The Effect of Diet on the Cardiac Circadian Clock in Mice: A Systematic Review

Circadian rhythms play important roles in regulating physiological and behavioral processes. These are adjusted by environmental cues, such as diet, which acts by synchronizing or attenuating the circadian rhythms of peripheral clocks, such as the liver, intestine, pancreas, white and brown adipose tissue, lungs, kidneys, as well as the heart. Some studies point to the influence of diet composition, feeding timing, and dietary restriction on metabolic homeostasis and circadian rhythms at various levels. Therefore, this systematic review aimed to discuss studies addressing the effect of diet on the heart clock in animal models and, additionally, the chronodisruption of the clock and its relation to the development of cardiovascular disorders in the last 15 years. A search was conducted in the PubMed, Scopus, and Embase databases. The PRISMA guide was used to construct the article. Nineteen studies met all inclusion and exclusion criteria. In summary, these studies have linked the circadian clock to cardiovascular health and suggested that maintaining a robust circadian system may reduce the risks of cardiometabolic and cardiovascular diseases. The effect of time-of-day-dependent eating on the modulation of circadian rhythms of the cardiac clock and energy homeostasis is notable, among its deleterious effects predominantly in the sleep (light) phase and/or at the end of the active phase.


Introduction
The rotation of the Earth on its axis is marked by a light phase and a dark phase, both with distinct temperature and radiation conditions. This light/dark cycle (LD) is interpreted through the circadian system, represented by a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and peripheral clocks distributed in other regions of the brain and peripheral organs [1][2][3]. Each nucleated cell has a clock, which adjusts itself through external or internal clues also called zeitgebers (ZT).
The central clock is adjusted daily by light, the main environmental cue. In this way, the central clock sends signals to the peripheral clocks, thus synchronizing their circadian rhythms [4,5]. The cellular clock machinery is represented by transcriptional, translational, and post-translational events, loops of positive and negative feedback, performed by a set of genes. The genes encoding the clock mechanism include Clock and Bmal1 (positive loop) and Per1/2/3 and Cry1/2 (negative loop) [5].
In mammals, the circadian clock influences practically all physiological and behavioral aspects, such as the sleep-wake cycle, body temperature, energy metabolism, and the physiology of various organs. [6]. Using the heart as an example, about 6 to 13% of its transcriptome can be controlled by the clock [7,8].
Considering peripheral oscillators, the role of external cues in modulating circadian rhythms is already well described. Food is considered an important synchronizer for peripheral clocks [9,10], as well as metabolism, which has an important effect on both central and peripheral clocks [11] Thus, restricted feeding (RF) to a certain period profoundly affects the physiology and behavior of animals. Among these changes, one may mention changes in locomotor activity, body temperature, food anticipatory behavior, and hormonal secretions [12]. Studies on rodents have shown the beneficial effects of RF on metabolic pathways [13,14].
Mice fed control or high-fat diet (HFD) by RF only in the dark phase showed increased fatty acid oxidation in cardiac muscle, stimulation of fatty acid-responsive genes, improvement of myocardial contractile function, and no alteration in cardiac hypertrophic. RF in wakefulness resulted in metabolic flexibility for cardiac lipid metabolism [15].
Thus, it is important to investigate the relationship between diet and the circadian clock. Changes in the functioning of the clock by environmental signals, especially food, can lead to a better or worse functional picture of physiological and behavioral processes.
In light of the above, this systematic review aims to discuss studies that address the effect of diet on the heart clock in mouse models and the chronorupture of the clock and its relationship to the development of cardiovascular disorders in the last 15 years.
For the purpose of this study, the most current publications, produced between 2007 and 2022, were considered. This was considered important, considering the evolution of studies in the area. The database search was performed by two researchers: A.B.R.P. and L.T.R. Both researchers read and selected the articles. In cases of conflict, the articles were reevaluated by the same two researchers, A.B.R.P. and L.T.R.
Duplicates were removed before screening the articles retrieved. Before establishing the first selection, the pre-defined criteria according to PICOS ("Population", "Intervention", "Comparison", "Results", and "Study Design") were adopted as inclusion criteria to elect the articles ( Table 1). The online software Rayyan (https://www.rayyan.ai/ accessed on 3 August 2022) was used to select the articles. A detailed search flowchart ( Figure 1) illustrates articles that have been shown to meet the established eligibility criteria. The study protocol was registered in the international database PROSPERO with the reference CRD42022360982.
After reading the articles, the information was recorded in a catalog file for each study, which contained the following data: title, publication year, population, study objective, methodology, intervention, results, and conclusion. Only the most relevant data for the construction of this article were cataloged; from this summary, data were used in order to synthesize the results. "Intervention", "Comparison", "Results", and "Study Design") were adopted as inclusion criteria to elect the articles ( Table 1). The online software Rayyan (https://www.rayyan.ai/ accessed on 3 August 2022) was used to select the articles. A detailed search flowchart ( Figure 1) illustrates articles that have been shown to meet the established eligibility criteria. The study protocol was registered in the international database PROSPERO with the reference CRD42022360982.

Quality Assessment of Studies
The risk of bias (RoB) was assessed for each study by "SYRCLE's RoB tool" [17]. This tool was based on the Cochrane Collaboration RoB Tool and it aims to assess the methodological quality in animal experiments. The quality assessment was performed by two researchers and disagreements were resolved between them.

Literature Data
The database search returned 414 articles, 51 from PubMed, 61 from Scopus, and 302 from Embase. Duplicate articles removed prior to screening were 99, leaving 317. Inclusion and exclusion criteria were applied according to PICOS. A total of 59 articles were selected, of which 40 were excluded: publication type, results, and study design. Thus, 19 studies that met all inclusion and exclusion criteria were contemplated ( Figure 1).
Normal diet (ND, D12450B, fat content 10%; Research Diets Inc., New Brunswick, NJ, USA) or HFD (D12492, fat content 60%) The animals were fed normal diet or HFD for 6 weeks until mating, during gestation and lactation (until day 16 of lactation). On day 16 of lactation, both groups were fed ND. The pups were suckled until day 21 of life and then fed ND until the day of euthanasia.
Gene and protein expression by qPCR and Western blot, respectively; measurement of the body weight; serological analyses.
To investigate the effect of the short-term, mild CR before induction of experimental MI to protect the heart from ischemic injury and to understand the underlying molecular pathways.
Regular chow diet or CR (30% less than the calculated mean daily AL food consumption) Mice were fed ad libitum, stressed AL diet, or CR diet for 7 days, prior to MI via permanent coronary ligation and then euthanized. To investigate molecular mechanisms generated by shifting feeding to the rest phase and how this environmental cue alters the expression of circadian clock components, thereby leading to obesity and metabolic syndrome-like pathology.

Control diet
Mice were fed with a control diet ad libitum or RF during the 12 h light phase (ZT0-ZT12) under LD 12h:12h.
Oishi et al., 2017 [29] Male C57Bl/6J mice To investigate the involvement of feeding cycle-dependent endogenous insulin rhythms in the circadian regulation of peripheral clocks, and the effect of exogenous insulin on the expression of clock genes.
Mice were fed HFSD for 8 h during nighttime (ZT14-22) or daytime (ZT2-10) for one week. After this period mice were euthanized and the tissues were collected.
Measurement of blood hormones; gene expression by qPCR; assay of phosphorylated AKT; wheel-running activity analyses. Mice were fed with a high-fiber diet or acetate supplementation for 3 weeks before sham or DOCA surgery.
Morphological analyses in the heart, kidney, and lung; histological analyses in the heart and kidney; bioinformatic analyses; renal and cardiac transcriptome; analyses of the composition of the gut microbiota. Female mice were fed with normal chow diet for 7 days, following DRF or NRF for 7 or 36 days. They were submitted to LL for 9 days, following DRF and LL for 9 additional days. Male mice were fed with normal chow diet for 7 days, following DRF or NRF for 7 additional days. After this period, female and male mice were euthanized. Transcriptome and metabolomic profiling; food intake, body weight, and locomotor activity analyses; global profiling of transcripts; untargeted metabolomics; targeted lipidomics; Acyl-CoA quantification by LC/MS; gene expression by qPCR; transcriptome analyses; circadian rhythmicity analyses; phase set and cistrome enrichment analyses; heatmap of expression profile.

EGFP-pA flox mice
To investigate the effect of biotin diet on protein biotinylation in several tissues in the BMAL1-BioID mouse model.
Mice were fed with a biotin-rich diet or chow diet ad libitum for 7 days and then euthanized.
Protein expression by Western blotting; histological analyses; streptavidin blot analysis; biotin labeling assay in vitro; co-immunoprecipitation.
Latimer et al., 2021 [36] Male C57Bl/6J, CBK, CON mice To investigate the effect of time of day of dietary BCAA consumption on physiological responses (cardiac growth) and its pathological implications Low BCAA diet (Teklad TD.150662 custom diet; with leucine, isoleucine, and valine 3-fold lower than the standard diet), high BCAA diet (Teklad TD.170323 custom diet; with leucine, isoleucine, and valine 2-fold higher than the standard diet) or a standard diet (Teklad TD.170323 custom diet).
The dietary intervention occurred acutely and chronically. Acute intervention: mice were fed with an early high BCAA diet or early low BCAA diet, and a late high BCAA diet or late low BCAA diet for 4 h. Chronic intervention: mice were fed with an early high BCAA diet, and a late high BCAA diet for 4 weeks or 6 weeks.
Transverse aortic constriction; CLAMS for evaluation of food/calorie intake, energy expenditure, and physical activity; spectrometry (plasma BCAA levels); quantitative magnetic resonance imaging (lean and fat body mass); gene and protein expression by qPCR and Western blot, respectively; histological evaluation.
WT and Pparα-null mice: similar expression profiles and amplitudes for Per1 and Per3 genes with mean acrophase of ZT11.4 and ZT10.6, respectively (liver, BAT, and eWAT) reflecting a 10 h time difference from Bmal1 and Npas2. WT mice fed regular diet: higher Bmal1 and Per2 mRNA expression levels in CT20 and CT8, respectively. Lower levels in CT8 and CT20, respectively.
ApoE −/− mice fed HFD: higher levels of Bmal1 and Per2 mRNA in CT0 and CT12, respectively. Lower levels in CT12 and CT0, respectively. No changes in Cry1 mRNA expression levels in both genotypes on regular diet.
(−) WT mice with RF: altered expression of clock genes (Bmal1, Per2, Cry2, and Rev-Erbα) and clock-controlled genes (Dbp); lower and less consistent effects on the phases of clock component and output gene oscillations; average phase shifts and repression of amplitude were 3.90 ± 0.83 h and 54 ± 5%, respectively.
WT mice with RF: changes in expression of clock genes (Bmal1, Per2, Cry2, and Rev-erbα) and clock-controlled genes (Dbp); dramatic phase shifts in gene expression of clock components and output genes (liver); phase differences within the range of 6 and 11 h (mean 8.38 ± 0.84 h) (liver); smaller and less consistent effects on phase shifts of clock and output gene components (epididymal fat and gastrocnemius muscle); average phase shifts and repression of amplitude were 6.88 ± 2.06 h and 69 ± 3% (epididymal), 3.46 ± 1.41 h and 24 ± 20% (gastrocnemius muscle), respectively. (−) High-fat diet Wang et al., 2015 [28] P17 pups from HFD-fed dams: higher mRNA levels of Bmal1 in ZT1 with a circadian pattern and oscillates in antiphase for the Per2 gene. P35 pups from HFD-fed dams: improved phase changes while maintaining amplitude defects.
P17 pups from HFD-fed dams: Fas exhibited a rhythmic expression pattern in control animals, which peaked at ZT9, the late stage of the light phase. Pgc-1α exhibited a significantly rhythmic and lower expression (liver). P35 pups from HFD-fed dams: abolished the circadian expression rhythm of Fas and Pgc-1α (liver). (−) Restricted feeding Noyan et al., 2015 [22] WT mice under short-term CR: modulation in the mRNA profiles of pre-MI genes associated with the circadian clock.
WT mice under short-term CR: global change in gene expression associated with oxidative stress, immune function, apoptosis, metabolism angiogenesis, cytoskeleton and extracellular matrix.
(+)  Female mice on RF for 36 days: phase-locked to LD cycles. Female mice on LL cycle for 9 days: reversed the phase of clock genes. Cardiac transcriptome showed resistance in phase drag by reversed feeding and the fatty acid rhythm was entrained.
Female mice on RF for 36 days: phase shift of clock genes similar to animals on 7 days RF (liver and adipose tissue). Female mice on LL cycle for 9 days: increased the behavioral rhythm by 1.7 h, and did not change the phase of clock genes (liver). Induced oscillations in clock genes (adipose tissue); reversed the phase of clock genes (kidney). The liver and adipose tissue transcriptomes were entrained by the reversed feeding.
The kidney transcriptome is more resistant to phase drag by reversed feeding.  WT and Per2/Tg mice with HFSD: increased body weight, plasma insulin, total cholesterol, and insulin/glucose ratio. PAI-1 mRNA expression levels did not differ. Per2/Tg with HFSD or ND mice: dampening of PAI-1 expression rhythms in the heart. Jcl:ICR mice with KD: reduced body weight and glucose levels, increased plasma levels of FFA and total ketone bodies, increased PAI-1 mRNA levels (heart and liver) with advanced acrophase to 4.7 h (heart), 7.9 h (kidney), and 7.8 h (epididymal fat), and led to phase advancement of the endogenous circadian clock that governs rhythmic behavior. Pparα-null mice fed KD: decreased BW, plasma FFA levels, and total ketone bodies; induced fatty liver; and increased hepatic total cholesterol levels. WT mice fed KD: increased circadian expression of PAI-1 mRNA (heart and liver). Benzafibrate: induced the expression of the Pai-1, Cy4A10, and Fgf21 genes in a PPARα-dependent manner. WT mice on RF: changes in whole-body energy balance, higher food intake during DP, little influence on physical activity rhythms, diurnal variation in plasma glucose and triglyceride levels, body weight gain, and tissue-specific changes in metabolic genes (Accα, Glut2, Lpk, Lgs, Mcad, Dgat2, Acsl1, Atgl, Lipe, Mcp1, Glut4, Pdk4). WT mice with high-fiber diet: altered the composition of the gut microbiota and increased acetate levels. WT mice supplemented with acetate: altered the composition of the intestinal microbiota and increased the percentage of acetate-producing bacteria. WT mice with high-fiber diet and acetate: reduced systolic and diastolic BP levels, altered the renal transcriptome (Rasal1, Cyp414, and Cck) of genes related to renal fibrosis, fluid absorption through sodium channel regulation, anti-inflammatory action, and the cardiac transcriptome (Tcap and Timp4) of genes related to cardiac diseases, pathways acting on cell cycle, replication, translation, mRNA metabolism, respiratory electron chain, mitogen-activated protein kinase signaling, and renin-angiotensin system.

(+)
Low-phosphate diet Noguchi et al., 2018 [34] Mice with hypophosphatemic diet: increased total cartilage volume fraction, reduced TMD and BV/TV, increased osteochondromic progenitor lineage and impaired chondrocytes, reduced the size of proliferative matrix-forming cells, and affected systemic regulation of mineral metabolism. Transcriptome analyses revealed that 1.879 genes associated with diet and having a circadian pattern of regulation, those with mitochondrial function, including oxidative metabolism and canonical regulatory pathways associated with apoptotic signaling.

(N)
High-fat diet Mia et al., 2020 [31] HFD increased body weight, adiposity, daily energy expenditure, reduced physical activity, and RER, increased stroke volume, left posterior ventricular wall thickness during systole, the BVW/TL ratio, cardiomyocyte area, cardiac fibrosis, and altered the temporal regulation of the cardiac transcriptome, especially of metabolism-related genes. Day-night differences affected cardiac glucose oxidation, lactate release, and the cardiac lipidome. The diurnal rhythms of lipid metabolism genes (Cd36, Mcd, Lcad, and Lipe) and plasma levels were altered. Time-of-day-restricted feeding restored body metabolic rhythms, normalized the adverse effects of cardiac remodeling (BVW/TL ratio, cardiomyocyte size, cardiac fibrosis, cardiac steatosis), and increased the day-night difference in cardiac lipid metabolism. (−)

Quality Assessment of Studies
All the included studies in the systematic review had inappropriate random sequence generation. Overall, the studies presented a high risk for selection bias (random sequence generation, baseline characteristics, and allocation concealment), performance bias (random housing and blinding of participants and personnel), and detection bias (random outcome assessment and blinding of outcome assessment). Attrition bias (incomplete outcome data) was intermediate. Reporting bias (selective reporting) was low. The results of the risk of bias in the included studies are shown in Figure S1.

Discussion
Light is an important environmental cue in dragging biological rhythms. However, other cues are capable of adjusting circadian rhythms, such as diet. Some studies point to the influence of diet composition, meal timing, and dietary restriction on metabolic homeostasis and circadian rhythms at various levels. Understanding the mechanisms underlying these influences will likely provide important insights into the pathogenesis of diet-associated cardiometabolic disorders.
Feeding is a strong synchronizer for the peripheral clocks, as is the timing of the day feeding. Given this, we sought to include in this review studies that evaluated the effects of restriction feeding (RF) on clock genes. RF is characterized by a limited period and duration of food access without caloric reduction. Some studies have evaluated the effects of dietary restriction on the expression of clock genes [17,18,24,27,33]. Bray et al. [20] sought to understand the effect of RF in the dark phase in male C57Bl/6J mice. The authors observed markedly different diurnal variations among those animals that consumed the diet in the dark phase compared to those in the light phase. The animals fed in the light phase consumed a larger amount of food immediately after accessing the diet, whereas those in the dark phase did not show the same response. The authors observed that the heart's circadian clock genes did not change phase, but the amplitude of oscillations of clock gene expression was often decreased in this organ. Such findings were observed in adipose tissue and skeletal muscle as well, whereas, in the liver, there was a phase shift of circadian clock genes in those mice fed in the light phase. These results suggest that entrainment-induced feeding is more robust in the liver, and RF in the light phase led to a desynchronization between metabolically active tissues. Furthermore, the authors point out that RF, in the dark phase, resulted in increased caloric intake, reduced energy expenditure, and dependence on fatty acid oxidation. Additionally, Goh et al. [18], when investigating the effects of RF on clock genes, found that access to dietary restriction led to phase shifting in the peripheral clocks of wild-type animals. In this same assay, using PPARα-deficient mice, they observed significant modulation in the heart muscle clock, shifting the acrophase of circadian gene expression by up to an additional 8 h. They observed that dietary restriction reduced the amplitude of expression of Bmal1 and Rev-Erbα genes in WT and homozygous Pparα-null (Pparα-null) mice, respectively, and increased Bmal1 in Pparα-null mice, whereas, under ad libitum conditions, the amplitude and acrophase of clock genes were similar in both genotypes. These knockout animals showed altered cardiac metabolism using glucose as an energy source, leading to loss of contractile function and decreased energy reserves. Under prolonged fasting conditions, these animals developed hypothermia, due to the altered brown adipose tissue (BAT). These findings may be linked to the current observation that BAT and cardiac tissue from Pparα null mice showed altered circadian food transcription factor gene expression.
Reilly et al. [19] investigated the possibility of catecholamines to modulate the rhythmicity of peripheral clocks in dopamine β-hydroxylase knockout mouse models (Dbh −/− ) under RF during the light phase. This model is characterized by the non-expression of the enzyme dopamine B-hydroxylase, which takes part in catecholamine biosynthesis [37]. They observed that endogenous concentrations of the catecholamines, norepinephrine, and epinephrine, exerted no effect on the function of peripheral circadian clocks in vivo, among them, the heart. On the contrary, feeding time was shown to be an important modulator of peripheral circadian oscillators.
Despite this, they did not study the effect of the RF; Noyan et al. [22] worked with short-term caloric restriction (CR) (30% less of total calories) and investigated its protective effect on ischemic mouse hearts. CR caused a change in gene expression. Bioinformatics analyses showed enriched pathways associated with antioxidant processes, circadian rhythms, and the biological clock. Moreover, short-term CR resulted in increased expression of the clock genes, Per1 and Per2. Studies point to the involvement of clock genes in physiological processes such as energy balance, coordinating and modulating energy metabolism, transcription, signaling, and contractile functions in the heart [38]. In view of this, heart clock genes may be associated with the beneficial effects of calorie restriction [39]. Further, studies point to the protective effect of the Per2 gene in myocardial ischemia [40]. Therefore, cardiac clock genes may be involved in mechanisms protecting the heart against ischemia associated with short-term CR by adapting cellular metabolism.
Mukherji et al. [21], however, sought to understand the effect of switching feed from the active to the resting phase (RF condition) on peripheral clock genes. After 8 days of RF in the resting phase, transcript analyses of cardiac clock components showed that the clock genes Per1, Per2, and Rev-Erbα were affected by this condition. RF led to an extra production of corticosterone. Notwithstanding, under ad libitum conditions, endogenous corticosterone did not affect Rev-Erbα expression in the heart, since they were at basal levels. Subsequently, in the 4 days of RF, there was a delay in Rev-Erbα expression and, consequently, a delay in peripheral clock shift. Administration of the glucocorticoid antagonist RU486 or adrenalectomy led to early activation of PPARα in the heart, consequently, stimulating Rev-Erbα expression. The authors concluded that the change in clock gene components under RF conditions is associated with metabolic reprogramming that directly affects circadian clock expression. In the study by Xin et al. [23], they evaluated the effects of reverse feeding in peripheral tissues on metabolism and circadian physiology in mice, among them, the heart. The diurnal rhythms of the clock genes in the heart exhibited a phase shift from 0-3 h. On the other hand, when comparing male and female mice, the diurnal rhythms were damped by RF in male mice. That is, there is a sex-related difference in clock drag under RF. Even though the authors observed a greater resilience in phase drag by reverse feeding in the heart transcriptome, cardiac diurnal metabolites were dragged within one week. In addition, removing the timing signals from the SCN by exposing the animals to constant light (LL) cycle-facilitated phase drag by feeding in both the heart and the other tissues except the liver. Analyses of the cardiac metabolome showed that reversed feeding dragged the diurnal rhythms of fatty acid oxidation and acylcarnitine metabolites. These findings show that cardiac metabolism is influenced by feeding cycles and the circadian clock.
Some studies evaluated the effects of HFD in WT mice [25,28,32] or knockout models, such as ApoE −/− mice [24], Clock ∆19/∆19 mice [30], and cardiomyocyte clock mutant (CCM) mice [27], as well as a transgenic model that overexpresses PER2 [26]. Hou et al. [24] investigated the effect of hyperlipidemia induced by an HFD on the expression of clock genes in ApoE-deficient mouse model of atherosclerosis (ApoE −/− ). The authors observed that diet affected the peripheral circadian clocks, but had no effects on the central clock.
In the cardiac circadian clock, the peak mRNA levels of the clock genes, Bmal1, Per2, and Cry1, showed a four-hour delay in the onset of the subjective dark period in knockout animals, independent of diet, reinforcing that apolipoprotein E (ApoE) is involved in the expression of these genes. The same phenomenon was observed for plasma lipid levels, having a peak at the onset of the dark period, CT12, in ApoE −/− mice fed with HFD, with no variation in serum levels for WT mice. The authors point out that these variations in serum lipid levels possibly affected the expression of circadian clock genes, mediated by the transcription factors PPARα, retinoid X alpha receptor (RXRα), and REV-ERBα. This circadian disruption associated with the absence of ApoE may be related to the development of atherosclerotic processes and some acute cardiovascular diseases, as pointed out by more recent studies [41][42][43].
Mia et al. [31] sought to evaluate the effect of HFD diet-induced obesity on cardiac metabolic flexibility. Of note, metabolic flexibility is characterized by the adaptation to metabolic and energetic changes in response to physiological stimuli. The authors observed that HFD-induced obesity resulted in increased body weight and adiposity, and altered the 24-h rhythms of body substrate selection during the LD cycle. However, the oxidation of glucose and/or fatty acids by cardiomyocytes during the LD cycle was preserved. That is, metabolic flexibility is preserved for cardiac substrate oxidation in high-fat-fed mice. This diet also stimulated markers related to cardiac hypertrophy, cardiac fibrosis, and steatosis. RNA-sequencing (RNAseq) analyses evidenced diurnal changes in the cardiac transcriptome, particularly, in metabolism-related genes, with only 22% of transcripts unaffected by HFD. Importantly, of the transcripts that were not affected, the clock genes, Bmal1, Clock, Npas2, Nr1d1, Nr1d2, Per2, Per3, and Cry2 stand out. According to the authors, there is the possibility that the heart clock orchestrates the persistent day-night differences in cardiac oxidative metabolism during obesity. In lipid metabolism, triglyceride synthesis was impaired by obesity, which was associated with attenuation in day-night fluctuations of cardiac lipidome. At another time, the authors investigated the effect of RF with HFD in the dark phase only. RF restored the changes in lipid metabolism and cardiac remodeling. Given this, a detrimental effect of HFD-induced obesity on the metabolic flexibility of lipid metabolism is evidenced, and it is, in turn, partially reversed by modulating the timing of food intake. Reitz et al. [30], meanwhile, evaluated whether HFD-fed Clock ∆19/19 mice develop cardiovascular disease since this diet, in this model, results in metabolic syndrome and obesity, risk factors for cardiovascular disorders. In spite of the fact that the animals exhibited a cardiometabolic risk profile, surprisingly, they did not develop cardiac dysfunction and showed preserved cardiac structure and function. Microarray and bioinformatics analyses revealed a pattern of antioxidant activity associated with increased serum levels of the enzymes cardiac catalase (CAT) and glutathione peroxidase (GPx) and the Ppary gene expression, and reduced activation of oxidative stress-related pathways. These findings demonstrate the important role of circadian mechanisms in mediating resilience to cardiovascular disease outcomes. These studies [31,32] only reinforce the influence of the clock on metabolic homeostasis, since, under a condition of circadian chronorupture, there is impaired cardiac metabolism, but the cardiac function is maintained. Studies point out that even under conditions of a non-intact circadian mechanism, cardiac remodeling can be enhanced. However, it is important to note that circadian mechanisms are important since the genes and proteins involved in the observed outcomes are under circadian transcriptional control. Tsai et al. [27] studied the role of the cardiac circadian clock in cardiac metabolic adaptation under HFD for 16 weeks. For this, the authors used a mouse model, in which, CLOCK protein expression is selectively impaired, termed the cardiomyocyte clock mutant (CCM) mice. The animals showed an altered myocardial response to HFD, as well as altered diurnal rhythms of triglyceride and fatty acid metabolism. The diurnal rhythms of myocardial triglyceride levels were markedly attenuated in the heart of the CCM mice, which was associated with circadian mechanisms mediating the regulation of lipolysis over synthesis. Nonetheless, when subjected to an RF condition, the heart lipid metabolism responded differently. Feeding at the end of the active phase resulted in myocardial steatosis with a greater propensity for triglyceride synthesis.
Wang et al. [28] evaluated the effects of HDF-induced maternal obesity on clock and metabolism genes in the liver and heart of their offspring. In this study, they evaluated the pups at two time points, pups with 17 days of age (P17) and pups with 35 days of age (P35). The authors observed that HFD during pregnancy and lactation strongly impacted the expression of clock genes, metabolism genes, and inflammatory pathways in both the heart and liver. In the heart, Bmal1 and Per2 genes showed a robust oscillation compared to the metabolism genes carnitine palmitoyltransferase 1b (Cpt1b) and Pparα, which was associated with the early developmental stage of HFD pups. That is, the phase and amplitude changes were more expressive in the pups at 17 days postnatal of HFD-fed female mice. The expression of genes in inflammatory processes was higher in P17 proles from obese females. As for metabolism genes, there was a difference in the pattern of oscillation between the P17 and P35 groups. The authors associated the maternal cues during the first postnatal weeks, whereas, the more "mature" pups (P35) were already influenced by feeding, with peripheral clocks being adjusted by the feeding schedule, in addition to food intake being an important environmental cue for dragging circadian rhythms of peripheral clock genes [9]. Furthermore, diet composition and the prenatal microenvironment would strongly affect the oscillation pattern of circadian rhythms in the heart [28].
Oishi and colleagues have developed studies involving the combination of a high-fat, high-sucrose diet [19,28] on fibrinolysis [19] and on the effect of endogenous insulin [29] at two time points. In the study [26], Oishi et al. [19] evaluated the role of PER2 in plasminogen activator inhibitor-1 (PAI-1) gene expression in a transgenic mouse model overexpressing Per2 (Per2/Tg) and WT mice, both with and without obesity induced by a high-fat/high-sucrose diet (HFSD). HFDS-fed animals showed body weight gain, hypercholesterolemia, and hyperinsulinemia and developed insulin resistance in both genotypes, but did not have their plasma triglyceride levels increased. However, these findings did not differ significantly between the groups. Therefore, the authors suggest that the PER2 protein has no involvement in the metabolic regulation of obese animals induced by an HFSD diet. The PAI-1 gene was suppressed in the heart of Per2/Tg animals, regardless of diet type. This was associated with higher cardiac Per2 gene expression since no PAI-1 gene suppression and no change in Per2 mRNA levels was observed in adipose tissue and liver. However, the expression levels of Bmal1 mRNA were not altered in the heart of Per2/Tg mice, but its attenuation was observed in the liver and adipose tissue. Since PAI-1 levels oscillate over the 24-h rhythm in various organs, such as the liver, adipose tissue, and heart [44], the findings of this study suggest that components of the circadian machinery are strongly involved in regulating its expression in the heart. In summary, diet-induced obesity increases PAI-1 levels, but its transcription is suppressed by the Per2 gene. In 2017, Oishi et al. [29] conducted interventions with the same diet, HFSD. In this study, the authors investigated the effect of endogenous insulin dependent in the feeding cycle on the regulation of peripheral clocks. The animals were fed either in the light phase or in the dark phase for one week. RF led to the synchronization of the circadian rhythms in the insulin of the hormones, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and hyperinsulinemia in the light period. When analyzing the expression profile of the clock genes, Per1, Per2, and Dbp, no marked influence of light phase feeding on the heart clock was observed. Only the liver was affected concerning the circadian phase of expression. For that reason, the authors concluded that insulin and RF are not dominant ZT for some peripheral clocks, except for the liver. Nevertheless, the exogenous insulin was able to drag the peripheral clocks. Given these findings, humoral signals involved in synchronizing peripheral clocks are unlikely dominant ZT, since they are strongly influenced by some environmental cues, such as temperature, diet composition, meal timing, physical activity, and light [45]. For example, circulating insulin concentrations increase dramatically in response to diets. Therefore, humoral time signals, such as glucocorticoids and insulin, may serve to stabilize rather than phase-determine peripheral clocks in mammals [46]. Some studies [20,23] have assessed the effect of the ketogenic diet (KD), characterized by high concentrations of lipids and low carbohydrate and protein content [47]. Commonly used in weight loss and diabetes, little is known about its effect on cardiovascular health [48]. Oishi et al. [32] investigated the effect of KD on the temporal expression profile of PAI-1 and clock in peripheral tissues, liver, kidney, adipose tissue, and heart. KD led to hypoglycemia, increased FFA and ketone body levels, and a phase advance on clock genes, PAI-1 mRNA levels, and the rate of behavioral activity in ad libitum-fed mice. The mRNA expression acrophases of the Per2 and Dbp genes were advanced by 5.6 and 6.0 h, respectively, in the heart. When transferred from LD to DD, the phase diet advanced the clocks that govern rhythmic behavior. The authors point out that KD exerted an effect similar to that of CR, fasting, and hypoglycemia, which was associated with cellular energy status. In another report, Oishi et al. [25] compared the effect of KD on the temporal expression profile of clock genes (Bmal1 and Rev-Erbα) and clock-controlled genes (Dbp), and on the induction of PAI-1 gene expression in the liver and heart of PPARα-free mice. A phase advance in Bmal1 expression levels and a decrease in mean Dbp gene expression level were observed in the heart of both genotypes. Similar to the 2009 study [32], Oishi et al. [25] again observed a phase-advancing effect on the rate of behavioral activity in KD-fed animals, independent of PPARα, when transferred from an LD to a constant darkness (DD) condition. They showed that PPARα does not influence the phase-advancing effect on the rate of expression in clock genes and peripheral behavioral activity. This phase change of the KD-induced circadian clock may be influenced by the cellular energy status, such as the ratio of reduced and oxidized nicotinamide adenosine dinucleotide energy [NAD(P)H/NAD(P)+] [49]. Energy homeostasis is maintained by AMP kinase (AMPK), which is activated by some factors such as CR, fasting, hypoglycemia, and KD [50]. Its activation induces PER2 degradation, activating casein kinase Iε, leading to a phase advancement of the circadian clock in vitro [50]. Thus, activated AMPK may be involved in mediating circadian rhythms induced by KD clock regulation in tissues.
Finally, we found reports on other dietary profiles, such as low/high-branched chain amino acids (BCAA) diet [35], high-fiber diet associated with acetate supplementation [33], biotin-rich diet [35], and low-phosphate diet [34]. Latimer et al. [36] observed that the time of day of BCAA intake influences cardiac parameters, which was associated with the circadian clock of the heart. WT mice that consumed a BCAA-rich meal at the end of the active phase (dark phase) revealed cardiac remodeling and influence on cardiometabolic parameters, with increased responsiveness of BCAA-induced mechanistic target of rapamycin (mTOR), the signaling pathway involved in cardiac hypertrophy [51]. However, cardiomyocyte-specific Bmal1 knockout (CBK) lost these time-of-day-dependent differences in BCAA-induced activation of mTOR signaling. Components of BCAA metabolism, such as cardiac amino acid levels, ribosomal RNA, and DEP domain-containing mTORinteracting protein (DEPTOR), a repressor of mTOR activation, showed significant 24-h cardiac clock-dependent oscillations in WT animals. In CBK animals, on the other hand, repression of BCAA catabolism genes was observed, leading to increased cardiac BCAA levels and, ultimately, an exacerbated activation of mTOR signaling and cardiac hypertrophy.
Macro-and micronutrient content and sources have a strong impact on health and the risk of developing chronic non-communicable diseases [52,53]. For example, fruit and vegetable consumption are related to a lower incidence of diabetes, hypertension, and metabolic syndrome. In the study by Marques et al. [33], the effect of a high-fiber diet and acetate supplementation on the gut microbiota, and the cross-talk between the kidney, liver, and heart in hypertensive mice were investigated. Dietary fiber and acetate positively modified the size and population diversity of the gut microbiome, and also reduced diastolic and systolic blood pressure and renal fibrosis, which was associated with the downregulation of a marker related to cardiovascular disease, renal fibrosis, and inflammation. The authors observed an upregulation of circadian clock genes in the kidney and heart. In other words, dietary fiber and acetate would be acting as ZT for the renal and cardiac circadian clocks, and these, possibly, may be involved in molecular pathways that culminated in improved cardiovascular health and function. However, further studies are needed on the molecular mechanisms involved.
Circadian clocks are important agents in modulating metabolism. Conversely, the mechanism involved is not well defined. The processes of transcription, translation, and post-translational modifications also have circadian regulation. Protein biotinylation is an important post-translational modification for protein activity [54]. Murata et al. [35] described the effect of dietary biotin intake on a brain and muscle ARNT-Like 1 (Bmal1)-BirA* knock-in (Bmal1-BioID) mouse model for protein biotinylation in various tissues.
In order to build the model, the authors used a biotin ligase, BirA*. In addition, BMAL1 protein acts as a transcription factor in clock-controlled genes. Consequently, this mouse model was used to investigate the tissue-specific protein-protein interaction of BMAL1 protein. The biotin-rich diet induced protein biotinylation in the brain and in other tissues such as the heart.
In another study [34], the effect of a low-phosphate diet on the circadian clock of bone tissue and the heart was evaluated. That is, would a condition of hypophosphatemia affect circadian function? The authors observed that the expression levels of clock genes, in the tissues evaluated, were higher in the mice on a low phosphate diet. In the heart, there was phase advancement and significantly higher levels for the Per1, Per2, and Per3 genes; the Bmal1 gene expression peak shifted from ZT24 to ZT21. Therefore, a diet-induced hypophosphatemia condition results in phase shifting for the clock genes. In conjunction, 1.879 genes were associated with diet and showed a circadian expression pattern; among them, there were genes involved in hypoxia signaling in the cardiovascular system and cardiac morphology. Thus, it was suggested that circulating phosphate levels modulate the heart clock and control the circadian functions of the heart.
In summary, studies have linked the circadian clock to cardiovascular health and suggest that maintaining a robust circadian system may reduce the risks of cardiovascular and cardiometabolic diseases. Noteworthy is the effect of the time-of-day-dependent feeding on the modulation of the circadian rhythms of the heart clock and energy homeostasis, its deleterious effects predominantly occurring in the sleep (light) phase and/or at the end of the active phase. Another important point is the composition of the diet in macro-and/or micronutrients, such as fat, carbohydrates, protein, fiber, and minerals. Some of these nutrients may act on molecular and/or metabolic pathways by modulating the circadian clock of the heart and of the other peripheral organs. The circadian clock plays an important role in metabolic regulation, and a disrupted condition may contribute to the development of heart disorders.

Limitations and Future Research
As a limitation of the study, only the articles selected by the three databases were cataloged. Therefore, articles that were not included in the databases were not considered, even those articles that were cited in the selected papers. Moreover, there may be studies that have indirectly evaluated the heart, but due to the restriction of the keywords, they were not found in the databases. According to the articles evaluated, the effect of food restriction on the biological clock is notorious, and it can be harmful or beneficial, depending on the timing of the intervention. This may reflect in the experimental design and outcome of studies and may be another bias for research involving diet, clock, and metabolic parameters. More research is needed in the area in order to better understand the effects of various diets on the biological clock and metabolism.

Conclusions
Based on the findings of this systematic review, it highlights the important role of diet in modulating peripheral clocks, especially the heart, and cardiac metabolism. Furthermore, diet composition and feeding schedule (restricted feeding) can affect cardiac parameters and the expression of clock genes.