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Scheduled meals and scheduled palatable snacks synchronize circadian rhythms:Consequences for ingestive behavior
Carolina Escobar a,⁎, Roberto Salgado b, Katia Rodriguez a, Aurea Susana Blancas Vázquez a,Manuel Angeles-Castellanos a, Ruud M. Buijs b
a Departmento de Anatomía Facultad de Medicina, Universidad Nacional Autónoma de México, DF CP 04360, Mexicob Departmento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, DF CP 04360, Mexico
⁎ Corresponding author at: Depto. de Anatomía 4° pUNAM, Av Ciudad Universitaria 3000, DF 04360, México
Food is a potent time signal for the circadian system and has shown to entrain and override temporal signalstransmitted by the biological clock, the suprachiasmatic nucleus, which adjusts mainly to the daily light/dark(LD) alternation. Organisms mostly ingest food in their active period and this permits a correct coordinationbetween the LD and the food elicited time signals with the circadian system. Under conditions when feedingopportunities are shifted to the usual resting/sleep phase, the potent entraining force of food, shifts circadianfluctuations in several tissues, organs, and brain structures toward meal time, resulting a desynchrony withinthe body and between the organism and the external LD cycle. The daily scheduled access to a palatable snackexerts similar changes specifically to brain areas involved in motivation and reward responses. This reviewdescribes the phenomenology of food entrainment and entrainment by a palatable snack. It suggests howscheduled feeding can lead to food addiction and how shifted feeding schedules toward the sleep phase canresult in altered ingestive behavior, obesity and disturbed metabolic responses.
iso Edificio B, Fac de Medicina. Tel./fax: +52 5556 232422.).
1. Ingestive behavior is strongly regulated by the circadian system
In nature, animals spend several hours daily seeking food and theirefficiency for feeding determines their survival and reproduction.Feeding behavior strongly depends on circadian cycles because accessto food sources varies along the day. Some animals exhibit dailyactivity cycles aimed at avoiding being preyed upon by their hunters.Likewise hunters have developed daily cycles of activity to be efficientin catching their prey. Thus the capacity to estimate time givesanimals the possibility to anticipate the coming feeding opportunityby approaching the right location and to prepare physiological anddigestive functions for the expectedmeal. This results in adaptation toa cycling environment and better opportunities for survival.
The daily alternation of feeding/fasting is strongly coupled to thedaily cycle of wakefulness and sleep, since animals predominantly eatin their active period. Thus, feeding behavior is strongly regulated by atime keeping system organized by the biological clock, the supra-chiasmatic nucleus of the anterior hypothalamus (SCN). Thisbiological clock receives direct light information from the retina and
performs daily adjustments of the clock mechanisms to keep internaloscillations coupled to the external cycles [1,2]. The SCN controls anddrives circadian rhythms of the body by transmitting temporal signalsvia neuroendocrine, and autonomic pathways [3–6]. A completebilateral lesion of the SCN is known to abolish circadian rhythmicity ofthe sleep–wake cycle and also leads to arrhythmic patterns of thefeeding/fasting cycle [7,8].
2. Feeding schedules are potent entraining signals forcircadian rhythms
The strong interaction between the circadian system and feeding isreciprocal, since meal time also influences circadian rhythms. Inrodents, limiting food access to two or 3 h and shifting it towards theirresting phase (which corresponds to the light phase) modifies thetemporal organization of behavior [9]. Animals to which food access isscheduled to a few hours during the day develop anticipatory activitypreceding the feeding event, at a time when normally they would besleeping (Fig. 1). Anticipatory activity comprises arousal, increasedgeneral activity, exploratory behaviors (Fig. 2), sniffing, increasedwheel running and increased instrumental behaviors like pressing alever in a Skinner box to obtain food, or approaching a food source[9,10]. Restricted feeding schedules (RFS) also induce a daily peak ofcorticosterone [11] and a peak of ghrelin production by the stomach[12,13] while plasma insulin decreases[14] anticipating the dailymeal.
Fig. 1. Restricted feeding schedule (RFS) and chocolate entrainment induce food anticipatory activity (FAA). Actogram (A) and average profiles (B and C) showing generallocomotion of a rat under a light-dark cycle with chow andwater ad libitum during baseline and exposed to RFS with daily access to food at 13 h, indicated by the vertical square. Theactogram and the average profile indicate that anticipating rats are active 2-3 h before meal time. In rats receiving daily a restricted ratio of chocolate, anticipatory is reduced and isprecise. In D the actogram shows activity of a rat under chocolate entrainment, the vertical line at 13 hours indicates the time of chocolate delivery. The 18 activity profile (E and F)evidence a reduced but precise anticipatory activity of rats under chocolate entrainment (data modified from Angeles-Castellanos etal. 2008).
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The strong entraining force of RFS for the temporal organization ofphysiology is evidenced by temporal changes in body temperature[11,15,16] by adjustments in metabolic rhythms e.g. glucose, tri-glycerides, free fatty acids [16,17] and liver enzymes [18].
2.1. Entraining effects of meal time on peripheral organs
In the SCN, as well as in other brain areas and peripheral organs, aseries of genes (cry 1, cry2, per1, per2, per3, clock, bmal1), known asclock genes are expressed that exhibit autonomous 24 h cycles oftranscription/translation. It is suggested that they constitute thecellular clock machinery that dictates rhythmicity to the SCN totransmit its neuronal oscillations to cells, tissues and systems [19].Clock genes are also expressed in other tissues and brain areas, wherethey depend on signals of the SCN to maintain coordinated and
synchronized oscillations. Feeding schedules characterized by feed-ing/fasting cycles, however, have potent synchronizing effects on theclockwork of peripheral organs [20–22]. Some organs are moresensitive than others to food elicited signals, while the pineal glandresponds to both, the light/dark (LD) cycle and to feeding schedules[23,24]. The liver is exclusively driven by feeding schedules [25–27]and the heart and the adrenal gland respond mainly to signalsprovided by the SCN via the autonomic nervous system [28]. Themechanisms by which feeding associated signals reset peripheraloscillators are not yet fully understood. More than likely it is thecombination of hormonal (e.g. glucocorticoids), metabolic (e.g.glucose) and autonomic signals initially controlled by the SCN andthen controlled by food entrainment and the feeding/fasting cycle,which drive peripheral clocks [29]. Such signals elicit intracellularsignaling pathways that involve cAMP, AMP-activated protein kinase,
Fig. 2. Persistent anticipatory activity in rats previously entrained to food (black triangles)or chocolate (black circles) as compared with the ad libitum base line (grey circles. Thevertical gray line indicates the time when food or chocolate was given. -1, -2 and +1indicate thehours previous and after the expectedmealtime. Seven days after interruptionof the scheduled meal, rats still exhibit behavioral activation at the expected meal time.
NAD+ or SIRT1, which are possible mediators between metabolicchanges in the cells and the daily cycles of clock genes [29–33].Recently, changes in temperature have also been suggested as possiblelink between energy availability and clock gene entrainment [34].
Fig. 3.Mean temporal pattern of cells positive to the protein c-Fos in hypothalamic structureschedules (grey bars). The time point “0” on the abscissa represents food access. Data indicatfood ingestion (3) Asterisks represent significant statistical difference between ad libitum a2004 and 2007).
2.2. Entraining effects of meal time on the brain
These circadian rhythms in clock gene expression are not onlyobserved in the master circadian clock but also in brain areas withdiverse roles in behavior and physiology [35–40]. Interestingly and asobserved in the periphery, food is a relevant entraining signal for brainfunction. RFS shift the daily rhythms of vasopressin release in the SCN[41] and produce an anticipatory peak of NPY release in the PVN [42].Our group and others have shown that a few hours before meal time,when rodents are exhibiting food anticipatory activity, hypothalamicand brain stem nuclei involved in regulation of energy balance haveincreased c-Fos expression [15,43–45], a protein used as marker ofneuronal activity (Fig. 3; [46]). Likewise, RFS induce a daily anticipatorypeak of c-Fos in limbic structures involved inmotivational response andreward (Fig. 3) [47]. The samebrain areas showing c-Fos food-entrainedpatterns exhibit temporal shifts of clock gene expression (Per1 andPer2) uncoupling them from the LD signal transmitted by the SCN(Fig. 4). Such effects indicate a powerful influence of food elicited signalson the cellular rhythmicity in those areas. Thus, RFS modify the clockmachinery in cells of the hippocampus, prefrontal cortex, striatum,paraventricular hypothalamic nucleus, arcuate nucleus, olfactory bulb,thenucleus accumbens, pituitary and several limbic forebrain structuresthat are important in the regulation of stress, motivation, emotion andingestive behaviors; including the oval nucleus of the bed nucleus of thestria terminalis, central amygdala, basolateral amygdala and dentategyrus of the hippocampus. [47–54].
Taken together, present data indicate that RFS are a strong drivingforce for behavior and physiology. RFS induce anticipatory activity,changes in temperature and hormonal release. Such peripheralchanges in the body occur associated with shifts in daily rhythms of
s, and cortico-limbic system in ad libitum conditions (black bars) and restricted feedinge a strong cellular activation in brains associated with anticipatory activity (-3) and withnd restricted food schedules: (pb0.001) (Data modified from Angeles- Castellanos etal,
Fig. 4. Daily oscillations of the clock protein PER1 in hypothalamic and limbic areas of rats entrained to food (grey squares) to chocolate (grey triangles) or ad libitum (black circles).Feeding schedules have a main effect on hypothalamic structures, while chocolate drives high amplitude cycles in limbic areas. The vertical bar indicates meal time (data modifiedfrom Angeles-Castellanos et al, 2008).
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brain structures involved in homeostatic regulation, metabolicbalance, feeding and of other areas involved in motivation andreward responses. Importantly, the overall cellular activity and overallclock gene expression in the SCN remain coupled to the signalsprovided by the LD cycle [20,50,55] and this produces a desynchronybetween the time signals transmitted by the biological clock, the brainand peripheral oscillators. A desynchrony also occurs in the SCNbecause during anticipatory activity c-Fos is suppressed in the ventralarea, uncoupling the temporal pattern from its dorsal area. Thisinhibition of neuronal activity is aimed to allow the animal to becomeactive during the rest phase [56].
2.3. Daily scheduled access to a palatable snack is also a strong entrainingsignal
As described above, RFS induces a daily feeding/fasting (anabolic–catabolic) cycle, which is the main stimulus inducing anticipatoryactivation and food seeking behaviors. On the other hand this daily andpredictable food access and the resulting alternation of metabolic statesmay build up a timed mediated motivational condition of expectationand seeking food. The food-entrained activation in hypothalamic and
limbic areas suggests that both processes may contribute to behavioralactivation. In order to dissect the contribution of the motivational fromthe homeostatic factors we exposed rats to a protocol which alloweddiscarding the anabolic/catabolic cycle. Rats had free access to theirregular food andwere exposed to adaily restrictedand scheduledaccessto a palatable snack of 5 g of chocolate, which is normally ingested byrats in less than5 min [57]. Contrastingwith theRFSprotocolwhere ratsstart seeking food 2–3 h before meal time, rats receiving daily achocolate snack anticipate briefly, however very strongly (Figs. 1 and 2),exhibiting behavioral activation 30–15 min prior to snack delivery[48,57]. Someother groups have not detected this behavioral activation,whichdepends on the type of palatable snack, theduration of access andwhich type of behavior is monitored [58–60]. Furthermore, we haveobserved that after 3 weeks of daily scheduled access to a palatablesnack, the interruption of this protocol leads rats to continue seekingand waiting daily at the same hour for at least 10 days, suggesting astrong timedependentmotivation for the sweet food [48]. Interestingly,daily access to a palatable snack produces differential anticipatingneuronal activation as indicated by increased c-Fos in cortico-limbicstructures (Fig. 3) including the prefrontal cortex, nucleus accumbens,amygdala and thalamus, while hypothalamic nuclei normally activated
during RFS do not exhibit modified activity and exhibit similar values asundisturbed controls. Likewise the daily palatable snack entrains andshifts the daily peak of the clock protein PER1 in limbic areas [48]suggesting an entraining effect on temporal activity patterns (Fig. 4).Oscillations of PER1 driven by the daily palatable snack persisted for upto 5 cycles after interrupting the snack delivery, confirming theparticipation of a clock mechanism in the process of seeking sweetfood. This effect however, was not observed inmeasuring daily rhythmsof the clock protein PER2 [59,60] suggesting a differential effect of apalatable snack entrainment on the clockmachinery. Differential effectson clock genes by feeding schedules have also been described by Feilletet al. [37].
Altogether the present evidence suggests that scheduled dailysnacks may be sufficient to induce temporal cycles of expectancy andanticipatory search. This effect is selective on limbic areas involved inthe regulation of motivation and reward and do not depend onmetabolic anabolic/catabolic cycles, as observed with RFS. Thus,physiological signals elicited by the taste or the caloric contents of thesweet snack, by the arousal and motivation state elicited daily by thesweet snack accessmay be the driving force that starts such oscillations.
3. Does food entrainment underlie food addiction?
The potent entraining effect of a scheduled palatable snack onbehavior and corticolimbic structures, as well as the persistent searchand expectancy after interrupting the daily snack access, suggests thatstimuli representing a reward for the individual can influence thecircadian system and can drive daily rhythms of behavior and ofneuronal activity [61]. It also suggests that the daily arousal andseeking behavior might result from similar mechanisms as thoseunderlying addictive behaviors.
It is now reported that drugs of abuse can start circadian cycles inthe brain including the biological clock in a similar way as describedfor chocolate [62]. Since behavioral arousal produces phase shifts oflocomotor activity [63] and interferes with light signals drivinglocomotor activity [64] this drug entrainment may be initiated bymotivational states producing arousal and seeking behavior. Drugsthat influence vigilance and arousal also alter the expression ofcircadian rhythms by direct effects on clock genes and on the SCN [65].Recent evidence points out that also drugs of abuse modify clockgenes andmay induce temporal cycles of activity in the brain [65–67].In rodents, arrhythmic due to a bilateral lesion of the SCN, dailyadministration of metamphetamines induces circadian oscillations indifferent areas of the brain and in locomotor activity [68]. All thisevidence together supports the possible role of drugs as drivingsignals of circadian processes.
Likewise time signals associated with reward may be a drivingforce for clock genes in different brain areas and for circadian cycles ofactivity. Specifically the daily rise of dopamine showed to be essentialfor daily oscillations of the clock gene PER2 in the striatum [69]. It iswell described that after ingestion of a sweet snack, dopamine isreleased in the nucleus accumbens, a main neural structure regulatingreward and goal directed responses for both drugs and food [70].Thus, wemay speculate that a scheduled daily snack triggering a dailydopamine increase may result in entrainment of reward respondingareas in the brain, including the nucleus accumbens. This relationship,however, requires further research and opens an important perspec-tive of a possible involvement of the circadian system in foodaddiction.
4. Disturbed feeding schedules lead to desynchrony, obesity andaltered ingestive behavior
The protocol of RFS as well as entrainment with a daily palatablesnack have provided important knowledge on the powerful influencethat meal time can exert on physiological and behavioral temporal
patterns. Feeding schedules drive differentially metabolic and genecycles in cells, tissues, organs and in neuronal activity; they overridethe influence of the LD cycle, the SCN and some, but not all systems.Thus, food or snack ingestion when scheduled at the wrong time canbe a cause of circadian desynchrony between the external cycles,internal cycles and the internal homeostastic systems, leading toaltered responses of the body to food ingestion. Recent studiesindicate that in experimental rodents food ingestion at the wrongtime can lead to obesity and metabolic disturbances [71,72]. In thehuman population, the shift of the main daily food ingestion towardthe night has shown to promote body weight increase and thusoverweight, obesity and metabolic disruption [73,74]. Also, studieswith young adults have evidenced that shifting food intake to thenight leads to metabolic disturbance characterized by a reducedinsulin secretion, high levels of glucose and of triacylglycerols [75,76],all of them indicators of metabolic syndrome. All these indicate therelevance of organized feeding schedules coupled to the normalactivity time (the light phase for humans) in order to maintain energyhomeostasis [77].
5. Conclusion
Data here discussed indicate that scheduling a meal or a snack on adaily basis leads to expectancy and anticipation in experimentalmodels. This circadian process, could explain learned eating patternsin which individuals search for food or a palatable snack at specifichours of the day and may explain conditions of food addiction inwhich the search for food is associated to specific moments of the day.Consequently binge eating and night eating syndrome, that arecharacterized by altered circadian patterns of food ingestion mayreflect such interaction with the circadian system.
Acknowledgments
The group receives support from CONACYT 82462 and 79797 andPAPIIT IN-224911 and IN-205809.
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