Meal Timing Regulates the Human Circadian System
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Human life clock also know as circadian clock is not only responsible for timing our sleep, but it can effect out eating, social and economical behavior. This can be seen now a days with most of the young and working people.
A scientific paper posted on www.cell.com tell us about the relation between our circadian system and our eating habits and at which time do we prefer to take our food in a day. It was seen that people having their meal after of before their eating time had much less sleep or had trouble sleeping.
Human life clock also know as circadian clock is not only responsible for timing our sleep, but it can effect out eating, social and economical behavior. This can be seen now a days with most of the young and working people.
A scientific paper posted on www.cell.com tell us about the relation between our circadian system and our eating habits and at which time do we prefer to take our food in a day. It was seen that people having their meal after of before their eating time had much less sleep or had trouble sleeping.
Highlights
- •A 5-hr delay in meal times changes the phase relationship of human circadian rhythms
- •Plasma glucose, but not insulin or triglyceride, rhythms are delayed by late meals
- •Adipose PER2 rhythms are delayed by late meals
- •Rhythm changes occur without altered subjective or actigraphic sleep markers
Summary
Circadian rhythms, metabolism, and nutrition are intimately linked [1, 2], although effects of meal timing on the human circadian system are poorly understood. We investigated the effect of a 5-hr delay in meals on markers of the human master clock and multiple peripheral circadian rhythms. Ten healthy young men undertook a 13-day laboratory protocol. Three meals (breakfast, lunch, dinner) were given at 5-hr intervals, beginning either 0.5 (early) or 5.5 (late) hr after wake. Participants were acclimated to early meals and then switched to late meals for 6 days. After each meal schedule, participants’ circadian rhythms were measured in a 37-hr constant routine that removes sleep and environmental rhythms while replacing meals with hourly isocaloric snacks. Meal timing did not alter actigraphic sleep parameters before circadian rhythm measurement. In constant routines, meal timing did not affect rhythms of subjective hunger and sleepiness, master clock markers (plasma melatonin and cortisol), plasma triglycerides, or clock gene expression in whole blood. Following late meals, however, plasma glucose rhythms were delayed by 5.69 ± 1.29 hr (p < 0.001), and average glucose concentration decreased by 0.27 ± 0.05 mM (p < 0.001). In adipose tissue, PER2 mRNA rhythms were delayed by 0.97 ± 0.29 hr (p < 0.01), indicating that human molecular clocks may be regulated by feeding time and could underpin plasma glucose changes. Timed meals therefore play a role in synchronizing peripheral circadian rhythms in humans and may have particular relevance for patients with circadian rhythm disorders, shift workers, and transmeridian travelers.
Results
No Change in Rhythms of SCN Clock-Driven Hormones, Markers of Sleep, or Subjective Appetite
Mammalian circadian rhythms are driven by a master clock, within the suprachiasmatic nuclei (SCN) of the hypothalamus, and peripheral clocks located throughout the body [3]. For the circadian system to function optimally, individual clocks must be correctly synchronized to one another and to the external environment. Abnormal circadian rhythms or defects in synchronization pathways can result in circadian misalignment or desynchrony, which are associated with poor health and metabolic disorders [4, 5]. In most individuals, the SCN clock is set to solar time by photic input pathways originating in the retina [6]; the SCN then synchronize peripheral clocks through neuronal pathways, hormone rhythms, core body temperature, and behaviors such as the cycle of feeding and fasting [3]. Photic cues are of primary importance for resetting human rhythms [7]. Regularly timed non-photic cues, however, can regulate rhythms in non-human species; for example, temporal restriction of food availability resets the phase of rodent peripheral clocks [8, 9], with more subtle effects on the rodent SCN [10]. Human studies have revealed that post-prandial responses are dependent on meal timing [11, 12, 13, 14], but little is known of the ability of meals per se to alter the timing of human circadian rhythms.
We investigated a 5-hr delay in three isocaloric daily meals (breakfast, lunch, and dinner) with identical macronutrient content on circadian rhythms using a 13-day laboratory protocol (Figure 1A). The overarching hypothesis was that the delay in meal timing delays peripheral rhythms, but not markers of the SCN clock. Phase changes were indirectly assessed by meal × time-of-day interactions in ANOVA analysis of grouped data and directly assessed by cosinor analysis of individual participant data (see STAR Methods).
We first measured the effect of meal time on plasma melatonin and cortisol rhythms, which are well-validated markers of the SCN clock. No significant changes were found in the temporal profiles of either hormone (Figures 1B and 1C). Next, in each individual, melatonin phase was measured using the dim light melatonin onset (DLMO), and cortisol acrophase was calculated using cosinor analysis. Delayed meals had no significant effect on either DLMO or cortisol phase (DLMO: t(9) = 0.94, p = 0.372; cortisol: t(9) = 0.96, p = 0.182; paired t test).
As sleep disruption is known to modulate metabolic physiology [15], we assessed subjective sleepiness throughout each constant routine using the Karolinska Sleepiness Scale (KSS). The expected temporal variation was observed, but there was no significant effect of meal timing (Figure S1). Furthermore, we were unable to detect any effects of meal timing on objective markers of sleep assessed by actigraphy (Figure S1). We assessed the influence of meal time on subjective appetite using a visual analog scale (VAS) but again found no significant effect (Figure S2).
Plasma Glucose, but Not Insulin or Triglyceride, Rhythms Are Affected by Meal Time
Plasma glucose concentration exhibited significant effects of time of day, meals, and meal × time-of-day interaction (Figure 2A). In order to quantify the effect of timed meals on glucose rhythm phase, we used cosinor analysis. The glucose acrophase occurred 1.31 ± 0.82 hr before DLMO following early meals but 4.38 ± 0.83 hr after DLMO following late meals. The 5-hr change in meal time delayed the relative phase of glucose rhythms by 5.69 ± 1.29 hr (Figure 2D).
The possible contribution of insulin to the delayed glucose rhythms was also investigated. Despite a significant effect of time of day, there was no significant effect of meals or meal × time-of-day interaction on plasma insulin concentration (Figure 2B). Cosinor analysis estimated an insulin acrophase 7.99 ± 1.99 hr after DLMO following early meals and 11.36 ± 0.89 hr after DLMO following late meals (Figure 2E).
There was a significant effect of time of day, but no significant effect of meals or meal × time-of-day interaction on plasma triglyceride concentration (Figure 2C). Cosinor analysis estimated a triglyceride acrophase 6.59 ± 0.62 hr after DLMO following early meals and 7.38 ± 0.30 hr after DLMO following late meals (Figure 2F).
Differential Response of Clock Gene Rhythms in White Adipose Tissue and Blood
To test the hypothesis that delayed meals delay molecular circadian rhythms in peripheral tissues, we measured clock gene transcripts in serial biopsies of white adipose tissue (WAT) using a refinement of our previously published protocol [16, 17]. Gene expression was measured in the seven participants from whom we were able to obtain five biopsies, one every 6 hr, in both constant routines. Data were obtained by RT-PCR for three canonical clock genes and Z scored prior to analysis (Figures 3A–3C). There was a significant effect of time of day, but no overall effect of meals on all three genes. There was a significant meal × time-of-day interaction for PER2, but not for PER3 or BMAL1. Cosinor analysis also revealed a significant effect of meal timing on PER2 phase, but not on the phase of PER3 or BMAL1 (Figures 3D–3F).
We next studied clock gene rhythmicity in whole blood samples. Consistent with previously published constant routine data [18], we found weak rhythms in BMAL1 (Figure S3A) and robust rhythms in PER3 gene expression (Figure S3B). However, no significant effect of delayed meals on either rhythm was observed.
Reduced Glucose Concentration Following Late Meals
Two-way repeated-measures ANOVA analysis of the time series data indicated a significant decrease in glucose concentration in the constant routine following late meals (Figure 2A). To investigate this in more detail, we compared each participant’s mean glucose concentration in the two constant routines. There was a significant decrease in the mean glucose concentration following late meals (Figure 4A), with all ten of the participants exhibiting lower plasma glucose after late meals. There was, however, no significant decrease in the mean concentration of plasma insulin (Figure 4B) or triglyceride (Figure 4C) following late meals. We next compared the peak and trough values for each participant in each constant routine to determine whether the lower glucose concentration was due to a reduced peak, trough, or both (Figure 4D). There was an overall effect of meals and a significant difference between peak and trough values. There was no significant interaction between the two factors, however, indicating a similar lowering of both peak and trough plasma glucose following the late meals.
Discussion
This report demonstrates that meal timing exerts a variable influence over human physiological rhythms, with notable changes occurring in aspects of glucose homeostasis. A 5-hr delay in meal times induced a comparable delay in the phase of circadian plasma glucose rhythms, as assessed under constant routine conditions. These altered glucose rhythms were accompanied by a 1-hr delay in the phase of WAT PER2 rhythms, but no change in markers of the SCN clock (melatonin, cortisol), rhythms of plasma insulin and triglyceride, or clock gene rhythms in whole blood. We also observed a reduction in plasma glucose concentration during the constant routine following late meals.
To limit our intervention to meal timing, participants maintained identical light-dark and sleep-wake schedules on days when timed meals were given. Sample collection then occurred in constant routine conditions after both early and late meals. Constant routines remove environmental fluctuations and sleep and replace meals with equally spaced isocaloric snacks [19]; the rhythms obtained are thus the product of endogenous circadian processes and not the result of acute post-prandial responses. Subjective sleepiness and hunger exhibited the expected temporal patterns. Sleepiness increased over the course of each constant routine, due to continuous wakefulness, and was highest during the subjective night. Self-reported hunger scores dipped in the early subjective morning, as observed by others [20, 21]. Meal timing had no effect on these subjective sleep and appetite markers, or actigraphic sleep parameters recorded prior to each constant routine, indicating that responses to a shift in meal times are unlikely to be driven by changes in sleep propensity or appetite.
Circadian regulation of plasma glucose and triglyceride concentration in humans has been reported by others using constant routine [12, 13, 22] and forced desynchrony [14] protocols. In addition, one study has reported minor (∼1 hr) phase shifts of human temperature and heart rate rhythms following morning or evening carbohydrate-rich meals, but with no effect on melatonin timing [23]. Very little research has addressed how temporal aspects of feeding regulate the circadian system of humans, however. The altered glucose rhythms in our study did not coincide with changes in plasma insulin rhythms and could thus be driven by altered rhythms of insulin sensitivity and/or glucose release from storage tissues. We observed no change in plasma triglyceride rhythm. Meal timing therefore appears to exert greater control over glucose homeostasis than lipid metabolism and can dissociate the temporal regulation of these key physiological processes.
We also investigated the effect of meal timing on markers of both central and peripheral circadian clocks. On the basis of previous animal and human experiments, we hypothesized that meal time would not alter the phase of melatonin and cortisol rhythms, reliable markers of the SCN clock. Clock gene rhythms in the SCN of rodents permitted ad libitum quantities of food do not synchronize to meal time [8, 9]. Furthermore, melatonin and cortisol rhythms in totally blind humans do not readily entrain to ad libitum non-photic cues [24]. Our melatonin and cortisol data demonstrated no differences after early compared to late meals. This suggests that the observed changes in rhythms of metabolic parameters are SCN independent, presumably occurring via effects on peripheral clocks.
Data from animal studies indicate that circadian clocks in multiple peripheral tissues contribute to glucose homeostasis [25, 26, 27, 28, 29, 30]. We therefore tested the hypothesis that late meals delay the phase of human peripheral clocks. We and others have previously demonstrated robust gene expression rhythms in serial WAT biopsies and blood samples [16, 18, 31, 32]. Here we observed a significant 1-hr delay in WAT PER2 expression. Although this change is smaller than the phase delay of plasma glucose rhythms, it nonetheless indicates for the first time that feeding patterns may be capable of synchronizing human peripheral clocks. Based on the differential resynchronization rate of murine clocks to food [8, 9], we predict that the effect of meal time on clocks in other peripheral tissues involved in glucose homeostasis (e.g., liver, pancreas) would be larger than in WAT. Indeed, tissue-specific responsiveness of peripheral tissue clocks is demonstrated by the lack of shift in PER3 rhythms in our blood samples.
Mean concentration of plasma glucose was 0.27 mM (4.7%) lower following late meals. The reduction of both peak and trough concentrations implies lower plasma glucose across the circadian cycle, with no change in rhythm amplitude. The cause of this change is unknown, but may involve the uncoupling of clocks in tissues that regulate glucose metabolism. Alternatively, experimental design may have resulted in an order effect on glucose, but not triglyceride, concentration. Order effects are extremely unlikely to contribute to the reported phase delays, however, as metabolite and gene expression data were analyzed relative to each individual’s endogenous melatonin phase. It is currently unclear how plasma glucose concentrations in a constant routine, where participants receive small hourly snacks, relate to the elevated post-prandial glucose excursion that occurs in the biological evening and night, compared to the early morning [12, 13]. These questions will be the focus of future research.
Limitations of the current study include the restricted participant demographics (all young men) and the fact that it is impossible to serially biopsy most human tissues closely associated with glucose homeostasis. The use of tightly controlled demographics is standard for this type of human laboratory trial. However, now that we have identified physiological responses in young male volunteers, it will be possible to target future studies to other groups. Serial sampling of human tissues has obvious practical considerations, limiting the number of study participants and the sampling resolution. Use of our WAT biopsy protocol has nonetheless enabled us to uncover novel effects of meal timing on gene expression rhythms in a metabolically important human tissue.
Our study reveals clear effects of meal timing on glucose homeostasis in a controlled laboratory setting. It is possible that timed meals could have a different effect on individuals not as tightly entrained as our study participants. Nonetheless, the implications of this novel finding include insight into the effects of eating behavior on human physiology, e.g., in patients with night eating disorder. The most wide-ranging impact, however, could be an addition to the existing light and sleep strategies for treating people with circadian desynchrony, which occurs following shift work and transmeridian flight. Prolonged desynchrony and shift work have been associated with obesity and cardiometabolic disease, so measures to appropriately synchronize the circadian system could benefit long-term health in many people. Timed interventions such as light exposure, or administration of oral agents including melatonin and caffeine, regulate the phase of human SCN-driven hormonal rhythms [33, 34, 35, 36, 37]. Oral administration of glucocorticoid can also phase shift clock gene rhythms in human blood mononuclear cells [38]. We now provide a non-pharmacological means by which some peripheral metabolic rhythms can be phase shifted in humans. Future work will need to examine the effects of timed meal patterns in simulated and real-life models of human jet lag and shift work. Animal studies [39] indicate this could be a very fruitful area of research.
Author Contributions
S.M.T.W., M.A.G., S.N.A., D.J.S., and J.D.J. carried out study design. C.I. carried out diet design. S.M.T.W., S.C., and C.I. handled data collection. S.M.T.W., S.C., C.I., B.M., S.N.A., D.J.S., and J.D.J. performed data analysis. S.M.T.W., S.C., C.I., B.M., M.A.G., S.N.A., D.J.S., and J.D.J. worked on manuscript preparation.
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