1R E V I E W Open Access
Time-restricted feeding and the realignment of
biological rhythms: translational opportunities
, Stavroula Sofou
, Kubra Kamisoglu
, Vassiliki Karantza
and Ioannis P Androulakis
11 It has been argued that circadian dysregulation is not only a critical inducer and promoter of adverse health effects,
12 exacerbating symptom burden, but also hampers recovery. Therefore understanding the health-promoting roles of
13 regulating (i.e., restoring) circadian rhythms, thus suppressing harmful effects of circadian dysregulation, would likely
14 improve treatment. At a critical care setting it has been argued that studies are warranted to determine whether
15 there is any use in restoring circadian rhythms in critically ill patients, what therapeutic goals should be targeted,
16 and how these could be achieved. Particularly interesting are interventional approaches aiming at optimizing the
17 time of feeding in relation to individualized day–night cycles for patients receiving enteral nutrition, in an attempt
18 to re-establish circadian patterns of molecular expression. In this short review we wish to explore the idea of transiently
19 imposing (appropriate, but yet to be determined) circadian rhythmicity via regulation of food intake as a means of
20 exploring rhythm-setting properties of metabolic cues in the context of improving immune response. We highlight some
21 of the key elements associated with his complex question particularly as they relate to: a) stress and rhythmic variability;
22 and b) metabolic entrainment of peripheral tissues as a possible intervention strategy through time-restricted feeding.
23 Finally, we discuss the challenges and opportunities for translating these ideas to the bedside.
25 Biological rhythms are major determinants of behavioural
26 outcome [1,2] and are controlled by a tightly regulated
27 network of genes and proteins entrained by external
28 signals (light and food). The suprachiasmatic nucleus
29 (SCN) is the fundamental, central, regulator of circadian
30 rhythmicity (biological rhythms of, roughly, 24 h period)
31 and is considered the master clock designed to align, and
32 coordinate the independent, self-sustained, peripheral
33 oscillators (a.k.a. peripheral clocks) found in every cell,
34 tissue and organ [3-6]. In that respect, understanding
35 the mechanisms by which the various pacemakers interact
36 to coordinate functions becomes a critical question .
37 Despite the fact that all peripheral clocks effectively utilize
38 the same time-keeping machinery [8-11] (FigureF1 1) each
39 peripheral entity is impacted by unique stimuli capable of
40setting clock rhythmicity locally, directly or indirectly. As
41such, core physiological functions are strongly impacted
42by the appropriate alignment of peripheral clocks to cen-
43tral (SCN) rhythms [12,13] likely mediated via circulating
44hormones [14,15]. While biological rhythms convey antici-
45patory signals priming the host for periods of food intake,
46increased activity and rest [16-18] (Figure F22) the loss of
47these rhythms has deleterious effects on overall health
48. The interplay between a host’s well-being and its
49biological rhythms is critical and bi-directional: disrupted
50rhythms impact the response to stress whereas stress
51alters the characteristics of biological rhythms [20-22].
52Emerging evidence suggesting that rhythmic signals play
53a major role in immune [25-27] and metabolic  func-
54tions naturally leads to the possibility of exploring biological
55rhythms as targets of intervention strategies, and in par-
56ticular in the context of intensive care units (ICU) where
57non-natural light schedules and time-invariant nutritional
58and/or pharmaceutical interventions may deprive patients
59of the rhythmic cues necessary to maintain appropriate
60biological rhythmicity during the recovery phase [29,30]
* Correspondence: email@example.com
Biomedical Engineering Department, Rutgers University, Piscataway, NJ
Chemical & Biochemical Engineering Department, Rutgers University,
Piscataway, NJ 08854, USA
Full list of author information is available at the end of the article
© 2014 Sunderram et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public
Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this
article, unless otherwise stated.
Sunderram et al. Journal of Translational Medicine 2014, 12:79
61 and loss of entraining inputs may significantly impact
62 recovery [10,31-34]. In fact circadian abnormalities correl-
63 ate with severity of illness and outcome . Due to the
64 strong role rhythmicity plays in recovering from trauma
65 [36,37], its regulation and realignment are emerging as
66 potentially critical controllers influencing patient outcome
67 by regulating entraining signals in a non-invasive manner.
68 Circadian cues that control rest cycles and metabolism are
69primarily driven by light and food [38,39]. These play a
70fundamental role in that they maintain proper synchrony
71between the peripheral clocks (Figure F33). The importance
72of maintaining good coordination between the peripheral
73oscillators is so critical that physicians have speculated
74that “[…]healthy organs behave as biological oscillators,
75which couple to one another during human development,
76and that this orderly coupling is maintained through a
Figure 1 The periodic expression of clock genes is driven by Per and Cry inhibiting the activity of the CLOCK/BMAL1 dimer (negative
feedback) and stimulating Bmal1 gene transcription (positive feedback). Through a negative feedback loop, the heterocomplex CLOCK/
BMAL1 activates the transcription of period (Per) and cryptochrome (Cry) genes upon binding to the E-box promoter region. After the expression
of PER/CRY proteins in the cytoplasm, they translocate to the nucleus where they inhibit their own transcription by shutting off the transcriptional
activity of the CLOCK/BMAL1 heterocomplex . Through the positive feedback loop the nuclear compartment of PER/CRY protein (y3) activates
indirectly Bmal1 mRNA (y4) transcription, which after its translation to BMAL1 protein and its translocation to the nucleus, increases the expression
of CLOCK/BMAL1 heterodimer. However, the peripheral clocks are “entrained”by external signals –cortisol (F) in this case. The role of the entertainer is
to synchronize the responses across a collection of cells. Figure adapted from .
Sunderram et al. Journal of Translational Medicine 2014, 12:79 Page 2 of 9
77 communications network, including neural, humoral,
78 and cytokine components. [We] suggest that the systemic
79 inflammatory response syndrome initiates disruption of
80 communication and uncoupling, and further suggest that
81 progression into the multiple organ dysfunction syndrome
82 reflects progressive uncoupling that can become irreversible.
83 Resolution of the inflammatory response and reestablish-
84 ment of the communications network are necessary but
85 may not be, by itself, sufficient to allow organs to appro-
86 priately recouple”.
87Exploring these cycles in order to realign patients’bio-
88logical rhythms during the recovery phase may prove to
89be highly rewarding in terms of outcome . Therefore,
90understanding the mechanisms that entrain the central and
91peripheral clocks, and the ways in which these rhythms
92influence the ability of the host organism to respond to,
93and recover from, external threats and challenges is critical
94to developing new models of patient care capable of
95engaging these rhythms in an attempt to, potentially,
96improve outcome. It must be noted that although it is
Figure 3 Systemic signals act as coordinators of peripheral oscillators maintaining synchrony of function and health.
Figure 2 Biological clocks enable the integration of behavioural cycles (sleep/wake –feed/fast) and metabolic processes across
different organs. While each tissue maintains its own clock ad intrinsic rhythms, external signals (zeitgebers) coordinate functions inorder to
maintain appropriate balances. (Figure adapted from ).
Sunderram et al. Journal of Translational Medicine 2014, 12:79 Page 3 of 9
97 well established that ICU patients have abnormal circadian
98 patterns [35,42] the overall environment in the ICU,
99 including the patient’s condition, the lighting and noise
100 levels in ICU as well as –and likely very importantly –the
101 treatment the patient receives, induces significant circa-
102 dian alterations [43,44].
103 In this short review we focus on one particular approach
104 to resetting biological rhythmicity in the context of time-
105 restricted feeding (TRF; access to food is restricted for
106 specific time intervals during the day without calorie
107 restrictions) and explore the possibility of pursuing circa-
108 dian re-alignment via nutritionally-inspired interventions.
109 Although the focus of the review is on the implications
110 of restoring circadian rhythms we should point out that
111 appropriate sampling and analysis of biochemical and
112 physiological circadian data requires careful design and
113 execution and these have been the subject of numerous
114 excellent reviews .
116 Circadian reprogramming as an intervention
117 strategy: opportunities for time-restricted feeding
118 Stress-induced loss of circadian rhythmicity
119 Evidence establishing the strong links between biological
120 rhythms and stress response is overwhelming and, by now,
121 very well established and accepted [14,46]. However, the
122 translational implications, opportunities and challenges of
123 how to manipulate rhythms in an ICU environment are
124 only now beginning to emerge in the scientific discourse
125 . A number of recent, and older, reviews have discussed
126 the connections between immune function and biological
127 rhythms  where the bi-directional relationship between
128 disrupted rhythms and immune dysfunction; and its impli-
129 cation on the bedside have been clearly identified [36,37].
130 What is even more interesting is the fact that we begin to
131 realize that circadian dysfunction following stress may have
132 long lasting ramifications  pointing to possible sources
133 of comorbidities. In fact, it has been argued that different
134 procedures impact post-operative circadian disruption in a
135 differential manner, thus affecting recovery, raising the
136 possibility of guiding operative procedures based on their
137 capacity to minimize impact on biological rhythms .
138 Clinical studies specifically emphasized that biological
139 night and day cycles (measured by urinary 6-sulfatoxyme-
140 latonin) were phase-delayed and normal features of sleep
141 were lacking (REM sleep was identified only in 2 patients
142 out of 21) in the critical care patients . Studies on
143 patients undergoing elective maxillofacial surgery showed
144 that strengthening circadian rhythms in anticipation of
145 disruption following surgery can be efficacious for improv-
146 ing the recovery phase. Patients whose circadian rhythms
147 were adjusted pre-operatively by combined sleep/wake
148 cycle alteration and timed food and caffeine ingestion
149 had reduced disruption in their body temperature cycles
150throughout their recovery in comparison to the control
152One of the most active areas of research pointing dir-
153ectly to circadian disruption and biological rhythm-setting
154interventions relate to mood disorders [51-55]. A vast
155literature exists on enhancing circadian rhythms for treat-
156ing depression, bipolar disorder and other related mood
157disorders either via pharmacological (melatonin) [55,56]
158or non-pharmacological means (light)  aimed at boost-
159ing circadian rhythms.
160Circadian (re)alignment and time-restricted feeding
161Time restricted feeding (TRF) is essentially imposing
162rhythms on nutrient availability. Entrainment by TRF
163has generated significant interest due to the possibility
164of synchronizing peripheral clocks without clear influences
165on (or from) the central pacemaker (SCN) [28,58]. It
166has been speculated that restricted feeding (RF) entrains
167rhythms in peripheral tissues (liver and lung)  is likely
168independent of the SCN. These works challenge the basic
169hierarchical paradigm that light entrains the SCN which
170subsequently entrains the peripheral clocks and empha-
171sized the role of RF as an entraining signal. The hypothesis
172of independently entrained peripheral clocks has been
173further reinforced by the observation that even lesions
174in brain nuclei do not eliminate food anticipatory activity,
175thus pointing to likelihood of a distributed system main-
176taining and regulating food-anticipatory activities [59,60].
177One of the main justifications is that when food acces-
178sibility adopts specific rhythmic characteristics so will the
179physiology and behaviour to match nutritional resource
180availability . It has been shown that feeding mice
181during the day completely reverses the phase of circadian
182oscillators (specifically, four clock components, Per1, Per2,
183Per3, Cry1; and the two circadian transcription factors
184DBP and Rev-erbα) in multiple peripheral cells (liver,
185kidney, heart and pancreas), but has little if any effect
186on the central oscillator in the SCN . However, we
187must point out that RF entrains the rhythm of clock
188protein Per2 even in the SCN as was shown in studies
189that eliminated photic stimulation by keeping mice in
190constant darkness , or at constant light conditions
191, thus raising the possibility of peripheral oscillators
192resetting the central clock.
193In a carefully designed study of a murine obesity model
194 the authors convincingly show the intimate relation-
195ship between the signalling and transcriptional components
196of energy metabolism and the circadian system. The study
197hypothesized that TRF improves diurnal rhythms; drives
198lipid homeostasis while preventing weight gain, hepatostea-
199tosis and liver damage; improves adipose homeostasis
200and reduces inflammation. The study demonstrated that
201preserving natural feeding rhythms significantly dampens
202metabolic disruption induced by a high fat diet, including
Sunderram et al. Journal of Translational Medicine 2014, 12:79 Page 4 of 9
203 improving oscillations of the liver circadian clock compo-
204 nents. Therefore, while the total calorie intake and food
205 composition (high fat) remained constant, the study clearly
206 demonstrated that an apparent lifestyle, i.e.,non-pharma-
207 cological, intervention prevented obesity, and related co-
208 morbidities, possibly by resetting metabolic cycles. The role
209 of food-anticipatory activity has also been explored with a
210 focus on energy metabolism, defined by oxygen consump-
211 tion . Animals were allowed access to food for only few
212 hours during either the light or the dark phases. Locomotor
213 activity, body temperature, clock gene expression in liver
214 and energy metabolism were recorded and their changes
215 assessed as the time window over which food became
216 available was changing. Continuous monitoring of energy
217 metabolism and core body temperature indicated expected,
218 robust diurnal rhythmic characteristics but also rapid
219 re-entrainment and adaptation to restricted food access.
220 A series of publications has focused on comparing
221 protein synthesis under a continuous and, a likely more
222 physiologically realistic, intermittent bolus feeding regimen,
223 delivered by orogastric tube, in neonatal pigs in the context
224 of regulating protein synthesis [66-68]. The analysis
225 demonstrated that intermittent feeding (delivered every
226 4 hrs as a bolus feed) enhances muscle protein synthe-
227 sis by imposing pulsatile patterns of amino-acid and
228 insulin-induced translation initiation. In this very inter-
229 esting series of papers it has been argued that bolus
230 feeding promotes a more physiological surge of intes-
231 tinal hormones. The studies effectively hypothesize that
232 “[…]cyclic surge of amino acids and insulin is needed
233 to maximally stimulate protein synthesis in skeletal
234 muscle”and that “[…]bolus compared to continuous
235 feeding has been advocated to promote more normal
236 feed-fast hormonal profiles”. It has been further demon-
237 strated that either advancing or delaying meal time in
238 young adult mice results in reversible alterations of
239 temperature and overall cage activities . Longer
240 time restriction (one week) alters rhythms in glucose,
241 triglyceride and HDL levels. Food restriction results in
242 behavioral arousal in anticipation of food presentation
243 and induces a shift in the circadian phase of many
244 physiological variables, likely independent of the SCN. As
245 such, RF is expected to exert changes in organs “handling
246 nutrients”(such as liver). As previous work had suggested
247 RF could be associated with significant stress due to hy-
248 perphagia, In a study examining the effect of restricted
249 feeding on stress markers, no marked changes in body
250 weight, retroperitoneal decrease in lipid deposits and peak
251 in glucocorticoids accompanying expectation to food ac-
252 cess were identified . Given the probable relationship
253 between stress and metabolic alterations (in this case
254 interest was in liver) the study explored whether an in-
255 crease in acute phase proteins (APR) or pro-inflammatory
256 state occurred after 2 weeks of 2hr food restriction. The
257“positive control”for APR consisting of a group injected
258with LPS showed a significant increase in systems APR
259while neither the ad libitum nor restricted feeding induced
260a marked increase in any of the inflammatory markers.
261Furthermore, a marked change in the diurnal patterns of
262circulating cytokines was observed as a consequence of RF.
263The authors advance an interesting hypothesis stating that
265earlier introduced in ) likely enabling the system to
266adopt a transient functional state “change in set-point”,
267boosting the rhythms and the overall fitness of the host.
268Time-restricted feeding and disease progression
269Peripheral circadian de-synchrony may be an early indica-
270tor of metabolic disruption in shift workers due to sleep
271deprivation mediated disruption of circadian rhythms. By
272extension, strengthening the peripheral circadian rhythm, by
273imposing metabolic rhythms via limiting food intake during
274the night, may counteract comorbidities seen in human shift
275workers . This study further implies that the manipula-
276tion of circadian rhythms need not be such that it aims
277at restoring the homeostatic nature of the internal clock.
278Rather it implies that, at least in the short term, strength-
279ening other rhythmic frequencies may be more beneficial.
280Particularly interesting is the work investigating the effect
281of resetting circadian clocks in peripheral tissues using
282non-photic signals on tumor growth rate in rats [73,74].
283Restricting the timing of meals to light time in contrast
284to restricted feeding during the night (active phase of
285rats) thereby, imposing a reversed metabolic rhythm,
286induced, what is referred to as, “internal desynchronization”
287(described as loss of phase relationship between central –
288light entrained –and peripheral clocks) resulted in pro-
289longed survival and slowed down tumor growth. The
290authors speculate that meal timing during the light period
291amplifies host rhythms and assigns their peak in a time
292window when the tumor is most susceptible to host-
293mediated control and that tumor growth is hampered
294when the internal (metabolic) clock adopts specific
295rhythmic characteristics, interestingly the opposite of
296what would have been otherwise considered “natural”.
297Therefore, the emerging hypothesis is that, a radically
298different metabolic rhythmicity appears to be most effect-
299ive at least in the short term.
300Restricted-time feeding vs. calorie restriction
301It is important to draw a distinction between time-
302restricted feeding and caloric restriction. The former
303entails the delivery of a certain amount of calories albeit
304at specific time intervals of specific duration. Therefore
305subjects still receive a standard nutritional intake. Calorie
306restriction entails an overall reduction in caloric intake,
307albeit without malnutrition. While evidence for the bene-
308fits of calorie restriction in animals has been promising,
Sunderram et al. Journal of Translational Medicine 2014, 12:79 Page 5 of 9
309 the issue as it relates to humans is still debated as con-
310 ducting long term studies assessing the implications of
311 prolonged calorie restriction in a controlled manner is
312 rather complicated . Although studies have shown
313 calorie restriction improves post-trauma outcomes [76-78],
314 it is likely that the long term effects of calorie restriction
315 are related to alterations of biological mechanisms respon-
316 sible for maintenance of health . Recent work has
317 indicated the possibility of caloric restriction impacting
318 circadian clocks as well . However, it is argued that
319 this may be a secondary effect of calorie restriction
320 resulting in time restricted feeding imposing specific
321 rhythms on metabolic function and entraining periph-
322 eral clocks. Nevertheless, the focus of this discussion is
323 on TRF and not on calorie restriction.
324 Clinical studies comparing continuous vs. bolus feeding
325 A number of fairly comprehensive clinical studies have
326 considered the impact of temporal delivery of enteral feed-
327 ing in critical patients [81-88]. Although these studies have
328 to be acknowledged in the context of our discussion, one
329 should be aware of the fact that clinical studies comparing
330 continuous vs. bolus feeding were motivated mostly by
331 the need to address some of the key practical limitations
332 associated with delivering nutritional support, such as in-
333 terruptions of continuous feeding leading to an inability to
334 achieve nutritional goals, gastrointestinal complications,
335 modulation of aspiration pneumonia, stool frequency etc.,
336 rather than as an attempt to capitalize on potentially advan-
337 tageous physiological and/or biochemical routes linking
338 metabolic rhythms and immune response. Earlier stud-
339 ies examined various parameters influenced by delivering
340enteral nutrition in the form of either continuous or bolus
341(intermittent) delivery and the conclusions are still de-
342bated in the clinical community . Studies comparing
343continuous to intermittent tube feeding in adult burn
344patients concluded that patients continuously fed had
345reduced stool frequency and time required to achieve
346nutritional goals. More recent studies, however, despite
347minor differences in specific goals and targets, in general
348do not provide evidence of significant difference in terms
349of patient outcome. Results show that patients intermit-
350tently fed have a higher total intake volume, are extubated
351earlier, and have a lower risk of aspiration pneumonia.
352Postoperatively, feeding at night only is more energy effi-
353cient than is feeding continuously for 24 h, but is associ-
354ated with poorer nitrogen balance . In one of the very
355few studies which complemented intermittent feeding
356in a clinical setting with monitoring of biomarkers, the
357observed decrease in urinary catecholamine secretion
358indicated a possible role of sympatho-adrenal mechanisms.
359This study provides a link between feeding patterns and
360putatively modulated pathways. However, no studies have
361been performed where time restricted feeding has been
362compared to either bolus or continuous feeding in the ICU.
364Time restricted delivery of metabolites imposes rhythmic
365availability of nutrients which resets peripheral clocks
366in a way that potentially exerts a positive impact on the
367immune response. Recent clinical evidence indicates that
368restoring circadian rhythms in critically ill patients is
369important. We hypothesize that providing circadian cues
370in the ICU could be explored as a mechanism to improve
Figure 4 Robust circadian entrainment characterizes homeostasis, whereas disruptions (amplitude and phase) characterize stressful
critical conditions. Whereas in homeostasis circadian rhythms are properly aligned with clearly identifiable phase locking, circadian disruption
shifts peripheral clock rhythms. Restoration of peripheral rhythms, including nutritionally-driven metabolic rhythms through time-restricted feeding
will re-entrain the system and provide appropriate systemic cues.
Sunderram et al. Journal of Translational Medicine 2014, 12:79 Page 6 of 9
371 ICU outcome by reinforcing appropriate rhythms of
372 hormonal release [30,34] (FigureF4 4). As it is becoming
373 increasingly more evident that exploring alternatives
374 measures to re-establish circadian patters of molecular
375 expression via non-pharmacological means could hold
376 significant potential, feeding entrainment through the
377 possibility of optimizing the time of feeding in relation to
378 the light/dark cycle for patients receiving enteral nutrition
379 appears to beg for more investigation .
380 In this brief review we elaborated on the idea that
381 establishing abolished rhythms would have a beneficial
382 effect on the host response to stress. We highlighted some
383 of the key elements associated with this complex question
384 particularly as they relate to: a) stress and rhythmic vari-
385 ability; and b) metabolic entrainment of peripheral tissues
386 as a possible intervention strategy through time-restricted
387 feeding. Positive effects have been shown in the context
388 of psychological stress, mood disorders etc., using either
389 pharmacologic agents, aiming at restoring circadian sig-
390 nals, or using photic signals to activate the central pace
391 maker. The question, however, remains whether imposing
392 appropriate metabolic rhythms, likely not maintaining
393 homeostatic phase relations with the central clock, through
394 time-restricted feeding would lead to beneficial entrainment
395 of peripheral clocks resulting in improved health outcomes
396 with a host under stress.
397 Competing interests
398 The authors declare that they have no competing interests.
400 JS, SS, KK, VK edited the manuscript; IPA conceived the idea, prepared and
401 edited the manuscript. All authors read and approved the final manuscript.
402 Author details
Department of Medicine, Division of Pulmonary and Critical Care Medicine,
404 Rutgers - Robert Wood Johnson Medical School, New Brunswick, NJ 08901,
Biomedical Engineering Department, Rutgers University, Piscataway, NJ
406 08854, USA.
Chemical & Biochemical Engineering Department, Rutgers
407 University, Piscataway, NJ 08854, USA.
Rutgers Cancer Institute of New
408 Jersey, Rutgers University, New Brunswick 08901, USA.
409 Received: 21 December 2013 Accepted: 10 March 2014
410 Published: 28 March 2014
Reppert SM, Weaver DR: Coordination of circadian timing in mammals.
Nature 2002, 418:935–941.
Lowrey PL, Takahashi JS: Mammalian circadian biology: elucidating
genome-wide levels of temporal organization. Annu Rev Genomics Hum
Genet 2004, 5:407–441.
Liu C, Weaver DR, Strogatz SH, Reppert SM: Cellular construction of a
circadian clock: period determination in the suprachiasmatic nuclei.
Cell 1997, 91:855–860.
Kohsaka A, Bass J: A sense of time: how molecular clocks organize
metabolism. Trends Endocrinol Metab 2007, 18:4–11.
Grechez-Cassiau A, Rayet B, Guillaumond F, Teboul M, Delaunay F:
The circadian clock component BMAL1 is a critical regulator of
p21WAF1/CIP1 expression and hepatocyte proliferation. J Biol Chem 2008,
Stokkan K-A, Yamazaki S, Tei H, Sakaki Y, Menaker M: Entrainment of the
circadian clock in the liver by feeding. Science 2001, 291:490–493.
Schibler U, Sassone-Corsi P: A web of circadian pacemakers. Cell 2002,
Eisele L, Prinz R, Klein-Hitpass L, Nuckel H, Lowinski K, Thomale J, Moeller LC,
Duhrsen U, Durig J: Combined PER2 and CRY1 expression predicts out-
come in chronic lymphocytic leukemia. Eur J Haematol 2009, 83:320–327.
Everson CA: Functional consequences of sustained sleep deprivation in
the rat. Behav Brain Res 1995, 69:43–54.
Fu L, Pelicano H, Liu J, Huang P, Lee C: The circadian gene Period2 plays
an important role in tumor suppression and DNA damage response
in vivo. Cell 2002, 111:41–50.
Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP,
Takahashi JS, Weitz CJ: Role of the CLOCK protein in the mammalian
circadian mechanism. Science 1998, 280:1564–1569.
Green CB, Takahashi JS, Bass J: The meter of metabolism. Cell 2008, 134:728–742.
Lamia KA, Storch KF, Weitz CJ: Physiological significance of a peripheral
tissue circadian clock. Proc Natl Acad Sci U S A 2008, 105:15172–15177.
Arjona A, Silver AC, Walker WE, Fikrig E: Immunity's fourth dimension:
approaching the circadian-immune connection. Trends Immunol 2012,
Le Minh N, Damiola F, Tronche F, Schutz G, Schibler U: Glucocorticoid
hormones inhibit food-induced phase-shifting of peripheral circadian
oscillators. EMBO J 2001, 20:7128–7136.
Koyanagi S, Ohdo S: Alteration of intrinsic biological rhythms during
interferon treatment and its possible mechanism. Mol Pharmacol 2002,
Vitalini MW, de Paula RM, Park WD, Bell-Pedersen D: The rhythms of life:
circadian output pathways in Neurospora. JBiolRhythms2006, 21:432–444.
Edery I: Circadian rhythms in a nutshell. Physiol Genomics 2000, 3:59–74.
Rana S, Mahmood S: Circadian rhythm and its role in malignancy.
J Circadian Rhythms 2010, 8:3.
Rechtschaffen A, Bergmann BM, Gilliland MA, Bauer K: Effects of method,
duration, and sleep stage on rebounds from sleep deprivation in the rat.
Sleep 1999, 22:11–31.
Reilly DF, Westgate EJ, FitzGerald GA: Peripheral circadian clocks in the
vasculature. Arterioscler Thromb Vasc Biol 2007, 27:1694–1705.
Haimovich B, Calvano J, Haimovich AD, Calvano SE, Coyle SM, Lowry SF: In
vivo endotoxin synchronizes and suppresses clock gene expression in
human peripheral blood leukocytes. Crit Care Med 2010, 38:751–758.
Mavroudis PD, Scheff JD, Calvano SE, Lowry SF, Androulakis IP: Entrainment
of peripheral clock genes by cortisol. Physiol Genomics 2012, 44:607–621.
Bass J, Takahashi JS: Circadian integration of metabolism and energetics.
Science 2010, 330:1349–1354.
Lee JE, Edery I: Circadian regulation in the ability of Drosophila to
combat pathogenic infections. Curr Biol 2008, 18:195–199.
Paladino N, Leone MJ, Plano SA, Golombek DA: Paying the circadian toll:
the circadian response to LPS injection is dependent on the Toll-like
receptor 4. J Neuroimmunol 2010, 225:62–67.
Silver AC, Arjona A, Walker WE, Fikrig E: The circadian clock controls toll-
like receptor 9-mediated innate and adaptive immunity. Immunity 2012,
Feillet CA, Albrecht U, Challet E: “Feeding time”for the brain: a matter of
clocks. J Physiol Paris 2006, 100:252–260.
Carlson DE: Are you having a good day: a passing nicety or a fundamental
question in the intensive care unit? Crit Care Med 2012, 40:344–345.
Chan MC, Spieth PM, Quinn K, Parotto M, Zhang H, Slutsky AS: Circadian
rhythms: from basic mechanisms to the intensive care unit. Crit Care Med
Cao Q, Gery S, Dashti A, Yin D, Zhou Y, Gu J, Koeffler HP: A role for the
clock gene Per1 in prostate cancer. Cancer Res 2001, 69:7619–7625.
Filipski E, Levi F: Circadian disruption in experimental cancer processes.
Integr Cancer Ther 2009, 8:298–302.
Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrão AB, Gold P,
Chrousos GP: Plasma leptin levels Are increased in survivors of acute
sepsis: associated loss of diurnal rhythm in cortisol and leptin secretion.
J Clin Endocrinol Metabol 1998, 83:280–283.
Carlson DE, Chiu WC: The absence of circadian cues during recovery from
sepsis modifies pituitary-adrenocortical function and impairs survival.
Shock 2008, 29:127–132. 110.1097/shk.1090b1013e318142c318145a318142.
Gazendam JA, Van Dongen HP, Grant DA, Freedman NS, Zwaveling JH,
Schwab RJ: Altered circadian rhythmicity in patients in the ICU. Chest
Sunderram et al. Journal of Translational Medicine 2014, 12:79 Page 7 of 9
Lowry SF: The evolution of an inflammatory response. Surg Infect
(Larchmt) 2009, 10:419–425.
Lowry SF: The stressed host response to infection: the disruptive signals and
rhythms of systemic inflammation. Surg Clin North Am 2009, 89:311–326. vii.
Cardone L, Hirayama J, Giordano F, Tamaru T, Palvimo JJ, Sassone-Corsi P:
Circadian clock control by SUMOylation of BMAL1. Science 2005,
Cassone VM: Effects of melatonin on vertebrate circadian systems. Trends
Neurosci 1990, 13:457–464.
Godin PJ, Buchman TG: Uncoupling of biological oscillators: a
complementary hypothesis concerning the pathogenesis of multiple
organ dysfunction syndrome. Crit Care Med 1996, 24:1107–1116.
Taguchi T, Y ano M, Kido Y: Influence of bright light therapy on postoperative
patients: a pilot study. Intensive Crit Care Nurs 2007, 23:289–297.
Mundigler G, Delle-Karth G, Koreny M, Zehetgruber M, Steindl-Munda P,
Marktl W, Ferti L, Siostrzonek P: Impaired circadian rhythm of melatonin
secretion in sedated critically ill patients with severe sepsis. Crit Care Med
Wenham T, Pittard A: Intensive care unit environment. Cont Educ Anaesth
Crit Care Pain 2009, 9:178–183.
Campbell IT, Minors DS, Waterhouse JM: Are circadian rhythms important
in intensive care? Intensive Care Nurs 1986, 1:144–150.
Refinetti R, Lissen GC, Halberg F: Procedures for numerical analysis of
circadian rhythms. Biol Rhythm Res 2007, 38:275–325.
Logan RW, Sarkar DK: Circadian nature of immune function. Mol Cell
Endocrinol 2012, 349:82–90.
O'Callaghan EK, Anderson ST, Moynagh PN, Coogan AN: Long-lasting effects
of sepsis on circadian rhythms in the mouse. PLoS ONE 2012, 7:e47087.
Gogenur I, Bisgaard T, Burgdorf S, van Someren E, Rosenberg J: Disturbances
in the circadian pattern of activity and sleep after laparoscopic versus open
abdominal surgery. Surg Endosc 2009, 23:1026–1031.
Gehlbach BK, Chapotot F, Leproult R, Whitmore H, Poston J, Pohlman M,
Miller A, Pohlman AS, Nedeltcheva A, Jacobsen JH, Hall JB, Van Cauter E:
Temporal disorganization of circadian rhythmicity and sleep-wake
regulation in mechanically ventilated patients receiving continuous
intravenous sedation. Sleep 2012, 35:1105–1114.
Farr L, Todero C, Boen L: Reducing disruption of circadian temperature
rhythm following surgery. Biol Res Nurs 2001, 2:257–266.
Antoch MP, Chernov MV: Pharmacological modulators of the circadian
clock as potential therapeutic drugs. Mutat Res 2009, 679:17–23.
Albrecht U: Circadian clocks and mood-related behaviors. Ann Med 2010,
McClung CA: Circadian rhythms and mood regulation: insights from
pre-clinical models. Eur Neuropsychopharmacol 2011, 21(Suppl 4):S683–S693.
Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc
M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S: Time-restricted
feeding without reducing caloric intake prevents metabolic diseases in
mice fed a high-fat diet. Cell Metab 2012, 15:848–860.
Sprouse J: Pharmacological modulation of circadian rhythms: a new drug
target in psychotherapeutics. Expert Opin Ther Targets 2004, 8:25–38.
Lanfumey L, Mongeau R, Hamon M: Biological rhythms and melatonin in
mood disorders and their treatments. Pharmacol Ther 2013, 138:176–184.
Naus T, Burger A, Malkoc A, Molendijk M, Haffmans J: Is there a difference
in clinical efficacy of bright light therapy for different types of
depression? A pilot study. J Affect Disord 2013, 151:1135–1137.
Hara R, Wan K, Wakamatsu H, Aida R, Moriya T, Akiyama M, Shibata S:
Restricted feeding entrains liver clock without participation of the
suprachiasmatic nucleus. Genes Cells 2001, 6:269–278.
Verwey M, Amir S: Food-entrainable circadian oscillators in the brain.
Eur J Neurosci 2009, 30:1650–1657.
Froy O: The relationship between nutrition and circadian rhythms in
mammals. Front Neuroendocrinol 2007, 28:61–71.
Feillet CA: Food for thoughts: feeding time and hormonal secretion.
J Neuroendocrinol 2010, 22:620–628.
Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F, Schibler U:
Restricted feeding uncouples circadian oscillators in peripheral tissues
from the central pacemaker in the suprachiasmatic nucleus. Genes Dev
Castillo MR, Hochstetler KJ, Tavernier RJ Jr, Greene DM, Bult-Ito A: Entrainment
of the master circadian clock by scheduled feeding. Am J Physiol Regul Integr
Comp Physiol 2004, 287:R551–R555.
Lamont EW, Diaz LR, Barry-Shaw J, Stewart J, Amir S: Daily restricted feeding
rescues a rhythm of period2 expression in the arrhythmic suprachiasmatic
nucleus. Neuroscience 2005, 132:245–248.
Satoh Y, Kawai H, Kudo N, Kawashima Y, Mitsumoto A: Time-restricted
feeding entrains daily rhythms of energy metabolism in mice. Am J
Physiol Regul Integr Comp Physiol 2006, 290:R1276–R1283.
El-Kadi SW, Gazzaneo MC, Suryawan A, Orellana RA, Torrazza RM, Srivastava N,
Kimball SR, Nguyen HV, Fiorotto ML, Davis TA: Viscera and muscle protein
synthesis in neonatal pigs is increased more by intermittent bolus than
continuous feeding. Pediatr Res 2013, 74:154–162.
El-Kadi SW, Suryawan A, Gazzaneo MC, Srivastava N, Orellana RA,
Nguyen HV, Lobley GE, Davis TA: Anabolic signaling and protein
deposition are enhanced by intermittent compared with continuous
feeding in skeletal muscle of neonates. Am J Physiol Endocrinol Metab
Gazzaneo MC, Suryawan A, Orellana RA, Torrazza RM, El-Kadi SW, Wilson FA,
Kimball SR, Srivastava N, Nguyen HV, Fiorotto ML, Davis TA: Intermittent
bolus feeding has a greater stimulatory effect on protein synthesis in
skeletal muscle than continuous feeding in neonatal pigs. J Nutr 2011,
Yoon JA, Han DH, Noh JY, Kim MH, Son GH, Kim K, Kim CJ, Pak YK, Cho S:
Meal time shift disturbs circadian rhythmicity along with metabolic and
behavioral alterations in mice. PLoS ONE 2012, 7:e44053.
Luna-Moreno D, Aguilar-Roblero R, Diaz-Munoz M: Restricted feeding
entrains rhythms of inflammation-related factors without promoting an
acute-phase response. Chronobiol Int 2009, 26:1409–1429.
Rossi FM, Kringstein AM, Spicher A, Guicherit OM, Blau HM: Transcriptional
control: rheostat converted to on/off switch. Mol Cell 2000, 6:723–728.
Barclay JL, Husse J, Bode B, Naujokat N, Meyer-Kovac J, Schmid SM, Lehnert H,
Oster H: Circadian desynchrony promotes metabolic disruption in a mouse
model of shiftwork. PLoS ONE 2012, 7:e37150.
Li XM, Delaunay F, Dulong S, Claustrat B, Zampera S, Fujii Y, Teboul M, Beau J,
Levi F: Cancer inhibition through circadian reprogramming of tumor
transcriptome with meal timing. Cancer Res 2010, 70:3351–3360.
Wu MW, Li XM, Xian LJ, Levi F: Effects of meal timing on tumor
progression in mice. Life Sci 2004, 75:1181–1193.
Redman LM, Ravussin E: Caloric restriction in humans: impact on
physiological, psychological, and behavioral outcomes. Antioxid Redox
Signal 2011, 14:275–287.
Plunet WT, Streijger F, Lam CK, Lee JH, Liu J, Tetzlaff W: Dietary restriction
started after spinal cord injury improves functional recovery. Exp Neurol
Hasegawa A, Iwasaka H, Hagiwara S, Asai N, Nishida T, Noguchi T: Alternate
day calorie restriction improves systemic inflammation in a mouse
model of sepsis induced by cecal ligation and puncture. J Surg Res 2012,
Jeong MA, Plunet W, Streijger F, Lee JH, Plemel JR, Park S, Lam CK, Liu J,
Tetzlaff W: Intermittent fasting improves functional recovery after rat
thoracic contusion spinal cord injury. J Neurotrauma 2011, 28:479–492.
Hou C, Bolt K, Bergman A: A general life history theory for effects of
caloric restriction on health maintenance. BMC Syst Biol 2011, 5:78.
Froy O, Chapnik N, Miskin R: Relationship between calorie restriction and
the biological clock: lessons from long-lived transgenic mice.
Rejuvenation Res 2008, 11:467–471.
Aguilera-Martínez R, Ramis-Ortega E, Carratalá-Munuera C, Fernández-Medina
JM, Saiz-Vinuesa MD, Barrado-Narvión MJ: Enteral Feeding via Nasogastric
Tube. Effectiveness of continuous versus intermittent administration for
greater tolerance in adult patients in Intensive Care. JBI Libr Syst Rev 2011,
Campbell IT, Morton RP, Macdonald IA, Judd S, Shapiro L, Stell PM:
Comparison of the metabolic effects of continuous postoperative enteral
feeding and feeding at night only. Am J Clin Nutr 1990, 52:1107–1112.
Chen YC, Chou SS, Lin LH, Wu LF: The effect of intermittent nasogastric
feeding on preventing aspiration pneumonia in ventilated critically ill
patients. J Nurs Res 2006, 14:167–180.
Hiebert JM, Brown A, Anderson RG, Halfacre S, Rodeheaver GT, Edlich RF:
Comparison of continuous vs intermittent tube feedings in adult burn
patients. J Parenter Enteral Nutr 1981, 5:73–75.
MacLeod JB, Lefton J, Houghton D, Roland C, Doherty J, Cohn SM, Barquist ES:
Prospective randomized control trial of intermittent versus continuous
gastric feeds for critically ill trauma patients. JTrauma2007, 63:57–61.
Sunderram et al. Journal of Translational Medicine 2014, 12:79 Page 8 of 9
Marshall A, West SH: Enteral feeding in the critically ill: Are nurse practices
contributing to hypocaloric feeding? Int Crit Care Nursing 2006, 22:95–105.
McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B,
Ochoa JB, Napolitano L, Cresci G: Guidelines for the Provision and
Assessment of Nutrition Support Therapy in the Adult Critically Ill
Patient: Society of Critical Care Medicine (SCCM) and American Society
for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nutr
Steevens EC, Lipscomb AF, Poole GV, Sacks GS: Comparison of continuous
vs intermittent nasogastric enteral feeding in trauma patients:
perceptions and practice. Nutr Clin Pract 2002, 17:118–122.
653 Cite this article as: Sunderram et al.:Time-restricted feeding and the
654 realignment of biological rhythms: translational opportunities and
655 challenges. Journal of Translational Medicine 2014 12:79.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color ﬁgure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
Sunderram et al. Journal of Translational Medicine 2014, 12:79 Page 9 of 9