Life is a rhythmic phenomenon. When we study any vital activity in relationship with time, we always find oscillations that clearly indicate that these activities are not carried out continuously throughout the day. Circadian rhythms (derived from the Latin phrase circa diem, or about a day) are such an innate part of our behavior that we rarely pause to speculate why they even exist.
During the last century, life has changed dramatically, and three coincident trends with significant impact on society and healthcare system emerged: food has become abundant, snacking frequency has increased and feeding has shifted towards the end of the day; sleep time has been gradually reduced together with an increase in irregular patterns of sleep which differ from day to day; and exposure to bright light during the night has increased, inhibiting melatonin secretion .
In this context, a quarter of the world's adults have metabolic syndrome (MetS). The MetS is a cluster of health risk factors characterized by the impairment of carbohydrate and lipid metabolism, adipose tissue function and heart, vascular and hemostatic function. Recently, some studies [2•] have suggested that the disruption of the circadian system (chronodisruption) may lead to manifestations of MetS. Shift work, sleep deprivation and exposure to bright light at night increase the prevalence of adiposity and MetS. Surprisingly, circadian system impairment is not only the result of obligatory shift work schedules but is also an emerging issue in adolescent and young adults because their leisure activities result in voluntary sleep curtailment [3••]. Some of the evidences supporting chronodisruption as a cause or predisposing factor for the MetS are presented in the following sections.
Clinical and epidemiological evidence of this interesting relationship
Circadian rhythmicity of cardiovascular function is firmly established. A long history of clinical epidemiology in humans indicates that myocardial infarction and hypertensive crises all peak at certain times during the day [4–7].
Circadian control of glucose metabolism has also been recognized from studies demonstrating variation in glucose tolerance and insulin action across the day. In humans, it has been repeatedly shown that glucose tolerance is impaired in the afternoon and evening compared with the morning hours. This situation has been ascribed to the impaired insulin sensitivity of the peripheral tissues and to a relative decrease in insulin secretion during the evening hours .
Industrialization has given rise to the adoption of 24-h continuous operations that has resulted in an increase in the proportion of the population routinely engaged in shift work, around 20% of the industrialized world. Epidemiological studies [9,10,11•] show that shift work is associated with obesity, hypertrigliceridemia, low HDL, abdominal obesity, diabetes and cardiovascular diseases. Moreover, increased glucose, insulin resistance and triglyceride postprandial response are observed in shift workers with chronodisruption of the melatonin profile . One of the most interesting recent findings is that shift work is an independent risk factor in the development of MetS . A study performed in 341 male participants (165 day workers and 176 shift workers) indicated that shift workers had higher BMI even though the diet quality was even better in shift workers, and the level of physical activity was similar between day and shift workers.
Interesting results come from the studies relating sleep duration and metabolic risk. The amount of sleep has declined by 1.5 h over the past century, with an important increase in obesity. Moreover, one-third of adults sleep less than 6 h a night [13,14]. Clinical studies [15••] show that healthy individuals restricted to 4 h of sleep for six consecutive nights exhibit impaired glucose tolerance and reduced insulin responsiveness following a glucose challenge. Furthermore, short sleepers had significantly reduced circulating levels of anorectic hormone leptin and increased levels of the orexigenic hormone ghrelin . This situation is rather important among children in which short sleep duration, a consequence of schedules on weekdays, variation in daylight hours with changes in seasons and having younger siblings in the home has been described as an independent risk factor for obesity [15••].
Functional organization of the circadian system in humans
The circadian system of mammals is composed of a hierarchically organized network of structures responsible for the generation and synchronization of circadian rhythms to environment. It is composed of a central pacemaker, located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and several peripheral clocks [16–18].
Circadian rhythms, under artificially constant environmental condition, run with a period slightly different from 24 h. However, under natural conditions, the SCN is reset every day by the light through a nonvisual pathway consisting in the melanopsin ganglionar cells  and the retinohypothalamic tract . Although the photic input is the main SCN entraining signal, other periodical cues such as feeding time and scheduled exercise can also entrain the mammalian circadian system [21,22]. When food availability is limited to short-time periods (restricted feeding), many circadian rhythms can phase-shift to adapt the organism physiology to the time of food availability . Evidence from SCN-lesioned animals, which are able to maintain circadian rhythmicity entrained to restricted feeding, has suggested that in addition to the light entrainable pacemaker (SCN) another circadian pacemaker, called feeding entrainable pacemaker, probably located in the dorsomedial nucleus of the hypothalamus, may supersede the SCN [23,24••].
Others brain areas have been proposed as self-sustained circadian pacemaker. Among these, retina and olfactory bulb are master oscillators that are able of self-sustained circadian output under isolation .
Circadian oscillations can be also observed in some organs and tissues such as heart, lung, liver, intestine, adrenal and adipose tissue. These peripheral oscillators must receive periodical inputs from the SCN in order to prevent the spontaneous dampening of their rhythmical activity with time. However, they are also sensitive to their own synchronizers such as feeding time, local temperature, glucocorticoids, retinoic acid and others. The presence of a functional circadian clock mechanism within adipose tissue has been demonstrated in experimental animal models . In adipose tissue from humans, we have recently reported that clock genes are expressed in both subcutaneous and visceral fat [26••].
In contrast to the relatively well known structure and function of photic inputs and SCN pacemaker, the outputs through which SCN exerts its circadian control remain poorly understood. Selective activation of parasympathetic and sympathetic nerves, nocturnal secretion of pineal melatonin and time-release of different metabolites are the major known temporal mediators of the SCN (Fig. 1).
The biological clock at a molecular level
Circadian clocks are composed of a set of proteins that generate self-sustained circadian oscillations through positive and negative transcriptional/translational feedback loops. Although the whole picture of the clock model is continuously evolving, the positive limb of the molecular clock comprises two transcription factors, CLOCK and brain and muscle aryl hydrocarbon receptor nuclear translocator (ANRT)-like protein 1 (BMAL1), whereas periods (PERs) and cryptochromes (CRYs) are responsible for the negative limb. In addition to these core clock genes, other genes of SCN neurons, which are not components of the circadian mechanisms, but whose expression is regulated by clock genes, oscillate with a periodicity close to 24 h. They are the so-called clock-controlled genes (CCG) or circadian output genes. A large percentage (10–20%) of the mammalian transcriptome exhibits circadian rhythms, including both direct CCGs and downstream outputs of these CCGs [2•,3••,16,27••] (Fig. 2).
Circadian system and metabolic syndrome components
Recent findings suggest that circadian system and metabolism directly influence one another. The circadian system regulates metabolism in all tissues and organs implicated in the pathological changes leading to the MetS. Moreover, the rhythms in core clock genes and their proteins, in addition to their role in the circadian pacemaker, seem to play noncircadian functions essential in the control of metabolism . It is known that many hormones involved in metabolism such as insulin, glucagon, growth hormone (GH) and cortisol exhibit circadian oscillation with different daily pattern. In addition to the endocrine control, the circadian system has been reported to regulate metabolism throughout the expression or activity of some metabolic enzymes or both and transport systems involved in cholesterol metabolism [2•,29]. A large number of nuclear receptors involved in lipid and glucose metabolism have also been found to exhibit circadian expression .
Excess of adiposity plays a major role in the development of the MetS. Studies performed in experimental animals show that adipose tissue has the circadian clock machinery required to be considered as a peripheral circadian oscillator. In human adipose tissue, we have recently provided evidence of clock genes expression and demonstrated that it is associated with different components of the MetS [26••]. It remains to be elucidated whether this circadian clockwork can oscillate accurately and independently of the SCN in human adipose tissue and which other genes are controlled by this process.
Some examples of adipose-specific molecules implicated in MetS are leptin, adipsin, resistin, adiponectin and visfatin, all of them exhibiting circadian rhythmicity. Glucocorticoids are also key factors in the pathogenesis of MetS that show circadian rythmicity in human adipose tissue . Adiponectin, defined as the ‘guardian angel’ against MetS disturbances , exhibits both ultradian pulsatility and a diurnal variation. The daily pattern of this adipocytokine is out of phase with leptin, showing a significant decline at night and reaching a nadir in the early morning .
Circadian rhythms in the ability of cardiomyocyte to use fatty acids have also been considered essential in the development of MetS . Thus, the inability of cardiomyocyte to cope with the periodical increases in fatty acid availability and results in accumulation of intracellular long-chain fatty acid derivatives, causing contractile dysfunction of the heart.
Of particular relevance to MetS is the effect that circadian system has on blood pressure (BP), endothelial and hemostatic function. BP varies diurnally, rising during the day and dipping at night. The loss of this pattern is correlated with insulin resistance and is associated with increased end-organ damage . Recently, this circadian BP alteration has been observed in obese children [36•].
Hemostasis constitutes another critical function whose impairment is associated to MetS. Plasminogen activator inhibitor 1 (PAI-1) is the major inhibitor of fibrinolysis in vivo. It is produced by the liver, adipocyte and vascular endothelium. PAI-1 levels in the circulation fluctuate diurnally, with a peak in the morning. Sustained increased levels of PAI-1 are observed in association with MetS .
Although the precise mechanisms linking MetS to chronodisruption are not well known, most hypotheses point to the internal desynchronization between different circadian rhythms involved in metabolism as a key factor in the development of MetS. This process can be produced by at least two means: the variable speed of resynchronization of different biological variables after an abrupt time shift (e.g. jet lag or rotating shift work), or the impact of conflicting zeitgebers (external synchronizers) on the same organism. One example of this situation is that a 12-h phase shift in the light–dark cycle leads to a faster resynchronization of heart rate and BP than the molecular circadian clock of the heart [34,38]. Thus, during some days, the heart molecular clock is desynchronized from its environment following reversal of the light–dark cycle. On the contrary, light and food are the two main synchronizing factors of central and peripheral oscillators, respectively [39•]. Therefore, it is conceivable that when feeding time is scheduled during the nocturnal time or when its daily periodical signal is suppressed by constant snacking or high-fat feeding, some circadian rhythms driven by peripheral oscillators became desynchronized from the rhythms controlled by SCN and entrained by light [40•].
Genetics aspects in this interaction
Very few studies have examined the relationship between the circadian clock genes and development of MetS during the last years. By contrast, nowadays, new findings support the hypothesis of a functional connection between them. Genetic effects have been observed between insomnia and both sleepiness and obesity, which suggest that they share genetic contributions . For instance, a point mutation in a human clock gene (Per2) was shown to produce the rare advanced sleep phase syndrome, whereas a functional polymorphism in Per3 is associated with the more frequent delayed sleep phase syndrome. Furthermore, a study examining the association between CLOCK gene polymorphisms and insomnia revealed a higher recurrence of insomnia in patients homozygous for the CLOCK genotype, and recent studies have demonstrated a higher BMI in individuals homozygous for this polymorphism. These findings suggest that the genetic contribution to sleep disorders is more important than originally thought and could be implicated in obesity .
In addition, genetic mouse models of obesity have demonstrated disrupted circadian sleep–wake patterns. Leptin-deficient ob/ob mouse and leptin-receptor db/db mouse show increased nonrapid eye movement sleep time, decreased sleep consolidation, decreased locomotory activity and a smaller compensatory rebound response to acute sleep deprivation [42,43•]. The circadian expression of a number of clock genes is also attenuated in the fat and liver of a polygenic model for noninsulin-dependent diabetes mellitus .
These results have sparked new interest in the interaction between chronobiology and MetS. However, it was not until Turek et al.'s  study had been performed that the evidence of a molecular interaction between Clock genes and MetS came out. This study revealed that mice with disruption of the Clock gene were prone to develop a phenotype resembling MetS. Previously, in 2004, Rudic et al. already showed that mutations in Clock and BMAL genes were associated with impaired glucose tolerance, and more recently it has been also demonstrated that these mutant mice exhibit altered circadian variation in glucose and triglyceride . Other authors have looked at the effect of Clock disruption in leptin-deficient mice (ob/ob) and found that it led to more weight gain, raised triglycerides, cholesterol and adipocyte hypertrophy than leptin deficiency alone .
Another interesting genetic aspect in the interaction between MetS and chronobiology is that most of the nuclear receptor proteins exhibit circadian patterns of gene expression in a variety of metabolic tissues [49•]. These transcription factors are activated by hormones, vitamins and dietary lipids and can regulate lipid and carbohydrate metabolism. Two examples are peroxisome proliferator-activated receptor-α (PPAR-α) and reverse of erythroblastic leukemia virus-α (REV-ERBα) [50,51•]. It is possible that their circadian rhythmicity contributes in part to the well documented diurnal variations in lipid and glucose metabolism. Nocturnin, a CCG, has also been implicated in the molecular circadian control of metabolism . It appears to exert rhythmic posttranscriptional control of genes necessary for metabolic functions including nutrient absorption, glucose/insulin sensitivity and lipid storage .
Given the above evidence in experimental models and the results of emerging epidemiological studies [53,54•,55–57] showing that alteration in circadian rhythmicity results in pathophysiological changes resembling MetS, different authors are currently investigating the role of CLOCK gene variants and their predicted haplotypes in human obesity and MetS alterations. A summary of the studies related to BMI, obesity or MetS is presented in Table 1. It is interesting to remark that from the wide range of genes within the clock machinery, only single-nucleotide polymorphisms (SNPs) at the loci encoding CLOCK and BMAL have shown an association with obesity; just two studies have been focused on obesity or MetS, and none of them have been able to relate individual CLOCK gene polymorphisms with particular MetS traits. Moreover, main outcomes were obtained only with haplotypes. Definitely, we have still a long way to go, and further studies are needed.
Treatment of the metabolic syndrome from the circadian perspective
Chronobiology has the potential to become a valuable tool in the future treatment of MetS. New directions should take into account general recommendations such as switching evening habits to more morning ones, reduction of carbohydrates intake in the evening, sleeping the appropriate number of hours and preventing stress. Assessment of cortisol, melatonin and body temperature circadian rythmicity in patients could be useful for the diagnosis of MetS [58•,59•].
Questionnaires about individual aspects of the timing of daily activities and sleep [59•], temporal food intakes , seasonal changes in mood behavior  and annual variations in weight could also be helpful.
Pharmacological drugs may be used in this chronobiologic interpretation. It has been proposed that the inactivation of 11ß-hydroxysteroid-dehydrogenase-1 (11βHSD1) may represent a novel treatment for the MetS . Interestingly, the time of the day for administration is important in achieving efficacy [63•].
A new target drug is melatonin , of interest in the treatment of sleep disorders, and recently proposed as an insulin sensitizing drug. It is essential to inform medical doctors that the pharmacological efficacy of drugs on MetS will radically change depending on the time of the day.
Clinical and epidemiological studies over the last few years coupled with a large body of evidence have shown the interaction between the circadian system and different MetS components such as impairment of carbohydrate and lipid metabolism, adipose tissue function and heart, vascular and hemostatic function. Experiments performed in animal models and in tissue culture are contributing to a deeper knowledge of this relationship. However, some questions remain poorly understood, particularly those related to the outputs through which SCN exerts its circadian control and how the human adipose tissue circadian clock works. A better knowledge of clock genes polymorphisms and their particular role in MetS may yield important information to this new area of research.
This work was supported by the Government of Education, Science and Research of Murcia (Project BIO/FFA 07/01-0004), by The Spanish Ministry of Education and Science (projects AGL2008-01655/ALI and BFU2007-60658/BFI), by Seneca Foundation (PI/05700/07) and by The Institute of Health Carlos III (RETICEF, RD06/0013/0019).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 141).
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