Regular Article
Ameliorative Effects of Sweeteners on a Mouse Jet Lag Model
2025 年 48 巻 6 号 p. 919-927
詳細
2025 年 48 巻 6 号 p. 919-927
Circadian rhythms regulate essential physiological functions, including body temperature and hormone secretion, in a 24-h cycle. These rhythms are synchronized with environmental cues, primarily light, through the suprachiasmatic nucleus. Disruptions, such as jet lag, misalign internal rhythms with external time, leading to fatigue and insomnia. This study explores the potential of dietary sweetening agents as non-pharmacological interventions to facilitate circadian re-entrainment in a mouse jet lag model. Male C57BL/6 mice, maintained on a 12-h light/dark cycle, underwent a 6-h phase advance to simulate jet lag. Mice received drinking water with or without sweeteners (sucrose, sucralose, xylitol, maltitol), and locomotor activity was assessed using wheel-running behavior and intraperitoneally implanted nanotags measuring 3dimensional acceleration and body temperature. Sucrose and sucralose significantly accelerated re-entrainment, with phase-shifting rates of 0.93 and 1.28 h/d, respectively, compared to 0.76 h/d in controls. Both sweeteners also enhanced post-shift activity, whereas xylitol had a minor effect and maltitol showed no significant impact. Sweeteners did not affect rest duration during the jet lag period. These findings indicate that sweet taste can facilitate circadian adaptation, offering a potential dietary approach to mitigate jet lag symptoms. This study provides insights into how taste perception influences circadian regulation, with implications for managing circadian misalignment in frequent travelers and shift workers.
Living organisms have the ability to actively adjust their internal environments according to the 24-h cycle of day and night driven by the Earth’s rotation. In humans, fundamental physiological functions such as body temperature and hormone secretion are known to follow this approximate 24-h rhythm, referred to as the circadian rhythm. Even under constant conditions without external stimuli like light or temperature changes, the circadian rhythm persists, indicating the presence of an internal timekeeping mechanism, known as the biological clock or internal clock.
This internal clock is primarily located in the suprachiasmatic nucleus (SCN) in the brain, which serves as the central pacemaker for the circadian rhythms. The SCN is synchronized to the 24-h day by light signals that stimulate melanopsin-containing retinal ganglion cells,1) which, in turn, relay light–dark information to the SCN via the retinohypothalamic tract.2) These physiological and behavioral cycles, with a periodicity of approximately 24 h, are synchronized with solar time and regulate many critical functions. Circadian rhythms dictate the 24-h rhythmicity in rest–activity behavior, feeding, body temperature, hormone levels, and many other biological processes of the organism. Any disruption of this system can, therefore, negatively affect sleep quality, alertness, cognitive performance, motor control, mental health, and metabolism.3)
However, in real-world situations, environmental conditions can shift, leading to disturbances. One well-known example is jet lag, a condition caused by a misalignment between the internal body clock and the external environment’s time cues, particularly the light–dark cycle. When an individual rapidly crosses multiple time zones, the body’s internal rhythms, which were synchronized with the departure time zone, become desynchronized with the new light–dark cycle of the destination. This misalignment between the internal clock and external environment prevents the body from immediately adjusting to the new conditions. As a result, various symptoms can occur, such as daytime fatigue, insomnia, chronic tiredness, and a feeling of heaviness in the head.4–6) Social jet lag is also an issue, which is also studied in experimental animals.7,8)
In previous studies, it has been demonstrated that dietary interventions, among other factors, can effectively aid in recovery from jet lag. The internal clock was synchronized with mealtimes at specific periods. Moreover, the circadian rhythm and meal timing mutually interact,9) meaning that the timing of food intake can either reinforce or disturb the synchronization of the circadian rhythms. Furthermore, the timing of food intake has been recognized as a powerful environmental cue that can restore the synchrony of circadian rhythms, particularly in metabolic processes.10) Interestingly, chocolates given to mice and rats are effective in coordination of behavioral rhythm after jet lag.11,12)
Drosophila have long been used as a model organism in the study of sleep and circadian rhythms due to their well-characterized genetic background and the ease with which their behavioral patterns can be monitored. The circadian rhythms of Drosophila are regulated by a genetic network that shares significant similarities with the circadian clock mechanisms in mammals, making them an ideal model for studying the molecular underpinnings of biological rhythms. Additionally, Drosophila exhibit robust and measurable sleep–wake cycles that respond to external cues such as light and temperature, further enhancing their utility in circadian research. For instance, it has been shown that in Drosophila, fasting can reduce sleep, while sweetening agents, such as sugar, and even nonnutritive artificial sweeteners, can increase sleep time.13)
While Drosophila serves as a valuable model for studying sleep and circadian rhythms, there are inherent limitations when translating findings to mammals. The physiological and neurological differences between insects and mammals mean that certain mechanisms observed in fruit flies may not fully replicate the complexities of mammalian circadian regulation and sleep architecture. Moreover, the effects of sweetening agents on sleep modulation, as observed in Drosophila, have yet to be thoroughly investigated in mammalian models.
This study aims to explore the effects of sweetening agents on sleep and circadian rhythms in a mammalian model of jet lag, specifically using mice, to bridge the gap between insect models and more complex organisms.
Male C57BL/6 mice aged 6–12 weeks were individually housed under a 12-h light/12-h dark (LD) cycle at a room temperature of approximately 25°C, with each cage equipped with a flat-type running wheel with a rotation counter (MK-713, Muromachi-Kikai, Tokyo, Japan, or LCW-M4, Melquest, Toyama, Japan) for voluntary activity. Food and water were provided ad libitum. All mice were pre-acclimated for 2 weeks under a LD cycle with access to a running wheel. Before starting the experiment, we calculated the circadian period for each mouse using Lomb–Scargle periodograms. Arrhythmic mice or those with circadian periods that deviated significantly from 23.5 h were excluded from this study. The numbers of animals used for the analysis are described in the figure legends.
Animal EthicsAll experiments in this study were approved by the Animal Care and Use Committee of Nagoya City University (Approval Number: R3-P-01) and performed in accordance with the guidelines of the National Institutes of Health and the Japanese Pharmacological Society.
Jet Lag ModelTo simulate a rapid time zone shift causing circadian rhythm disruption, the onset of the dark phase was advanced by 6 h, creating a light–dark environment resembling jet lag from east-bound transmeridian travel. Before the experiment, mice were individually housed under the LD cycles for 2 weeks, during which their activity patterns were monitored using running wheels. They became accustomed to using running wheels, and their activity rhythm synchronized with the dark period (indicating normal nocturnal behavior) during this period. A 3-d baseline (pre-phase) was recorded before advancing the dark phase by 6 h. Data collection continued for 8 d after the phase shift to assess the effects of the jet lag model. In the sweetener pre-treatment experiments, mice were provided with regular drinking water for the first 3 d. On the 4th day, the drinking water was replaced with water containing sweeteners, and this condition continued for an additional 3 d. On the 7th day, a 6-h phase advance was implemented to induce jet lag.
Feeding ProtocolThe mice were fed ad libitum throughout the study. After the 3-d pre-phase, the drinking water was replaced with one containing the sweetening agents at the same time as the 6-h phase advance in the dark cycle. The sweetening agents used in this study were categorized as follows:
Sugars: Sucrose, sucralose
Sugar alcohols: Xylitol, maltitol
Based on a preliminary preference drinking test, the concentrations were set at 2 and 5% for sucrose and xylitol, and 5% for maltitol. For sucralose, due to its high sweetness and toxicity at higher concentrations, the concentrations were set at 0.2 and 0.5%. During the jet lag period, mice continued to have free access to food and drinking water.
Below is a comparison table of the sweetness and caloric content of the sweetening agents used:14)
Sweetening agents: Sucrose Sucralose Xylitol Maltitol
Sweetness: 1 × 600 × 1 × 0.9 ×
(Relative to sucrose)
Calories (kcal/g): 4.0 0 2.4 2.1
Activity MeasurementsMice activity was measured using the rotation counts per 1 min of a flat-type running wheel with a mechanical rotation counter (MK-713, Muromachi-Kikai, Tokyo, Japan, or LCW-M4, Melquest, Toyama, Japan) connected either to the Trikinetics DAM system through SwM (Trikinetics, Waltham, MA, U.S.A.), or to the LabView system through an NI-6501, 32 channel DIO interface with a custom-made software to acquire the data every 1 min. Additionally, each mouse was implanted with a Nanotag (Kissei Comtec, Nagano, Japan), an intraperitoneal sensor capable of measuring 3D acceleration speed and core body temperature. The Nanotag records activity by counting the number of times the combined acceleration of the mouse’s 3D (xyz)-axes exceeds a preset threshold, as detected by the accelerometer. Core body temperature was measured using the tag’s temperature sensor, and the data were stored and extracted via a FeliCa near-field communication device reader. The determination of the daily activity phase was done manually. Two scientists or graduate students independently determined the onset and offset points for each day of each mouse using the double-plotted printout, without any information on the experimental conditions (i.e., with or without sweeteners). They then drew a fitted line for each mouse’s plot, measured the slope of the line, and calculated the speed of re-entrainment. Other measurements included tracking changes in body weight and water consumption before and after the experiment.
Statistical AnalysisStudent’s t-test, repeated-measures 2-way ANOVA with post hoc multiple pairwise comparisons with Tukey’s correction, and Dunnett’s test were used. Statistical significance was set at p < 0.05. In this study, periods in which the Nanotag data recorded values below 10 for more than 5 consecutive mins within any 30-min window were classified as rest time.
We utilized the jet lag model in mice by advancing the dark phase by 6 h to simulate a rapid time zone change (Fig. 1a). We then analyzed the activity patterns of the mice to investigate how sucrose might affect their phase re-entrainment. All mice underwent surgery for intraperitoneal implantation of the nanotags (Kissei Comtec. Japan), which have a three direction accelerometer and thermometer and are capable of recording the parameters for 2 months. Mice were allowed to recover for at least 1 week before the experiments were started. The baseline activity levels and phases were recorded for 3 d in the precondition, then the dark phase was advanced by 6 h. At the same time, the drinking water was changed to one containing one kind of sweetening agent or to a control without them. In this mouse model, during the 3 d before the phase advance, all mice exhibited a nocturnal activity rhythm, starting their activity immediately after the onset of the dark phase (Figs. 1b, 1c). After the 6-h phase advance, the activities of all mice became desynchronized from the onset of the dark phase, and after a period of time, they re-synchronized to the new light/dark conditions. In humans, when experiencing jet lag, the internal biological clock becomes desynchronized with the external environment, making it initially challenging to adapt to a new sleep–wake cycle. It often requires a certain amount of time for individuals to fully synchronize with the new light–dark conditions. Thus, these results were analogous to the human jet lag condition.
(a) Schematic diagram of the mouse model and experimental procedure. Activities were measured for 3 d with water and then for 8 d after a 6-h phase advance with or without 5% sucrose administration. (b, c) Double-plot of activity profile by Nanotag for each group during the experiment: water (b) and 5% sucrose (c). Break lines indicate the fitted line on the onset of activity. (d) Average re-entrainment speed (h) per day of each group. Error bars indicate standard error of the mean (S.E.M.). Circles indicate each data. n (number of animals) = 6 (water), 11 (5% sucrose). *indicates a significant difference (p < 0.05) from water control by Student’s t-test.
Figures 1b and 1c show the average nanotag activities of the mice given water or water with 5% sucrose and Fig. 1d shows the average speed of re-entrainment. Mice given 5% sucrose re-entrained to the advanced phase significantly faster compared to those given water. The re-entrainment speed was calculated for each group: 0.76 h/d for water and 0.93 h/d for 5% sucrose. We also analyzed wheel-running activity data and found results that were largely consistent with the Nanotag data described above (Supplementary Data: Supplementary Figs. S1a, S1b, S1e). The average body temperature measured by Nanotag also showed a similar trend (Supplementary Figs. S1c, S1d). However, we could not accurately determine the onset of body temperature rise in individual animals and thus were unable to quantitatively compare the 2 groups using the body temperature data.
Sweetening Agents Also Facilitated Phase Re-Entrainment after 6-h Jet Lag in MiceNext, we examined the effects of other sweetening agents, many of which are used as artificial sweeteners with low calorie, on re-entrainment after phase shift. Interestingly, sucralose and xylitol, but not maltitol, showed accelerating effects on re-entrainment (Figs. 2a–2f), We then quantified the re-entrainment speed of each group, and 0.2% sucralose, 0.5% sucralose, and 2% xylitol showed significant differences in the average re-entrainment speed (Fig. 2g). The re-entrainment speeds calculated for each group were: 0.73 h/d for water, 1.15 and 1.28 h/d for 0.2 and 0.5% sucralose, 0.97 and 0.93 h/d for 2 and 5% xylitol, and 0.6 h/d for 5% maltitol. These correspond to the following re-entrainment durations to the 6-h phase advance: 8.2, 5.2, 4.7, 6.2, 6.5, and 10 d, respectively. These results suggest that the time required to re-entrain to the new phase was significantly reduced by some sweetening agents.
Similar to Fig. 1, mice were administered various sweeteners after a 6-h phase shift. (a–g) Double-plot of activity profile by Nanotag for each group during the experiment: water (a), 0.2% sucralose (b), 0.5% sucralose (c), 2% xylitol (d), 5% xylitol (e), and 5% maltitol (f). (g) Average re-entrainment speed (h) per day of each group. Error bars indicate S.E.M. Circles indicate each data. n (number of animals) = 8 (water), 6 (0.2% sucralose), 9 (0.5% sucralose), 6 (2% xylitol), 5 (5% xylitol), 4 (5% maltitol), *indicates a significant difference (p < 0.05) from water control by Dunnett’s test.
In addition to the adjustment of the activity phase, the overall activity level, especially during the dark phase (active phase), is also an important physiological indicator affected by jet lag. In humans, individuals experiencing jet lag often feel daytime fatigue in a new environment, leading to a significant decline in work efficiency. Similarly, in the mouse model used in this study, we focused on the activity level during the active phase (dark phase) to further investigate the role of sweeteners in the adjustment of circadian rhythm.
We therefore quantified the total activity both during the whole day and the dark phase (active phase), and Fig. 3 shows the activity level as the ratio to that of the baseline before phase advance. The control group showed a significant decrease in activity level on the 1st day after jet lag both during the whole day and during the dark period (Fig. 3, gray line), which persisted for 1 week after the phase shift, when the onset almost re-entrained to the new advanced phase. The addition of 5% sucrose increased the activity levels, which returned to baseline a few days after the phase shift (Figs. 3a, 3b, red line). Sucralose at both 0.2 and 0.5% also increased activity level after the phase shift, and the activity level during the dark phase apparently stayed at the baseline level after the phase shift (Figs. 3c, 3d). Xylitol at 2 and 5% also had e similar effects, but the activity level was more variable (Figs. 3e, 3f). Maltitol did not show increasing effects on activity levels (Figs. 3g, 3h).
Daily activity profiles for the whole day (a, c, e, g) and in the dark (active) phase (b, d, f, h) are shown as percentages relative to the pre-phase activity (average of 3 d before jet lag, indicated as “Day 0”). Plotted lines indicate the mean activity levels (± S.E.M.) of mice during 8 d after the phase shift (a, b: 5% sucrose vs. water; c, d: sucralose vs. water; e, f: xylitol vs. water; g, h: 5% maltitol vs. water). The numbers of the animals were the same as those in Figs. 1 and 2. *(5% sucrose, 0.5% sucralose) or + (0.2% sucralose, 2% xylitol) indicates a significant difference (p < 0.05) from water control by repeated-measures two-way ANOVA with post hoc multiple comparisons.
From these results, sucrose and some other sweeteners are considered to increase the activity level, which may be one reason why they accelerate the re-entrainment to the phase shift. Maltitol did not have either effect, indicating the difference among the sweeteners.
Sweetening Agents Did Not Affect the Rest Time of Mice after Jet Lag SignificantlyIn humans, jet lag often leads to disruptions in sleep patterns, such as insomnia, due to the body’s misalignment with the new light–dark environment. This inability to synchronize with the new circadian rhythm can be one of the most common symptoms associated with jet lag, further contributing to daytime fatigue and reduced performance. Having established that sweetening agents promoted the recovery of activity levels in mice from the jet lag state, we then examined their effects on sleep and rest.
In this study, the Nanotag, which can record data related only to activity and body temperature, was used for recording. To overcome this limitation and analyze sleep-related behavior, we devised a method to define rest time based on the activity data. We defined periods in which the Nanotag data recorded values below 10 for more than 5 consecutive min within any 30-min window as rest time. By this definition, we confirmed that the control mice showed approximately 600 min rest per day, which is almost equivalent to the sleep time of mice under similar conditions (data not shown). Using this definition, we analyzed the rest time of the mice given different sweeteners. As shown in Figs. 4a–4c, both sucrose and sucralose groups appeared to show slight increases in rest time compared to the control group. However, there were no significant changes between sugars either before jet lag or after jet lag (Fig. 4d). All the groups showed a slight increase in rest time after jet lag, but these changes were also not significant. Therefore, there were no significant effects of sweeteners on rest amount.
(a–c) Rest time profiles of each sweetener group (5% sucrose, 0.2% sucralose, 0.5% sucralose) compared to the water control group during the jet lag period. (d) Quantitative comparison of rest time during the initial 4 d of jet lag and the pre-phase. The numbers of the animals were the same as those in Figs. 1 and 2. Error bars indicate S.E.M. Circles indicate each data. No significant differences were observed in both intergroup (PRE vs. JET LAG) and intragroup comparisons (repeated-measures two-way ANOVA with post hoc multiple comparisons, p > 0.05).
To confirm if the sweeteners facilitated re-entrainment only when they were given after jet lag, we compared 2 conditions. For 1 group, we started to give the sweeteners (5% sucrose or 0.5% sucralose) 3 d before jet lag. As shown in Figs. 5a and 5b, even when the sweetener administrations were started before the phase shift, the mice re-entrained to the new phase faster than the control (Fig. 1a). The average speed of re-entrainment was significantly higher than the control (Figs. 5c, 5d). The activity level of mice given 5% sucrose increased before the phase shift and remained higher than that of the control after the phase shift (Figs. 5e, 5f). Interestingly, 0.5% sucralose alone did not increase the activity before the phase shift, but it increased activity after the phase shift (Figs. 5g, 5h).
Activities were measured for 3 d with water, for 3 d with 5% sucrose or 0.5% sucralose and then for 8 d after a 6-h phase advance with 5% sucrose (a, c, e, f) or 0.5% sucralose administration (b, e, g, h). For comparison, data from the water control group and sweetener addition after phase shift are used from Figs. 1 and 2. n (number of animals) = 4 (5% sucrose from pre), 5 (0.5% sucralose from pre). (a, b) Double-plot of activity profile by Nanotag for each group during the experiment. (c, d) Average re-entrainment speed (h) per day of each group. Error bars indicate S.E.M. Circles indicate each data point. * indicates a significant difference (p < 0.05) from water control by Dunnett’s test. (e–h) Daily activity profiles during the whole day (e, g) and in the dark (active) phase (f, h) are shown as a percentage relative to the pre-phase activity. No significant difference (p < 0.05) from water control was found by repeated-measures two-way ANOVA with post hoc multiple comparisons for activity level.
Since this study used ad libitum feeding, it is necessary to consider whether excessive intake of sweetening agents could induce physiological changes. During the experiment, we measured changes in water intake and body weight (Fig. 6).
(a) Average total water intake during 8 d for each group. (b) Average body weight changes of each group during 11-d, including 3 d of water and 8 d of each sweetener administration. n (number of animals) was the same as those in Figs. 1 and 2. Bars indicate the average for one mouse and error bars indicate S.E.M. Circles indicate each data point. *indicates a significant difference (p < 0.05) from water control by Dunnett’s test, N.S.: not significant.
In terms of water intake, sucrose significantly increased water intake in all groups compared to water, except for the xylitol group. These results are consistent with the preference test conducted in the preliminary experiments, indicating that mice prefer sweeteners, highlighting the sensory role of sweet substances. Regarding body weight, all groups of mice experienced weight gain after the 11 d free-feeding experiment. Specifically, the 5% sucrose, 5% xylitol, and 0.5% sucralose groups showed relatively higher increases, although none were statistically significant. Additionally, considering the caloric content, xylitol has a lower calorie value, and sucralose has no calories, suggesting that the intake of sweeteners during the jet lag period does not impose a caloric burden on the body.
In this study, we investigated the effects of various sweetening agents on the recovery of circadian rhythm, activity levels, rest time, and physiological indicators in a mouse model of jet lag. Our findings revealed that certain sweeteners, particularly sucrose and sucralose, promoted a faster re-entrainment to the new light–dark cycle and improved activity levels following a phase shift. It is noteworthy that sweet taste, rather than calorie or nutritional content, was critical for their effects. From a clinical perspective, this provides valuable insights into the challenges people face when crossing time zones, such as difficulty in adjusting to new schedules and experiencing daytime fatigue, which can lead to decreased productivity. Research has shown that jet lag and shift work often result in circadian misalignment, contributing to fatigue, impaired cognitive performance, and reduced productivity.15) Moreover, disruptions to the circadian rhythm caused by time zone shifts can have broader health implications, affecting sleep quality, mood, and metabolic processes.
Sucrose is the most commonly used sweetener and an ingredient in many foods, including sweet fruits. It has both sweetness and nutritional value. Almost all animals, including mice, have a preference for the sweetness of sucrose since it is regarded as one of the best sources of nutrition. The addition of 5% sucrose in the drinking water increased water intake, physical activity, and facilitated re-entrainment after jet lag. Human studies indicate that increased physical activity facilitates jet lag adjustment.16) Sucrose may improve re-entrainment through its ability to enhance physical activity.
Sucralose is an artificial sweetener with a very sweet taste, which is regarded as hundreds of times sweeter than sucrose. It has, however, no nutritional value, and is used in diets for caloric restriction. Lower concentrations (0.2 and 0.5%) of sucralose had similar or stronger effects than 5% sucrose in enhancing of re-entrainment after a phase shift. Sucralose also increased physical activity after jet lag. These results indicate that sweet taste has beneficial effects on re-entrainment, which is interesting and informative when considering countermeasures against jet lag.
Xylitol has been widely studied for its role in reducing dental caries, as it inhibits the growth of oral bacteria and promotes enamel remineralization, making it a popular sweetener in dental products.17,18) Although in this experiment, the onset advancement and re-entrainment speed of the xylitol groups did not show a significant difference from the control group, and their activity levels during the active phase fluctuated greatly, both concentrations of xylitol showed higher activity levels after the phase shift, which was close to their state before the phase shift. Since xylitol cannot be metabolized, some mice in this experiment showed varying degrees of diarrhea, which may have affected the results.
The maltitol group did not show any improvement in overcoming jet lag. Due to the small sample size and large individual differences, although the re-entrainment speed was roughly similar to the control group, the significantly lower activity levels indicate that maltitol is not effective in improving jet lag symptoms.
As for rest, while the rest time of mice increased under jet lag conditions, the intake of sweeteners did not significantly alter this parameter, suggesting a limited impact on sleep patterns. In this study, we defined rest time as a state in which mice showed relatively little movement, based on their activity levels. According to the results, rest time during the first 4 d after the phase shift increased compared to the pre-phase state, although the difference was not statistically significant. This increase may reflect a response to discomfort caused by the new light–dark conditions, akin to the fatigue humans experience when adapting to a new time zone. Additionally, comparisons between groups showed no significant differences, suggesting that the intake of sweeteners did not have a noticeable effect on alleviating the sense of fatigue or lethargy during the jet lag period. Regarding sleep, previous studies in Drosophila have reported that sucrose and sucralose can increase sleep duration.13) However, our current research did not confirm this effect. Therefore, future studies should consider using electroencephalogram measurements to assess actual sleep patterns and explore the effects of sweeteners on sleep more directly.
In terms of physiological responses, water intake increased in most sweetener groups except for xylitol, aligning with the preference for sweetness observed in preliminary tests. Despite some weight gain across groups during the free-feeding period, the differences were not statistically significant (Fig. 6). Overall, these results suggest that sweetening agents can facilitate adaptation to new light–dark conditions without imposing an additional metabolic burden on the body.
Regarding the mechanisms through which sweetening agents alleviate jet lag, previous research has discussed the role of sweet taste receptors in regulating the sleep–wake cycle.10) Since the effective sweeteners in our study all exerted their effects through their sweet taste, it is plausible that their impact is related to this mechanism. Additionally, considering the reward circuitry in the mammalian nervous system, the mice’s preference for sweeteners suggests that the action of getting up (onset) to drink sweetened water can be seen as a form of motivated behavior. This motivation might help the mice overcome the discomfort caused by the new light–dark environment. Moreover, previous studies have shown that mice consuming sweetened water are motivated by the sweet reward, which suggests that such mice exhibit enhanced spontaneous behaviors and improved learning abilities.19) In addition, a recent study showed that the addition of sweetener to caffeine facilitated the arousal effects of caffeine, and this effect was not due to a simple increase of caffeine by sweet taste.20) Additionally, there is evidence that the reward system, particularly the dopaminergic pathways, interacts with circadian regulation, and dopamine signaling has been shown to modulate SCN activity.21) This raises the possibility that sweeteners may influence circadian entrainment through reward-associated mechanisms rather than metabolic pathways alone. Moreover, it is well established that meal timing and dietary composition can significantly impact circadian rhythms, suggesting that the results of this study may reflect an interaction between dietary sweeteners and the circadian clock system. While the SCN is primarily regulated by light cues, metabolic signals also play a crucial role in circadian regulation,22) suggesting that dietary components, including sweeteners, could influence circadian rhythms via metabolic pathways. As food intake also acts as a strong zeitgeber for peripheral oscillators, sweeteners may affect peripheral clocks in addition to the SCN.23) Taken together, our results suggest that sweet taste induces various changes in the brain. However, the mechanisms underlying this phenomenon require further investigation in future studies.
In summary, this study provides a potential dietary intervention to alleviate the physical discomfort caused by jet lag due to long-distance travel across time zones and the resulting changes in light–dark cycles. By exploring the effects of different sweeteners on the re-entrainment of circadian rhythms and activity levels, our research opens up new possibilities for using dietary components to ease the adaptation process. Although further investigations are needed to fully understand the underlying mechanisms, the findings of this study highlight the potential of using simple, accessible food-based interventions as a means to mitigate the negative effects of jet lag. This approach could offer a convenient and non-pharmacological strategy to support individuals facing frequent time zone changes, enhancing overall well-being and daily performance.
We acknowledge Drs. T. Doi, T. Ichikawa, and T. Okuyama at the Central Research Institute, Lotte Co. for their help in the initial phase of this project, and the members of the Kume Laboratory, especially Dr. Hiroyuki Nakagawa, for their support. This study was supported in part by the Grants-in-Aid from JSPS, Japan (21H02529, 24K02065) to K.K.
The authors declare no conflict of interest.
This article contains supplementary materials.
