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ARTIFICIAL LIGHT AT NIGHT AS A RISK FACTOR FOR HEALTH
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Disturbance of circadian rhythms underlies various metabolic diseases. Constant light exposure (LL) is known to disrupt both central and peripheral circadian rhythms. Here, we attempted to determine whether the effects of LL are different between various peripheral tissues and whether time-restricted feeding restores the circadian rhythms especially in white adipose tissue (WAT). Six-week-old mice were subjected to three feeding regimes: ad libitum feeding under light/dark phase (LD), ad libitum feeding under LL cycle, and restricted feeding at night-time under LL cycle with a normal chow. After 3 weeks, we compared body weight, food intake, plasma levels of lipids and glucose, and the expression patterns of the clock genes and the genes involved in lipid metabolism in the liver and WAT. The mice kept under LL with or without time-restricted feeding were 5.2% heavier (p<0.001, n = 16) than the mice kept under LD even though the food intakes of the two groups were the same. Food intake occurred mostly in the dark phase. LL disrupted this pattern, causing disruptions in circadian rhythms of plasma levels of triglycerides (TG) and glucose. Time-restricted feeding partially restored the rhythms. LL eliminated the circadian rhythms of the expression of the clock genes as well as most of the genes involved in lipid metabolism in both liver and WAT. More notably, LL markedly decreased not only the amplitude but also the average levels of the expression of the genes in the liver, but not in the WAT, suggesting that transcription in the liver is sensitive to constant light exposure. Time-restricted feeding restored the circadian rhythms of most of the genes to various degrees in both liver and WAT. In conclusion, LL disrupted the peripheral circadian rhythms more severely in liver than in WAT. Time-restricted feeding restored the circadian rhythms in both tissues.
Besides generating vision, light modulates various physiological functions, including mood. While light therapy applied in the daytime is known to have anti-depressive properties, excessive light exposure at night has been reportedly associated with depressive symptoms. The neural mechanisms underlying this day–night difference in the effects of light are unknown. Using a light-at-night (LAN) paradigm in mice, we showed that LAN induced depressive-like behaviors without disturbing the circadian rhythm. This effect was mediated by a neural pathway from retinal melanopsin-expressing ganglion cells to the dorsal perihabenular nucleus (dpHb) to the nucleus accumbens (NAc). Importantly, the dpHb was gated by the circadian rhythm, being more excitable at night than during the day. This indicates that the ipRGC→dpHb→NAc pathway preferentially conducts light signals at night, thereby mediating LAN-induced depressive-like behaviors. These findings may be relevant when considering the mental health effects of the prevalent nighttime illumination in the industrial world.
Objective
Eating out of phase with the endogenous biological clock alters clock and metabolic gene expression in rodents and can induce obesity and type 2 diabetes mellitus. Diet composition can also affect clock gene expression. Here, we assessed the combined effect of diet composition and feeding time on (1) body composition, (2) energy balance, and (3) circadian expression of hepatic clock and metabolic genes.
Methods
Male Wistar rats were fed a chow or a free‐choice high‐fat, high‐sugar (fcHFHS) diet, either ad libitum or with food access restricted to either the light or dark period. Body weight, adiposity, and hepatic fat accumulation as well as hepatic clock and metabolic mRNA expression were measured after 5 weeks of diet. Energy expenditure was measured using calorimetric cages.
Results
Animals with access to the fcHFHS diet only during the light period showed more hepatic fat accumulation than fcHFHS dark‐fed animals despite less calories consumed. In contrast, within the chow‐fed groups, light‐fed animals showed the lowest hepatic fat content, but they also showed the lowest caloric intake. Locomotor activity and heat production followed feeding times, except in the fcHFHS light‐fed group. Hepatic clock and metabolic gene expression rhythms also followed timing of food intake. Yet, in the fcHFHS light‐fed animals, clock gene expression appeared 3 hours advanced compared with chow light‐fed animals, an effect not observed in the fcHFHS dark‐fed animals.
Conclusions
A fcHFHS diet consumed in the light period promotes hepatic fat accumulation and advances clock gene expression in male Wistar rats, likely because of a mismatch between energy intake and expenditure.
The growing presence of artificial lighting across the globe presents a number of challenges to human and ecological health despite its societal benefits. Exposure to artificial light at night, a seemingly innocuous aspect of modern life, disrupts behavior and physiological functions. Specifically, light at night induces neuroinflammation, which is implicated in neuropathic and nociceptive pain states, including hyperalgesia and allodynia. Because of its influence on neuroinflammation, we investigated the effects of dim light at night exposure on pain responsiveness in male mice. In this study, mice exposed to four days of dim (5 lux) light at night exhibited cold hyperalgesia. Further, after 28 days of exposure, mice exhibited both cold hyperalgesia and mechanical allodynia. No heat/hot hyperalgesia was observed in this experiment. Altered nociception in mice exposed to dim light at night was concurrent with upregulated interleukin-6 and nerve growth factor mRNA expression in the medulla and elevated μ-opioid receptor mRNA expression in the periaqueductal gray region of the brain. The current results support the relationship between disrupted circadian rhythms and altered pain sensitivity. In summary, we observed that dim light at night induces cold hyperalgesia and mechanical allodynia, potentially through elevated central neuroinflammation and dysregulation of the endogenous opioid system.
Misalignment between natural light rhythm and modern life activities induces disruption of the circadian rhythm. It is mainly evident that light at night (LAN) interferes with the human endocrine system and contributes to the increasing rates of obesity and lipid metabolic disease. Maintaining hepatointestinal circadian homeostasis is vital for improving lipid homeostasis. Melatonin is a chronobiotic substance that plays a main role in stabilizing bodily rhythm and has shown beneficial effects in protecting against obesity. Based on the dual effect of circadian rhythm regulation and antiobesity, we tested the effect of melatonin in mice under constant light exposure. Exposure to 24-h constant light (LL) increased weight and insulin resistance compared with those of the control group (12-h light–12-h dark cycle, LD), and simultaneous supplementation in the melatonin group (LLM) ameliorated this phenotype. Constant light exposure disturbed the expression pattern of a series of transcripts, including lipid metabolism, circadian regulation and nuclear receptors in the liver. Melatonin also showed beneficial effects in improving lipid metabolism and circadian rhythm homeostasis. Furthermore, the LL group had increased absorption and digestion of lipids in the intestine as evidenced by the elevated influx of lipids in the duodenum and decrease in the efflux of lipids in the jejunum. More interestingly, melatonin ameliorated the gut microbiota dysbiosis and improved lipid efflux from the intestine. Thus, these findings offer a novel clue regarding the obesity-promoting effect attributed to LAN and suggest a possibility for obesity therapy by melatonin in which melatonin could ameliorate rhythm disorder and intestinal dysbiosis.
Artificial light at night (ALAN) is increasing exponentially worldwide, accelerated by the transition to new efficient lighting technologies. However, ALAN and resulting light pollution can cause unintended physiological consequences. In vertebrates, production of melatonin-the "hormone of darkness" and a key player in circadian regulation-can be suppressed by ALAN. In this paper, we provide an overview of research on melatonin and ALAN in vertebrates. We discuss how ALAN disrupts natural photic environments, its effect on melatonin and circadian rhythms, and different photoreceptor systems across vertebrate taxa. We then present the results of a systematic review in which we identified studies on melatonin under typical light-polluted conditions in fishes, amphibians, reptiles, birds, and mammals, including humans. Melatonin is suppressed by extremely low light intensities in many vertebrates, ranging from 0.01-0.03 lx for fishes and rodents to 6 lx for sensitive humans. Even lower, wavelength-dependent intensities are implied by some studies and require rigorous testing in ecological contexts. In many studies, melatonin suppression occurs at the minimum light levels tested, and, in better-studied groups, melatonin suppression is reported to occur at lower light levels. We identify major research gaps and conclude that, for most groups, crucial information is lacking. No studies were identified for amphibians and reptiles and long-term impacts of low-level ALAN exposure are unknown. Given the high sensitivity of vertebrate melatonin production to ALAN and the paucity of available information, it is crucial to research impacts of ALAN further in order to inform effective mitigation strategies for human health and the wellbeing and fitness of vertebrates in natural ecosystems.
Artificial light at night (ALAN) is an increasing phenomenon worldwide that can cause a series of biological and ecological effects, yet little is known about its potential interaction with other stressors in aquatic ecosystems. Here, we tested whether the impact of lead (Pb) on litter decomposition was altered by ALAN exposure using an indoor microcosm experiment. The results showed that ALAN exposure alone significantly increased leaf litter decomposition, decreased the lignin content of leaf litter, and altered fungal community composition and structure. The decomposition rate was 51% higher in Pb with ALAN exposure treatments than in Pb without ALAN treatments, resulting in increased microbial biomass, β-glucosidase (β-G) activity, and the enhanced correlation between β-G and litter decomposition rate. These results indicate that the negative effect of Pb on leaf litter decomposition in aquatic ecosystems may be alleviated by ALAN. In addition, ALAN exposure also alters the correlation among fungi associated with leaf litter decomposition. In summary, this study expands our understanding of Pb toxicity on litter decomposition in freshwater ecosystems and highlights the importance of considering ALAN when assessing environmental metal pollutions.
The influence of light on mammalian physiology and behavior is due to the entrainment of circadian rhythms complemented with a direct modulation of light that would be unlikely an outcome of circadian system. In mammals, physiological and behavioral circadian rhythms are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus. This central control allows organisms to predict and anticipate environmental change, as well as to coordinate different rhythmic modalities within an individual. In adult mammals, direct retinal projections to the SCN are responsible for resetting and synchronizing physiological and behavioral rhythms to the light-dark (LD) cycle. Apart from its circadian effects, light also has direct effects on certain biological functions in such a way that the participation of the SCN would not be fundamental for this network. The objective of this review is to increase awareness, within the scientific community and commercial providers, of the fact that laboratory rodents can experience a number of adverse health and welfare outcomes attributed to commonly-used lighting conditions in animal facilities during routine husbandry and scientific procedures, widely considered as “environmentally friendly.” There is increasing evidence that exposure to dim light at night, as well as chronic constant darkness, challenges mammalian physiology and behavior resulting in disrupted circadian rhythms, neural death, a depressive-behavioral phenotype, cognitive impairment, and the deregulation of metabolic, physiological, and synaptic plasticity in both the short and long terms. The normal development and good health of laboratory rodents requires cyclical light entrainment, adapted to the solar cycle of day and night, with null light at night and safe illuminating qualities during the day. We therefore recommend increased awareness of the limited information available with regards to lighting conditions, and therefore that lighting protocols must be taken into consideration when designing experiments and duly highlighted in scientific papers. This practice will help to ensure the welfare of laboratory animals and increase the likelihood of producing reliable and reproducible results.
Ab]stract
Consumer electronic devices play an important role in modern society. Technological advancements continually improve their utility and portability, making possible the near‐constant use of electronic devices during waking hours. For most people, this includes the evening hours close to bedtime. Evening exposure to light‐emitting (LE) devices can adversely affect circadian timing, sleep, and alertness, even when participants maintain a fixed 8‐hour sleep episode in darkness and the duration of evening LE‐device exposure is limited. Here, we tested the effects of evening LE‐device use when participants were allowed to self‐select their bedtimes, with wake times fixed as on work/school days. Nine healthy adults (3 women, 25.7 ± 3.0 years) participated in a randomized and counterbalanced study comparing five consecutive evenings of unrestricted LE‐tablet computer use versus evenings reading from printed materials. On evenings when using LE‐tablets, participants' self‐selected bedtimes were on average half an hour later (22:03 ± 00:48 vs. 21:32 ± 00:27 h; P = 0.030), and they showed suppressed melatonin levels (54.17 ± 18.00 vs. 9.75 ± 22.75%; P < 0.001), delayed timing of melatonin secretion onset (20:23 ± 01:06 vs. 19:35 ± 00:59 h; P < 0.001), and later sleep onset (22:25 ± 00:54 vs. 21:54 ± 00:25 h; P = 0.041). When using LE‐tablets, participants rated themselves as less sleepy in the evenings (P = 0.030) and less alert in the first hour after awakening on the following mornings (P < 0.001). These findings demonstrate that evening use of LE‐tablets can induce delays in self‐selected bedtimes, suppress melatonin secretion, and impair next‐morning alertness, which may impact the health, performance, and safety of users.
Significance
Our innate circadian clocks control myriad aspects of behavior and physiology. Disruption of our clocks by shift work, jet lag, or inherited mutation leads to metabolic dysregulation and contributes to diseases, including diabetes and cancer. A central step in clock control is phosphorylation of the PERIOD 2 (PER2) protein. Here we conclusively identify the elusive PER2 priming kinase and find it to be the well-known circadian kinase, casein kinase 1 (CK1). Surprisingly, different forms of CK1 have differing abilities to phosphorylate the PER2 priming site, adding to the complexity of circadian regulation. These insights into the phosphoregulation of PER2 will be of broad interest to circadian biologists, computational modelers, and those seeking to pharmacologically manipulate the circadian clock.
Adrenal glucocorticoids (GCs) control a wide range of physiological processes, including metabolism, cardiovascular and pulmonary activities, immune and inflammatory responses, and various brain functions. During stress responses, GCs are secreted through activation of the hypothalamic-pituitary-adrenal axis, whereas circulating GC levels in unstressed states follow a robust circadian oscillation with a peak around the onset of the active period of a day. A recent advance in chronobiological research has revealed that multiple regulatory mechanisms, along with classical neuroendocrine regulation, underlie this GC circadian rhythm. The hierarchically organized circadian system, with a central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus and local oscillators in peripheral tissues including the adrenal gland, mediates periodicities in physiological processes in mammals. In this review, we primarily focus on our understanding of the circadian regulation of adrenal GC rhythm, with particular attention to the cooperative actions of the SCN central and adrenal local clocks, and the clinical implications of this rhythm in human diseases.
Lipogenesis in liver is highest in the postprandial state; insulin activates SREBP-1c, which transcriptionally activates genes involved in fatty acid (FA) synthesis, whereas glucose activates ChREBP, which activates both glycolysis and FA synthesis. Whether SREBP-1c and ChREBP act independently of one another is unknown. Here, we characterized mice with liver-specific deletion of ChREBP (L-Chrebp-/- mice). Hepatic ChREBP deficiency resulted in reduced mRNA levels of glycolytic and lipogenic enzymes, particularly in response to sucrose refeeding following fasting, a dietary regimen that elicits maximal lipogenesis. mRNA and protein levels of SREBP-1c, a master transcriptional regulator of lipogenesis, were also reduced in L-Chrebp-/- livers. Adeno-associated virus-mediated restoration of nuclear SREBP-1c in L-Chrebp-/- mice normalized expression of a subset of lipogenic genes, while not affecting glycolytic genes. Conversely, ChREBP overexpression alone failed to support expression of lipogenic genes in livers of mice lacking active SREBPs as a result of Scap deficiency. Together, these data show that SREBP-1c and ChREBP are both required for coordinated induction of glycolytic and lipogenic mRNAs. Whereas SREBP-1c mediates insulin's induction of lipogenic genes, ChREBP mediates glucose's induction of both glycolytic and lipogenic genes. These overlapping but distinct actions ensure that the liver synthesizes FAs only when insulin and carbohydrates are both present.
Appropriately timed light is critical for circadian organization; exposure to dim light at night (dLAN) disrupts temporal organization of endogenous biological timing. Exposure to dLAN in adult mice is associated with elevated body mass and changes in metabolism putatively driven by voluntary changes in the time of food intake. We predicted that exposure of young mice to LAN could affect adult metabolic function. At 3 weeks (Experiment 1) or 5 weeks (Experiment 2) of age, mice were either maintained in standard light-dark (DARK) cycles or exposed to nightly dLAN (5 lux). In the first two experiments, food intake and locomotor activity were assessed after 4 weeks and a glucose tolerance test was administered after 6 weeks in experimental lighting conditions. In Experiment 3, tissues were collected around the clock at 6 h intervals to investigate rhythmic hepatic clock gene expression in mice exposed to dLAN from 3 or 5 weeks of age. Male and female mice exposed to dLAN beginning at 3 weeks of age displayed similar growth rates and body mass to DARK-reared offspring, despite increasing day-time food intake. Exposure to dLAN beginning at 5 weeks of age increased body mass and daytime food intake in male, but not female, mice. Consistent with the body mass phenotype, clock gene expression was unaltered in the liver. In contrast to adults, dLAN exposure during the development of the peripheral circadian system has sex- and development-dependent effects on body mass gain.
Artificial lights raise night sky luminance, creating the most visible effect of light pollution-artificial skyglow. Despite the increasing interest among scientists in fields such as ecology, astronomy, health care, and land-use planning, light pollution lacks a current quantification of its magnitude on a global scale. To overcome this, we present the world atlas of artificial sky luminance, computed with our light pollution propagation software using new high-resolution satellite data and new precision sky brightness measurements. This atlas shows that more than 80% of the world and more than 99% of the U.S. and European populations live under light-polluted skies. The Milky Way is hidden from more than one-third of humanity, including 60% of Europeans and nearly 80% of North Americans. Moreover, 23% of the world's land surfaces between 75°N and 60°S, 88% of Europe, and almost half of the United States experience light-polluted nights.
Importance:
Prospective studies linking shift work to coronary heart disease (CHD) have been inconsistent and limited by short follow-up.
Objective:
To determine whether rotating night shift work is associated with CHD risk.
Design, setting, and participants:
Prospective cohort study of 189,158 initially healthy women followed up over 24 years in the Nurses' Health Studies (NHS [1988-2012]: N = 73,623 and NHS2 [1989-2013]: N = 115,535).
Exposures:
Lifetime history of rotating night shift work (≥3 night shifts per month in addition to day and evening shifts) at baseline (updated every 2 to 4 years in the NHS2).
Main outcomes and measures:
Incident CHD; ie, nonfatal myocardial infarction, CHD death, angiogram-confirmed angina pectoris, coronary artery bypass graft surgery, stents, and angioplasty.
Results:
During follow-up, 7303 incident CHD cases occurred in the NHS (mean age at baseline, 54.5 years) and 3519 in the NHS2 (mean age, 34.8 years). In multivariable-adjusted Cox proportional hazards models, increasing years of baseline rotating night shift work was associated with significantly higher CHD risk in both cohorts. In the NHS, the association between duration of shift work and CHD was stronger in the first half of follow-up than in the second half (P=.02 for interaction), suggesting waning risk after cessation of shift work. Longer time since quitting shift work was associated with decreased CHD risk among ever shift workers in the NHS2 (P<.001 for trend). [table: see text]
Conclusions and relevance:
Among women who worked as registered nurses, longer duration of rotating night shift work was associated with a statistically significant but small absolute increase in CHD risk. Further research is needed to explore whether the association is related to specific work hours and individual characteristics.
Nonalcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar-sweetened beverages are major risk factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced DNL. Hepatic DNL is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism, and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation, resulting in increased production of reactive oxygen species. Furthermore, fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.
Significance
Increased light exposure has been associated with obesity in both humans and mice. In this article, we elucidate a mechanistic basis of this association by performing studies in mice. We report that prolonging daily light exposure increases adiposity by decreasing energy expenditure rather than increasing food intake or locomotor activity. This was caused by a light-exposure period-dependent attenuation of the noradrenergic activation of brown adipose tissue that has recently been shown to contribute substantially to energy expenditure by converting fatty acids and glucose into heat. Therefore, we conclude that impaired brown adipose tissue activity may mediate the relationship between increased light exposure and adiposity.
Improvements in the luminous efficiency of outdoor lamps might not result in energy savings or reductions in greenhouse gas emissions. The reason for this is a rebound effect: when light becomes cheaper, many users will increase illumination, and some previously unlit areas may become lit. We present three policy recommendations that work together to guarantee major energy reductions in street lighting systems. First, taking advantage of new technologies to use light only when and where it is needed. Second, defining maximum permitted illuminances for roadway lighting. Third, defining street lighting system efficiency in terms of kilowatt hours per kilometer per year. Adoption of these policies would not only save energy, but would greatly reduce the amount of light pollution produced by cities. The goal of lighting policy should be to provide the light needed for any given task while minimizing both the energy use and negative environmental side effects of the light.
Early studies on rodents showed that short-term exposure to high-intensity light (> 70 lx) above 600 nm (red-appearing) influences circadian neuroendocrine and metabolic physiology. Here we addressed the hypothesis that long-term, low-intensity red light exposure at night (rLEN) from a 'safelight' emitting no light below approximately 620 nm disrupts the nocturnal circadian melatonin signal as well as circadian rhythms in circulating metabolites, related regulatory hormones, and physi- ologic parameters. Male Sprague-Dawley rats (n = 12 per group) were maintained on control 12:12-h light:dark (300 lx; lights on, 0600) or experimental 12:12 rLEN (8.1 lx) lighting regimens. After 1 wk, rats underwent 6 low-volume blood draws via cardiocentesis (0400, 0800, 1200, 1600, 2000, and 2400) over a 4-wk period to assess arterial plasma melatonin, total fatty acid, glucose, lactic acid, pO2, pCO2, insulin, leptin and corticosterone concentrations. Results revealed plasma melatonin levels (mean ± 1 SD) were high in the dark phase (197.5 ± 4.6 pg/mL) and low in the light phase (2.6 ± 1.2 pg/mL) of control condi- tions and significantly lower than controls under experimental conditions throughout the 24-h period (P < 0.001). Prominent circadian rhythms of plasma levels of total fatty acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were significantly (P < 0.05) disrupted under experimental conditions as compared with the corresponding entrained rhythms under control conditions. Therefore, chronic use of low-intensity rLEN from a common safelight disrupts the circadian organization of neuroendocrine, metabolic, and physiologic parameters indicative of animal health and wellbeing.
The circadian system is primarily entrained by the ambient light environment and is fundamentally linked to metabolism. Mounting evidence suggests a causal relationship among aberrant light exposure, shift work, and metabolic disease. Previous research has demonstrated deleterious metabolic phenotypes elicited by chronic (>4 weeks) exposure to dim light at night (DLAN) (∼5 lux). However, the metabolic effects of short-term (<2 weeks) exposure to DLAN are unspecified. We hypothesized that metabolic alterations would arise in response to just 2 weeks of DLAN. Specifically, we predicted that mice exposed to dim light would gain more body mass, alter whole body metabolism, and display altered body temperature (Tb) and activity rhythms compared to mice maintained in dark nights. Our data largely support these predictions; DLAN mice gained significantly more mass, reduced whole body energy expenditure, increased carbohydrate over fat oxidation, and altered temperature circadian rhythms. Importantly, these alterations occurred despite similar activity locomotor levels (and rhythms) and total food intake between groups. Peripheral clocks are potently entrained by body temperature rhythms, and the deregulation of body temperature we observed may contribute to metabolic problems due to “internal desynchrony” between the central circadian oscillator and temperature sensitive peripheral clocks. We conclude that even relatively short-term exposure to low levels of nighttime light can influence metabolism to increase mass gain.
The past decade has witnessed a revival of interest in the hormone melatonin, partly attributable to the discovery that genetic variation in MTNR1B - the melatonin receptor gene - is a risk factor for impaired fasting glucose and type 2 diabetes (T2D). Despite intensive investigation, there is considerable confusion and seemingly conflicting data on the metabolic effects of melatonin and MTNR1B variation, and disagreement on whether melatonin is metabolically beneficial or deleterious, a crucial issue for melatonin agonist/antagonist drug development and dosing time. We provide a conceptual framework - anchored in the dimension of 'time' - to reconcile paradoxical findings in the literature. We propose that the relative timing between elevated melatonin concentrations and glycemic challenge should be considered to better understand the mechanisms and therapeutic opportunities of melatonin signaling in glycemic health and disease.
Dim-light-at-night (DLAN) exposure is associated with health problems, such as metabolic disruptions, immunological modulations, oxidative stress, sleep problems, and altered circadian timing. Neurophysiological parameters, including sleep patterns, are altered in the course of aging in a similar way. Here, we investigated the effect of chronic (three months) DLAN exposure (12L:12Dim-light, 75:5lux) on sleep and the sleep electroencephalogram (EEG), and rest-activity behavior in young (6-month-old, n=9) and aged (18- n=8, 24-month-old, n=6) C57BL/6J mice and compared with age-matched controls (n=11, n=9 and n=8, respectively). We recorded the EEG and electromyogram continuously for 48-h and conducted a 6-h sleep-deprivation. A delay in the phase angle of entrainment of locomotor activity and daily vigilance state rhythms was apparent in mice following DLAN exposure, throughout the whole age spectrum, rendering sleep characteristics similar among the three age DLAN groups and significantly different from the age-matched controls. Notably, slow-wave-activity in NREM sleep (SWA, EEG power density in 0.5-4.0 Hz) was differentially altered in young and aged DLAN mice. Particularly, SWA increased as a function of age, which was further accentuated following DLAN exposure. However, this was not found in the young DLAN animals, which were characterized by the lowest SWA levels. Concluding, long-term DLAN exposure induced more pronounced alterations in the sleep architecture of young mice, towards an aging phenotype, while it enhanced age-associated sleep changes in the older groups. Our data suggest that irrespective of age, chronic DLAN exposure deteriorates sleep behavior and may consequently impact general health.
The mammalian circadian clock has evolved as an adaptation to the 24-hour light/dark cycle on earth. Maintaining cellular activities in synchrony with the activities of the organism (such as eating and sleeping) helps different tissue and organ systems coordinate and optimize their performance. The full extent of the mechanisms by which cells maintain the clock are still under investigation, but involve a core set of clock genes that regulate large networks of gene transcription both by direct transcriptional activation/repression as well as the recruitment of proteins that modify chromatin states more broadly
Circadian rhythms are an inherent property of physiological processes and can be disturbed by irregular environmental cycles, including artificial light at night (ALAN). Circadian disruption may contribute to many pathologies, such as hypertension, obesity, and type 2 diabetes, but the underlying mechanisms are not understood. Our study investigated the consequences of ALAN on cardiovascular and metabolic parameters in spontaneously hypertensive rats, which represent an animal model of essential hypertension and insulin resistance. Adult males were exposed to a 12 h light - 12 h dark cycle and the ALAN group experienced dim light at night (1-2 lx), either for 2 or 5 weeks. Rats on ALAN showed a loss of light-dark variability for systolic blood pressure, but not for heart rate. Moreover, a gradual increase of systolic blood pressure was recorded over 5 weeks of ALAN. Exposure to ALAN increased plasma insulin and hepatic triglyceride levels. An increased expression of metabolic transcription factors, Pparα and Pparγ, in the epididymal fat and a decreased expression of Glut4 in the heart was found in the ALAN group. Our results demonstrate that low-intensity ALAN can disturb blood pressure control and augment insulin resistance in spontaneously hypertensive rats, and may represent a serious risk factor for cardiometabolic diseases.
Aims:
Electric lighting is beneficial to modern society; however, it is becoming apparent that light at night (LAN) is not without biological consequences. Several studies have reported negative effects of LAN on health and behavior in humans and nonhuman animals. Exposure of non-diabetic mice to dim LAN impairs glucose tolerance, whereas a return to dark nights (LD) reverses this impairment. We predicted that exposure to LAN would exacerbate the metabolic abnormalities in TALLYHO/JngJ (TH) mice, a polygenic model of type 2 diabetes mellitus (T2DM).
Materials and methods:
We exposed 7-week old male TH mice to either LD or LAN for 8-10 weeks in two separate experiments. After 8 weeks of light treatment, we conducted intraperitoneal glucose tolerance testing (ipGTT) followed by intraperitoneal insulin tolerance testing (ipITT). In Experiment 1, all mice were returned to LD for 4 weeks, and ipITT was repeated.
Key findings:
The major results of this study are i) LAN exposure for 8 weeks exacerbates glucose intolerance and insulin resistance ii) the effects of LAN on insulin resistance are reversed upon return to LD, iii) LAN exposure results in a greater increase in body weight compared to LD exposure, iv) LAN increases the incidence of mice developing overt T2DM, and v) LAN exposure decreases survival of mice with T2DM.
Significance:
In conclusion, LAN exacerbated metabolic abnormalities in a polygenic mouse model of T2DM, and these effects were reversed upon return to dark nights. The applicability of these findings to humans with T2DM needs to be determined.
Aims:
Cardiovascular parameters exhibit significant 24-h variability, which is coordinated by the suprachiasmatic nucleus (SCN), and light/dark cycles control SCN activity. We aimed to study the effects of light at night (ALAN; 1-2 lx) on cardiovascular system control in normotensive rats.
Main methods:
Heart rate (HR) and blood pressure (BP) were measured by telemetry during five weeks of ALAN exposure. From beat-to-beat telemetry data, we evaluated spontaneous baroreflex sensitivity (sBRS). After 2 (A2) and 5 (A5) weeks of ALAN, plasma melatonin concentrations and the response of BP and HR to norepinephrine administration were measured. The expression of endothelial nitric oxide synthase (eNOS) and endothelin-1 was determined in the aorta. Spontaneous exploratory behaviour was evaluated in an open-field test.
Key findings:
ALAN significantly suppressed the 24-h variability in the HR, BP, and sBRS after A2, although the parameters were partially restored after A5. The daily variability in the BP response to norepinephrine was reduced after A2 and restored after A5. ALAN increased the BP response to norepinephrine compared to the control after A5. Increased eNOS expression was found in arteries after A2 but not A5. Endothelin-1 expression was not affected by ALAN. Plasma melatonin levels were suppressed after A2 and A5. Spontaneous exploratory behaviour was reduced.
Significance:
ALAN decreased plasma melatonin and the 24-h variability in the haemodynamic parameters and increased the BP response to norepinephrine. A low intensity ALAN can suppress circadian control of the cardiovascular system with negative consequences on the anticipation of a load.
Despite considerable advances in the past few years, obesity and type 2 diabetes mellitus (T2DM) remain two major challenges for public health systems globally. In the past 9 years, genome-wide association studies (GWAS) have established a major role for genetic variation within the MTNR1B locus in regulating fasting plasma levels of glucose and in affecting the risk of T2DM. This discovery generated a major interest in the melatonergic system, in particular the melatonin MT2 receptor (which is encoded by MTNR1B). In this Review, we discuss the effect of melatonin and its receptors on glucose homeostasis, obesity and T2DM. Preclinical and clinical post-GWAS evidence of frequent and rare variants of the MTNR1B locus confirmed its importance in regulating glucose homeostasis and T2DM risk with minor effects on obesity. However, these studies did not solve the question of whether melatonin is beneficial or detrimental, an issue that will be discussed in the context of the peculiarities of the melatonergic system. Melatonin receptors might have therapeutic potential as they belong to the highly druggable G protein-coupled receptor superfamily. Clarifying the precise role of melatonin and its receptors on glucose homeostasis is urgent, as melatonin is widely used for other indications, either as a prescribed medication or as a supplement without medical prescription, in many countries in Europe and in the USA.
The circadian system regulates physiology and behavior. Acute challenges to the system, such as those experienced during travel across time zones, will eventually result in re‐synchronization to the local environmental time cues, but this re‐synchronization is oftentimes accompanied by adverse short‐term consequences. When such challenges are experienced chronically, adaptation may not be achieved, as for example in the case of rotating night shift workers. The transient and chronic disturbance of the circadian system is most frequently referred to as “circadian disruption”, but many other terms have been proposed and used to refer to similar situations. It is now beyond doubt that the circadian system contributes to health and disease, emphasizing the need for clear terminology when describing challenges to the circadian system and their consequences. The goal of this review is to provide an overview of the terms used to describe disruption of the circadian system, discuss proposed quantifications of disruption in experimental and observational settings with a focus on human research, and highlight limitations and challenges of currently available tools. For circadian research to advance as a translational science, clear, operationalizable, and scalable quantifications of circadian disruption are key, as they will enable improved assessment and reproducibility of results, ideally ranging from mechanistic settings, including animal research, to large‐scale randomized clinical trials.
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Light pollution or artificial lighting at night (ALAN) is an emerging threat to biodiversity that can disrupt physiological processes and behaviors. Because ALAN stressful effects are little studied in diurnal amphibian species, we investigated if chronic ALAN exposure affects the leukocyte profile, body condition, and blood cell sizes of a diurnal toad. We hand‐captured male toads of Melanophryniscus rubriventris in Angosto de Jaire (Jujuy, Argentina). We prepared blood smears from three groups of toads: “field” (toads processed in the field immediately after capture), “natural light” (toads kept in the laboratory under captivity with natural photoperiod), and “constant light” (toads kept in the laboratory under captivity with constant photoperiod/ALAN). We significantly observed higher neutrophil proportions and neutrophils to lymphocytes ratio in toads under constant light treatment. In addition, we observed significantly better body condition and higher erythrocyte size in field toads compared with captive toads. In summary, ALAN can trigger a leukocyte response to stress in males of the diurnal toad M. rubriventris. In addition, captivity can affect the body condition and erythrocyte size of these toads.
HIGHLIGHTS
• Exposure to artificial light at night induces leukocyte redistribution in diurnal toad Melanophryniscus rubriventris.
• Captivity changes body condition and erythrocyte size of M. rubriventris toad.
Disruptions to the circadian rhythm can lead to altered metabolism. Modification of thyroid function may be a reason why circadian misalignment may contribute to future metabolic disorders. We investigated whether circadian disruption through constant light (LL) can lead to variations in hormone levels associated with thyroid function. Mice were exposed to LL or a 12:12 Light:Dark (LD) cycle for 6 weeks; then glucose tolerance and thyroid hormone levels were measured at ZT 6 and ZT 18. There was day/night variation in glucose tolerance, but LL had no effect. LL reduced TSH, increased fT4, and abolished day/night variation in fT3 and leptin. These findings illustrate that LL alters thyroid-related hormones, providing evidence of a link between circadian disruption and thyroid function.
Desynchronization of circadian rhythms is a hallmark of depression. The antidepressant agomelatine, which is an MT1/MT2 melatonin receptor agonist/5-HT2C serotonin receptor antagonist has advantages compared to the selective serotonin reuptake inhibitors as a circadian phase-shifting agent. The present study was designed to explore whether agomelatine is able to have an antidepressant effect on rats exposed to chronic constant light (CCL) for 6 weeks. Focus is also placed on whether this activity affects diurnal rhythms of depressive-like symptoms and is associated with restoration of impaired circadian rhythms in plasma melatonin and corticosterone. We report that CCL induced a depressive-like symptoms associated with decreased grooming in the splash test during the subjective light/inactive phase. Anhedonia-like deficit in the saccharine preference test and increased immobility in the forced swimming test were both detected during the subjective dark/active phase. The disturbed emotional fluctuations due to CCL were corrected by agomelatine treatment (40 mg/kg, i.p. for 3 weeks). Agomelatine also restored novelty-induced hypophagia, which reflects an anxiety state, during the subjective Light and Dark phase, respectively, in rats exposed to CCL. Parallel to the observed positive influence on behavior, this melatonin analogue restored impaired circadian patterns of plasma melatonin but not that of corticosterone. These findings demonstrated the antidepressant-like effect of agomelatine in rats exposed to CCL possibly exerted via correction of melatonin rhythms and are suggestive of the therapeutic potential of this drug in a subpopulation of people characterized by a melatonin deficit.
Objective:
The exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In this study, we aimed to assess whether altered miRNAs expression in the liver underlies metabolic disorders caused by disrupted biological rhythms.
Results:
We found that C3H/HePas mice exposed to ALAN developed obesity, and hepatic steatosis, which was paralleled by decreased expression of Rev-erbα and up-regulation of its lipogenic targets ACL and FAS in liver. Furthermore, the expression of Rev-erbα-targeting miRNAs, miR-140-5p, 185-5p, 326-5p and 328-5p were increased in this group. Consistently, overexpression of these miRNAs in primary hepatocytes reduced Rev-erbα expression at the mRNA and protein levels. Importantly, overexpression of Rev-erbα-targeting miRNAs increased mRNA levels of Acly and Fasn.
Conclusion:
Thus, altered miRNA profile is an important mechanism underlying the disruption of the peripheral clock caused by exposure to ALAN, which could lead to hepatic steatosis.
Circadian rhythms are recurring patterns in a range of behavioural, physiological and molecular parameters that display periods of near 24 h, and are underpinned by an endogenous biological timekeeping system. Circadian clocks are increasingly recognised as being key for health. Environmental light is the key stimulus that synchronises the internal circadian system with the external time cues. There are emergent health concerns regarding increasing worldwide prevalence of electric lighting, especially man-made light-at-night, and light's impact on the circadian system may be central to these effects. A number of previous studies have demonstrated increased depression-like behaviour in various rodent experimental models exposed to dim light-at-night. In this study we set out to study the impact of dim light-at-night on circadian and affective behaviours in C57Bl/6 mice. We set out specifically to examine the impact of sex on light at night's effects, as well as the impact of housing conditions. We report minimal impact of light-at-night on circadian and affective behaviours, as measured by the tail suspension test, the forced swim test, the sucrose preference test and the elevated plus maze. Light-at-night was also not associated with an increase in body weight, but was associated with a decrease in the cell proliferation marker Ki-67 in the dentate gyrus. In summary, we conclude that experimental contextual factors, such as model species or strain, may be considerable importance in the investigation of the impact of light at night on mood-related parameters.
Objective:
To examine the effects of past and current night shift work and genetic type 2 diabetes vulnerability on type 2 diabetes odds.
Research design and methods:
In the UK Biobank, we examined associations of current (N= 272,214) and lifetime (N= 70,480) night shift work exposure with type 2 diabetes risk (6,770 and 1,191 prevalent cases, respectively). For 180,704 and 44,141 unrelated participants of European ancestry (4,002 and 726 cases, respectively) with genetic data, we assessed whether shift work exposure modified the relationship between a genetic risk score (comprising 110 single-nucleotide polymorphisms) for type 2 diabetes and prevalent diabetes.
Results:
Compared with day workers, all current night shift workers were at higher multivariable-adjusted odds for type 2 diabetes (none or rare night shifts: odds ratio [OR] 1.15 [95% CI 1.05-1.26]; some nights: OR 1.18 [95% CI 1.05-1.32]; and usual nights: OR 1.44 [95% CI 1.19-1.73]), except current permanent night shift workers (OR 1.09 [95% CI 0.93-1.27]). Considering a person's lifetime work schedule and compared with never shift workers, working more night shifts per month was associated with higher type 2 diabetes odds (<3/month: OR 1.24 [95% CI 0.90-1.68]; 3-8/month: OR 1.11 [95% CI 0.90-1.37]; and >8/month: OR 1.36 [95% CI 1.14-1.62];Ptrend= 0.001). The association between genetic type 2 diabetes predisposition and type 2 diabetes odds was not modified by shift work exposure.
Conclusions:
Our findings show that night shift work, especially rotating shift work including night shifts, is associated with higher type 2 diabetes odds and that the number of night shifts worked per month appears most relevant for type 2 diabetes odds. Also, shift work exposure does not modify genetic risk for type 2 diabetes, a novel finding that warrants replication.
Circadian disruption is associated with metabolic disturbances such as hepatic-steatosis (HS), obesity and type-2 diabetes. We hypothesized that HS, resulting from constant-light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine driven suprachiasmatic nucleus (SCN) outputs. Indeed exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with development of HS. We investigated whether providing temporal signals such as 12-hour food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5µg/Kg) and melatonin (2.5 mg/Kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone.
This chapter summarizes AMPK function in the regulation of substrate and energy metabolism with the main emphasis on carbohydrate and lipid metabolism, protein turnover, mitochondrial biogenesis, and whole-body energy homeostasis. AMPK acts as whole-body energy sensor and integrates different signaling pathway to meet both cellular and body energy requirements while inhibiting energy-consuming processes but also activating energy-producing ones. AMPK mainly promotes glucose and fatty acid catabolism, whereas it prevents protein, glycogen, and fatty acid synthesis.
In 2007, the International Agency for Research on Cancer declared shift work involving circadian disruption to be a "probable" carcinogen (group 2A), noting that human evidence was limited. This study examined associations between rotating night shift work and breast cancer risk in two prospective cohorts, the Nurses' Health Studies (NHS: 1988-2012, n = 78,516; NHS2: 1989-2013, n = 114,559), with 9,541 incident invasive breast malignancies and 24 years of follow-up. Women in NHS with 30+ years of shift work had no increased risk of breast cancer (Hazard ratio (HR) = 0.95, 95% Confidence interval (95% CI): 0.77, 1.17; Ptrend = 0.63), compared to never shift workers, though follow-up occurred primarily post-retirement from shift work. In the younger NHS2, breast cancer risk was significantly increased for women with 20+ years of shift work at baseline, reflecting young adult exposure (HR = 2.15, 95% CI: 1.23, 3.73; Ptrend = 0.23), and was marginally significantly increased for women with 20+ years of cumulative shift work, using updated exposure information (HR = 1.40, 95% CI: 1.00, 1.97; Ptrend = 0.74). In conclusion, long-term rotating night shift work was associated with increased risk of breast cancer among women who performed shift work during young adulthood. Further studies should explore the role of shift work timing on breast cancer risk.
Christopher Kyba, Andrej Mohar and Thomas Posch seek a standard figure for moonlight illuminance.
Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.
A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.
Exposure to light at night (LAN) is associated with insomnia in humans. Light provides the main input to the master clock in the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the sleep-wake cycle. We aimed to develop a rodent model for the effects of LAN on sleep. Therefore, we exposed male Wistar rats to either a 12 h light (150–200lux):12 h dark (LD) schedule or a 12 h light (150–200 lux):12 h dim white light (5 lux) (LDim) schedule. LDim acutely decreased the amplitude of daily rhythms of REM and NREM sleep, with a further decrease over the following days. LDim diminished the rhythms of 1) the circadian 16–19 Hz frequency domain within the NREM sleep EEG, and 2) SCN clock gene expression. LDim also induced internal desynchronization in locomotor activity by introducing a free running rhythm with a period of ~25 h next to the entrained 24 h rhythm. LDim did not affect body weight or glucose tolerance. In conclusion, we introduce the first rodent model for disturbed circadian control of sleep due to LAN. We show that internal desynchronization is possible in a 24 h L:D cycle which suggests that a similar desynchronization may explain the association between LAN and human insomnia.
Significance
Most physiological processes exhibit circadian oscillations, which are synchronized by a central pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). For this pacemaker to be biologically relevant, it must be entrained with external environmental cues such as the daily light/dark cycle. At present, details of how photic information is relayed from the retina to the SCN remain unclear. Using an array of genetic mouse lines, we found that the major peptidergic SCN neurons receive direct retinal input and that a single intrinsically photosensitive retinal ganglion cell (ipRGC) bilaterally targets the SCN and sends axonal collaterals to several non-SCN regions. Together, our results suggest that the retina provides multifaceted synaptic inputs to the brain to mediate proper photic inputs to coordinately influence non-image–forming visual functions.
Hepatic lipid metabolism is modulated by multiple pathways, including hormones (e.g., insulin and glucagon), energy/nutrient-sensing signaling, and circadian rhythm. The latter constitutes a pre-programmed transcriptional mechanism in anticipation of upcoming feeding/fasting metabolic cycles. Although the central clock is controlled by light, the peripheral clock, such as that in the liver, is very sensitive to the nutrient status. As such, studies in mice and humans have demonstrated that disrupted circadian rhythm is linked to metabolic diseases. This chapter will describe roles of the molecular clock and downstream nuclear receptors in the control of liver lipid metabolism. Potential mechanisms through which hepatic lipogenesis may affect peripheral metabolic homeostasis via lipid metabolites will also be discussed.
There are clear epidemiological associations between circadian disruption, obesity and pathogenesis of Type 2 Diabetes (T2DM). The mechanisms driving these associations are unclear. In the current study, we hypothesized that continuous exposure to constant light compromises pancreatic beta cell functional and morphological adaption to diet-induced obesity leading to development of T2DM. To address this hypothesis, we studied wild type Sprague Dawley (SD) as well as Per1-LUC transgenic rats for 10 weeks under standard light dark cycle (LD) or circadian disruption (LL, constant light) with concomitant ad libitum access to either standard chow or 60% high fat diet (HFD). Exposure to HFD led to a comparable increase in food intake, body weight and adiposity in both LD and LL-treated rats. However, LL rats displayed profound loss of behavioral circadian rhythms as well as disrupted pancreatic islet clock function characterized by the impairment in the amplitude and the phase islet clock oscillations. Under LD cycle, HFD did not adversely alter diurnal glycemia, diurnal insulinemia, beta cell secretory function as well as beta cell survival indicating successful adaptation to increased metabolic demand. In contrast, concomitant exposure to LL and HFD resulted in development of hyperglycemia characterized by loss of diurnal changes in insulin secretion, compromised beta cell function and induction of beta cell apoptosis. This study suggests that circadian disruption and diet-induced obesity synergize to promote development of beta cell failure, likely mediated as a consequence of impaired islet clock function.
Daily variations of metabolism, physiology and behaviour are controlled by a network of coupled circadian clocks, comprising a master clock in the suprachiasmatic nuclei of the hypothalamus and a multitude of secondary clocks in the brain and peripheral organs. Light cues synchronize the master clock that conveys temporal cues to other body clocks via neuronal and hormonal signals. Feeding at unusual times can reset the phase of most peripheral clocks. While the neuroendocrine aspect of circadian regulation has been underappreciated, this review aims at showing that the role of hormonal rhythms as internal time-givers is the rule rather than the exception. Adrenal glucocorticoids, pineal melatonin and adipocyte-derived leptin participate in internal synchronization (coupling) within the multi-oscillatory network. Furthermore, pancreatic insulin is involved in food synchronization of peripheral clocks, while stomach ghrelin provides temporal signals modulating behavioural anticipation of mealtime. Circadian desynchronization induced by shift work or chronic jet lag has harmful effects on metabolic regulation, thus favouring diabetes and obesity. Circadian deregulation of hormonal rhythms may participate in internal desynchronization and associated increase in metabolic risks. Conversely, adequate timing of endocrine therapies can promote phase-adjustment of the master clock (e.g. via melatonin agonists) and peripheral clocks (e.g. via glucocorticoid agonists).
© 2015 John Wiley & Sons Ltd.
Night-shift work (NSW) has previously been related to incidents of breast cancer and all-cause mortality, but many published studies have reported inconclusive results. The aim of the present study was to quantify a potential dose–effect relationship between NSW and morbidity of breast cancer, and to evaluate the association between NSW and risk of all-cause mortality. The outcomes included NSW, morbidity of breast cancer, cardiovascular mortality, cancer-related mortality, and all-cause mortality.
Sixteen investigations were included, involving 2,020,641 participants, 10,004 incident breast cancer cases, 7185 cancer-related deaths, 4820 cardiovascular end points, and 2480 all-cause mortalities. The summary risk ratio (RR) of incident breast cancer for an increase of NSW was 1.057 [95% confidence interval (CI) 1.014–1.102; test for heterogeneity p = 0.358, I² = 9.2%]. The combined RR (95% CI) of breast cancer risk for NSW vs daytime work was: 1.029 (0.969–1.093) in the <5-year subgroup, 1.019 (1.001–1.038) for 5-year incremental risk, 1.025 (1.006–1.044) for 5- to 10-year exposure times, 1.074 (1.010–1.142) in the 10- to 20-year subgroup, and 1.088 (1.012–1.169) for >20-year exposure lengths. The overall RR was 1.089 (95% CI 1.016–1.166) in a fixed-effects model (test for heterogeneity p = 0.838, I² = 0%) comparing rotating NSW and day work. Night-shift work was associated with an increased risk of cardiovascular death (RR 1.027, 95% CI 1.001–1.053), and all-cause death 1.253 (95% CI 0.786–1.997). In summary, NSW increased the risk of breast cancer morbidity by: 1.9% for 5 years, 2.5% for 5–10 years, 7.4% for 10–20 years, and 8.8% for >20-years of NSW. Additionally, rotating NSW enhanced the morbidity of breast cancer by 8.9%. Moreover, NSW was associated with a 2.7% increase in cardiovascular death.
Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal light/dark conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be evaluated by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body structures. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas under field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlations between clinical observations and melatonin secretion, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions depend also on the melatonin signal, for instance immune, antioxidant defences, haemostasis and glucose regulation. The difference between physiological and pharmacological effects of melatonin is not always clear but is based upon consideration of dose and not of duration of the hormone message. It is admitted that a "physiological" dose provides plasma melatonin levels in the same order of magnitude as a nocturnal peak. Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where melatonin secretion can be disturbed. The resulting alteration could increase the predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder. Since melatonin receptors display a very wide distribution in the body, putative therapeutic indications of this compound are multiple. Great advances in this field could be achieved by developing multicentre trials in a large series of patients, in order to establish efficacy of melatonin and absence of long-term toxicity.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
During the past century, the prevalence of light at night has increased in parallel with obesity rates. Dim light at night (dLAN) increases body mass in male mice. However, the effects of light at night on female body mass remain unspecified. Thus, female mice were exposed to a standard light/dark (LD; 16 h light at ∼150 lux/8 h dark at ∼0 lux) cycle or to light/dim light at night (dLAN; 16 h light at ∼150 lux/8 h dim light at ∼5 lux) cycles for six weeks. Females exposed to dLAN increased the rate of change in body mass compared to LD mice despite reduced total food intake during weeks five and six, suggesting that dLAN disrupted circadian rhythms resulting in deranged metabolism.
Objectives This study aims to quantitatively summarise the association between night shift work and the risk of metabolic syndrome (MetS).
Method We systematically searched all observational studies published in English on Pubmed and Embase from 1971 to 2013. We extracted effect measures (relative risk, RR; or odd ratio, OR) with 95% confidence interval (CI) from individual studies to generate pooled results using meta-analysis approach. Pooled RR was calculated using random- or fixed effect model. Downs and Black scale was applied to assess the methodological quality of included studies.
Results A total of 13 studies were included in the meta-analysis. The pooled adjusted RR for the association between “ever exposed to night shift work” and MetS risk was 1.57 (95% CI = 1.24–1.98, pheterogeneity = 0.001). Further stratification analysis for gender, MetS definition and study population demonstrated similar trends. The sensitivity analysis confirmed the stability of the results and no publication bias was detected.
Conclusions The present meta-analysis suggests that night shift work is significantly associated with the risk of MetS, showing a positive dose-response relationship with the intensity of night shifts. Large-scale well-design prospective studies are required to further investigate the association, especially in Asia countries.[National Natural Science Foundation of China (Project number 81273172 and 81372964), Shelly@cuhk.edu.hk (Lap Ah Tse)]
Most organisms display circadian rhythms that coordinate complex physiological and behavioral processes to optimize energy acquisition, storage, and expenditure. Disruptions to the circadian system with environmental manipulations such as nighttime light exposure alter metabolic energy homeostasis. Exercise is known to strengthen circadian rhythms and to prevent weight gain. Therefore, we hypothesized providing mice a running wheel for voluntary exercise would buffer against the effects of light at night (LAN) on weight gain. Mice were maintained in either dark (LD) or dim (dLAN) nights and provided either a running wheel or a locked wheel. Mice exposed to dim, rather than dark, nights increased weight gain. Access to a functional running wheel prevented body mass gain in mice exposed to dLAN. Voluntary exercise appeared to limit weight gain independently of rescuing changes to the circadian system caused by dLAN; increases in daytime food intake induced by dLAN were not diminished by increased voluntary exercise. Furthermore, although all of the LD mice displayed a 24h rhythm in wheel running, nearly half (4 out of 9) of the dLAN mice did not display a dominant 24h rhythm in wheel running. These results indicate that voluntary exercise can prevent weight gain induced by dLAN without rescuing circadian rhythm disruptions.