Circadian gene variants in cancer

Abstract

Humans as diurnal beings are active during the day and rest at night. This daily oscillation of behavior and physiology is driven by an endogenous circadian clock not environmental cues. In modern societies, changes in lifestyle have led to a frequent disruption of the endogenous circadian homeostasis leading to increased risk of various diseases including cancer. The clock is operated by the feedback loops of circadian genes and controls daily physiology by coupling cell proliferation and metabolism, DNA damage repair, and apoptosis in peripheral tissues with physical activity, energy homeostasis, immune and neuroendocrine functions at the organismal level. Recent studies have revealed that defects in circadian genes due to targeted gene ablation in animal models or single nucleotide polymorphism, deletion, deregulation and/or epigenetic silencing in humans are closely associated with increased risk of cancer. In addition, disruption of circadian rhythm can disrupt the molecular clock in peripheral tissues in the absence of circadian gene mutations. Circadian disruption has recently been recognized as an independent cancer risk factor. Further study of the mechanism of clock-controlled tumor suppression will have a significant impact on human health by improving the efficiencies of cancer prevention and treatment.     

The circadian timing system in clinical oncology

Abstract

The circadian timing system (CTS) controls several critical molecular pathways for cancer processes and treatment effects over the 24 hours, including drug metabolism, cell cycle, apoptosis, and DNA damage repair mechanisms. This results in the circadian time dependency of whole-body and cellular pharmacokinetics and pharmacodynamics of anticancer agents. However, CTS robustness and phase varies among cancer patients, based on circadian monitoring of rest– activity, body temperature, sleep, and/or hormonal secretion rhythms. Circadian disruption has been further found in up to 50% of patients with metastatic cancer. Such disruption was associated with poor outcomes, including fatigue, anorexia, sleep disorders, and short progression-free and overall survival. Novel, minimally invasive devices have enabled continuous CTS assessment in non-hospitalized cancer patients. They revealed up to 12-hour differences in individual circadian phase. Taken together, the data support the personalization of chronotherapy. This treatment method aims at the adjustment of cancer treatment delivery according to circadian rhythms, using programmable-in-time pumps or novel release formulations, in order to increase both efficacy and tolerability. A fixed oxaliplatin, 5-fluorouracil and leucovorin chronotherapy protocol prolonged median overall survival in men with metastatic colorectal cancer by 3.3 months as compared to conventional delivery, according to a meta-analysis (P = 0.009). Further analyses revealed the need for the prevention of circadian disruption or the restoration of robust circadian function in patients on chronotherapy, in order to further optimize treatment effects. The strengthening of external synchronizers could meet such a goal, through programmed exercise, meal timing, light exposure, improved social support, sleep scheduling, and the properly timed administration of drugs that target circadian clocks. Chrono-rehabilitation warrants clinical testing for improving quality of life and survival in cancer patients.     

Interconnections between circadian clocks and metabolism

Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.

To adapt to daily environmental changes caused by our Earth’s rotation, most organisms on the planet evolved near-24-hour cycles of behavioral, physiological, and metabolic rhythms (1). In addition to the entrained environmental stimuli, the internal timekeeping system of the circadian clock has evolved to anticipate external changes (2, 3). These conserved rhythms synchronize internal biological and behavioral processes to the external temporal environment, presumably providing organisms with selective advantages for survival. However, over the past century, modern industrialized society has profoundly changed our external environment (4). For example, the boundaries between day and night have been blurred by electric light and travel across different time zones. Disrupted circadian rhythms are highly associated with metabolic disorders (5). Conversely, obesity induced by overeating or overnutritional environment leads to circadian remodeling (6, 7). Understanding the reciprocal regulation of circadian rhythm and metabolism may provide mechanistic insights into circadian physiology and advance new chronotherapy approaches and therapeutic targets for metabolic disorders.     

Links between circadian system and human health

There is now reason to speculate that disruption of circadian rhythms of physiology and behavior may have broader implications for human health. A long history of clinical epidemiology in humans demonstrates an increased incidence of obesity, cardiovascular disease and cancer among shift workers. Clues from studies on the molecular genetics of circadian clock genes may offer insight into the molecular mechanisms underlying the circadian variation of metabolic coordination. A better understanding of the impact of circadian gene networks on nutrient balance at the molecular, cellular, and system levels promises to shed light on the emerging association between disorders of diabetes, obesity, sleep, and circadian timing.     

Cross-talk between the circadian clock and the cell cycle in cancer

Abstract

The circadian clock is an endogenous timekeeper system that controls the daily rhythms of a variety of physiological processes. Accumulating evidence indicates that genetic changes or unhealthy lifestyle can lead to a disruption of circadian homeostasis, which is a risk factor for severe dysfunctions and pathologies including cancer. Cell cycle, proliferation, and cell death are closely intertwined with the circadian clock, and thus disruption of circadian rhythms appears to be linked to cancer development and progression. At the molecular level, the cell cycle machinery and the circadian clocks are controlled by similar mechanisms, including feedback loops of genes and protein products that display periodic activation and repression. Here, we review the circadian rhythmicity of genes associated with the cell cycle, proliferation, and apoptosis, and we highlight the potential connection between these processes, the circadian clock, and neoplastic transformations. Understanding these interconnections might have potential implications for the prevention and therapy of malignant diseases.     

Body-temperature circadian rhythm in 67 patients after heart valve replacement surgery secondary to valvular heart disease

PurposePatient body temperature was monitored after cardiac valve replacement, in order to explore the characteristics of body-temperature circadian rhythm and the factors influencing that rhythm.MethodsA cohort of 67 patients who received cardiac valve replacement in a Fuzhou, Fujian province, China, general hospital underwent temperature measurements and analysis (by cosine curve) of their body-temperature circadian rhythm. A biological rhythm model was established through principal component analysis and evaluation of biological rhythm features. Multiple circadian parameters were included through linear regression analysis.ResultsPatients' temperature after cardiac valve replacement exhibited circadian characteristics (p < 0.05), among which the scores of temperature mesor, amplitude, and acrophase were respectively (37.61 ± 0.08), (0.10 ± 0.09), and −33 (–355, –119). Body-temperature rhythms were influenced by both gender and cardiopulmonary bypass time (p < 0.05).ConclusionAlthough some patients' circadian characteristics disappeared after cardiac valve replacement, circadian rhythms remained intact for most patients. Measures that were found to mitigate body-temperature circadian rhythm disruption included building a natural rhythm of light/darkness and decreasing cardiopulmonary bypass time.     

Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndrome

SUMMARY. Many patients with chronic fatigue syndrome (CFS) display features of hypothalamic dysfunction. We have investigated aspects of circadian rhythmicity, an important hypothalamic function, in 20 CFS patients and in 17 age- and sex-matched healthy control subjects. There were no differences between the two groups in the amplitude, mesor (mean value) or timing of the peak (acrophase) of the circardian rhythm of core temperature, or in the timing of the onset of melatonin secretion. However, the CFS patients showed no significant correlation between the timing of the temperature acrophase and the melatonin onset (P< 0.5), whereas the normal significant correlation was observed in the controls (P< 0.05). Dissociation of circadian rhythms could be due to the sleep deprivation and social disruption, and/or the reduction in physical activity which typically accompany CFS. By analogy with jet-lag and shift-working, circadian dysrhythmia could be an important factor in initiating and perpetuating the cardinal symptoms of CFS, notably tiredness, impaired concentration and intellectual impairment.     

Associations Between Exposure to Gestational Diabetes Mellitus In Utero and Daily Energy Intake,Brain Responses to Food Cues,and Adiposity in Children

OBJECTIVEChildren exposed to gestational diabetes mellitus (GDM) or maternal obesity in utero have an increased propensity to develop obesity. Little is known about the mechanisms underlying this phenomenon. We aimed to examine relationships between exposure to GDM or maternal obesity and daily energy intake (EI), brain responses to food cues within reward regions, and adiposity in children.RESEARCH DESIGN AND METHODSParticipants were 159 children ages 7–11 years. Repeated 24-h recalls were conducted to assess mean daily EI. A subset of children (n = 102) completed a food cue task in the MRI scanner. A priori regions of interest included the orbital frontal cortex (OFC), insula, amygdala, ventral striatum, and dorsal striatum. Adiposity measurements, BMI z-scores, percent body fat, waist-to-height ratio (WtHR), and waist-to-hip ratio (WHR) were assessed.RESULTSExposure to GDM was associated with greater daily EI, and children exposed to GDM diagnosed before 26 weeks gestation had greater OFC food cue reactivity. Children exposed to GDM also had larger WHR. Results remained significant after adjusting for child’s age and sex, maternal education and race/ethnicity, maternal prepregnancy BMI, and child’s physical activity levels. Furthermore, children who consumed more daily calories had greater WHR, and the relationship between GDM exposure and WHR was attenuated after adjustment for daily EI. Prepregnancy BMI was not significantly related to daily EI or food cue reactivity in reward regions. However, prepregnancy BMI was significantly related to all adiposity measurements; results remained significant for BMI z-scores, WtHR, and WHR after controlling for child’s age and sex, maternal education and race/ethnicity, maternal GDM exposure, and child’s physical activity levels.CONCLUSIONSExposure to GDM in utero, in particular before 26 weeks gestation, is associated with increased EI, enhanced OFC food cue reactivity, and increased WHR. Future study with longitudinal follow-up is merited to assess potential pathways of daily EI and food cue reactivity in reward regions on the associations between GDM exposure and childhood adiposity.     

Exacerbation of circadian rhythms of core body temperature and sepsis in trauma patients

PurposeThis study aimed to describe by mathematical modeling an accurate course of core body temperature (CBT) in severe trauma patients and its relation to sepsis.MethodsIn a cohort of severe trauma, the CBT measurements were collected for 24 h on day 2 after admission and rhythmicity assessed by Fourier transform and Cosinor analysis to describe circadian features (frequency and amplitude). CBT was compared between patients who developed sepsis or not during the early ICU stay.Results33 patients were included in this analysis. 24 patients (73%) had a predominant rhythm of 24 h (period). The main period was lower in the 9 remaining patients (6 of 12 h, 1 of 8 h, and 2 of 6 h). Other significant frequencies of oscillation (second and third frequencies) were found, which showed an association of several well-marked rhythms. Patients with sepsis (n = 12) had a significantly higher level of CBT, but also more intense rhythms and higher amplitudes of CBT.ConclusionTrauma patients exhibit complex temperature circadian rhythms. Early exacerbation of the temperature rhythmicity (in frequency and amplitude) is associated with the development of sepsis. This observation accentuates the concept of circadian disruption and sepsis in ICU patients.     

Goal Setting and Achievement in Individualized Rehabilitation of Younger Total and Unicondylar Knee Arthroplasty Patients: A Cohort Study

ObjectiveTo investigate activity goals, intensity and achievement of these activity goals in younger knee arthroplasty (KA) patients, and to identify the differences between total knee arthroplasty (TKA) and unicondylar knee arthroplasty (UKA) patients.DesignProspective cohort study.SettingDepartment of orthopedic surgery and physical therapy practices.ParticipantsPatients (N=48) aged 65 years or younger who underwent KA.InterventionRehabilitation with goal attainment scaling (GAS).Main Outcome MeasuresGAS goals for daily life activity, work and leisure time, corresponding metabolic equivalent of task (MET) values, corrected MET values, and GAS scores at 3 and 6 months.ResultsThe intensity levels of all 144 formulated activity goals were light in 16% of cases, moderate in 63%, and vigorous in 21%. Intensity levels did not differ between TKA and UKA patients. Following rehabilitation using GAS, 54% of daily life activity goals, 65% of work activity goals, and 46% of leisure time activity goals were attained after 3 months. After 6 months, 91% of daily life activity goals, 93% of work activity goals, and 89% of leisure time activity goals were attained. Goal attainment did not differ between MET intensity levels. Higher goal attainment was achieved in the UKA group (100%) compared with the TKA patients (82%) after 6 months (P<.001).ConclusionsYounger patients aim to perform many different activities of varying metabolic intensity levels following KA. After 6 months of rehabilitation using GAS, in these patients attain 91% of their preoperatively formulated activity goals, independent of the MET intensity level. After 6 months, UKA patients attain significantly more activity goals than TKA patients. GAS might be a useful objective outcome measure in evaluating clinical outcomes of individual KA patients.     

Effectiveness of patient education focusing on circadian pain rhythms: A case report and review of literature

BACKGROUNDNeuropathic pain management should aim at improving quality of life and daily living activities of patients; therefore, emphasis should be placed on pain management including understanding the pain patterns during daily activity. Therefore, lifestyle guidance should be based on a detailed understanding of pain; however, previous studies commonly evaluated pain intensity at a single point in time. We report a case on patient education intervention based on the relationship between pain circadian rhythms and detailed physical activity during the day.CASE SUMMARYA man in his 60s, who suffered a brachial plexus injury in a traffic accident, presented with neuropathic pain. Early assessment of the importance of daily living activities to the patient, pain rhythmicity, and physical activity, was performed. The early assessments showed that the pain intensity was lower on days when more light-intensity physical activity (LIPA) was performed, than on days when less LIPA was performed. Consequently, patient education focused on methods to decrease the pain intensity that tended to worsen in the afternoon, and encouraged behavioral changes by suggesting the patient to take walks,” which could be used to maintain LIPA in the afternoon. On reassessment, the afternoon LIPA, which had been the focus of attention, had increased and a change was noted in the circadian rhythm of pain.CONCLUSIONPatient education based on a composite assessment elicited positive results in relation to the pain circadian rhythm and physical activity.     

Chronotype Is Independently Associated With Glycemic Control in Type 2 Diabetes

OBJECTIVE

To examine whether chronotype and daily caloric distribution are associated with glycemic control in patients with type 2 diabetes independently of sleep disturbances.

RESEARCH DESIGN AND METHODS

Patients with type 2 diabetes had a structured interview and completed questionnaires to collect information on diabetes history and habitual sleep duration, quality, and timing. Shift workers were excluded. A recently validated construct derived from mid-sleep time on weekends was used as an indicator of chronotype. One-day food recall was used to compute the temporal distribution of caloric intake. Hierarchical linear regression analyses controlling for demographic and sleep variables were computed to determine whether chronotype was associated with HbA_1c values and whether this association was mediated by a higher proportion of caloric intake at dinner.

RESULTS

We analyzed 194 completed questionnaires. Multiple regression analyses adjusting for age, sex, race, BMI, insulin use, depressed mood, diabetes complications, and perceived sleep debt found that chronotype was significantly associated with glycemic control (P = 0.001). This association was partially mediated by a greater percentage of total daily calories consumed at dinner.

CONCLUSIONS

Later chronotype and larger dinner were associated with poorer glycemic control in patients with type 2 diabetes independently of sleep disturbances. These results suggest that chronotype may be predictive of disease outcomes and lend further support to the role of the circadian system in metabolic regulation.The circadian system, controlled by the master circadian clock located in the suprachiasmatic nuclei of the hypothalamus, plays a major role in regulating daily rhythms of sleep/wake and various metabolic outputs, such as feeding behavior, peripheral tissue metabolism, and hormone secretions (1–3). Despite having this genetically regulated master circadian clock, humans living in modern industrialized societies with 24-h access to light often engage in behaviors that are inappropriately timed relative to their endogenous circadian rhythms. This mismatch in timing is termed “circadian misalignment” and has been associated with a number of negative health outcomes. Night shift work is an example of severe circadian misalignment, as workers are awake, active, and eating during their circadian night and trying to sleep and fast during their circadian day. Epidemiologic studies reveal that shift work is associated with health problems including peptic ulcer disease, coronary heart disease, and metabolic syndrome, as well as certain types of cancers (4). In controlled laboratory studies, experimentally induced circadian misalignment in healthy human volunteers resulted in impaired glucose tolerance (5,6). In animal experiments, mice fed a high-fat diet during their inactive period gained significantly more weight than mice fed during their active phase, despite consuming the equivalent amount of calories (7). Taken together, these data suggest that severe circadian misalignment involving eating and sleeping at an abnormal circadian time leads to impaired energy metabolism.Many individuals in modern society experience a form of mild circadian misalignment, especially during the work or school week as they follow social rhythms imposed by professional obligation, school schedules, family, and other commitments (8). The degree of misalignment is dependent on the individual’s “chronotype” (8). Chronotype is a construct that captures an individual’s preference for being a “morning” or “evening” person. Late chronotype is typically associated with a greater degree of misalignment between social rhythms and the circadian clock (8). This misalignment phenomenon has been termed “social jetlag,” as it resembles the condition experienced after traveling across time zones (8) and can be observed by comparing the difference in sleep timing between work/school days and free days. In a large population study, larger amounts of social jetlag were recently reported to be associated with higher BMI in overweight individuals (9). In addition, a recent study found that patients with type 2 diabetes had significantly later bedtimes and wake times than participants without diabetes, suggesting that chronotype may play a role in glucose metabolism (10).In addition to chronic circadian misalignment, late chronotypes or “evening types” tend to minimize or skip breakfast (11,12). Therefore, the daily distribution of food intake may be mismatched with circadian-controlled metabolic rhythms. It is well recognized that glucose tolerance is worse in the evening (13), suggesting that eating late may result in adverse metabolic consequences. Indeed, a study of healthy volunteers reported that the amount of calories consumed after 8:00 p.m. predicted a higher BMI after controlling for sleep timing and duration (14), suggesting that the timing of food intake across the waking day is of metabolic relevance.To date, little is known about chronotypic variations in patients with type 2 diabetes and the potential associations with glycemic control. There is abundant evidence that sleep disturbances such as short sleep duration and poor sleep quality are linked to the risk of diabetes and obesity, as well as glycemic control in subjects with type 2 diabetes (15,16), but little is known about the association between chronotype and metabolism independently of these sleep characteristics. The aim of this study was to examine whether chronotype was independently associated with glycemic control in patients with type 2 diabetes. We hypothesized that late chronotype would be associated with worse glycemic control independently of sleep disturbances. Because the distribution of food intake across the day is associated with chronotype, we also examined whether daily caloric distribution contributed to glycemic control. We hypothesized that a greater percentage of daily calories consumed at dinner would be associated with worse glycemic control.     

Prospects for circadian treatment of mood disorders

Abstract

Disruption of circadian clocks is strongly associated with mood disorders. Chronotherapies targeting circadian rhythms have been shown to be very effective treatments of mood disorders, but still are not widely used in clinical practice. The mechanisms by which circadian disruption leads to mood disorders are poorly characterized and, therefore, may not convince clinicians to apply chronotherapies. Hence, in this review, we describe specific potential mechanisms, in order to make this connection more credible to clinicians. We believe that four major features of disrupted clocks may contribute to the development of mood disorders: (1) loss of synchronization to environmental 24-h rhythms, (2) internal desynchronization among body clocks, (3) low rhythm amplitude, and (4) changes in sleep architecture. Discussing these attributes and giving plausible examples, we will discuss prospects for relatively simple chronotherapies addressing these features that are easy to implement in clinical practice.

• Key messages

• In this review, we describe specific potential mechanisms by which disrupted clocks may contribute to the development of mood disorders: (1) loss of synchronization to environmental 24-h rhythms, (2) internal desynchronization among body clocks, (3) low rhythm amplitude, and (4) changes in sleep architecture.

• We provide prospects for relatively simple chronotherapies addressing these features that are easy to implement in clinical practice.

     

Circadian rhythms, sleep, and metabolism

The discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal organization of behavior and physiology. The observations that the circadian gene network is present in most living organisms from eubacteria to humans, that most cells and tissues express autonomous clocks, and that disruption of clock genes results in metabolic dysregulation have revealed interactions between metabolism and circadian rhythms at neural, molecular, and cellular levels. A major challenge remains in understanding the interplay between brain and peripheral clocks and in determining how these interactions promote energy homeostasis across the sleep-wake cycle. In this Review, we evaluate how investigation of molecular timing may create new opportunities to understand and develop therapies for obesity and diabetes.     

Reducing disruption of circadian temperature rhythm following surgery

Temperature and other circadian rhythms are disrupted following surgery and other traumatic events. During recovery, coordination between temperature rhythms and other rhythmic physiologic processes is reduced. Studies of animals and humans have shown that return of synchrony is not immediate, but that it is important in the recovery process. The purpose of this study was to test a combination of cues that have been shown to adjust the timing of circadian temperature rhythm. The combined cues consisted of timed ingestion of caffeine and protein foods and adjustment of the sleep/wake cycle. The intervention was tested in 26 age- and gender-matched maxillofacial surgery patients. Patients were randomly assigned to control or experimental groups. Circadian temperature rhythm was measured by continuous monitoring with axillary probes and miniature recorders before and after surgery. Following surgery, both experimental and control subjects displayed 24-hour circadian temperature rhythms; however, the peak-to-trough difference was decreased more following surgery in the control subjects than in the subjects who had prepared for surgery by practicing the intervention. Control subjects also had less day-to-day stability in the phase of their rhythms following surgery. These results suggest that the intervention reduced circadian disruption following surgery and provides a way for patients to prepare themselves to resist rhythm changes.     

Circadian Profile of an Emergency Medicine Department: Scheduling Practices and Their Effects on Sleep and Performance

BackgroundShiftwork causes circadian disruption and is the primary reason for attrition from Emergency Medicine.ObjectivesWe aimed to develop concrete recommendations to mitigate negative effects of shiftwork based on measures of work, sleep, alertness, and performance in emergency physicians.MethodsThirty-one Emergency Medicine residents were surveyed retrospectively about sleep and alertness on different shifts. Additionally, the sleep, performance, and alertness of 22 Emergency Medicine resident and attending physicians was tracked continuously over 4 weeks via sleep logs, actigraphy, real-time reported sleepiness, and performance on a vigilance task. Schedules were analyzed for circadian disruption. Physicians also predicted their sleep schedules, which were compared with actual schedules; participants tracked extensions of shifts, schedule changes, and shifts in other hospitals.ResultsDaily rhythms were apparent in real-time performance and alertness data, with peaks at around 4 pm. Sleep difficulty was highest, sleep shortest, and alertness and performance lowest for night shifts. Emergency Medicine residents tended to cluster multiple night shifts in a row, despite evidence of accumulating sleep debt over consecutive shifts. There were many shifts that caused high circadian disruption, which could be avoided by simple amendments to scheduling practices.ConclusionsCircadian principles should be applied as suggested by the American College of Emergency Physicians. Chronotype should be considered in scheduling. Night shifts, particularly, should not be extended. Clustering all night shifts in a row should probably be discouraged. The additional vulnerabilities for night shift could be mitigated by adopting napping mid- or post night shift and by providing pay differentials.     

Does exposure to an artificial ULF magnetic field affect blood pressure,heart rate variability and mood?

The aim of this study was to determine whether an artificial magnetic field with an amplitude and frequency equivalent to those of geomagnetic pulsations during geomagnetic storms could affect physiology and psychology. Three healthy volunteers wore an ambulatory BP monitor and an ECG recorder around the clock for 12 consecutive weekends in Winnipeg, Manitoba, Canada. In a room shielded against ELF and VLF waves, they were exposed for 8 hours per week to either a 50 nT 0.0016 Hz or a sham magnetic field at one of six circadian stages. Real exposure randomly alternated with sham exposure. They provided saliva and recorded mood and reaction time every 4 hours while awake. Systolic (S) and diastolic (D) blood pressure (BP), and heart rate (HR) were recorded every 30 minutes. Spectral analysis of HR variability (HRV) was performed using the maximum entropy method and a complex demodulation method. For these variables, daily means were compared between real and sham exposure, using paired t-tests. Their circadian MESOR, amplitude, and acrophase were analyzed and summarized using single cosinor and population-mean cosinor. Circadian rhythms were demonstrated for HR, SBP, DBP for sham exposure, salivary flow rate, positive affect, vigor, and subjective alertness (p<0.001, ∼0.02). One participant showed higher HR, lower LF, HF, and VLF powers, and a steeper power-law slope (p<0.005, ∼0.0001) in an early night exposure to the real magnetic field, but not in other circadian stages. There was no significant difference between circadian responses to real and sham exposure in any variable at any circadian stage.     

Effect of Different Spectral Transmittances through Tinted Animal Cages on Circadian Metabolism and Physiology in Sprague–Dawley Rats

The suprachiasmatic nucleus is synchronized by the light:dark cycle and is the master biologic clock that serves as a pacemaker to regulate circadian rhythms. We explored the hypothesis that spectral transmittance (tint) of light through caging alters circadian rhythms of endocrine and metabolic plasma constituents in nonpigmented Sprague–Dawley rats. Rats (Crl:SD; n = 12 per group) were housed in a 12:12-h light:dark environment (300 lx; 123.0 μW/cm²; lights on, 0600) in either clear-, amber-, blue-, or red-tinted rodent cages. Blood was collected at 0400, 0800, 1200, 1600, 2000, and 2400 and measured for melatonin, total fatty acids, pH, glucose, lactic acid, corticosterone, insulin, and leptin. As expected, plasma melatonin levels were low during the light phase but higher during the dark phase in all groups; however, when compared with the clear-cage group, rats in amber-, blue-, and red-tinted cages had 29%, 74%, and 48%, respectively, greater total daily melatonin levels due to an increased duration and, in some cases, amplitude of the nocturnal melatonin signal. No differences were found in dietary and water intake, body growth rates, total fatty acids, pH, or glucose among groups. Disruptions in circadian rhythms, manifesting as alterations in phase timing, amplitude, or duration, occurred in the melatonin, lactic acid, corticosterone, insulin, and leptin levels of rats in tinted compared with clear cages. Therefore, the use of variously tinted animal cages significantly alters circadian rhythms in plasma measures of metabolism and physiology in laboratory rats, thus potentially altering the outcomes of scientific investigations.Abbreviations: ipRGC, intrinsically photosensitive retinal ganglion cells; SCN, suprachiasmatic nucleusLight prompts photobiological changes by way of the photopigment melanopsin in intrinsically photosensitive retinal ganglion cells (ipRGC),¹⁹ with some modulation by the visual rod and cone photoreceptors.^2,17 This stimulus leads to a cascade of molecular events sending signals via the neural pathway of the retinohypothalmic tract to the suprachiasmatic nucleus (SCN), the master biologic clock⁵ which is located in the brain. The SCN synchronizes numerous circadian rhythms and contributes to regulation of homeostasis and circadian physiology via several circadian outputs including the pineal gland''s production of melatonin. Studies have shown that changes in lighting intensity, duration, wavelength, and timing can disturb these circadian rhythms.^7-9 Not all light is equivalent. The responses to different wavelengths produced by visible and nonvisual electromagnetic radiation in an organism form what is known as an action spectrum. These wavelengths are perceived as a color or tint by the visual system of the primary optic tract. In mammals, the range generally between 450 and 550 nm (that is, blue light) has the strongest influence on neuroendocrine and circadian responses; however, longer wavelength (that is, red) light at high intensities can have this effect also.^7,18,29Melanopsin is a photosensitive pigment in the plasma membrane of ipRGC, which are directly activated by light to drive photoentrainment of the circadian system.^14,28 The ipRGC reside in the ganglion cell layer, which is the first retinal layer to receive incoming light. Melanin, however, is a distinctly different pigment from the chromaphore melanopsin. Commonly, animals are considered to be pigmented due to the presence of melanin, a derivative of tyrosine. Such is the case of the nude rats used in our previous studies.¹¹ An animal with a deficiency or absence of melanin in the retinal epithelium, hair, or skin is considered to be nonpigmented. Animals commonly used in biomedical research include albino (nonpigmented) Sprague–Dawley rats that lack melanin in the eyes, hair, and skin. Studies have found that the lack of melanin results in the abnormal development of the retinal pigmented epithelium and central retina and rods, as well as abnormal neural connections between the eye and brain.^21,26 Previous studies conducted with tinted laboratory cages demonstrated significant disruptions of metabolic and endocrine parameters in pigmented female nude rats.¹¹ To our knowledge, testing of a nonpigmented rat has not been attempted.As the field of laboratory animal science grows and advances, changes are being made in industry standards for laboratory animal housing and care for various reasons. These changes include the use of materials more suitable for high-temperature cleaning and of cage designs that accommodate viewing. In response to these shifting needs, alterations in cage design, material, or coloration that have been implemented may have unintended consequences for animal physiology. Unfortunately, most of these changes have little to no scientific basis supporting their use. For example, researchers and animal care personnel commonly expose animals to red light for extended periods of time for continual dark-phase observation or procedures when, in fact, such exposure may be detrimental to animal physiology, metabolism, and behavior depending on exposure duration.¹⁸ In addition, the eighth edition of the Guide²² suggests the use of red-tinted windows for rat and mouse holding rooms for animal observation and blocking hallway light from entering the room.In this regard, our previous research investigated the effect of spectral transmittance (for example, cage tint) through standard laboratory caging in female pigmented athymic nude rats and showed that animals developed chronobiologic disruptions in various endocrine and metabolic constituents in plasma.¹¹ Although the circadian rhythm of total fatty acids in plasma remained unchanged, all other metabolic and physiologic rhythms measured were significantly altered when rats were housed in either amber- or blue-tinted cages as compared with clear cages. These disruptions in plasma analyte levels encompassed changes in rhythm duration, phasing (for example, timing), amplitude, or some combination of these elements. Clear cages allowed the full spectrum of animal room polychromatic fluorescent light to pass through the cage, whereas tinted cages limited the transmittance of specific wavelengths.In the present study, we expand our previous findings in pigmented rats by exploring the effect of changes in spectral transmittance during the light period in male albino Sprague–Dawley rats. These animals were selected not only because they are nonpigmented but also because they are among the most widely used rat strains in scientific research. We hypothesized that changes in the tint (for example, spectral transmittance) of laboratory cages disrupts circadian rhythmicity and therefore the production of various endocrine and metabolic plasma constituents in Sprague–Dawley rats throughout a 24-h light:dark cycle.     

Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study

OBJECTIVEWeight loss achieved with very-low-calorie diets (VLCDs) can produce remission of type 2 diabetes (T2D), but weight regain very often occurs with reintroduction of higher calorie intakes. In contrast, bariatric surgery produces clinically significant and durable weight loss, with diabetes remission that translates into reductions in mortality. We hypothesized that in patients living with obesity and prediabetes/T2D, longitudinal changes in brain activity in response to food cues as measured using functional MRI would explain this difference.RESEARCH DESIGN AND METHODSSixteen participants underwent gastric bypass surgery, and 19 matched participants undertook a VLCD (meal replacement) for 4 weeks. Brain responses to food cues and resting-state functional connectivity were assessed with functional MRI pre- and postintervention and compared across groups.RESULTSWe show that Roux-en-Y gastric bypass surgery (RYGB) results in three divergent brain responses compared with VLCD-induced weight loss: 1) VLCD resulted in increased brain reward center food cue responsiveness, whereas in RYGB, this was reduced; 2) VLCD resulted in higher neural activation of cognitive control regions in response to food cues associated with exercising increased cognitive restraint over eating, whereas RYGB did not; and 3) a homeostatic appetitive system (centered on the hypothalamus) is better engaged following RYGB-induced weight loss than VLCD.CONCLUSIONSTaken together, these findings point to divergent brain responses to different methods of weight loss in patients with diabetes, which may explain weight regain after a short-term VLCD in contrast to enduring weight loss after RYGB.     

Sirtuin 1 in lipid metabolism and obesity

Abstract

Sirtuin 1 (SIRT1), the mammalian ortholog of yeast Sir2, is a highly conserved NAD⁺-dependent protein deacetylase that has emerged as a key metabolic sensor that directly links environmental nutrient signals to animal metabolic homeostasis. SIRT1 is known to be involved in gluconeogenesis in the liver, fat mobilization in white adipose tissue, and insulin secretion in the pancreas. Recent studies have shown SIRT1 to regulate fatty acid oxidation in the liver, sense nutrient availability in the hypothalamus, influence obesity-induced inflammation in macrophages, and modulate the activity of the circadian clock in metabolic tissues. The activity of SIRT1 also appears to be under the control of AMPK and adiponectin. This review focuses on the involvement of SIRT1 in regulating metabolic diseases associated with obesity. It includes brief overviews of sirtuin signaling, with emphasis on SIRT1's role in the liver, macrophage, brain, and adipose tissue as it relates to obesity.