It is well known that several hormones that are related to obesity, such as cortisol, leptin and adiponectin, among others, display circadian rhythmicity(1–3). The alteration of this normal pattern is called chronodisruption (CD), and it is related to several disturbances in many systems and organs of our body. In recent years, it has been demonstrated that CD is related to obesity.
CD or circadian disruption can be defined as ‘a serious disruption of the internal temporal order of the biochemical, physiological and behavioural circadian rhythms’(4). In our modern society, CD may be produced by several environmental factors, or external situations that are relatively common in the current society such as jet lag, shift work, night light pollution or overnight recreational activities (social jet lag)(5).
Indeed, several studies performed in mutant animals have demonstrated that mutations in clock genes are related to obesity, ageing and other metabolic alterations implicated in several chronic diseases(6,7).
In human subjects, mutations are very rare. Nevertheless, it is rather common to have genetic variations in one single nucleotide (SNP) that underlie differences in our vulnerability to disease. Regarding the circadian machinery, it is well known that several genetic variants are related to obesity, obesogenic behaviours and also to the effectiveness of the treatment in weight-loss programmes.
From epigenetics, the message is even more positive: it is demonstrated that by changing our behaviour we can even change our genome. For example, we have demonstrated in CLOCK that DNA methylation levels at different CpG sites of CLOCK are higher in obese than in non-obese women, and these methylation levels were associated with several obesogenic behaviours such as snacking frequently, eating when bored or eating from large packages.
Chronodisruption and failures in the central clock
Impairments can be present in the inputs or outputs to the circadian central clock located in the suprachiasmatic nucleous, but also in the central clock. With regard to the inputs, failures appear due to different circumstances, such as: (1) no changes between day/night synchronizing agents, such as light/dark, timing of food intake (eating/ fasting) or programmed exercise (activity/rest); (2) different periods or unusual phasing of synchronising agents, for example: light at night, nocturnal feeding or physical activity; and (3) shifts in the time provided by zeitgebers (i.e. jet lag, shift work). Outputs of the central pacemaker may also be altered: suppression of melatonin at night or loss of glucocorticoids rhythm like cortisol. Other problems in the central clock can result for example from the desynchronisation between the central pacemaker and peripheral oscillators or alterations in the so-called clock genes.
Nowadays we know that the internal clock regulates our physiological changes throughout the day. This clock works as a result of the expression of several clock genes that may activate and deactivate the clock to display a general pattern of 24 h. These clock genes can be classified into two groups: positive and negative. CLOCK and BMAL1 act as positive genes (they activate this clock) and are responsible for the synthesis of two transcriptional factors which, after dimerization (CLOCK–BMAL1), induce the expression of negative genes; these are PER and cryptochrome (CRY), together with nuclear receptor subfamily 1, group D, member 2 alpha (a transcription factor). These negative elements, after dimerisation (PER–CRY), undergo a nuclear translocation and act as suppressors of CLOCK and BMAL1 expression, consequently slowing and stopping the clock.
The levels of positive and negative elements oscillate in antiphase generating circadian rhythms (with a period of approximately 24 h) in suprachiasmatic nucleus in vitro(9). Although the circadian system is mainly formed by the central pacemaker in suprachiasmatic nucleus, it is known since 2001 that this central clock, in turn, synchronises the activity of several peripheral clocks present in our organs and tissues, such as heart, lung, liver, oral mucosa, pancreas and adipose tissue, among others, by a cyclical secretion of hormones and the activation of the autonomic nervous system(10).
Failures in the central clock: mutations in experimental animals
One of the first studies which showed the effect of genetic mutations on chronic illnesses was conducted in 2005 by Turek et al.(6) This study proved that homozygous Clock mutant mice were hyperphagic and obese, displayed adipocyte hypertrophy and developed metabolic syndrome (MetS). However, there is already controversy. Results have not proved to be consistent across different experiments.
Genetic variations of clock genes in human subjects
Clock genes associate with obesity in human subjects.
In this sense, the work performed by Sookoian et al. in 2008 was the first to demonstrate that several variants at CLOCK were associated with obesity, especially with abdominal obesity(12). In addition, in the same year, Scott et al. confirmed these results by showing that CLOCK could play a relevant role in the development of MetS, type 2 diabetes and CVD(13).
Other results from our group also showed that different genetic variants of the clock such as nuclear receptor subfamily 1, group D, member 2 alpha rs2314339 were also associated with obesity.
Clock genes interact with several behaviours for obesity in human subjects. Clock genes may also interact with behaviours for obesity. This is the case of those behaviours directly related to emotional eating. For example, seeking refuge in food (especially high-energy foods) is a very common strategy to reduce anxiety, sadness and negative emotions that occur when following a long-term diet or due to difficult circumstances of our daily lives. Our results demonstrated that those participants of our weight-loss programme who were carriers of the risk allele C at CLOCK 3111T > C and displayed emotional eating behaviours more frequently, had more difficulties to lose weight during the treatment.
Clock genes are related to weight loss
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Nutrigenetics says: our genome may interact with our behaviours
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Epigenomics says: we can change our genome with our behaviour
In 2012, the present group published a study, which demonstrated significant associations between the methylation levels of several CpG located in CLOCK with MetS, weight loss and obesity(1).
What can we do? We can change what, how and when we eat
One novel aspect to consider in dietary interventions may be when we eat: the timing of food intake. If we take into account that eating is an external synchroniser of our peripheral clock, and that an unusual eating time may cause a disruption of our circadian system( 37,38), the ‘when’ we eat may have a significant role in obesity treatment. In this line, a novel observational study performed in 2013 revealed that eating late may influence the success of weight-loss therapy, leading to a decrease of its effectiveness. This study was performed on 411 overweight and obese subjects who underwent a dietary weight-loss treatment: 199 subjects were early eaters (had their main meal of the day, lunch, before 15·00 hours) and 212 subjects were late eaters (had lunch after 15·00 hours). Late eaters lost significantly less weight than early eaters although having similar age, appetite hormones values, energy intake, sleep duration or macronutrients distribution. It is remarkable that late eaters were more evening types(14,15).
More recently, another observational study developed in Barcelona showed that the timing of food intake might also influence the effectiveness of bariatric surgery in severely obese subjects. About 11 % of the population is defined as ‘primarily weight loss poor responders’; these subjects lose only about 40 % of their initial excess weight during the first year after surgery. The results of this study demonstrated that the percentage of late eaters was significantly higher among the primarily poor weight-loss responders (about 70 %) than in good weight-loss responders (about 37 %).
To discover why the timing of food intake could influence weight loss, we carried out a randomised study in which thirty-two lean and young women completed two protocols: one including assessments of resting energy expenditure (indirect calorimetry) and glucose tolerance, and the other including circadian-related measurements, such as profiles in salivary cortisol and WT (Fig. 2)(2). Participants received standardised meals during both meal interventions weeks and were studied under two timings: early eating (lunch at 13·00 hours) and late eating (lunch 16·30 hours). The results of this study showed that these lean women, after 1 week of eating late, suffered from metabolic alterations that usually characterise obese women, such as decreased glucose tolerance, decreased resting energy expenditure and decreased carbohydrate oxidation. Moreover, late eaters had a flattened pattern of daily cortisol and alterations in daily rhythms of body temperature similar to those that characterise obese women as previously described(39).
Referência :
(1) Proc Nutr Soc. 2016 Nov;75(4):501-511.