Time-restricted feeding and the realignment of biological rhythms: translational opportunities and challenges

Abstract

It has been argued that circadian dysregulation is not only a critical inducer and promoter of adverse health effects, exacerbating symptom burden, but also hampers recovery. Therefore understanding the health-promoting roles of regulating (i.e., restoring) circadian rhythms, thus suppressing harmful effects of circadian dysregulation, would likely improve treatment. At a critical care setting it has been argued that studies are warranted to determine whether there is any use in restoring circadian rhythms in critically ill patients, what therapeutic goals should be targeted, and how these could be achieved. Particularly interesting are interventional approaches aiming at optimizing the time of feeding in relation to individualized day-night cycles for patients receiving enteral nutrition, in an attempt to re-establish circadian patterns of molecular expression. In this short review we wish to explore the idea of transiently imposing (appropriate, but yet to be determined) circadian rhythmicity via regulation of food intake as a means of exploring rhythm-setting properties of metabolic cues in the context of improving immune response. We highlight some of the key elements associated with his complex question particularly as they relate to: a) stress and rhythmic variability; and b) metabolic entrainment of peripheral tissues as a possible intervention strategy through time-restricted feeding. Finally, we discuss the challenges and opportunities for translating these ideas to the bedside.

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 [23].

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 [24]).

Figure 3

Systemic signals act as coordinators of peripheral oscillators maintaining synchrony of function and health.

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.