTS: The search revealed 17,481 articles, and 29 were included in this systematic review based on inclusion and exclusion criteria. Randomized control trials were selected, and the methodological validity of articles was evaluated using the 'Cochrane risk of bias tool'. Findings suggest that outcome variables muscle peak power output (p < 0.0001, Z = 7.22, I2 = 57.42, SMD = - 0.91, 95% confidence interval CI = - 1.16, - 0.67), muscle mean power output (p < 0.0001, Z = 5.66, I2 = 83.85, SMD = - 0.75, 95% CI = - 1.01, - 0.49), and fatigue index (p = 0.02, Z = 2.41, I2 = 2.49, SMD = - 0.39, 95% CI = - 0.72, - 0.07) were higher in the evening while the level of blood lactate was higher in the morning (p = 0.79, Z = 0.27, I2 = 0.73, SMD = - 0.05, 95% CI = - 0.46, - 0.35). CONCLUSION: The results show that diurnal variation affects both peak and mean power output of muscle as well as fatigue index. However, there is no remarkable effect of circadian rhythm on blood lactate level. A major factor attributed to this finding was the variation in the training experience of participants. For an effective training prescription, it is very important to consider the effect of the biological clock on muscle power output since anaerobic exercise performance is discernibly influenced by the time of the day.

Using Epigenetic Clocks to Characterize Biological Aging in Studies of Children and Childhood Exposures: a Systematic Review.

Biological age, measured via epigenetic clocks, offers a unique and useful tool for prevention scientists to explore the short- and long-term implications of age deviations for health, development, and behavior. The use of epigenetic clocks in pediatric research is rapidly increasing, and there is a need to review the landscape of this work to understand the utility of these clocks for prevention scientists. We summarize the current state of the literature on the use of specific epigenetic clocks in childhood. Using systematic review methods, we identified studies published through February 2023 that used one of three epigenetic clocks as a measure of biological aging. These epigenetic clocks could either be used as a predictor of health outcomes or as a health outcome of interest. The database search identified 982 records, 908 of which were included in a title and abstract review. After full-text screening, 68 studies were eligible for inclusion. While findings were somewhat mixed, a majority of included studies found significant associations between the epigenetic clock used and the health outcome of interest or between an exposure and the epigenetic clock used. From these results, we propose the use of epigenetic clocks as a tool to understand how exposures impact biologic aging pathways and development in early life, as well as to monitor the effectiveness of preventive interventions that aim to reduce exposure and associated adverse health outcomes.

Perfecting the Life Clock: The Journey from PTO to TTFL.

The ubiquity of biological rhythms in life implies that it results from selection in the evolutionary process. The origin of the biological clock has two possible hypotheses: the selective pressure hypothesis of the oxidative stress cycle and the light evasion hypothesis. Moreover, the biological clock gives life higher adaptability. Two biological clock mechanisms have been discovered: the negative feedback loop of transcription-translation (TTFL) and the post-translational oscillation mechanism (PTO). The TTFL mechanism is the most classic and relatively conservative circadian clock oscillation mechanism, commonly found in eukaryotes. We have introduced the TTFL mechanism of the classical model organisms. However, the biological clock of prokaryotes is based on the PTO mechanism. The Peroxiredoxin (PRX or PRDX) protein-based PTO mechanism circadian clock widely existing in eukaryotic and prokaryotic life is considered a more conservative oscillation mechanism. The coexistence of the PTO and TTFL mechanisms in eukaryotes prompted us to explain the relationship between the two. Finally, we speculated that there might be a driving force for the evolution of the biological clock. The biological clock may have an evolutionary trend from the PTO mechanism to the TTFL mechanism, resulting from the evolution of organisms adapting to the environment.

Studying the Human Microbiota: Advances in Understanding the Fundamentals, Origin, and Evolution of Biological Timekeeping.

The recently observed circadian oscillations of the intestinal microbiota underscore the profound nature of the human-microbiome relationship and its importance for health. Together with the discovery of circadian clocks in non-photosynthetic gut bacteria and circadian rhythms in anucleated cells, these findings have indicated the possibility that virtually all microorganisms may possess functional biological clocks. However, they have also raised many essential questions concerning the fundamentals of biological timekeeping, its evolution, and its origin. This narrative review provides a comprehensive overview of the recent literature in molecular chronobiology, aiming to bring together the latest evidence on the structure and mechanisms driving microbial biological clocks while pointing to potential applications of this knowledge in medicine. Moreover, it discusses the latest hypotheses regarding the evolution of timing mechanisms and describes the functions of peroxiredoxins in cells and their contribution to the cellular clockwork. The diversity of biological clocks among various human-associated microorganisms and the role of transcriptional and post-translational timekeeping mechanisms are also addressed. Finally, recent evidence on metabolic oscillators and host-microbiome communication is presented.

The influence of bright and dim light on substrate metabolism, energy expenditure and thermoregulation in insulin-resistant individuals depends on time of day.

AIMS/HYPOTHESIS: In our modern society, artificial light is available around the clock and most people expose themselves to electrical light and light-emissive screens during the dark period of the natural light/dark cycle. Such suboptimal lighting conditions have been associated with adverse metabolic effects, and redesigning indoor lighting conditions to mimic the natural light/dark cycle more closely holds promise to improve metabolic health. Our objective was to compare metabolic responses to lighting conditions that resemble the natural light/dark cycle in contrast to suboptimal lighting in individuals at risk of developing metabolic diseases. METHODS: Therefore, we here performed a non-blinded, randomised, controlled, crossover trial in which overweight insulin-resistant volunteers (n = 14) were exposed to two 40 h laboratory sessions with different 24 h lighting protocols while staying in a metabolic chamber under real-life conditions. In the Bright day-Dim evening condition, volunteers were exposed to electric bright light (~1250 lx) during the daytime (08:00-18:00 h) and to dim light (~5 lx) during the evening (18:00-23:00 h). Vice versa, in the Dim day-Bright evening condition, volunteers were exposed to dim light during the daytime and bright light during the evening. Randomisation and allocation to light conditions were carried out by sequential numbering. During both lighting protocols, we performed 24 h indirect calorimetry, and continuous core body and skin temperature measurements, and took frequent blood samples. The primary outcome was plasma glucose focusing on the pre- and postprandial periods of the intervention. RESULTS: Spending the day in bright light resulted in a greater increase in postprandial triacylglycerol levels following breakfast, but lower glucose levels preceding the dinner meal at 18:00 h, compared with dim light (5.0 ± 0.2 vs 5.2 ± 0.2 mmol/l, n = 13, p=0.02). Dim day-Bright evening reduced the increase in postprandial glucose after dinner compared with Bright day-Dim evening (incremental AUC: 307 ± 55 vs 394 ± 66 mmol/l × min, n = 13, p=0.009). After the Bright day-Dim evening condition the sleeping metabolic rate was identical compared with the baseline night, whereas it dropped after Dim day-Bright evening. Melatonin secretion in the evening was strongly suppressed for Dim day-Bright evening but not for Bright day-Dim evening. Distal skin temperature for Bright day-Dim evening was lower at 18:00 h (28.8 ± 0.3°C vs 29.9 ± 0.4°C, n = 13, p=0.039) and higher at 23:00 h compared with Dim day-Bright evening (30.1 ± 0.3°C vs 28.8 ± 0.3°C, n = 13, p=0.006). Fasting and postprandial plasma insulin levels and the respiratory exchange ratio were not different between the two lighting protocols at any time. CONCLUSIONS/INTERPRETATION: Together, these findings suggest that the indoor light environment modulates postprandial substrate handling, energy expenditure and thermoregulation of insulin-resistant volunteers in a time-of-day-dependent manner. TRIAL REGISTRATION: ClinicalTrials.gov NCT03829982. FUNDING: We acknowledge the financial support from the Netherlands Cardiovascular Research Initiative: an initiative with support from the Dutch Heart Foundation (CVON2014-02 ENERGISE).

The impact of stress and stress hormones on endogenous clocks and circadian rhythms.

In mammals, daily rhythms in physiology and behavior are under control of a circadian pacemaker situated in the suprachiasmatic nucleus (SCN). This master clock receives photic input from the retina and coordinates peripheral oscillators present in other tissues, maintaining all rhythms in the body synchronized to the environmental light-dark cycle. In line with its function as a master clock, the SCN appears to be well protected against unpredictable stressful stimuli. However, available data indicate that stress and stress hormones at certain times of day are capable of shifting peripheral oscillators in, e.g., liver, kidney and heart, which are normally under control of the SCN. Such shifts of peripheral oscillators may represent a temporary change in circadian organization that facilitates adaptation to repeated stress. Alternatively, these shifts of internal rhythms may represent an imbalance between precisely orchestrated physiological and behavioral processes that may have severe consequences for health and well-being.