Beneficial Effects of Early Time-Restricted Feeding on Metabolic Diseases: Importance of Aligning Food Habits with the Circadian Clock

The importance of metabolic health is a major societal concern due to the increasing prevalence of metabolic diseases such as obesity, diabetes, and various cardiovascular diseases. The circadian clock is clearly implicated in the development of these metabolic diseases. Indeed, it regulates physiological processes by hormone modulation, thus helping the body to perform them at the ideal time of day. Since the industrial revolution, the actions and rhythms of everyday life have been modified and are characterized by changes in sleep pattern, work schedules, and eating habits. These modifications have in turn lead to night shift, social jetlag, late-night eating, and meal skipping, a group of customs that causes circadian rhythm disruption and leads to an increase in metabolic risks. Intermittent fasting, especially the time-restricted eating, proposes a solution: restraining the feeding window from 6 to 10 h per day to match it with the circadian clock. This approach seems to improve metabolic health markers and could be a therapeutic solution to fight against metabolic diseases. This review summarizes the importance of matching life habits with circadian rhythms for metabolic health and assesses the advantages and limits of the application of time-restricted fasting with the objective of treating and preventing metabolic diseases.     

昼夜节律在病毒感染中的作用

昼夜节律是由内源性时钟调节的多个生物过程的日常振荡,调控机体的各种生理变化。节律紊乱会导致多种疾病的发生,包括代谢综合征和癌症等。最近将昼夜节律系统作用研究扩展到了感染的调控,宿主与病原体的相互作用以及由此产生的疾病结局。深入了解昼夜节律系统在调节病毒感染中的作用将为病毒性传染病的致病机理、抗病毒治疗、疫苗研发等提供新的思路。本文就昼夜节律与病毒感染的相互作用进行综述,包括昼夜节律如何影响病毒感染以及病毒如何调节节律以促进自身复制的关键发现,突出昼夜节律的重要性。     

Circadian activity rhythms in selectively bred ethanol-preferring and nonpreferring rats.

Chronic alcohol intake is associated with dramatic disruptions in sleep and other circadian biological rhythms in both humans and experimental animals. In human alcoholics, these disruptions persist during extended abstinence and appear to promote relapse to drinking. Whereas chronic ethanol intake alters fundamental properties of the circadian pacemaker in unselected rats, nothing is known concerning circadian pacemaker function in selectively bred ethanol-preferring and nonpreferring rats, which are the most widely accepted animal models of genetic predisposition to alcoholism. The present experiments were designed to characterize free-running circadian activity (wheel-running) rhythms under both constant darkness and constant light in selectively bred ethanol-preferring (P, HAD2) and nonpreferring (NP, LAD2) rats. Differences in circadian organization between ethanol-preferring and nonpreferring animals were seen for both pairs of selected lines (P vs. NP; HAD2 vs. LAD2), but these differences were not identical in the two line pairs. For example, although P rats showed shorter free-running periods than NP rats only in constant light, HAD2 rats showed shorter free-running periods than LAD2 rats only in constant darkness. In addition, ethanol-preferring HAD2 rats showed a high rate of rhythm "splitting" that was not seen in any of the other three lines. Taken together, these results suggest that the circadian pacemakers of P and NP rats differ mainly in light sensitivity, whereas those of HAD2 and LAD2 rats differ in their intrinsic period.     

Ethanol consumption in mice: relationships with circadian period and entrainment

A functional connection between the circadian timing system and alcohol consumption is suggested by multiple lines of converging evidence. Ethanol consumption perturbs physiological rhythms in hormone secretion, sleep, and body temperature; and conversely, genetic and environmental perturbations of the circadian system can alter alcohol intake. A fundamental property of the circadian pacemaker, the endogenous period of its cycle under free-running conditions, was previously shown to differ between selectively bred high- (HAP) and low- (LAP) alcohol preferring replicate 1 mice. To test whether there is a causal relationship between circadian period and ethanol intake, we induced experimental, rather than genetic, variations in free-running period. Male inbred C57Bl/6J mice and replicate 2 male and female HAP2 and LAP2 mice were entrained to light:dark cycles of 26 or 22 h or remained in a standard 24 h cycle. On discontinuation of the light:dark cycle, experimental animals exhibited longer and shorter free-running periods, respectively. Despite robust effects on circadian period and clear circadian rhythms in drinking, these manipulations failed to alter the daily ethanol intake of the inbred strain or selected lines. Likewise, driving the circadian system at long and short periods produced no change in alcohol intake. In contrast with replicate 1 HAP and LAP lines, there was no difference in free-running period between ethanol naïve HAP2 and LAP2 mice. HAP2 mice, however, were significantly more active than LAP2 mice as measured by general home-cage movement and wheel running, a motivated behavior implicating a selection effect on reward systems. Despite a marked circadian regulation of drinking behavior, the free-running and entrained period of the circadian clock does not determine daily ethanol intake.     

Influence of meal time on salivary circadian cortisol rhythms and weight loss in obese women

OBJECTIVE: We aimed to determine the influence of meal time on salivary circadian cortisol rhythms and weight loss in obese women. METHODS: Twelve obese subjects (body mass index >40 kg/m(2)) were hospitalized for 64 d and then randomly assigned to one of three 18-d stages with a 5-d interval between stages. In stage 1, the subjects received a hypocaloric diet (1000 kcal/d) portioned into five meals per day. In stage 2, the subjects received the same diet between 0900 and 1100 h. In stage 3, they received the same diet between 1800 and 2000 h. Between admissions, the subjects were discharged from the hospital and consumed their usual diet at home. Salivary cortisol rhythm (in six samples collected over a 24-h period) was determined during each stage, and anthropometric, bioimpedance, indirect calorimetric, and urinary nitrogen excretion variables were measured. RESULTS: Salivary cortisol circadian rhythms were similar during all stages when measured on day 1 or 18 of treatment. Despite significant reductions in all anthropometric measurements except waist/hip ratio, no significant changes were observed in salivary cortisol rhythm after alteration of the eating hours. Starting on day 4 of treatment, nitrogen ingestion and excretion levels decreased significantly; on day 10, nitrogen balance was negative in all study stages. CONCLUSION: Administration of a hypocaloric diet led to changes in weight, body composition, resting metabolic rate, and nitrogen balance but did not significantly alter salivary circadian cortisol rhythms.     

Pilot Clinical Trial of Time-Restricted Eating in Patients with Metabolic Syndrome

Metabolic syndrome (MetS) and erratic eating patterns are associated with circadian rhythm disruption which contributes to an increased cardiometabolic risks. Restricting eating period (time-restricted eating, TRE) can restore robust circadian rhythms and improve cardiometabolic health. We describe a protocol of the Time-Restricted Eating on Metabolic and Neuroendocrine homeostasis, Inflammation, and Oxidative Stress (TREMNIOS) pilot clinical trial in Polish adult patients with MetS and eating period of ≥14 h/day. The study aims to test the feasibility of TRE intervention and methodology for evaluating its efficacy for improving metabolic, neuroendocrine, inflammatory, oxidative stress and cardiac biomarkers, and daily rhythms of behavior for such population. Participants will apply 10-h TRE over a 12-week monitored intervention followed by a 12-week self-directed intervention. Changes in eating window, body weight and composition, biomarkers, and rhythms of behavior will be evaluated. Dietary intake, sleep, activity and wellbeing will be monitored with the myCircadianClock application and questionnaires. Adherence to TRE defined as the proportion of days recorded with app during the monitored intervention in which participants satisfied 10-h TRE is the primary outcome. TREMNIOS will also provide an exploratory framework to depict post-TRE changes in cardiometabolic outcomes and behavior rhythms. This protocol extends previous TRE-related protocols by targeting European population with diagnosed MetS and including long-term intervention, validated tools for monitoring dietary intake and adherence, and comprehensive range of biomarkers. TREMNIOS trial will lay the groundwork for a large-scale randomized controlled trial to determine TRE efficacy for improving cardiometabolic health in MetS population.     

In time for Beijing: influence of the biological clock on athletic performance

Circadian rhythms are a common characteristic ofmulticellular organisms and evolved as an adaptation to the earth's rotation on its axis. In humans, circadian rhythms are regulated by suprachiasmatic nuclei located at the base of the hypothalamus. The suprachiasmatic nuclei function as a biological clock that controls the daily rhythms of nearly all physiological functions. External light synchronises the endogenous clock to the environmental light-dark cycle. When travelling rapidly across multiple time zones, the endogenous clock must adjust to the new time. During the period of adjustment, many physiological circadian rhythms become desynchronised and jet lag occurs. Few studies have analysed the influence of jet lag on athletic performance. These studies indicate that performance levels can decline during jet lag. This seems to be a result of the desynchronized physiological state and sleep disturbances, leading to suboptimal values of blood pressure, heart rate, body temperature, and muscle strength. We give some advice for athletes who must cross multiple time zones shortly before a competition.     

Meal-timing, circadian rhythms and life span of mice

The possibility that circadian rhythm alteration may contribute to the life-prolonging effect of food restriction was investigated in female CD2F1 mice housed in a room with a 12-h span of fluorescent lighting daily. A control group was allowed to feed ad libitum throughout life while three other groups began lifelong restriction to about 75% of ad libitum intake when 6 wk old. The daily schedule of food accessibility differed among these three groups: a single meal during early darkness; a single meal during early light; six smaller meals at about 2-h intervals during darkness. Food restriction as such clearly prolonged life, but there were no statistically significant differences in overall mean life span or in 10th-decile life span among the three restricted groups. Telemetered body temperature data confirmed marked differences in the effects of these different restricted feeding schedules on circadian rhythms. The effect of food restriction on survival is probably not due to altered relations among circadian rhythmic variables. Possible contributing factors suggested by the results are a lower body temperature, a reduced overall metabolic rate and an increased circadian amplitude.     

成纤维细胞端粒酶重建对生物节律的调控

为探讨衰老对生物节律调控的分子机理,以青龄、衰老和端粒酶重建的皮肤成纤维细胞作为细胞模型,检测节律基因Per2,BMAL1和Clock表达。衰老细胞中节律基因表达受损,端粒酶重建细胞恢复了节律基因的节律性表达,提示端粒酶重建细胞可望用于衰老细胞的替代治疗。     

Gastrointestinal Vagal Afferents and Food Intake: Relevance of Circadian Rhythms

Gastrointestinal vagal afferents (VAs) play an important role in food intake regulation, providing the brain with information on the amount and nutrient composition of a meal. This is processed, eventually leading to meal termination. The response of gastric VAs, to food-related stimuli, is under circadian control and fluctuates depending on the time of day. These rhythms are highly correlated with meal size, with a nadir in VA sensitivity and increase in meal size during the dark phase and a peak in sensitivity and decrease in meal size during the light phase in mice. These rhythms are disrupted in diet-induced obesity and simulated shift work conditions and associated with disrupted food intake patterns. In diet-induced obesity the dampened responses during the light phase are not simply reversed by reverting back to a normal diet. However, time restricted feeding prevents loss of diurnal rhythms in VA signalling in high fat diet-fed mice and, therefore, provides a potential strategy to reset diurnal rhythms in VA signalling to a pre-obese phenotype. This review discusses the role of the circadian system in the regulation of gastrointestinal VA signals and the impact of factors, such as diet-induced obesity and shift work, on these rhythms.     

Circadian Rhythms of Occipital-cortex Temperature and Motor Activity in Young and Old Rats Under Chronic Protein Malnutrition

Abstract

The circadian rhythm of cortical temperature registered in the right occipital cortex and the circadian rhythm of motor activity were studied in young and old rats submitted to a chronic malnutrition paradigm. Circadian rhythms of cortical temperature and motor activity in Control (25% casein) and Malnourished (6% casein) Sprague-Dawley male rats were registered by telemetry along different lighting conditions. Results indicate that: (1) there are masking effects of light upon the period of cortical temperature in malnourished-old rats, (2) cortical temperature and motor-activity rhythms, show endogenous periods different from 24-h under free-running conditions, (3) protein malnutrition increases the amplitude and the mean value of cortical-temperature rhythm in malnourished-young rats, (4) aging decreases the amplitude and mean value of the motor-activity rhythm, (5) the acrophase of cortical temperature is delayed in malnourished-old rats, and (6) the temporal relationship between cortical temperature and motor-activity circadian rhythms is altered in malnourished-young and old rats. Therefore, this study provides evidence that protein malnutrition produces long-lasting alterations in the architecture of the circadian system, particularly affecting cortical-temperature oscillation. These changes might indicate thermoregulatory differences in the brain of malnourished rats that could be related to metabolic and behavioral alterations due to protein malnutrition.     

Circadian rhythms of occipital-cortex temperature and motor activity in young and old rats under chronic protein malnutrition

The circadian rhythm of cortical temperature registered in the right occipital cortex and the circadian rhythm of motor activity were studied in young and old rats submitted to a chronic malnutrition paradigm. Circadian rhythms of cortical temperature and motor activity in Control (25% casein) and Malnourished (6% casein) Sprague-Dawley male rats were registered by telemetry along different lighting conditions. Results indicate that: (1) there are masking effects of light upon the period of cortical temperature in malnourished-old rats, (2) cortical temperature and motor-activity rhythms, show endogenous periods different from 24-h under free-running conditions, (3) protein malnutrition increases the amplitude and the mean value of cortical-temperature rhythm in malnourished-young rats, (4) aging decreases the amplitude and mean value of the motor-activity rhythm, (5) the acrophase of cortical temperature is delayed in malnourished-old rats, and (6) the temporal relationship between cortical temperature and motor-activity circadian rhythms is altered in malnourished-young and old rats. Therefore, this study provides evidence that protein malnutrition produces long-lasting alterations in the architecture of the circadian system, particularly affecting cortical-temperature oscillation. These changes might indicate thermoregulatory differences in the brain of malnourished rats that could be related to metabolic and behavioral alterations due to protein malnutrition.     

Selective breeding for ethanol-related traits alters circadian phenotype

Previous studies in mice and rats have shown that selective breeding for high and low ethanol preference results in divergence of circadian phenotype in the selected lines. These results indicate that some alleles influencing ethanol preference also contribute to circadian rhythm regulation. Selective breeding has also been used to produce lines of mice differing in a number of other ethanol-related traits, while studies of phenotypic and genetic correlation indicate that diverse ethanol-related traits are influenced by both shared and unshared genetics. In the present study, we examined several features of circadian activity rhythms in a mouse line selected for binge-like drinking and in mouse lines selected for high and low severity of ethanol withdrawal convulsions. Specifically, Experiment 1 compared High Drinking in the Dark (HDID-1) mice to their genetically heterogeneous progenitor line (HS/Npt), and Experiment 2 compared Withdrawal Seizure-Prone (WSP-2) and Withdrawal Seizure-Resistant (WSR-2) mice. Both line pairs displayed differences in their daily activity patterns under light–dark conditions. In addition, HDID-1 mice showed shorter free-running periods in constant light and less coherent activity rhythms across lighting conditions relative to HS/Npt controls, while WSP-2 mice showed longer free-running periods in constant darkness relative to WSR-2 mice. These results strengthen the evidence for genetic linkages between responsiveness to ethanol and circadian regulation, and extend this evidence to include ethanol-related phenotypes other than preference drinking. However, the present results also indicate that the nature of genetic correlations between and within phenotypic domains is highly complex.     

成纤维细胞端粒酶重建对生物节律的调控

为探讨衰老对生物节律调控的分子机理,以青龄、衰老和端粒酶重建的皮肤成纤维细胞作为细胞模型,检测节律基因Per2,BMAL1和Clock表达.衰老细胞中节律基因表达受损,端粒酶重建细胞恢复了节律基因的节律性表达,提示端粒酶重建细胞可望用于衰老细胞的替代治疗.     

Food restriction, circadian disorder and longevity of rats and mice

Evidence that food restriction alters circadian rhythms as it prolongs the healthful life of rats and mice is reviewed. Because rhythms in different variables are changed in different ways, the circadian organization that is characteristic of freely feeding animals is disrupted. In the case of daily food restriction (meal feeding), the extent of disruption depends on the timing of the meal in relation to the daily light-dark schedule. Recent studies indicate that the extension of life span by a given level of food restriction is similar regardless of mealtime, whether fixed or shifted at weekly intervals throughout life. Such results suggest that the effects of food restriction on circadian organization are not involved in the effect on survival. On the other hand, changes in any given rhythm (such as an increased amplitude and a decreased overall average of body temperature) could point to the mechanism by which longevity is increased.     

Polyporus and Bupleuri radix effectively alter peripheral circadian clock phase acutely in male mice

In mammals, daily physiological events are precisely regulated by an internal circadian clock system. An important function of this system is to readjust the phase of the clock daily. In Japan, traditional herb medicines, so-called crude drugs (Shoyaku), are widely used for many diseases, and some are reported to affect circadian clock impairment, suggesting that some of them might have an ability to modify clock gene expression rhythms. Therefore, from selected 40 crude drugs, finding candidates that control the circadian clock phases was the first purpose of this study. As there are several crude drugs used for liver- and/or kidney-related diseases, the second aim of the present study was to find some crude drugs affecting liver/kidney circadian clock in vivo. To assess phase changes in the daily circadian rhythm, bioluminescence from the core clock gene product Period 2 was continuously monitored in mouse embryonic fibroblasts in vitro and in some peripheral tissues (kidney, liver, and submandibular gland) of PERIOD2::LUCIFERASE knock-in mice in vivo. In our screening, Polyporus and Bupleuri radix were found to be good candidates to effectively manipulate the peripheral circadian clock phase acutely, with stimulation time-of-day dependency in vitro as well as in vivo. Interestingly, Polyporus and Bupleuri radix are traditional herb medicines use for treating edema and promoting diuresis, and for chronic hepatitis, respectively. These crude drugs may be therefore good modulators of the circadian peripheral clocks including liver and kidney, and circadian clock genes become new molecular targets for these crude drugs.     

Sommeil et nutrition : approche chronobiologique par les rythmes hormonaux

The suprachiasmatic nuclei of the hypothalamus are the site of the master circadian clock in mammals. The suprachiasmatic clock modulates sleep and food intake, so that both do not occur at the same times of the daily cycle. Hormonal rhythms are, to various degrees, under the control of sleep and/or the suprachiasmatic clock. Drastic changes in homeostatic processes of sleep (e.g., sleep deprivation) or calorie intake (e.g., food restriction) can have an impact on the master circadian clock. Moreover, a chronic desynchronization affects sleep and it can also lead to metabolic changes. Interactions between the circadian clock, sleep-wake cycle and food intake are thus complex, and these systems regulate each other. Their alterations are associated with a host of major health problems.     

生物钟基因Per2与肿瘤

生物钟基因普遍存在于生物界,其作用在于产生和控制昼夜生物节律的运转。最新研究发现,生物钟系统不仅在昼夜生物节律方面起重要作用,而且参与机体其他功能的调节。该系统一旦失调可能引起一系列严重疾病发生,如淋巴瘤、白血病、乳腺癌和抑郁症等。就重要的生物钟基因Per2与肿瘤增殖凋亡的关系、Per2的抗肿瘤机制、及Per2在妇科肿瘤方面的研究近况做综述。     

Effects of cyclic (nocturnal) total parenteral nutrition and continuous enteral nutrition on circadian rhythms of blood lipids, lipoproteins and apolipoproteins in humans

The aim of the present study was to investigate the occurrence and characteristics (acrophase, amplitude) of circadian rhythms of serum total cholesterol, free-fatty acids (FFA), triglycerides, lipoproteins (HDL-, LDL-, and VLDL-cholesterol), apolipoproteins A and B, glucose and total proteins in hospitalized patients fed with 12 h nocturnal total parenteral nutrition (TPN) (from 8 PM to 8 AM) including lipids, patients fed with continuous enteral nutrition over 24 h daily spans, and patients eating 3 meals a day serving as controls. All the subjects were synchronized with diurnal activity and nocturnal rest in the hospital routine. The results showed the following: 1) circadian rhythms of total cholesterol, triglycerides, FFA, HDL-, LDL-cholesterol, apolipoprotein A and total proteins were detected in both TPN patients and controls, rhythms of apolipoprotein B and glucose in TPN patients only; in enteral nutrition patients, rhythms were detected for total proteins, glucose and triglycerides only; 2) a significant shift in triglyceride and FFA acrophases was observed in TPN patients, as compared with controls; 3) 24 h mean of both triglyceride and cholesterol concentrations remained unchanged after one month, in both TPN and enteral nutrition patients. The present approach, by extending results of previous investigations, leads one to conclude that, on both a metabolic and a chronobiological basis, cyclic nocturnal TPN is well-tolerated.