Chrononutrition: A Timely Intro to This Key Component of Your Health (Part 1)

“You are what you eat” is an aphorism that most of us are 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 an accumulating body of evidence supports the importance of the time of your body’s internal ‘clock’ in determining your metabolic responses to eating. In turn, your dietary choices have a reciprocal influence on your body’s clock. Additionally, your internal clock and sleep habits affect your decision making-including your dietary choices. Therefore, an appreciation of these interactions has many implications for your daily health practice. To appreciate the value of these implications, however, we must first understand some fundamental principles regarding regulation of our bodies’ clocks.

And this brings us to the crux of today’s blog: Just how is the circadian system that shapes our daily patterns of behaviour and physiology regulated?


A brief primer on the circadian system

The circadian (meaning about 24 hours) system is a hierarchical network of self-sustained clocks, orchestrated by a central clock in the anterior hypothalamus called the suprachiasmatic nuclei (SCN) (1). The central clock helps keep all other clocks (commonly referred to as peripheral clocks) in time, and it is important to understand that circadian clocks may be present in all human cells.

Most of these clocks result from gene transcription/translation feedback loops that produce daily oscillations in ‘clock’ gene proteins. These proteins act as transcription factors, meaning that they bind to promoter regions of other genes (known as ‘clock-controlled genes’) to help regulate the timing of gene expression according to the requirements of different tissues (2).

What is the significance of this?

Among other things, by having their own clocks, cells can ensure that the timing of incompatible processes like anabolism (building) and catabolism (breaking down) is separated.

The SCN relay temporal information to peripheral clocks through humoral signals, neural pathways, and regulation of the circadian rhythm in core body temperature. The SCN also shape daily patterns of behaviours such as fasting/eating and sleep/wake cycles. These behaviours then feedback to the SCN, as we will see.

In the absence of sufficient ‘zeitgeber’ (time cue) stimuli, the circadian system will ‘free run’ with a period that is not precisely 24 hours. The circadian system must therefore be ‘entrained’ (synchronised) with the 24 hour day, and the light/dark cycle is the primary zeitgeber for the SCN and hence the circadian system.

But is the light/dark cycle equally important in peripheral clocks?

The short answer is probably not.

Restricting food access to a limited but predictable time of day (known as time-restricted feeding) in rodents produces food-seeking behaviour at these times. This exemplifies how strong a zeitgeber food can be in some circumstances (3). Interestingly, this behaviour persists through subsequent days of food deprivation, and is present even in the absence of the SCN – suggesting that food is influencing peripheral clocks. And this is indeed the case: In rodents, diet is a principal zeitgeber for peripheral clocks, including clocks in key organs for metabolic regulation like the liver (4). Just last week, work was published showing that meal timing also influences the timing of the molecular clock in adipose tissue in humans, as well as daily changes in people’s blood glucose profiles, without influencing the timing of the central clock (5).

So how does nutritional status influence peripheral clocks?

Let’s use one example. Fasting/feeding cycles produce fluctuations in humoral factors, such as circulating nutrients. These are sensed by energy sensors, one of which is 5′ AMP-activated protein kinase (AMPK), an enzyme that stimulates cellular ATP production during periods of reduced energy availability, as occurs during fasting. AMPK then tags molecular clock proteins with phosphate groups, and doing so hastens breakdown of these components (6), thereby enhancing their oscillations. In this way, sharp and consistent fasting/eating cycles might help improve the function of your body’s clock.

In a well-functioning circadian system, clock-regulated changes optimise our bodies’ many systems according to the solar day. This can range from enhanced muscular strength, digestion, and energy storage during the day, to increased sleep propensity and energy mobilisation at night (7).


Another means by which discordance drives disease development

The troubling rise in chronic disease risk that we are seeing worldwide results from an unfathomably complex array of factors. With this said, is it possible that one contributing factor is disruption to our bodies’ clocks?

If we could jump in a TARDIS and transport ourselves to live in pre-industrial times, our lives would probably more closely align with the 24 hour light/dark cycle. We’d largely eat, hunt, and forage for food during daylight, and the night would predominately be a time of resting and fasting. In short, our bodies’ internal clocks would be tightly synchronised to the solar day.

But that’s not how many of us live now. Many developments have distorted our natural patterns of behavior and physiology. 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. And the result may be loss of appropriate ‘phase’ (timing) relationships between our bodies’ clocks, which is thought to 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, but so can well-timed eating patterns. It is this topic that we will turn to in the next blog…

… Stay tuned!

  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.