Obesity has emerged as a global health crisis, reaching epidemic proportions in recent decades. Defined as excessive accumulation of adipose tissue, obesity is associated with a myriad of metabolic, inflammatory, and cardiovascular complications, posing a significant burden on individuals and healthcare systems worldwide [1]. Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in individuals with obesity, highlighting the urgent need for a deeper understanding of the underlying mechanisms linking obesity to cardiovascular risk [2]. In recent years, there has been growing recognition of the role of circadian rhythms in cardiovascular health and disease. Circadian rhythms, governed by an endogenous biological clock, regulate a wide array of physiological processes, including sleep-wake cycles, hormone secretion, metabolism, and cardiovascular function [3]. Disruption of circadian rhythms, commonly observed in modern society due to factors such as shift work, jet lag, and irregular sleep and eating patterns, has been implicated in the pathogenesis of various chronic diseases, including obesity and cardiovascular disorders [4]. The relationship between circadian rhythms and cardiovascular health is bidirectional, with alterations in circadian timing influencing cardiovascular risk factors and vice versa [5].

In obesity, dysregulation of circadian rhythms exacerbates metabolic dysfunction, inflammation, endothelial dysfunction, and oxidative stress, contributing to the development and progression of CVD [6]. Conversely, cardiovascular risk factors such as hypertension, dyslipidemia, and insulin resistance can disrupt circadian rhythms, further exacerbating cardiovascular risk in individuals with obesity [7]. Key molecular components of the circadian clock, including clock genes and their protein products, play critical roles in coordinating circadian rhythms and modulating cardiovascular function [8]. The circadian clock is driven by a transcription-translation feedback loop involving core clock genes such as Period (PER1, PER2, PER3), Cryptochrome (CRY1, CRY2), CLOCK, and BMAL1 [9]. These clock genes regulate the rhythmic expression of genes involved in lipid metabolism, glucose homeostasis, vascular tone, and endothelial function, thereby influencing cardiovascular health [10]. Moreover, emerging evidence suggests a bidirectional relationship between the gut microbiota and circadian rhythms, with disruption of the gut microbiota composition influencing circadian rhythms and vice versa [11].

Dysbiosis of the gut microbiota, commonly observed in obesity, is associated with altered circadian oscillations of microbial metabolites, increased gut permeability, and systemic inflammation, all of which contribute to cardiovascular risk [12]. Despite the growing body of evidence implicating circadian rhythms in the pathogenesis of cardiovascular risk in obesity, there remains a need for a comprehensive understanding of the underlying mechanisms and potential therapeutic targets. This review aims to provide a comprehensive overview of the circadian mechanisms underlying cardiovascular risk in obesity, synthesizing current evidence from preclinical and clinical studies. By elucidating the intricate interplay between circadian rhythms and cardiovascular health in obesity, we hope to identify novel avenues for therapeutic intervention and improve clinical outcomes for individuals with obesity-associated CVD. Obesity represents a significant risk factor for CVD, and circadian rhythms play a crucial role in modulating this risk. Understanding the complex interplay between circadian mechanisms and cardiovascular health in obesity is essential for developing targeted interventions to reduce cardiovascular morbidity and mortality in this high-risk population. This review aims to provide a comprehensive synthesis of current knowledge in this field and identify promising avenues for future research and clinical practice.

The circadian system plays a critical role in regulating various metabolic processes, ensuring their temporal alignment with the daily light-dark cycle. These metabolic processes include glucose homeostasis, lipid metabolism, energy expenditure, and thermogenesis, among others. Circadian disruption, often observed in modern society due to factors such as shift work, jet lag, and irregular sleep patterns, has been implicated in the pathogenesis of metabolic disorders, including obesity, type 2 diabetes, and CVD. Understanding the circadian regulation of metabolic processes is essential for elucidating the underlying mechanisms of metabolic disorders and developing targeted therapeutic interventions. Circadian rhythms govern the temporal regulation of glucose metabolism, influencing glucose production, utilization, and storage. Key regulators of circadian glucose homeostasis include the clock genes, insulin signalling pathways, and clock-controlled transcription factors. The liver plays a central role in maintaining glucose homeostasis, with circadian rhythms orchestrating the rhythmic expression of genes involved in gluconeogenesis, glycogenolysis, and glucose uptake [13]. Disruption of circadian rhythms, as seen in shift workers and individuals with irregular sleep patterns, can lead to dysregulation of glucose metabolism, insulin resistance, and impaired glucose tolerance [14]. Chronically disrupted circadian rhythms have been associated with an increased risk of developing type 2 diabetes [15]. Circadian rhythms also regulate lipid metabolism, including the synthesis, storage, and utilization of lipids. Key enzymes involved in lipid metabolism, such as fatty acid synthase, acetyl-CoA carboxylase, and hormone-sensitive lipase, exhibit circadian oscillations in their expression and activity [16]. Circadian control of lipid metabolism is mediated by the clock genes and their downstream targets, which regulate lipid synthesis, oxidation, and transport [17]. Disruption of circadian rhythms, as observed in shift workers and individuals with irregular sleep patterns, can lead to dyslipidemia, characterized by elevated levels of triglycerides, low-density lipoprotein cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol [18]. Dyslipidemia is a major risk factor for CVD and is commonly observed in individuals with metabolic disorders such as obesity and type 2 diabetes.

Circadian rhythms also play a role in regulating energy expenditure and thermogenesis, influencing body weight and metabolic rate. The circadian clock regulates the rhythmic expression of genes involved in mitochondrial function, oxidative phosphorylation, and thermogenic pathways [19]. Disruption of circadian rhythms, as seen in shift workers and individuals with irregular sleep patterns, can lead to alterations in energy expenditure, favoring energy storage over expenditure [20]. Chronically disrupted circadian rhythms have been associated with an increased risk of obesity and metabolic syndrome [21]. Understanding the circadian regulation of metabolic processes has important implications for the development of novel therapeutic interventions for metabolic disorders. Chronotherapeutic approaches, such as timed feeding, light exposure, and pharmacological modulation of clock genes, hold promise for restoring circadian rhythms and improving metabolic health [22]. Lifestyle interventions aimed at promoting regular sleep-wake patterns and optimizing circadian alignment may also have beneficial effects on metabolic parameters [23]. Furthermore, targeting specific components of the circadian clock and metabolic pathways may offer novel therapeutic strategies for the treatment of metabolic disorders. The circadian system plays a critical role in regulating metabolic processes, including glucose homeostasis, lipid metabolism, energy expenditure, and thermogenesis. Disruption of circadian rhythms has been implicated in the pathogenesis of metabolic disorders, including obesity, type 2 diabetes, and CVD. Understanding the circadian regulation of metabolic processes has important implications for the development of novel therapeutic interventions for metabolic disorders. Further research is needed to elucidate the underlying mechanisms of circadian regulation of metabolism and to develop targeted therapeutic strategies for improving metabolic health.

The circadian system plays a crucial role in synchronizing energy homeostasis with the day-night cycle, thereby exerting significant control over body weight and metabolic health. The suprachiasmatic nucleus (SCN), as the master pacemaker, orchestrates the circadian regulation of metabolism through both direct and indirect mechanisms, including the release of hormones such as melatonin and cortisol, as well as the timing of feeding schedule, activity, and sleep [24]. During the daytime, when individuals are typically active and consume food, metabolic processes are geared towards energy utilization and storage. Glucose is metabolized for energy, while excess glucose is converted into glycogen and stored in the liver and muscles [25]. Additionally, lipid synthesis and storage are stimulated by increased insulin secretion, promoting the esterification of fatty acids in adipose tissue [26]. This process may involve the activation of lipoprotein lipase in adipocytes, facilitating the uptake of circulating lipids [27]. Hormonal regulation also contributes to the daytime metabolic state, with appetite-promoting hormones such as ghrelin being elevated, while levels of the satiety hormone leptin are decreased [28,29]. This hormonal milieu promotes food intake during daytime hours, supporting the energy demands associated with increased activity and metabolic rate [30]. Furthermore, energy expenditure is typically elevated during the daytime, reflecting the heightened metabolic activity and physical exertion [31]. Consistent with this diurnal pattern of metabolic activity, gut function is also enhanced during the daytime. Increased gut motility and secretion facilitate the digestion and absorption of nutrients from ingested food, ensuring efficient nutrient utilization and energy acquisition [32]. Daytime is the active period during which food is consumed, glucose is metabolized, and fat is stored in adipose tissue (Figure 1). Therefore, elevated insulin secretion stimulates glycogen synthesis and promotes lipid synthesis and esterification of fatty acids in adipose tissue, potentially through the activation of lipoprotein lipase in adipocytes. Appetite-regulatory hormones drive eating during the day, as evidenced by elevated levels of the appetite-promoting hormone ghrelin and decreased levels of leptin, the hormone associated with satiety. Energy expenditure also increases during this time. In line with this oscillatory pattern, gut activity is heightened during the daytime.

The circadian regulation of metabolism ensures that energy intake, expenditure, and storage are appropriately synchronized with the day-night cycle. This coordination is essential for maintaining metabolic homeostasis and overall health. Dysregulation of circadian rhythms, such as occurs with shift work or irregular sleep patterns, can disrupt this finely tuned balance and contribute to metabolic dysfunction and associated health consequences [33]. Fat mobilization is particularly pronounced during nighttime hours, leading to increased levels of circulating fatty acids in the bloodstream. This process, known as nocturnal lipolysis, is primarily driven by elevated levels of growth hormone [25]. Additionally, reduced insulin secretion during the night promotes lipolysis, while stimulating the liver to convert glycogen into glucose, which is then released into the bloodstream [26]. Furthermore, glucagon levels rise during the night, further promoting gluconeogenesis [24]. Therefore, the variations in glucose homeostasis are evident during nighttime, characterized by lower glucose tolerance and insulin sensitivity [34]. Endocrine regulation of appetite also undergoes modulation to suppress eating behavior during the biological night, primarily through elevated levels of leptin [35]. Moreover, in addition to decreased physical activity, energy expenditure is attenuated at night [36]. While metabolic compounds and functions exhibit fluctuations across the 24-hour period, the extent to which these oscillatory dynamics are directly governed by the master clock or are modulated by external cues such as sleep or food intake remains a subject of debate. For instance, Begemann et al. [37] demonstrated that diurnal variations in insulin and leptin levels are not primarily driven by the central pacemaker but rather by food intake. The feeding cycle serves as a potent zeitgeber for peripheral timekeepers, capable of entraining rhythms of local clocks and clock-controlled genes in various tissues and organs, including the pancreas, liver, and adipose tissue. Postulated mechanisms underlying the synchronization of peripheral clocks by food intake include the influence of food metabolites such as glucose and fatty acids, appetite-related hormones such as ghrelin, cellular redox state, body temperature, and cellular signaling pathways including SIRT1s, PPARs, and AMPK [38]. Recent evidence in humans has shown that fasting and feeding cycles regulate the phase of adipocyte mRNA expression of core clock genes and energy metabolism genes, including those controlling cholesterol biosynthesis and glucose transport [39].

Moreover, the macronutrient composition of meals can also modulate the expression of both central and peripheral clocks. Transitioning from a high-carbohydrate, low-fat diet to a low-carbohydrate, high-fat regimen has been shown to induce phase-delay and increase the amplitude of the cortisol rhythm (indicative of effects on the central pacemaker) and alter gene expression in blood monocytes, including genes from the PER family and those implicated in the regulation of energy and fat metabolism such as SIRT1, ACOX3, and IDH3A [40]. Overall, these findings underscore the significant role of meal timing and composition in regulating metabolic processes and highlight the intricate interplay between the circadian clock, food intake, and metabolic health. Oxidative stress and circadian rhythm are interconnected in regulating adipose tissue function. The circadian clock governs the rhythmic oscillation of cellular redox functions, while shifts in the cellular redox state can influence the circadian machinery (Figure 2). Oxidative stress arises when the production of oxidant molecules surpasses the antioxidant capacity to counteract them. It is known that the cellular redox state oscillates with the circadian cycle. Studies on animal models subjected to circadian disruption via hypoxia, knockout or mutant clock genes, night-shift work, and sleep disorders show increased oxidative stress and diminished antioxidant defenses. Such disruptions lead to decreased production of adipokines, impaired lipid metabolism, and reduced browning in adipose tissue. Metabolic and cardiovascular diseases resulting from circadian rhythm disruption and heightened oxidative stress can potentially be mitigated with antioxidant treatments and time-restricted feeding.

Circadian rhythms, the intrinsic 24-hour cycles governing physiological processes, have a profound impact on cardiovascular health. The bidirectional relationship between circadian rhythms and cardiovascular health is increasingly recognized, highlighting the complex interplay between these biological rhythms and CVD [41]. Obesity-induced disruption of circadian rhythms is a significant factor that can exacerbate various mechanisms implicated in CVD, including endothelial dysfunction, inflammation, oxidative stress, and autonomic dysregulation [42]. Endothelial dysfunction is a key early event in the development of atherosclerosis and other cardiovascular conditions. Circadian disruption, often resulting from obesity, adversely affects endothelial function. Studies have shown that the endothelium exhibits diurnal variations in function, with peak endothelial performance occurring at certain times of the day. Obesity, however, can disrupt these patterns, leading to impaired endothelial function. This impairment is partly due to altered expression of clock genes in endothelial cells, which are crucial for maintaining vascular homeostasis [43]. Inflammation is another critical pathway through which circadian disruption contributes to CVD. Obesity is associated with chronic low-grade inflammation, which can disturb circadian rhythms and exacerbate cardiovascular risk. Inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), show circadian variation, and their dysregulation due to obesity can lead to persistent inflammation. This chronic inflammatory state can promote atherosclerosis and increase the risk of acute cardiovascular events [44]. Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses, is another pathway linking circadian disruption and CVD. Obesity-induced circadian misalignment can enhance oxidative stress, as evidenced by increased ROS production and reduced antioxidant enzyme activity.

This oxidative stress can damage vascular cells, promote inflammation, and accelerate the progression of atherosclerosis [45]. Autonomic dysregulation, involving the imbalance between sympathetic and parasympathetic nervous system activity, is also implicated in the relationship between circadian rhythms and cardiovascular health. Circadian rhythms regulate autonomic function, influencing heart rate, blood pressure, and vascular tone. Obesity can disrupt these rhythms, leading to autonomic imbalance with increased sympathetic activity and reduced parasympathetic tone. This dysregulation can contribute to hypertension, arrhythmias, and other cardiovascular conditions [46,47]. The disruption of circadian rhythms induced by obesity significantly impacts cardiovascular health through mechanisms such as endothelial dysfunction, inflammation, oxidative stress, and autonomic dysregulation [48]. Disturbances in the interaction between the circadian system and environmental factors can disrupt the circadian clock. Misalignments such as night-time eating, exposure to artificial light at night, night shift work, and mutations in circadian clock genes negatively impact metabolism. A disrupted circadian system can lead to various cardiometabolic anomalies, including obesity, diabetes, and CVD. Figure 3 illustrates the physiological and behavioral processes influenced by circadian rhythms, including the impact of their disruption on various health conditions. Understanding the bidirectional relationship between circadian rhythms and cardiovascular health is crucial for developing interventions aimed at mitigating the cardiovascular risks associated with obesity and circadian misalignment.

Clock genes, pivotal components of the circadian machinery, have emerged as key players in cardiovascular health. These genes influence vascular tone, blood pressure regulation, and atherosclerotic processes, highlighting their potential as therapeutic targets. The SCN clock influences cardiovascular function through two primary mechanisms. First, it acts directly via the autonomic nervous system [49,50] and endocrine outputs, such as glucocorticoid rhythms, which primarily affect the cardiac muscle and blood vessels through receptors on the myocardium and vascular endothelium [51]. Second, it operates indirectly by synchronizing peripheral clocks, including the robust local clocks within cardiac tissues [52]. Iterative lifestyle alterations and circadian clock disruptions adversely affect metabolic health, increasing the risk of CVD and obesity. These disruptions lead to misaligned eating and activity patterns, impairing metabolic processes. Consequently, insulin resistance, inflammation, and lipid abnormalities arise, exacerbating obesity and CVD risk.

Maintaining consistent routines and synchronizing with natural circadian rhythms is crucial for metabolic health (Figure 4). This could be explained as, in cultured cardiomyocytes from rats, there is rhythmic expression of clock genes such as Bmal1, RevErbα, Per2, and Dbp [53]. Studies of the cardiac transcriptome have shown that approximately 10% of transcribed genes are regulated by the cardiomyocyte circadian clock [53]. Additionally, both in vivo and in vitro studies have demonstrated rhythmic oscillations in circadian clock gene transcripts, including Per2, Bmal1, and Dbp, in the mouse aorta and vascular tissue [54,55]. Notably, cardiomyocyte-specific Bmal1 knockout mice display disrupted systolic function, characterized by reduced fractional shortening and ejection fraction as they age, ultimately leading to a decreased lifespan [54,55]. Cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit circadian rhythms, controlled by a clock-dependent oscillator responsible for the rhythmic expression of the transient outward potassium current [56]. The circadian molecular machinery present in the vascular system, including endothelial cells, plays a crucial role in vascular function and potentially in vascular dysfunction, including blood clotting [57]. Given the kidney’s central role in maintaining fluid and ion homeostasis, circadian rhythms in kidney tissue may help explain circadian rhythms in blood pressure [58].

Lack of functional Per1 and Per2 genes exhibits dramatic alterations in the normal rhythms of mRNA of the renal alphaENaC (alpha subunit of the epithelial sodium channel, linked to renal absorption of sodium) [59]. Moreover, deficiency in the circadian Cry1 and Cry2 genes shows salt-sensitive hypertension, potentially driven by high aldosterone synthesis. Aldosterone (and corticosterone) also modulate the expression levels of Cry1, Per1, Per2, and Rev-Erbα genes in the heart over the 24-hour day [60]. The circadian timing system may also impact cardiovascular risk through the modulation of immune function or potentially via Rev-Erbα-sensitive cholesterol pathways and bile acid regulation [61-63]. Virtually all measures of the immune system show rhythmic oscillations, and the circadian system may influence inflammation responses by restricting the expression of inflammatory genes to specific times within the circadian cycle [62]. Circadian misalignment and intrinsic disturbances in the circadian clock gene, each of which can elevate cardiovascular risk. This disruption in the clock gene results in physiological alterations that are associated with and often precede CVD, as depicted in the middle of Figure 5. These changes include detrimental impacts on thrombogenic pathways, hemodynamic function, arterial stiffness, inflammation, and autonomic nervous system function. Chronodisruption has been directly linked to various forms of CVD, such as coronary artery disease, cardiomyopathy, hypertension, stroke, and chronic kidney disease. Additionally, chronodisruption may contribute to these physiological changes and CVDs through other risk factors, such as behavioral pattern alterations; therefore, misalignment disrupts normal metabolic processes, while genetic disturbances impair regulatory mechanisms. Both factors contribute to inflammation, insulin resistance, and lipid imbalances, ultimately increasing susceptibility to CVDs. Maintaining circadian rhythm integrity is essential for cardiovascular health (Figure 5).

Human physiological mechanistic studies provide translational evidence for the involvement of the circadian system in daily rhythms of adverse cardiovascular events, as well as the contribution of circadian disruption, such as misalignment, to increased cardiovascular risk factors [64-66]. Studies have revealed the presence of circadian clocks throughout the cardiovascular system and have shown that these clocks in myocardial tissue become altered in CVD. These insights suggest that the effects of the circadian system and its disruption on cardiovascular risk may have direct clinical implications. In humans, a randomized trial demonstrated that the timing of aortic valve surgery was associated with adverse cardiac events up to 500 days post-surgery, with fewer events and lower perioperative cardiac troponin T release observed in patients who underwent afternoon surgery compared to those who had morning surgery [67]. Analyses of myocardium indicated alterations in circadian gene expression, specifically Rev-Erbα gene deletion and antagonism, revealing higher levels of the nuclear receptor Rev-Erbα in the morning surgery group, which may be linked to increased cardiovascular risk. Importantly, night shift workers are repeatedly exposed to circadian misalignment and may face higher cardiovascular risk due to the progressive increase in blood pressure over time [68]. Epidemiological data also show time-of-day variations in adverse cardiovascular events [69,70]. Collectively, these studies provide strong evidence supporting the role of circadian disruption and misalignment in increasing cardiovascular risk.

While it does not address the cause and effect, there is evidence of decreased neurotransmitter content (both mRNA and protein levels) in the SCN of hypertensive patients [71], which is related to changes in corticotropin-releasing hormone expression neurons in the paraventricular nucleus of the hypothalamus [72]. Initial suggestions for potential beneficial effects of interventions influencing circadian function come from studies using melatonin in clinical populations with increased cardiovascular risk [73,74]. Melatonin, which affects the circadian system, may also exert additional or alternative mechanisms such as antioxidant and/or immunomodulatory effects [75].

Repeated use of 2.5 mg of melatonin for three weeks reduced blood pressure during sleep and increased the day-night amplitudes of blood pressure rhythms in hypertensive patients [73]. More recent data on patients with type 2 diabetes and essential hypertension who took melatonin (3 mg or 5 mg) in the evening for four weeks indicate that about 30% of non-dippers showed improvement in night blood pressure and night average blood pressure dipping, whereas no effects were observed in normal dippers or control groups without melatonin [74]. Although data are limited regarding other CVDs, there is some evidence that melatonin supplementation (10 mg nightly) for 12 weeks reduced blood pressure and serum high-sensitivity C-reactive protein in patients with type 2 diabetes and coronary heart disease [76]. These studies collectively raise the question of whether normalizing circadian rhythms in patients with CVD may offer a new approach to risk reduction. Treatment interventions targeting the morning peak in adverse cardiovascular events could include pharmacological chronotherapy, administering medication before the time of highest cardiovascular risk (morning), such as β-blockers and aspirin [77], and modifying the timing of behavioral triggers like adjusting the timing of behaviors to minimize their impact on cardiovascular risk, such as the optimal time for exercise [64].

The intricate relationship between circadian rhythms and cardiovascular health has paved the way for innovative strategies like chronotherapy and lifestyle modifications to mitigate cardiovascular risk. Chronotherapy involves the strategic timing of medication and lifestyle interventions to align with the body’s natural circadian rhythms, thereby optimizing therapeutic outcomes. By addressing disruptions in circadian rhythms, which are commonly seen in obesity and other metabolic disorders, these interventions can significantly ameliorate metabolic and cardiovascular disturbances. Timed eating, or time-restricted feeding, aligns food intake with the body’s circadian rhythms. Studies have shown that eating patterns synchronized with circadian rhythms can improve metabolic health and reduce cardiovascular risk factors. For instance, eating during the biological daytime and fasting during the night aligns with the body’s natural insulin sensitivity and digestive efficiency cycles, thereby reducing the risk of obesity, type 2 diabetes, and CVDs [77,78]. Research showed that early time-restricted feeding (eating within a 6-hour window early in the day) improved insulin sensitivity, blood pressure, and oxidative stress markers in prediabetic men [79]. Exercise is another powerful modulator of circadian rhythms. The timing of physical activity can influence its metabolic benefits. Morning exercise has been associated with improved fat oxidation and better insulin sensitivity, while evening exercise might benefit muscle performance and cardiovascular endurance [80,81]. A study indicated that the timing of exercise affects muscle gene expression related to circadian rhythms, suggesting that exercising at optimal times can enhance metabolic health and reduce cardiovascular risk [82]. Sleep is a cornerstone of circadian health. Poor sleep quality and irregular sleep patterns are strongly linked to increased cardiovascular risk. Ensuring sufficient and regular sleep can help maintain the synchronization of circadian rhythms, thereby supporting cardiovascular health.

The American Heart Association emphasizes the importance of sleep for cardiovascular health, noting that both short and long sleep durations are associated with an increased risk of cardiovascular events [83]. Improving sleep hygiene, such as maintaining a consistent sleep schedule, creating a restful environment, and avoiding stimulants before bedtime, can significantly reduce cardiovascular risk [84]. Chronotherapy, the timing of medication administration to coincide with biological rhythms, has shown promise in cardiovascular risk reduction. Medications such as antihypertensives, statins, and antidiabetic drugs can be more effective when timed according to the body’s circadian rhythms. For example, taking antihypertensive medications at bedtime rather than in the morning can better control nocturnal blood pressure and reduce the risk of cardiovascular events [85]. A study demonstrated that bedtime dosing of antihypertensives resulted in significantly lower nighttime blood pressure and reduced the incidence of major cardiovascular events compared to morning dosing [86]. Integrating chronotherapy with lifestyle interventions creates a holistic approach to cardiovascular health. Another study found that combining time-restricted eating with regular exercise and optimized sleep significantly improved cardiovascular risk factors in obese adults [87]. This integrated approach addresses multiple aspects of circadian disruption, offering a comprehensive strategy for reducing cardiovascular risk. Harnessing circadian rhythms through chronotherapy and lifestyle modifications presents a promising avenue for mitigating cardiovascular risk. Timed eating, exercise, and optimized sleep patterns are practical interventions that can realign circadian rhythms and improve metabolic and cardiovascular health. Continued research and clinical application of these strategies can potentially revolutionize the management of cardiovascular risk in populations affected by circadian disruption and metabolic disorders (Figure 6).

Emerging pharmacological interventions aimed at modulating circadian rhythms present promising strategies for attenuating cardiovascular risk. The synchronization of circadian rhythms is crucial for maintaining cardiovascular health, and disruptions to these rhythms are associated with increased risk of CVD. Innovative pharmacological approaches, including melatonin agonists, clock gene modulators, and circadian enhancers, offer potential therapeutic benefits, although more research is needed to fully understand their efficacy and safety. Melatonin, a hormone produced by the pineal gland, plays a key role in regulating circadian rhythms. Melatonin agonists, such as ramelteon, have been developed to mimic the effects of endogenous melatonin, thereby aiding in the realignment of disrupted circadian rhythms. Clinical studies have shown that melatonin administration can reduce blood pressure, improve sleep quality, and enhance overall cardiovascular health. For instance, Grossman et al. [88] demonstrated that melatonin reduced nighttime blood pressure in patients with nocturnal hypertension, suggesting its potential for reducing cardiovascular risk. Another study found that melatonin improved blood pressure profiles and oxidative stress markers in patients with metabolic syndrome [89]. Clock gene modulators represent another promising avenue for cardiovascular risk reduction. These agents target specific genes involved in the regulation of circadian rhythms, such as CLOCK, BMAL1, PER, and CRY. By modulating the expression or activity of these genes, it is possible to influence circadian rhythms at a molecular level, potentially correcting the dysregulation associated with CVDs. Research has shown that disruptions in clock gene function can lead to altered metabolic and cardiovascular functions, underscoring the therapeutic potential of targeting these genes [90].

Studies in animal models have demonstrated that pharmacological modulation of clock genes can improve metabolic health and reduce cardiovascular risk factors, such as hypertension and dyslipidemia [91]. Circadian enhancers are compounds that amplify the amplitude of circadian rhythms, thereby strengthening the overall circadian system. These agents can enhance the robustness of circadian oscillations, which may have beneficial effects on cardiovascular health. For example, REV-ERB agonists, which stabilize the expression of clock genes, have been shown to improve metabolic profiles and reduce inflammation in preclinical studies [92]. By enhancing circadian rhythms, these compounds may help mitigate the adverse cardiovascular effects associated with circadian disruption. Despite the promising potential of these pharmacological approaches, further research is needed to elucidate their long-term efficacy and safety in humans. Large-scale clinical trials are essential to determine the optimal dosages, treatment regimens, and potential side effects of these interventions. Additionally, a deeper understanding of the molecular mechanisms underlying circadian regulation and its impact on cardiovascular health will facilitate the development of more targeted and effective therapies. Pharmacological modulation of circadian rhythms offers exciting possibilities for reducing cardiovascular risk. Melatonin agonists, clock gene modulators, and circadian enhancers represent innovative strategies that could revolutionize the management of CVD. Continued research and clinical validation are crucial to fully harness the therapeutic potential of these emerging interventions.

The intricate interplay between circadian rhythms, obesity, and cardiovascular risk presents a compelling direction for future research. Understanding the underlying mechanisms linking circadian disruption to CVD in the context of obesity holds immense potential for developing innovative therapeutic strategies. Several avenues of investigation can drive this research forward.

Comprehending the intricate interplay between circadian rhythms and obesity-related cardiovascular risk is paramount for devising effective preventive and therapeutic strategies. By targeting circadian mechanisms, we can adopt a novel perspective in tackling the cardiovascular burden imposed by obesity. Integrating circadian-based interventions into clinical practice holds promise for mitigating the adverse cardiovascular effects associated with obesity, thereby improving patient outcomes and quality of life. As we delve deeper into the molecular underpinnings of circadian regulation and its relationship to obesity and CVD, we uncover opportunities to develop targeted interventions tailored to individual circadian profiles. From chronotherapeutic approaches to lifestyle modifications and pharmacological interventions, the potential avenues for intervention are diverse and promising. Furthermore, fostering interdisciplinary collaboration between researchers, clinicians, and industry stakeholders is essential for advancing our understanding of circadian biology and translating this knowledge into effective clinical interventions. By harnessing the power of circadian rhythms, we can forge new pathways towards reducing the cardiovascular burden of obesity and enhancing cardiovascular health on a global scale.