International Journal of

Molecular Sciences

Review
Chrono-Nutrition: Circadian Rhythm and
Personalized Nutrition
Marica Franzago 1,2 , Elisa Alessandrelli 2,3 , Stefania Notarangelo 2,3 , Liborio Stuppia 2,3
and Ester Vitacolonna 1,2, *

1 Department of Medicine and Aging, School of Medicine and Health Sciences, G. d’Annunzio University,
66100 Chieti, Italy
2 Center for Advanced Studies and Technology, G. d’Annunzio University, 66100 Chieti, Italy
3 Department of Psychological Health and Territorial Sciences, School of Medicine and Health Sciences,
G. d’Annunzio University, 66100 Chieti, Italy
* Correspondence: [email protected]

Abstract: The human circadian system has a period of approximately 24 h and studies on the
consequences of “chornodisruption” have greatly expanded. Lifestyle and environmental factors
of modern societies (i.e., artificial lighting, jetlag, shift work, and around-the-clock access to energy-
dense food) can induce disruptions of the circadian system and thereby adversely affect individual
health. Growing evidence demonstrates a complex reciprocal relationship between metabolism and
the circadian system, in which perturbations in one system affect the other one. From a nutritional
genomics perspective, genetic variants in clock genes can both influence metabolic health and modify
the individual response to diet. Moreover, an interplay between the circadian rhythm, gut microbiome,
and epigenome has been demonstrated, with the diet in turn able to modulate this complex link
suggesting a remarkable plasticity of the underlying mechanisms. In this view, the study of the
impact of the timing of eating by matching elements from nutritional research with chrono-biology,
that is, chrono-nutrition, could have significant implications for personalized nutrition in terms of
reducing the prevalence and burden of chronic diseases. This review provides an overview of the
current evidence on the interactions between the circadian system and nutrition, highlighting how
this link could in turn influence the epigenome and microbiome. In addition, possible nutritional
Citation: Franzago, M.; Alessandrelli,
strategies to manage circadian-aligned feeding are suggested.
E.; Notarangelo, S.; Stuppia, L.;
Vitacolonna, E. Chrono-Nutrition: Keywords: gut microbiome; clock genes; epigenetics; gene–diet interaction; nutrigenetics; personal-
Circadian Rhythm and Personalized ized nutrition; chronodisruption
Nutrition. Int. J. Mol. Sci. 2023, 24,
2571. https://doi.org/10.3390/
ijms24032571
1. Introduction
Academic Editor: Alfredo Miccheli
The circadian rhythms (circa = around and dies = one day), occurring at central and
Received: 27 December 2022 local levels by the involvement of clocks within several peripheral tissues [1,2], regulate
Revised: 23 January 2023
many behavioral and biochemical processes through the day/night cycle [2]. In addition,
Accepted: 25 January 2023
the core circadian clock machinery can be modulated by energy/nutrient input, thus
Published: 29 January 2023
pointing to the important role of energy metabolism [3,4]. In this context, a reciprocal
and complex interconnectivity between the circadian clock system and metabolism has
been identified; this relationship makes it likely that perturbations in one system affect the
Copyright: © 2023 by the authors.
other. Circadian desynchrony typical of modern societies and triggered by several chrono
Licensee MDPI, Basel, Switzerland. disruptors (such as shift work, stress, jetlag, sleep disruption) can impair human health,
This article is an open access article leading to an increased risk of metabolic diseases. Diet is one of the synchronizers of our
distributed under the terms and clock mechanisms, thus abnormal feeding times can lead to the separation of environmental
conditions of the Creative Commons oscillators from the central pacemaker inducing unhealthy consequences.
Attribution (CC BY) license (https:// From a nutrigenetics point of view, several genetic variants in circadian-related genes,
creativecommons.org/licenses/by/ interacting with dietary intakes and obesogenic behaviors, can influence the individual
4.0/). response to diet, suggesting that chronobiology should be taken into account in nutritional

Int. J. Mol. Sci. 2023, 24, 2571. https://doi.org/10.3390/ijms24032571 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2023, 24, 2571 2 of 17

practice [5–8]. On the other hand, the circadian rhythm is optimized for feeding in the light
phase [9], thus nutritional input improves circadian function by coordinating the peripheral
and central clocks.
Additionally, epigenomes and gut microbiomes show diurnal rhythms. The epigenetic
mechanisms play an important role in the regulation of the molecular clock machinery
transcription, and clock-controlled genes, gut microbiota (GM), and microbial metabolites
are known to mediate the effects of disruptions of circadian rhythms on human health.
Therefore, new opportunities have risen from recent findings on a dynamic crosstalk
among diet–biological rhythm-omics [10–12]. The effects of dietary components on health
outcomes are widely explored, nevertheless the complex relationship between meal timing
and the circadian machinery is still under investigation. Recently, chrono-nutrition has
emerged as a new area of research studying the impact of the timing of eating on the
well-being of an organism. In particular, the modification of the cycle between periods of
eating and fasting has been associated with a predisposition to nutrition-related diseases
including obesity, type 2 diabetes (T2DM), and cardiovascular disease (CVD). This review
provides an overview of the current evidence on the genetic and environmental factors
inducing molecular clock disruption with relevance to the onset of non-communicable
diseases (NCDs). It also explores the interactions between the circadian system and diet,
highlighting how this link in turn influences the epigenome and microbiome. Finally, it
suggests possible nutritional strategies to manage circadian-aligned feeding.

2. Circadian Rhythms
The circadian system, composed of a set of interconnected clock oscillators located in
the suprachiasmatic nuclei (SCN) of the hypothalamus and in some metabolically active
peripheral organs, regulates the behavioral and physiological daily rhythms of sleep/wake,
fasting/feeding and catabolic/anabolic cycles, body temperature, and endocrine func-
tions [13].
Although the hypothalamic SCN is considered as the dominant circadian pacemaker,
most peripheral organs and tissues can express circadian oscillations in isolation even if they
interact with each other and with the system as a whole. The synchronization of peripheral
clocks plays an important role in ensuring the temporally coordinated physiology [14].
Several factors are expressed and secreted following circadian stimuli, inducing functional
modifications including the following: (i) glucose tolerance peaks during daylight and is
lower during the night/dark cycle, (ii) melatonin drops at 7:00 and rises at 20:00, (iii) cortisol
rises at 8:00, (iv) sleep deepens at 1:00, (v) body temperature rises at 3:00 [15].
At the molecular level, circadian oscillations are generated by a complex array of
genes known as “clock genes”, including the clock circadian regulator (CLOCK), aryl
hydrocarbon receptor nuclear translocator-like (BMAL1, also known as ARNTL), period
circadian regulators (PER1 and PER2), and cryptochrome circadian regulators (CRY1
and CRY2). Proteins encoded by these genes play a crucial role in the regulation of the
circadian rhythmicity.
The molecular clock is based on a transcriptional autoregulatory feedback loop char-
acterized by the activation of BMAL1 and CLOCK, which positively regulate the expres-
sion of their target PER and CRY at the beginning of the cycle (Figure 1). The negative-
feedback repressor complex PER/CRY translocates into the nucleus to suppress activity of
BMAL1/CLOCK [13,16]. This feedback cycle has a genetically determined period length of
approximately 24 h and is synchronized to the environment mostly via light. Furthermore,
CLOCK-BMAL1 also drives another dozen downstream target genes known as clock-
controlled genes. The circadian network is a complex finely regulated system: the stability
of the PER and CRY proteins is controlled by SCF (Skp1-Cullin-F-box protein) E3 ubiquitin
ligase complexes. In addition, the phosphorylation of the PER and CRY proteins are trig-
gered by the kinases casein kinase 1ε/δ (CK1ε/δ) and AMP kinase (AMPK), respectively,
inducing the polyubiquitination by their respective E3 ubiquitin ligase complexes, which
in turn activate the 26S proteasome complex to degrade the PER and CRY proteins [17].
 are triggered by the kinases casein kinase 1ε/δ (CK1ε/δ) and AMP kinase (AMPK), respec-
tively, inducing the polyubiquitination by their respective E3 ubiquitin ligase complexes,
Int. J. Mol. Sci. 2023, 24, 2571 which in turn activate the 26S proteasome complex to degrade the PER and CRY proteins3 of 17
[17].

Figure
Figure 1. Molecular mechanisms
1. Molecular mechanismscontrolling
controllingthethecircadian
circadian rhythm.
rhythm. CLOCK
CLOCK andand BMAL1
BMAL1 regulate
regulate the
the expression of numerous genes including Per family (Per1-3), Cry family (Cry1-2), nuclear
expression of numerous genes including Per family (Per1-3), Cry family (Cry1-2), nuclear receptor recep-
tor family (Rev-erbα and Rorα), and many downstream target genes known as clock-controlled genes
family (Rev-erbα and Rorα), and many downstream target genes known as clock-controlled genes (Ccg).
(Ccg). CRY and PER proteins translocate to the nucleus to form a negative-feedback repressor com-
CRY and PER proteins translocate to the nucleus to form a negative-feedback repressor complex
plex of CLOCK/BMAL1 transcriptional activity. Another feedback loop, driven by CLOCK:BMAL1,
of CLOCK/BMAL1
involves Rev-erbα and transcriptional activity.
Rorα to regulate Bmal1 Another feedback
transcription. Atloop, driven by CLOCK:BMAL1,
a post-transcriptional level, SCF
involves Rev-erbα and
(Skp1-Cullin-F-box RorαE3toubiquitin
protein) regulate ligase
Bmal1complexes
transcription. At aPER
regulate post-transcriptional
and CRY proteins’ level, SCF
stability
(Skp1-Cullin-F-box
by protein)
recognizing specific E3 and
targets ubiquitin ligase
directing complexes
their regulate PERFinally,
polyubiquitination. and CRY proteins’
their stability
degradation is
regulated by thespecific
by recognizing 26S proteasome complex.
targets and directing their polyubiquitination. Finally, their degradation is
regulated by the 26S proteasome complex.
The auxiliary feedback loop involving Rev-erbα represses the transcription of Bmal1,
The auxiliary
triggering feedback
an antiphase loop involving
oscillation Rev-erbα
in Bmal1 gene represses
expression theAs
[18]. transcription
described inof Bmal1,
the par-
triggering an antiphase oscillation in Bmal1 gene expression [18]. As described
agraphs below, under circadian misalignment, the central and peripheral signals conflict in the para-
graphs
due below,
to the under circadian
misalignment misalignment,
of light/dark the central andcycles,
and feeding/fasting peripheral signals risk-associ-
promoting conflict due
to the misalignment of light/dark and feeding/fasting cycles,
ated metabolic patterns and chronic diseases such as obesity [19]. promoting risk-associated
metabolic patterns and chronic diseases such as obesity [19].
3. Chronotype
3. Chronotype
Several studies in chronobiology supported the importance of circadian rhythms in
Several studies in chronobiology supported the importance of circadian rhythms
metabolic regulation [15]. Although the circadian system is entrained to an external light–
in metabolic regulation [15]. Although the circadian system is entrained to an external
dark cycle with a period of approximately 24 h, there are interindividual circadian pref-
light–dark cycle with a period of approximately 24 h, there are interindividual circadian
erences influencing behavioral patterns, defined as chronotypes. Chronotype is a biologi-
preferences influencing behavioral patterns, defined as chronotypes. Chronotype is a bi-
cal characteristic leading interindividual differences in the circadian phase relative to the
ological characteristic leading interindividual differences in the circadian phase relative
light–dark cycle. There are three general categories of chronotypes usually divided by the
to the light–dark cycle. There are three general categories of chronotypes usually divided
terms: (i) “morning”, (ii) “evening”, and (iii) “intermediate” types [20]. Morning types
by the terms: (i) “morning”, (ii) “evening”, and (iii) “intermediate” types [20]. Morning
prefer activities at the beginning of the day, and evening types prefer main activities in
types prefer activities at the beginning of the day, and evening types prefer main activ-
the late afternoon or evening, and at their extreme this may be shifted by about 2–3 h in
ities in the late afternoon or evening, and at their extreme this may be shifted by about
circadian oscillations
2–3 h in circadian [21]. The[21].
oscillations intermediate chronotype
The intermediate occupies occupies
chronotype an intermediate position
an intermediate
between the morning and evening types. Several studies described the different
position between the morning and evening types. Several studies described the different features
between
features between extreme groups in circadian rhythmicity [22–24]. Regarding the chrono-
extreme groups in circadian rhythmicity [22–24]. Regarding the extreme extreme
types, morning types are characterized by a phase advance in the peak
chronotypes, morning types are characterized by a phase advance in the peak of body of body tempera-
ture and alertness,
temperature in the sleep–wake
and alertness, cycle, and
in the sleep–wake in performance
cycle, compared
and in performance with evening
compared with
evening types [21,25]. Some studies demonstrated that the evening chronotype is associated
with irregular eating and meal skipping, particularly breakfast skipping as well as being
related to a lower intake of fruits and vegetables and a higher intake of energy drinks and
fat, suggesting long-term consequences on cardiometabolic health [26]. In this view, the
evening chronotype has been also correlated with the risk of a variety of conditions, in-
Int. J. Mol. Sci. 2023, 24, 2571 4 of 17

cluding metabolic dysfunction, diabetes, gastrointestinal/abdominal disorders, psychiatric

symptoms, as well as with some cardiovascular risk factors (i.e., higher rates of smoking
and overweight/obesity) when compared with the morning chronotype [22,27,28].
The later chronotype has been associated with poorer glycemic control in T2DM pa-
tients [29] as well as the increased eveningness being related to an increased risk of all-cause
mortality over 6.5 years [28]. Moreover, an association between eveningness preference
and eating disorders (EDs) has been also suggested [30,31] since it has been shown that the
percentage of evening types in the ED group was twice that of the controls [25].
The above-described data suggest that chronotype may be predictive of disease out-
comes, highlighting a possible relevant role of the circadian system in metabolic regulation.
In this view, the relationships between circadian misalignment and metabolic diseases in
adolescence, which is considered a vulnerable period for obesity, have also been investi-
gated. Weiss and colleagues [32] reported that adolescents sleeping less than eight hours
consumed a higher proportion of calories from fats compared to those with a nocturnal
sleep of more than eight hours. Later-chronotype young adolescents are at risk of increased
BMI and poorer dietary behaviors with a higher frequency of consuming unhealthy snacks,
night-time caffeine consumption, and inadequate daily intake of fruit and vegetables [33].
In this view, future studies are needed to explore the role of the circadian system in the
regulation of body weight and metabolism in younger populations.

4. Chronodisruptions
The role of circadian disruption in the susceptibility to NCD has received an increasing
amount of attention. Circadian clock mutant mice regarding Bmal1, Clock, or Rev-erb genes
showed reduced insulin secretion, impaired glucose tolerance, defects in the proliferation
and size of pancreatic islets, abnormal lipid profiles, fatty liver, and hyperglycaemia,
demonstrating a potential link between clock gene dysregulation and obesity, diabetes,
and metabolic syndrome (MetS) [2,34–37]. Apart from abnormalities in the molecular
circadian clock observed in mice, environmental and lifestyle factors which are considered
“exposures” or “effectors” (chrono disruptors), can predispose to individual circadian
disruption centrally or peripherally, thereby paving the way for chronic disorders. Thus,
chronodisruption is defined by Erren et al. as a “disturbance of the circadian organization
of physiology, endocrinology, metabolism, and behaviour” [38]. Chronodisruption is
common and rising worldwide resulting from our personal modern lifestyles, including
excessive energy consumption, irregular times of food consumption, sleep disturbances,
and shift work.
It was also reported that prolonged short sleep durations and/or poor sleep quality
with circadian misalignment are correlated with metabolic dysfunctions, including obesity,
T2DM, and hypertension [39–43], as well as with decreased leptin, increased appetite,
and insulin resistance [42,44]. The night shift work is considered one of the negative
components strongly correlated with circadian disruption that induces adverse health
effects such as metabolism abnormalities [45]. A meta-analysis of 28 studies demonstrated
that shift work had a negative impact on the development of overweight and obesity (Odd
Ratio OR = 1.23 (95% confidence interval = 1.17–1.29)) [46]. Scheer et al. [47] examined
the deleterious effects of jetlag or shift work, exposing some subjects to a light–dark cycle
lengthened to 28 h, out of synchrony with the endogenous clock in which the melatonin
and body temperature rhythm free runs with a ~24-h period. The authors showed that this
experimental short-term circadian misalignment following a 10-day laboratory protocol
increased postprandial glucose, insulin, and mean arterial pressure, as well as induced the
decreases in leptin and sleep efficiency, and the complete inversion of the cortisol profile
across the behavioral cycle.
Regarding the young population, the effects of sleep duration and social jetlag have
been investigated in both adolescents and adults showing that social jetlag was a better
predictor of overweight/obesity [48]. Similarly, Chaput and Tremblay [39] also showed
that short sleep duration was significantly associated with increased central adiposity
Int. J. Mol. Sci. 2023, 24, 2571 5 of 17

in children. Beebe et al. [49] reported that chronic sleep restriction in adolescents (age
14–16 years) caused an increased consumption of foods with high glycemic index (par-
ticularly desserts and sweets) and a trend toward more calories and carbohydrates. A
randomized crossover design with two experimental conditions based on three consecutive
nights of short sleep (4 h/night) or long sleep (9 h/night) duration investigated the effects
of sleep deprivation on markers of glucose metabolism in normal-weight adolescents (mean
age 16.8 years) [50]. This study showed increased levels of fasting insulin and insulin resis-
tance and 24% reduced epinephrine following sleep restriction compared to adequate sleep
duration opportunity [50]. All these data confirmed that the chrono disruptors contribute
to various obesity markers.

5. Chrono-Nutrition
Modern lifestyle habits are characterized by being more often in a postprandial state,
exposure to unhealthy diets, being sedentary with prolonged sitting times, irregular times
of eating, skipping meals, chronic psychological stress, emotional eating, and food con-
sumption late at night [51,52].
Therefore, modern lifestyle habits trigger a vicious cycle, in which an obesity-causing
unhealthy lifestyle results in disrupted circadian rhythms, which in turn leads to obesity.
Several studies showed a beneficial effect of dietary regimens which are based on an
availability of food only at discrete windows of time within the daily cycle [15]. A growing
body of evidence suggests that these strategies can delay and often reverse the symptoms
associated with metabolic disorders, reducing insulin resistance and increasing glucose
tolerance [53–56].
These dietary approaches, through the manipulation of the feeding–fasting cycle, can
encompass (i) sustained periods of chronic energy restriction, characterized by a reduction
by up to 40% in daily energy intake, but meal frequency and timing remain unchanged;
(ii) intermittent fasting, in which one day or more days of fasting are interspersed with
normal ad libitum eating patterns; and (iii) chrono-nutrition in which food consumption is
restricted to specific times of day. In this context, feeding time restricted (FTR), requiring
a consistent daily eating window, is a form of chrono-nutrition. In FTR, the daily eating
duration, that is, the time between the first and last energy intake, is typically reduced from
a 12–14 h day to <10 h day [8,55,57,58].
The concept of chrono-nutrition was developed in 1986 by Dr. Alain Delabos [59]. It is
a nutritional regimen that follows our biological clock, which in turn is marked by changes
in metabolism that occur throughout the day. Since later meal timings and irregular eating,
which are not in line with the biological clock, are associated with increased adiposity,
T2DM, and cardiometabolic risk factors [60–62], chrono-nutrition is based on three different
dimensions of eating behavior, including timing, frequency, and regularity [26,63–65].
Among several dietary strategies available, the chrono-nutritive therapy based on
chronobiology is characterized by eating most calories and carbohydrates at lunch time and
in the early afternoon, avoiding late evening dinner. In this view, in addition to the amount
and content of macronutrients and micronutrients, the timing of food intake during light
time vs. evening vs. night is critical for the well-being of an organism and could represent
an interesting strategy to maintain metabolic health or to promote weight loss [66].

6. Clock Genes Variants

The effect of chronotype combined with the genotypes of several clock genes through
eating time has been also investigated. Several single nucleotide polymorphisms (SNPs)
in circadian-related genes have been associated with the susceptibility to obesity, CVD,
and MetS, as well as gene-diet interactions being described for some of these genetic
variants [67–70].
In this view, the CLOCK rs4580704 C > G is one of the most relevant SNPs. The carriers
of the minor allele (G) in this CLOCK variant showed a lower weight, 31% decreased
diabetes risk, and 46% lower risk of hypertension than non-carriers [71]. The SNP entitled
Int. J. Mol. Sci. 2023, 24, 2571 6 of 17

3111 T/C (rs1801260), a substitution of a thymine to cytosine in the 30 -flanking region in the
CLOCK gene, was associated with eating behaviors related to late eating and evening types,
higher BMI, higher ghrelin, and lower GLP-1 levels, thus influencing the susceptibility
to obesity and related diseases such as metabolic syndrome [35,72–75]. Rahati et al. [75]
showed a significant difference between CLOCK genotypes with a wide range of variables
related to human behaviors. Moreover, minor allele C carriers in rs1801260 were more of
the evening chronotype and tended to sleep less compared to TT carriers [35,74].
It is known that melatonin is produced when we are sleeping and fasting. The mela-
tonin receptor 1B (MTNR1B) SNPs affect melatonin signaling, decrease glucose sensitivity
of pancreatic β-cells, and negatively impact circadian insulin secretion [68]. Rs10830963 and
rs1387153 in MTNR1B were also significantly correlated with gestational diabetes mellitus
(GDM), the common metabolic disorder during pregnancy [76,77]. Other evidence for the
role of the BMAL1 gene in the increased risk of glucose intolerance, T2DM, and GDM has
been shown [78–80].
Other several SNPs, including polymorphisms of the PER2 gene (rs2304672 C > G and
rs4663302 C > T) and the Rev-erb-a gene (rs2314339), have been associated with abdominal
obesity, frequent snacking, and skipping breakfast [81,82]. In particular, minor allele
carriers G of PER2 rs2304672 displayed several obesogenic behaviors including a decreased
of success of the weight loss treatment, increased frequency of snacking, stress while
dieting, eating while bored, and skipping breakfast, when compared to carriers C [81].
This evidence underlines that individuals carrying specific genetic variants tend to eat
more, sleep less, and have greater risk of obesity [83]. To note, these relevant findings are
functionally explained since several variants triggering a change in the mRNA structure
may lead to a modification in gene expression [84].
Nutrigenetics, which is a branch of nutritional genomics, focuses on the role of genetic
susceptibility to diseases as well as on the link between genetic variants and response
to diet [85,86]. In the era of nutrigenetic research, the relationship between circadian
system gene variants and the effectiveness of dietary intervention is noteworthy (Table 1).
CRY1 rs2287161 represents an example of gene–diet interaction for insulin resistance in
Mediterranean and North American populations [87]. The CC carriers of CRY1 rs2287161
that ate high amounts of carbohydrates showed higher insulin resistance when compared
to G carriers whose values of model assessment of insulin resistance (HOMA-IR) were
independent of carbohydrate intake, remaining constant [87]. Moreover, other gene–diet
interactions associated with MetS at the CLOCK locus have been demonstrated. A protective
effect of minor allele CLOCK-rs4580704 on insulin sensitivity [71] has been shown when
MUFA intake was >13.2% of energy. An association between this variant combined with
other SNPs in linkage disequilibrium (i.e., rs1801260, rs3736544, rs4864548 and rs3749474)
and lower hyperglycemia and decreased risk of T2DM has also been reported [71,88].
Several studies suggested the association between CLOCK 3111T > C (rs1801260)
and weight loss effectiveness [74,83,89] showing C carriers to be more resistant to weight
loss than TT homozygotes during an energy-restricted diet [89]. In addition, the SIRT1
rs1467568 and CLOCK 3111T > C combined genotype was associated with the evening
chronotype and weight loss resistance in a behavioral therapy treatment for obesity [90].
The authors suggested that the additive effect of SIRT1 and CLOCK variants on resistance
to weight loss could be related to the chronotype of the subject, higher plasma levels of
ghrelin, and less adherence to Mediterranean diet patterns. Moreover, the deleterious
effect of CLOCK 3111T > C on waist circumference was only found with high saturated
fatty acid intakes (>11.8%) [71]. Regarding the interaction between CLOCK 3111T/C and
emotional eating behaviors to modulate total weight loss in overweight and obese subjects,
López-Guimerà et al. [91] showed that minor C allele carriers with a high emotional score
lost significantly less weight than those C carriers with a low emotional score.
These results are encouraging, since by changing our eating habits it is possible to
reduce or even eliminate the deleterious effect induced by a specific allele risk. The interplay
between gene variants in circadian machinery and diet demonstrated by some intervention
Int. J. Mol. Sci. 2023, 24, 2571 7 of 17

studies described above may help to design effective, personalized nutritional strategies
based on the identification of specific allele carriers. Further research is required to optimize
the individual’s response to the dietary interventions.

Table 1. Summary of human studies investigating the interaction between diet and SNPs in circadian
clock genes.

Authors Sample Size Target Gene Main

Study Design
(Ref) (N) (Genetic Variants) Findings
Association with obesity and MetS
The minor allele G of rs4580704 showed lower
CLOCK
risk of hypertension and diabetes.
rs4580704 C > G
Protective effect the minor allele G of
Garaulet et al., 2009 N = 1100 rs3749474 C > T
Cross-sectional study rs4580704 on insulin sensitivity when MUFA
[71] (540 men, 560 women) rs1801260 (3111T →C)
intake was >13.2% of energy.
rs1464490 C > T
Different effects across CLOCK 3111T →C
rs4864548 G > A
genotypes for saturated fatty acid intake (% of
energy) (p = 0.017).
CLOCK
Relationship between CLOCK SNPs and
Dietary program rs1801260 (3111T →C)
obesity.
Garaulet et al., 2010 N = 454 Overweight/obese, based on the rs3749474 C > T
CLOCK rs1801260 may predict the outcome of
[89] aged 20 to 65 Mediterranean diet rs4580704 C > G
body weight reduction strategies based on
(28 weeks) rs1464490 C > T
low-energy diets.
rs4864548 G > A
PER2 Association with abdominal obesity (p < 0.05)
rs230467 Minor allele carriers G of rs2304672 displayed
N = 454 overweight/obese, Weight loss C>G several obesogenic behaviors. The frequency
Garaulet et al., 2010a
aged 20 to 65 intervention based on rs4663302 of the carriers of rs4663307 minor allele who
[81]
(380 women, 74 men) the Mediterranean diet C>T withdrew was greater than in those who
rs4663307 successfully completed treatment.
G>A
N = 1106 Behavioral treatment A higher resistance to weight loss and a lower
SIRT1-CLOCK
Garaulet et al., 2012 (715 lean and for obesity based on a weekly weight loss rate in carriers of minor
rs1467568 G > A
[90] 391 overweight or obese, Mediterranean diet alleles at SIRT1 and CLOCK loci as compared
3111T > C
aged 20 to 65) (30 weeks) with homozygotes for both major alleles.
Significant difference between genotypes for
physical activity (p = 0.001), waist
circumference (p < 0.05), BMI (<0.01), weight
Rahati et al., 2022 N = 403 overweight and/or CLOCK (p = 0.001), GLP-1 (p = 0.02), ghrelin (p = 0.04),
Cross-sectional study
[75] obese, aged 20 to 50 rs1801260 (3111T →C) appetite (p < 0.001), chronotype (p < 0.001),
sleep (p < 0.001), food timing (p < 0.001),
energy (p < 0.05), carbohydrate (p < 0.05), and
fat intake (p < 0.001).
Lopez-Guimera
N = 1272 overweight/obese Prospective CLOCK SNP interacts with emotional eating behaviors
et al., 2014
aged 20 to 65 longitudinal study rs1801260 (3111T →C) for weight loss.
[91]
A lower probability of abdominal obesity in
minor allele A carriers (OR = 1.5).
N = 2414 No significantly association with energy
Garaulet et al., 2014a (1404 Spanish Mediterranean REV-ERB-ALPHA1- intake but the physical activity was different
Cross-sectional study
[82] 810 North American rs2314339 G > A by genotype.
populations) Interaction between the REV-ERB-ALPHA1
variant and MUFA intake for obesity in the
Mediterranean population (p = 0.014).
N = 1548
Significant interactions between the CRY1
Dashti et al., 2014 (728 Mediterranean and 820 CRY
Cross-sectional study variant and dietary carbohydrates for insulin
[87] European origin North rs2287161 G > C
resistance in both populations (p < 0.05).
American populations)
Carriers of the minor C allele were more
resistant to weight loss, showed shorter sleep
Cross-sectional study duration, higher plasma ghrelin
Garaulet et al., 2011 N = 1495 overweight/obese, CLOCK
(weight loss program concentrations, delayed breakfast time,
[92] aged 20 to 65 years rs1801260 (3111T →C)
12–14 weeks) evening preference, and less compliance with
a Mediterranean diet pattern than
TT individuals.
MeS: metabolic syndrome, OR: odd ratio, MUFA: monounsaturated fatty acids; BMI: body mass index.

7. Epigenetic Alterations in the Clock Genes

The epigenetic mechanisms including DNA methylation, micro-RNAs, and histone
modifications, regulate gene expression and control many cellular and physiological pro-
cesses [85,93,94]. The epigenetic alterations have been considered as potential contributors
to the developmental origin of health and disease [95]. Different dietary patterns, lifestyles,
Int. J. Mol. Sci. 2023, 24, 2571 8 of 17

and environmental insults are able to modulate the DNA methylation which occurs at
the 50 carbon of cytosines in CpG dinucleotides mainly in gene promoters, and recently
the influence of these mechanisms on the circadian rhythm has been reported [96]. In
support of this, Azzi et al. [97] suggested that modifications of DNA methylation, the most
intensely studied epigenetic mechanism, may have an important role in driving circadian
clock plasticity. The authors showed that a transient exposure to a 22 h light–dark cycle
induced long-lasting changes in the SCN transcriptome by altering global DNA methyla-
tion, which in turn correlated with many behavioral and physiological changes in mice [97].
Apart from the finding described above, this study demonstrated that these changes were
relatively stable, but were also reversible after prolonged re-entrainment to the 24-h day.
The question of whether the light itself directly regulates the enzyme activity involved in
DNA methylation remains to be clarified [98].
Several lifestyle habits involved in the circadian rhythm, such as job seniority, length
of shiftwork, and morning and evening types, have been associated with the promoter
methylation of the glucocorticoid receptor (GCR), tumor necrosis factor alpha (TNF-α), and
interferon gamma (IFN-γ) in blood [99].
Hypomethylation in the promotion of the CLOCK gene and hypermethylation of CRY2
in the peripheral blood DNA of subjects on long-term shiftwork have been shown [100].
In addition, DNA methylation patterns at clock genes have been correlated with several
outcomes in response to dietary weight loss interventions (Table 2) [101–103]. Different
DNA methylation levels of several CpG sites of CLOCK and BMAL1 were found between
normal-weight and overweight and obese subjects in white blood cells obtained before the
16 weeks weight reduction treatment [101]. In addition, the authors showed significant as-
sociations between the methylation in the CLOCK, BMAL1, and PER2 with anthropometric
parameters such as BMI, adiposity, and MetS score [101]. Moreover, methylation levels of
CLOCK and PER2 were associated with several obesogenic behaviors, including snacking
frequently and eating when bored, and at baseline were also correlated with the magnitude
of weight loss [101].
Ramos-Lopez [104] showed associations of DNA methylation profiles at circadian
genes (ROR, PRKAG2, PER3, BHLHE40, FBXL3, RORA, CREB1) with obesity, metabolic
disturbances, and carbohydrate intake, with potential impacts on weight homeostasis in
474 adults.
To date, little is known about the transcriptional regulation of clock genes by the
histone modifications. The rhythmic histone H3 acetylation in mPer1, mPer2, and Cry1
promoters was reported in the liver and heart, with the peaks occurring during the tran-
scriptionally active phase [105,106]. There are several chromatin modifications that change
over the circadian cycle, for example histone H3 serine 10 phosphorylation, the first chro-
matin mark related to circadian-regulated gene expression identified in mice, increased
in the SCN neurons when exposed to light at night [105]. However, some of the details
surrounding the histone-modifying enzymes are still underexplored.
Several studies in animal models also suggest that many microRNAs, small non-
coding RNA sequences of 22–24 nucleotides, oscillate following a circadian cycle but this is
still a poorly explored field of study in humans. A report showed that the microRNA cluster
composed of miR-96/miR-182/miR-183 influences the melatonin production, exhibiting
diurnal variation in a murine model [107]. In addition, the rhythmic oscillations of miR-
96-5p in the regulation of glutathione levels via excitatory amino acid carrier 1 have
been demonstrated [108]. Additionally, Zhang et al. 2014 [109] analyzed the circadian
expression of genes and non-coding RNAs in different mouse tissues and showed that
39 microRNA levels oscillated in opposite to their target genes. MiR-181, which was
previously associated with lipid metabolism, peaked between 8:00 a.m. and 16:00 p.m. in
human leukocytes [110]. It has been found that circulating levels of miR-181 decreased
in obese subjects, although weight loss normalized its expression. The understanding of
the effects of circadian microRNA’s misregulation in human disease is still in its infancy,
although several microRNAs influencing the circadian system [111,112] and some of them
Int. J. Mol. Sci. 2023, 24, 2571 9 of 17

also modulated by diet, have been considered as potential biomarkers of disease onset and
progression [7,113,114].
Nevertheless, despite these interesting data, it remains unclear whether the epigenetic
changes in the clock genes are causes or effects of obesity and MetS [101]. Moreover, future
research should elucidate whether stable changes in eating behaviors may modify the
epigenetic mechanisms and consequentially our destiny. In this regard, nutrimiromics,
which studies the influence of the diet on the modification of gene expression due to
microRNAs [115], and chronobiology should be merged to evaluate the circadian-related
microRNAs and their modulation by dietary compounds in order to understand if this
relationship may affect the risk of chronic diseases.

Table 2. Summary of human studies investigating the interaction between diet with DNA methylation
levels at circadian clock genes.

Authors Methylation Profiles in

Sample Size Study Design Evidence
(Ref) Target Genes
N = 20 Normal weight
Association between methylation status of CpG
(BMI < 25 kg/m2 ),
sites located in CLOCK, BMAL1, and PER2 with
Milagro et al., N = 20 overweight/obese Cross-sectional study CLOCK
obesity, MetS.
2012 (BMI = 29–35 kg/m2 ) (28 weeks of BMAL1
The methylation status of different CpG sites in
[101] N = 20 morbidly obese women treatment) PER2
CLOCK and PER2 has been proposed as
(BMI > 40 kg/m2 ),
biomarkers of weight loss success.
aged 25 to 53 years
Correlation between DNA methylation patterns
RORA at six circadian rhythm pathway genes with BMI.
PRKAG2 Correlation between methylation signatures at
PER3 cg09578018 (RORA), cg24061580 (PRKAG2),
Ramos-Lopez et al., BHLHE40 cg01180628 (BHLHE40), and cg10059324 (PER3)
N = 474 adults belonging to the
2018 Cross-sectional study FBXL3 with insulin resistance (p < 0.0001) and mean
MENA project
[104] RORA arterial blood pressure (p < 0.0001).
CREB1 Relevant correlations between methylation at
PRKAG2 cg09578018 (RORA) and cg01180628 (BHLHE40)
PRKAG2 with total energy and carbohydrate intakes
(p < 0.05).
The energy-restricted intervention modified the
methylation levels of different CpG sites in
BMAL1 and NR1D1.
The changes in BMAL1 methylation level with
the intervention, positively correlated with the
Cross-sectional study eveningness profile (p = 0.019).
Weight loss treatment The baseline methylation at BMAL1 positively
N = 61 women BMAL1
Samblas et al., 2016 (nutritional program correlated with energy (p = 0.047) and
(BMI = 28.6 ± 3.4 kg/m2 ; age: CLOCK
[102] based on a carbohydrate (p = 0.017) intake and negatively
42.2 ± 11.4 years) NR1D1
Mediterranean dietary correlated with the effect of the weight loss
pattern) intervention on TC (p = 0.032) and low-density
lipoprotein cholesterol (p = 0.005).
Significant and positive correlations were found
between changes in methylation levels in the
CpG region of BMAL1 due to the intervention
and changes in serum lipids (p < 0.05).
MENA: Methyl Epigenome Network Association (MENA) project; BMI: body mass index; TC: total cholesterol.

8. Gut Microbiome
In recent decades, there has been a growing interest in the study of the GM, which is a
complex and dynamic population of microorganisms living in the human gastrointestinal
tract, and hence it is considered as an auxiliary “metabolic organ” [116,117]. The GM itself,
or through interactions with the host, plays a crucial role in the preservation of the mucosal
integrity of the intestinal epithelial barrier and in the digestion, metabolism, as well as
in the regulation of many hormones’ levels [118]. The main bacterial phyla in healthy
individuals are Bacteroidetes and Firmicutes [119]. The GM has a symbiotic relationship
with the host [120]. Dietary regimes, food additives, prebiotic and probiotic supplements,
food processing, and cooking choices can contribute to shaping the GM [121,122], thus influ-
encing the related immune and metabolic response of the human host. On the other hand,
a high-fat diet (HFD) affects the composition of the GM, leading to a drastic reduction in
microbial diversity and the Firmicutes/Bacteroidetes ratio, as well as an increases in differ-
ent bacteria from the Firmicutes phylum [123,124]. Emerging data also demonstrated that
Int. J. Mol. Sci. 2023, 24, 2571 10 of 17

the disruption of the circadian system from the host can influence the composition of GM.
On the other hand, the gut microbial community can regulate host circadian and metabolic
homeostasis, also exhibiting diurnal oscillations [125–127]. Although this relationship re-
mains to be clarified, a combination of circadian-clock-dependent and -clock-independent
mechanisms has been proposed [10]. Thus, bacterial rhythms typically have a period of
24 h with variations of bacteria during light and dark periods regulated also by melatonin
and temperature [128,129]. As proof of day/night rhythms in microbiome composition
and metabolic activity, an increase primarily in Bacteroidetes, Verrucomicrobia, but also the
opportunistic Enterobacteriaceae during the sleeping/fasting phases has been found, as
opposed the Firmicutes peaks during the waking/eating phase which are diet-driven [130].
Several studies demonstrated that circadian disruptions in sleep, diet, and eating patterns
impact the diurnal dynamics of GM structure and activity, which may be associated with
host metabolic dysfunction and inflammatory pathways leading to an increased risk of
metabolic syndrome [10]. Some recent studies have suggested that personalized diets
may modify elevated postprandial blood glucose and its metabolic consequences. Zeevi
et al. [130], using a machine learning algorithm which integrates multi-dimensional data
(such as blood parameters, dietary habits, anthropometrics, physical activity, and GM),
accurately predicted personalized postprandial glycemic response to real-life meals. More-
over, these authors demonstrated that personally tailored dietary interventions, based
on these predictions, result not only in significantly improved postprandial (postmeal)
glycemic responses, but they also report consistent alterations to the GM. Then, Berry
et al. [131] developed a different machine learning model that predicted both triglyceride
and glycemic responses to food intake. The authors observed inter-individual differences in
postprandial metabolic responses to the same meals. The postprandial glycemic predictions
were similar to those reported previously [130], although the analysis methods and input
features are different. These interesting findings may be informative for the development
of population-wide personalized nutrition as a potential strategy for disease prevention.
Nutrients and bioactive compounds of food can modify gut microbial composition
and functions, thus several recent strategies based on the manipulation of GM may at least
partially consolidate host circadian rhythms. In particular, plant-food-derived fiber and
polyphenols can generate bioactive SCFAs, vitamins, and bioamines, which in turn might
help resynchronize circadian rhythms, mitigating some of the modern-lifestyle-associated
metabolic alterations [132–134].

9. Conclusions
Balanced nutrition, as well as the synchronization between clear feeding/fasting
cycles with clock-regulated metabolic changes, contribute to maintaining circadian rhythms
in behavior and physiology [135]. The link between circadian disruption and metabolic
disturbance has garnered much attention. A relationship between genetic variants in some
of the clock genes with dietary intake, obesity, T2DM, and metabolic risk (MetS)-related
variables has been demonstrated [84,92]. On the other hand, gene–diet interactions can
modulate the individual predisposition defined by those variants [7]. rs1801260 (3111T > C)
is one of the most relevant SNPs and C carriers, which is characterized by sleep reduction,
changes in ghrelin values, alterations in eating behaviors and evening preference, and
could cause individuals to be more prone to obesity and failure to lose weight [92]. The
assessment of risk genotypes of circadian clock genes could provide insight into the link
between chronotype and chrono-nutrition, with significant implications for the prevention
and treatment of NCDs.
Another point of interest is the effect of several chrono disruptors, such as sleep
curtailment, frequent snacking, nocturnal eating, and bright light exposure at night [81], on
risk of obesity, on modifications of the clock’s methylation pattern [101], or on changes in
transcriptomes [97]. In this view, dietary intake, an important synchronizer, particularly
for the peripheral clocks [136], has been associated with DNA methylation levels in the
Int. J. Mol. Sci. 2023, 24, 2571 11 of 17

CLOCK gene [101], suggesting that some of these CpGs could be used as biomarkers of
weight loss response.
On the other hand, promising findings have been recently reported regarding the role
of microRNA in circadian regulation. From a nutrimiromics point of view, this research
field should be greatly expanded to clarify if the circadian microRNA–diet interactions
could be a tool to epigenetically modulate the circadian system altered by chrono disruptors
of modern societies.
Moreover, a dynamic crosstalk exists between GM and the host and recent studies
have demonstrated that circadian disruption induced by eating food late at night or at
irregular times influences GM, increasing the susceptibility of the host to metabolic dys-
function and inflammation. Manipulating daily rhythms of the microbiome may therefore
be a promising chrono-nutrition-based approach to restore the host’s circadian rhythm
and metabolic homeostasis [132]. So, considering this, circadian-based strategies have
been proposed, such as chronotherapy and food intake only in daylight hours, which
might restore the gastrointestinal tract microbiome communities, promoting metabolic
health and homeostasis [10,117,137,138]. Therefore, it is possible that prebiotic or probiotic
supplements as well as primarily plant-based diets could beneficially alter the microbiota
community and circadian rhythms in high-risk populations (i.e., shift workers). Emerging
data demonstrated that the clock system influenced by metabolic and epigenetic levels is
characterized by remarkable plasticity in response to nutritional challenges. In conclusion,
the development of an omics-integral approach based on the knowledge of individual
Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW 13 of 19
epigenetic and genetic patterns as well as gut microbial composition and activity might
provide the basis for personalized nutrition by matching with chrono-nutrition (Figure 2).

A B

Figure
Figure2. 2.Panel
Panel(A) From
(A) Froma nutritional genomics
a nutritional genomics perspective, summary
perspective, summaryof the complex
of the diet–biological
complex diet–biolog-
ical rhythm-omics
rhythm-omics interplay
interplay related
related to health
to health outcomes.
outcomes. Personalized
Personalized nutrition
nutrition considering
considering an indi-
an individ-
vidual’s
ual’s genome genome and epigenome
and epigenome combined
combined with chrono-nutrition
with chrono-nutrition could contribute
could contribute to the
to the fight fight
against
against non-communicable diseases. Panel (B) Diet, chronotype, and several environmental
non-communicable diseases. Panel (B) Diet, chronotype, and several environmental disruptions of disrup-
tions of modern societies can impact the integration of circadian-triggering metabolic alterations
modern societies can impact the integration of circadian-triggering metabolic alterations and lead the
and lead the development of chronic disease mitigation.
development of chronic disease mitigation.

Abbreviations:
Author Contributions: M.F. and E.V. conceived this manuscript. M.F., E.A. and S.N. carried out the
SCN: suprachiasmatic nucleus, MetS: metabolic syndrome, SNPs: single-nucleotide, polymor-
search of the literature. The manuscript was drafted by M.F., E.V. and L.S. contributed to editing the
phisms: GM: gut microbiome, SCFAs: short-chain fatty acids, BMI: body mass index, HOMA: ho-
manuscript. All authors have read and agreed to the published version of the manuscript.
meostatic model assessment, MUFA: monounsaturated fatty acids, HOMA-IR: model assessment
of insulin
Funding: resistance,
This researchHFD: high-fat
received diets, NCDs:
no external non-communicable diseases.
funding.

Author Contributions: M.F. and E.V. conceived this manuscript. M.F., E.A. and S.N. carried out the
search of the literature. The manuscript was drafted by M.F., E.V. and L.S. contributed to editing
the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Int. J. Mol. Sci. 2023, 24, 2571 12 of 17

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: M.F. was supported by Fondazione Umberto Veronesi.
Conflicts of Interest: The authors declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential conflict of interest.

Abbreviations
SCN: suprachiasmatic nucleus, MetS: metabolic syndrome, SNPs: single-nucleotide, poly-
morphisms: GM: gut microbiome, SCFAs: short-chain fatty acids, BMI: body mass index, HOMA:
homeostatic model assessment, MUFA: monounsaturated fatty acids, HOMA-IR: model assessment
of insulin resistance, HFD: high-fat diets, NCDs: non-communicable diseases.

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