“You are what you eat” is an aphorism that you’re probably familiar with. The notion that when you eat and drink is also a critical determinant of the effects of diet on health may not be as widely recognised, but more and more evidence supports the importance of the timing of your body’s internal ‘clock’ (circadian system) in determining your metabolic responses to eating. In turn, your dietary choices influence the timing of your body’s clock. The study of these reciprocal interactions is named “chrononutrition”, an understanding of which has many implications for your health. To appreciate the importance of chrononutrition, however, we must first understand some fundamental principles regarding how our circadian systems shape our daily patterns of behavior and biology.

 

The circadian system

The circadian (meaning about 24 hours) system is a hierarchical network of self-sustained clocks, orchestrated by a “master” clock in the front of the hypothalamus (the suprachiasmatic nuclei) (1). The master clock helps keep all other clocks (“peripheral clocks”) in time, and circadian clocks are probably present in all of our cells.

Most of these clocks are driven by complex gene transcription/translation feedback loops that produce daily oscillations in levels of “clock” gene proteins. These proteins act as transcription factors, meaning that they bind to promoter regions of other genes (“clock-controlled genes”) to help regulate the timing of gene expression according to the requirements of different tissues (2). Okay, but what’s the significance of this?

Among other things, by having their own clocks, cells can ensure that incompatible processes like building new structures (anabolism) and breaking down existing structures (catabolism) take place at different times.

Now, the master clock relays information about time of day to peripheral clocks through circulating factors in the blood, electrical activity in neurons, and regulation of the circadian rhythm in core body temperature, which peaks during the day and falls at night. The master clock also shapes daily patterns of behaviors such as fasting/eating and sleep/wake cycles. These behaviors then feedback to the master clock, as we will see.

Okay, if you were to live in constant darkness then you’d probably find that your body’s clock is not precisely 24 hours. It must therefore be reset (“entrained”) by time cues (“zeitgebers”) each day, and the daily light/dark cycle is the most important of these in synchronizing your master clock. But is the light/dark cycle equally important to setting the timing of peripheral clocks?

The short answer is probably not.

 

Chrononutrition

If you restrict food when rodents can access food to a limited but predictable time of day (“time-restricted feeding”), these animals quickly learn to become active and seek out food at these times. This exemplifies how strong a time cue food can be in some circumstances (3) and suggests that food influences the timing of peripheral clocks.

Chrononutrition studies have shown that this is indeed the case: In rodents, diet is the main time cue for peripheral clocks, including clocks in key organs in metabolic regulation, like the liver (4). Just last week, work was published showing that meal timing also influences the timing of the clocks in fat tissue in humans, as well as daily changes in people’s blood glucose profiles, without influencing the timing of the master clock (5).

So, how does nutritional status influence peripheral clocks?

Let’s use one example. Fasting/feeding cycles produce fluctuations in factors that circulate in the blood, such as nutrients. Concentrations of these are perceived by energy sensors, one of which is 5′ AMP-activated protein kinase (AMPK), an enzyme that stimulates cellular energy (ATP) production during periods of reduced energy availability, as occurs during fasting. AMPK then tags molecular clock proteins with bulky phosphate groups, and doing so hastens breakdown of these clock gene proteins (6). This action enhances oscillations of the levels of these proteins, and this is one pathway by which sharp and consistent fasting/eating cycles might help improve the function of your body’s clock. 

But why is this so crucial to health?

Applying the principles of chrononutrition supports the function of your circadian system, hence optimizing your body’s many systems according to time of day. This results in enhanced muscular strength, digestion, and energy storage during the day, as well as increased sleep propensity and energy mobilisation at night (7). (For more on fasting, going Pro will give you access to the course on this topic by Dan and Jeff!)

 

Chrononutriton as a countermeasure against disease

The troubling rise in chronic disease risk that is occurring worldwide results from an unfathomably complex array of factors. This said, is it possible that disruption to our bodies’ clocks is one of these?

If you could jump in a TARDIS and transport yourself back to pre-industrial life, your daily patterns of behavior would probably more closely align with the 24-hour light/dark cycle. You’d largely eat, hunt, and forage for food during daylight, and the night would predominately be a time of resting and fasting. In short, your bodies’ clocks would be tightly synchronised to the solar day.

But that’s not how some of us live now. Many developments have distorted these natural patterns of behavior. These include Edison’s bright idea of incandescent lighting, the advent of round-the-clock food access, shifting work schedules, and high-speed trans-meridian travel (resulting in jetlag). And the result may be loss of appropriate timing (“phase”) relationships between our bodies’ clocks, which may contribute to the burgeoning prevalence of the so-called diseases of civilization that now afflict us (8).

Sleep, lighting, and exercise interventions that are timed according to our needs can help protect us against these modern maladies. As can applying the principles of chrononutrition.

It is this topic that we will turn to in the next blog… stay tuned!

 

References

1. Herzog ED, Hermanstyne T, Smyllie NJ, Hastings MH. Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms. Cold Spring Harb Perspect Biol. 2017;9(1).
2. Takahashi JS. Transcriptional architecture of the mammalian circadian clock. Nat Rev Genet. 2017;18(3):164-79.
3. Mistlberger RE. Food-anticipatory circadian rhythms: concepts and methods. Eur J Neurosci. 2009;30(9):1718-29.
4. 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. 2000;14(23):2950-61.
5. Wehrens SMT, Christou S, Isherwood C, Middleton B, Gibbs MA, Archer SN, et al. Meal Timing Regulates the Human Circadian System. Curr Biol. 2017. DOI: 10.1016/j.cub.2017.04.059.
6. Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science. 2009;326(5951):437-40.
7. Panda S. Circadian physiology of metabolism. Science. 2016;354(6315):1008-15.
8. Potter GD, Skene DJ, Arendt J, Cade JE, Grant PJ, Hardie LJ. Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences, and Countermeasures. Endocr Rev. 2016;37(6):584-608.