Introduction

Obesity is a multifactorial disease caused by an interaction between genetic and environmental factors. Negative consequences of obesity have been linked to a variety of chronic diseases, including type 2 diabetes, hypertension, cardiovascular pathologies, and different forms of cancer [6]. Among the behavioral factors that can cause obesity, insufficient sleep (short sleep duration and/or poor sleep quality) depends on the light-dark cycle (circadian rhythm) and is gaining attention in the literature. Sleep disturbances can alter brain functions involved in the control of appetite, which can generate overeating in the current obesogenic environment [3–5]. Genetic studies on obesity have described more than 600 genes, genetic markers, or chromosomal regions that have been linked to obesity [24]. Of them, the Circadian Locomotor Output Cycles Kaput (CLOCK) gene participates in the regulation of circadian rhythms as a transcription factor [7]. There is extensive literature showing how sleep reduction is associated with the development of obesity [3, 5, 16]. However, studies evaluating how genetics predisposes a person to obesity when sleep is reduced and how this modulates eating behavior are lacking.

The objective of this paper was to briefly review the studies examining the association between genetic variants of the CLOCK gene with obesity and sleep by focusing on aspects of adiposity, metabolic syndrome, eating behavior, and sleep duration. There is sufficient literature reviewing the associations among insufficient sleep, energy intake, and obesity. However, it remains unclear how a reduction in the hours of sleep affects homeostatic and non-homeostatic food intake and how it is associated with CLOCK polymorphisms and the susceptibility to obesity across different ethnic populations. We focused on cross-sectional studies that measured CLOCK polymorphisms associated with body mass index (BMI), weight loss interventions, and energy intake. The novel contribution of this paper is that it highlights the findings on the role of genetic factors in such relations and provides research avenues for future investigations.

Methods

The literature search was based on the following terms associated with the objective of this article: genetic variants or polymorphisms of the CLOCK gene (including the most studied variants), eating behavior, energy/food intake, obesity, BMI, weight, waist circumference, waist-to-hip ratio, body fat, adiposity, overweight, fat mass, metabolic syndrome, and sleep (including sleep duration, sleep deprivation, and insufficient sleep). We also considered mostly cross-sectional frequency studies from different populations (age, sex, and ethnicities) and sample sizes. Meta-analyses and CLOCK SNP (single nucleotide polymorphism) allele and genotype frequencies were analyzed. Studies that involved subjects with mental disorders and those that were performed under stressful conditions were not considered. The search was restricted to human studies. All of the studies reviewed had the full text, and the assessment of inclusion criteria in this review was independently performed by two co-authors of this study (MV and AMO).

Results

A total of 16 articles fully complied with the terms of the search (Table 1). The articles reported associations between CLOCK gene variants and (1) sleep duration, (2) BMI or metabolic syndrome, and (3) eating behavior, mostly related to energy intake. Given that sleep duration is related to factors associated with obesity, such as food intake, it is difficult to divide the latter into two variables, and in several articles, they are discussed together. Below, we present the most relevant aspects of the articles studying the abovementioned areas.

Table 1 Association between CLOCK gene variants, obesity, and energy intake in humans
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Associations between sleep duration and CLOCK gene variants

CLOCK gene variants have been reported to modify the association between sleep duration and energy intake in several studies. The meta-analysis by Allebrandt et al. [1] showed that sleep duration was lower in subjects carrying the A allele of the rs12649507 SNP. An additional significant interaction was observed between sleep duration and the rs12649507 CLOCK polymorphism on polyunsaturated fatty acids (PUFA) intake; the carriers of the A minor allele had a longer sleep duration with increased PUFA intake. The carriers with the minor allele (G) had a shorter sleep duration [4]. Additionally, sleep duration and rs6858749 were related to protein intake, with carriers of the minor allele (T) reporting lower protein intake with each additional hour of sleep [4]. Both studies suggested that more hours of sleep might act as a protective factor against the genetic predisposition to develop obesity from the CLOCK polymorphism [1, 4]. These two studies included an analysis of a large sample size to investigate the associations of CLOCK and its interactions with sleep duration and dietary intake. However, they only included a European population, and sleep was self-reported. Thus, including other populations and objective methods of measuring sleep is necessary for future studies. On the other hand, in European populations, the CLOCK variants rs11932595 and rs6843722 showed no association with sleep duration (self-reported) in three independent cohorts [19]; however, Allebrandt’s study showed that carriers with a homozygous AA in the rs11932595 variant had reduced sleep duration.

Screening the entire coding CLOCK region in subjects with delayed sleep phase syndrome and non-24-h sleep-wake syndrome showed that CLOCK polymorphisms are unlikely to play an important role in the development of these syndromes [17]. This study is the only CLOCK-wide association study related with a disease. More studies are needed to amplify the coding region of the CLOCK gene in different populations and to link it with other pathologies, such as obesity, involved with CLOCK functions. The Iwase et al. [17] study is interesting because it is the only one in which the entire CLOCK coding region has been analyzed to find new polymorphisms or mutations, and it should be an interesting study to replicate in populations of obese people.

Collectively, there is an absence of studies that measure the association between CLOCK gene variants and sleep duration in different populations, especially using an objective assessment of sleep, such as actigraphy. Additionally, it would be relevant to investigate the frequency of CLOCK gene variants in different populations and associate these frequencies with the amount of sleep in free-living conditions. It is also very important to investigate how CLOCK variants predispose a person to developing obesity when they are exposed to environmental conditions, such as reduced sleep. This concept is especially important in today’s society in which many people are sleep deprived [20, 29].

Associations of CLOCK variants with BMI and metabolic syndrome

There are pathways that connect the central nervous system (CNS) and peripheral tissues, which allow the CNS to activate or silence peripheral tissues at different times of the day. Thus, an imbalance between the rhythms of different fat compartments differentially controlled by the autonomous nervous system and in turn by the CNS may be a possible cause of the metabolic syndrome [18]. Related to this, CLOCK polymorphisms have been described and associated with obesity or eating behavior traits. The variant 3111T > C (rs1801260) in conjunction with a specific haplotype (a combination of alleles at different loci on a chromosome that are transmitted together) has been associated with obesity and metabolic syndrome in different populations [8, 10, 11, 25]. It was determined that carriers of the C minor allele of the rs1801260 polymorphism were more resistant to weight loss than individuals with TT [11, 12]. Additionally, overweight/obese individuals carrying the CC rs1801260 genotype had significantly higher BMI values compared to those carrying the CT or TT genotypes [22]. Moreover, in the same study, obese class III individuals had a significantly higher frequency of both the CC genotype and the C allele compared to individuals with a BMI <40 kg/m2. Additionally, the TT genotype of rs1801260 showed lower plasma insulin and insulin resistance, as well as higher insulin sensitivity, after 12 months of diet intervention [13]. Additionally, C carriers of rs1801260 were associated with an evening chronotype, which was also related to an obesity phenotype [2, 21]. However, the rs1801260 variant was not significantly associated with being overweight or with sleep duration in children [14].

In addition, the CLOCK polymorphisms rs1554483, rs6843722, rs6850524, and rs4864548 have been associated with overweight and obesity in an adult population [26], showing that carriers of haplotypes rs1554483-G and rs4864548-A have a 1.5 times (confidence interval (CI): 1.31, 2.54) greater risk of becoming overweight or obese. In another study, carriers of haplotype CGC (rs4864548, rs3736544, and rs1801260) were protected against the development of overweight and obesity, supporting the hypothesis that genetic variations of the CLOCK gene may play an important role in the development of metabolic syndrome, type 2 diabetes, and cardiovascular disease [25].

The observations found between the rs1801260 variant, obesity, and certain features of eating behavior can be explained by the fact that this polymorphism produces changes in the stability and half-life of mRNA, which influences mRNA translocation. Therefore, CLOCK protein levels affect circadian clock organization, sleep duration, and, consequently, eating behavior traits [17].

Eating behavior associated with genetic variants of CLOCK gene

One explanation of the relationship between CLOCK gene and obesity is that this gene regulates aspects of energy intake. In the case of the variant rs3749474, carriers of the minor T allele reported significantly higher energy intake than non-carrier subjects [8], which is concordant with a study by Garaulet et al. [9]. For rs4580704, the carriers of the minor C allele reported the lowest values of energy intake after adjusting for sex, age, family relationships, and BMI [8]. However, the authors did not achieve statistical significance with the rs1801260 SNP. Consistent with this, the homozygotes CC displayed a significant increase in HDL/apolipoprotein A1 ratio under a low fat diet [15]. These results show an association between SNP rs4580704 with energy intake aspects.

There is a definite lack of studies that associate CLOCK variants with different eating behavior traits, which could be assessed using validated questionnaires. For example, eating behavior traits measured with the Three-Factor Eating Questionnaire (TFEQ) have been previously associated with the MC4R, MC3R, LEP, and LEPR genes [23, 27, 28]. The role of CLOCK genetic variants on the association between insufficient sleep and obesity is summarized in Fig. 1.

Fig. 1
figure 1

Role of CLOCK genetic variants on the association of sleep reduction and obesity. CLOCK genetic variants may influence at diverse stages the association between sleep reduction and obesity. The figure shows different CLOCK genetic variants that have been described to be associated with reduction in sleep, energy intake, and development of obesity

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Differences found in the same variant in different populations may be due to a linkage disequilibrium or the frequency of the genotypes in each population. Additionally, these differences may be due to the contribution of other variants of the same gene or other genes in different populations or a heterogeneity of phenotypes in which the number of subjects tested is not representative of the distribution of sleep duration.

Conclusion

There are some CLOCK variants that are related with obesity and short sleep duration. However, this type of research needs to be performed in other populations in which other genetic variants could be identified. Identifying at risk CLOCK genotypes is a new area of study with potential relevance for establishing sleep duration and eating behavior requirements to help with the prevention and treatment of obesity.