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Keywords:

  • circadian;
  • latitude;
  • migration;
  • obesity

Circadian rhythmicity – the hidden cadence of homeostasis

  1. Top of page
  2. Circadian rhythmicity – the hidden cadence of homeostasis
  3. Circadian desynchrony and the global expansion of human obesity
  4. Do latitudinal clines in the circadian pacemaker affect susceptibility to circadian desynchrony?
  5. Human circadian rhythymicity – is it time for elective restoration of circadian resonance?
  6. References

The study of physiology has been shaped by the theses of Cannon and Bernard, whose concept of homeostasis states that physiology strives to maintain a constant, steady state. Unbeknown to these early scientists, their concept of the ‘steady state’ was challenged by the fact that an unwavering oscillation with a period approximating 24 hour characterises all living tissue.

The marriage of technology and biology in the late twentieth century revealed an extra dimension to physiology, and enabled scientists to show that the classic concept of homeostasis is only half right; rather than a constant, steady state, homeostasis is a constant, steady rhythm. The rhythms that permeate biology are generated by a network of molecular timing mechanisms that regulate the processes that typify life, from gene transcription to metabolism, reproduction and behaviour. Physiological rhythmicity shows a complexity that is reminiscent of the proverbial wheels-within-wheels, since daily or circadian rhythms also have annual rhythms with longer periods.

Endogenous rhythms entrain to environmental variations, mirroring these stimuli with appropriate physiological responses. Light is the most potent environmental signal for the physiological clock, and it is through this timing cue that physiological cycles are synchronised to those of the planetary bodies. The 24-hour photic metronome provided by the rotation of the Earth has entrained circadian rhythms throughout the millennia of mammalian evolution. In the absence of artificial light, the natural photoperiod is the principal factor influencing the daily rhythmicity of physiology.

Resonance of endogenous rhythms with environmental cycles defines successful adaptation and consequently, fitness, survival, or in the case of humans, health and well-being. This association between fitness and circadian resonance spans the spectrum of biology, with microbes (Cyanobacteriae) 1, insects (Drosophila melanogaster) 2, plants (Arabidopsis) 3, and mammals 4 all showing evidence of increased fitness and survival in environments that favour circadian resonance. Existence in rhythmic environments probably engenders fitness, by facilitating resonance, while variable environments challenge the capacity to maintain homeostasis.

Circadian desynchrony and the global expansion of human obesity

  1. Top of page
  2. Circadian rhythmicity – the hidden cadence of homeostasis
  3. Circadian desynchrony and the global expansion of human obesity
  4. Do latitudinal clines in the circadian pacemaker affect susceptibility to circadian desynchrony?
  5. Human circadian rhythymicity – is it time for elective restoration of circadian resonance?
  6. References

The dawn of the new millennium in 2,000 marked an unprecedented point in the evolution of Homo sapiens, when for the first time, the number of obese humans rivalled the number facing starvation 5. The inexorable expansion of human adiposity is now a global epidemic that seems frighteningly resistant to all forms of non-invasive intervention. It is evident that the mechanisms underlying the obesity epidemic are more complex than a simple interaction between diet and physical activity. Current lifestyle interventions seem doomed to failure, and in the absence of any feasible pharmacological agent, the average human BMI continues to rise across the developed world; no population is spared. The rapid global rise in obesity suggests an environmental cause, some factor that is common to all developed societies, and that acts in combination with genetic susceptibility. The loss of circadian resonance is one environmental factor that may contribute to the recent predilection to human obesity 6.

Human circadian resonance was greatly affected by the availability of artificial light in the 1800s which facilitated a progressive disintegration of the rhythms in human sleeping, eating and working patterns. The omnipresent synchronising cues provided by a daily sunrise and sunset were no longer the primary timing cue, resulting in uncoupling of physiological and environmental rhythms, and consequent compromise of the circadian resonance that is necessary for optimisation of physiology. This condition is termed circadian desynchrony (CD), and while its mechanisms are unclear, its physiological sequelae in experimental animals and in human shiftworkers, are widely reported. The most notable effect of CD is disruption of metabolism, causing alterations in glucose homeostasis, feeding behaviour and metabolic rate, and ultimately leading to obesity 7, 8. But, metabolic dysfunction is not the only effect of CD; behavioural changes and associated structural remodelling of the hippocampus have been recently reported in desynchronised rodents 7. These findings have clinical correlates in previous associations between desynchrony and cognitive deficits 9 and depression 9, 10 in humans. Circadian timing regulates almost every physiological parameter and it is likely that desynchrony has implications that reach far beyond the described metabolic and behavioural effects.

The metabolic effects of CD, and their apparent promotion of an obese phenotype, often in the absence of increased energy intake 7, are intriguing findings that underscore the significance of the endogenous timing system in the regulation of metabolism. The highly heritable functional properties of the circadian pacemaker 11, 12 could underlie genetic vulnerability to obesity. In support of this, the degree of CD was related to the inter-strain susceptibility to obesity in laboratory mice (Fig. 1). In agreement with the obesogenic effects of CD in rodents, epidemiological evidence links human obesity to exposure to mains electricity 8, and to CD 13. Furthermore, genetic evidence supports an association between obesity and variations in clock gene expression in humans 14 and in animals 15. Taken together, these data support the concept that human phenotype is driven towards obesity and metabolic dysfunction through an interaction of CD induced by artificial light, and the individual heritable properties of the circadian pacemaker.

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Figure 1. The relationship between circadian desynchrony (deviation of the endogenous circadian frequency (tau) from the environmental photoperiod, 24 hours) and susceptibility to obesity in strains of laboratory mice. Susceptibility to obesity is represented by increased % adiposity after 7 weeks on a high fat diet. From data reported by West et al. 29 and Schwartz and Zimmerman 12.

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Do latitudinal clines in the circadian pacemaker affect susceptibility to circadian desynchrony?

  1. Top of page
  2. Circadian rhythmicity – the hidden cadence of homeostasis
  3. Circadian desynchrony and the global expansion of human obesity
  4. Do latitudinal clines in the circadian pacemaker affect susceptibility to circadian desynchrony?
  5. Human circadian rhythymicity – is it time for elective restoration of circadian resonance?
  6. References

Humans evolved under Equatorial light, with light and dark evenly and regularly delivered every 12 hours, conditions that favoured physiological rhythms that tightly reciprocated the constant 24-hour environmental photoperiod. Close anticipation of this regular and predictable circadian photoperiod facilitates resonance between endogenous and environmental rhythms, a condition that optimises health, survival and lifespan in lower animals and plants 2, 3. In Equatorial regions, where light is regular and predictable, animals maximise fitness by relying strongly on robust endogenous rhythms. Experimental evidence supports this in fish, where Equatorial species were demonstrated to be more strongly reliant on their internal pacemakers than those originating from more northerly clines 16. Furthermore, latitudinal clines in the properties of the circadian pacemaker have been extensively studied in Drosophila spp., and these data convincingly demonstrate increased reliance on innate rhythmicity in flies originating from Equatorial regions 17–19. In contrast, in the variable photoperiods of northerly clines, rigid adherence to endogenous rhythmicity carries the risk that physiological events might be easily misaligned with environment changes. Thus, rhythms that are strongly entrained to the photoperiod are of adaptive advantage only in predictable (Equatorial) photoperiods. Variable northern photoperiods call for more flexible circadian timekeeping that can quickly respond to environmental changes 19.

Latitudinal clines in the properties of the circadian pacemaker demonstrate that the clock mechanism has evolved to enable accommodation of the variable photoperiods of northern regions, and have been demonstrated in fish 16, invertebrates 20 and birds 21. Pacemaking mechanisms that accommodate the variable northerly photoperiod are likely to be weakly entrained to environmental rhythms, and hence more responsive to sudden photoperiodic change. In agreement with this, animals endogenous to Equatorial regions show more robust entrainment to a 24-hour laboratory photoperiod compared to species from more northerly regions 22. Furthermore, Arctic rodents that survive in the far north exhibit highly erratic circadian rhythms with wide inter-individual variability 23, while reindeer show a complete absence of circadian rhythmicity 24. There is also some evidence of latitudinal clines in the human circadian clock. Data reported for the length of the innate circadian period in humans show an increasing gradient in length and in variability of tau away from the Equator (tau = 24.09 hour (0.78%) African; 24.25 hour (0.81%) Asian; and 24.3 hour (0.97%) European; mean (CV%)) 25. These data are evidence for adaptation of the human pacemaker to northern photoperiods and are in agreement with findings in lower animals. As early humans migrated north of the Equator, they encountered photoperiods that were less predictable, with the timing of sunrise and sunset showing daily variation. It is likely that human fitness was optimised by the regular photoperiod at the Equator and that migration into the variability of northern clines came at the expense of circadian resonance. But, this was most likely a worthwhile trade-off for better climatic conditions, food or extended territories.

Latitudinal clines in the properties of the human pacemaker are significant since they might affect individual susceptibility to CD and its metabolic consequences. For example, humans recently migrating north from Equatorial zones may be more strongly reliant on endogenous rhythmicity, leaving them more vulnerable to the metabolic effects of CD when they are exposed to the variable day length of temperate zones. In support of this theory, there is an association between latitude of origin and susceptibility to obesity in northern migrants (Fig. 2). Furthermore, northern migrants are generally considered to be at increased risk of obesity, with individuals of African descent particularly susceptible to obesity and metabolic dysfunction as they migrate north 26. An interesting corollary to this argument is the question of whether humans native to northern zones have developed more accommodating circadian timing mechanisms that make them less vulnerable to the effects of CD. There is indeed some epidemiological evidence to support this; humans native to some northern clines (e.g. Yup'ik Eskimos) show reduced susceptibility to metabolic syndrome despite evidence of westernisation and a high prevalence of increased central adiposity 27, 28. Thus, although this native North American people acquire a more modern American lifestyle, their circadian resilience might protect them against some of the effects of obesity.

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Figure 2. Migration north was associated with obesity in a sample of 27,808 Swedish immigrants. Data are corrected for age, height, smoking, physical activity and occupation. (WHR, waist to hip ratio). From data reported by Lahmann et al. 30.

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Nevertheless, even in northern clines, the human clock retains characteristics suggesting strong reliance on innate rhythms, including a free-running pacemaker that runs close to 24 hours, and low inter-subject variation in tau. The human circadian rhythm was optimised for survival under the rhythmic 24 hour photoperiod under which it evolved. Exposure to variable light cycles compromises circadian resonance, with consequent implications for fitness.

Human circadian rhythymicity – is it time for elective restoration of circadian resonance?

  1. Top of page
  2. Circadian rhythmicity – the hidden cadence of homeostasis
  3. Circadian desynchrony and the global expansion of human obesity
  4. Do latitudinal clines in the circadian pacemaker affect susceptibility to circadian desynchrony?
  5. Human circadian rhythymicity – is it time for elective restoration of circadian resonance?
  6. References

Circadian rhythmicity underpins the central regulation of behaviour, reproduction, metabolism and virtually every other physiological parameter. The circadian pacemaker synchronises physiology to the environment, and disruption of this mechanism through its principal input pathway, light, might underlie many of the diseases associated with human progress.

Experimental and epidemiological evidence support the hypothesis that optimisation of human health in the 21st century will require attention to circadian resonance. The 24-hour society of the developed world has come at the high price of circadian desynchrony, and its physiological consequences. Restoration of circadian resonance would entail abolition of shiftwork, and restriction or even elimination of light at night. Such radical changes to human lifestyle cannot be justified in the current absence of scientific evidence for a causative association between CD and metabolic dysfunction and obesity in humans. As for many physiological conundrums, the answer to the obesity epidemic probably lies in our genes and in understanding the relationships between genetic variation and the functional properties of the human clock, might lead us to the mechanism that underlies the metabolic dysfunction of obesity. For example, studies of the effects of shiftwork on humans native to Equatorial regions might reveal increased susceptibility to the metabolic effect of circadian desynchrony in these individuals. Two unsuspected modern phenomena affect variation in human susceptibility to obesity; the migration of humans into photoperiods that differ from those which shaped the evolution of their circadian pacemaker, in combination with the circadian desynchrony that is facilitated by artificial light. Future studies should focus on understanding how the functional parameters of the human clock interact with a desynchronised environment to affect metabolic health and promote obesity. In the meantime, clinical studies applying the principles of circadian resonance to the treatment of human obesity must proceed; their success would most strongly support a causative association between desynchrony and metabolic dysfunction. Medical science has no other effective, non-invasive intervention to offer, and our increasing obese population have nothing to lose but their waistlines.

References

  1. Top of page
  2. Circadian rhythmicity – the hidden cadence of homeostasis
  3. Circadian desynchrony and the global expansion of human obesity
  4. Do latitudinal clines in the circadian pacemaker affect susceptibility to circadian desynchrony?
  5. Human circadian rhythymicity – is it time for elective restoration of circadian resonance?
  6. References