Liver clock: Malalignment and entrainment therapeutics

Abstract

The mammalian circadian system comprises of a central clock in the suprachiasmatic nucleus (SCN) and peripheral clocks in body tissues and organs i.e. liver clock. Both the central and liver clocks are based on clock genes and their protein products, which regulate circadian rhythms in metabolism, physiology, and behavior by modulating nervous and harmone signaling, including the sympathetic nervous system, fasting and eating behavior. The SCN is primarily entrained by light-dark cycles. Liver clock genes can be influenced by other factors, such as feeding cycles and specific nutrients. Light is the major entraining factor, reaching the SCN through the retina and retinal hypothalamic tract. The liver clock regulates the expression of 10%-15% of the transcriptome, including key metabolic genes. Disruptions in either the central or liver clock can lead to various health issues, including an increased cancer risk and metabolic disorders. Various lifestyle measures, including time-restricted eating, light therapy, temperature control, and melatonin agonists, have been studied for circadian realignment. We reviewed the mechanism of malalignment of central and liver clock genes and existing therapeutic measures for realignment.

Key Words: Circadian rhythm; Liver clock; Metabolic dysfunction-associated steatotic liver disease; Suprachiasmatic nucleus; Clock gene; Melatonin; Life style disorders

Core Tip: Liver clock is peripheral clock of hepatocytes concerned with metabolic genes and functions. It is desynchronised to central clock in metabolic and life style disorders. It can be resynchronised by various life style and therapeutic measures including modifying eating behaviours, light exposure, excercise or activity modification. This mini-review discusses causes of misalignment of liver clock and how to fix them.

INTRODUCTION

The mammalian circadian timing system includes a central clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus, alongside peripheral clocks distributed across various body tissues and organs[1]. The SCN functions as the primary pacemaker, coordinating peripheral clocks to maintain appropriate physiological rhythms[2]. Both central and peripheral clocks depend on clock genes and their protein products, which modulate circadian rhythms in metabolism, physiology, and behavior by influencing nervous and harmonal signals, such as the sympathetic nervous system, stress signaling, and eating patterns[3]. The circadian clock system is adjusted daily by external cues known as entrainment factors, which include light and food intake. The SCN is primarily synchronized by light-dark cycles, whereas peripheral clocks, particularly those in the liver, can be influenced by other factors, such as feeding cycles and specific nutrients. Light is the major entraining factor that signals the SCN through visual pathway. The interaction between the central and peripheral clocks is crucial for sustaining overall circadian physiology and behavior. Disruptions in either the central or peripheral clocks can result in various health problems, such as an increased risk of cancer, metabolic disorders, and cardiovascular diseases. Peripheral clocks are circadian timekeeping mechanisms found in tissues and organs throughout the body, different from the principal clock in the SCN of the hypothalamus[4]. These peripheral clocks share a molecular structure similar to that of the central pacemaker and play vital roles in regulating various physiological processes. They operate by forming feedback loops between transcriptional and translational factors, primarily involving protein families such as CLOCK, BMAL, PER, and CRY. While the SCN functions as the master regulator, peripheral clocks can independently sustain their own rhythm, contributing to an organism's overall circadian physiology[5]. Peripheral clocks are significantly influenced by feeding rhythms. Intake of meal stimulates release of oxyntomodulin in the gut and resets the liver transcription rhythms by activating the core clock genes PER1 and PER2[6]. Peripheral clocks, including the liver clock, gradually develop during postnatal ontogenesis. In rats, the molecular clock in the liver is completed approximately 30 days after birth, with different clock genes rhythmically expressed at various developmental stages[7]. The interaction between the liver clock and meal timing are enough to regulate chronological carbohydrate homeostasis, whereas other metabolic processes require communication with other peripheral clocks, such as the skeletal muscle clock[4].

Canonical clock genes, including PER1, PER2, PER3, CRY1, CRY2, BMAL1, CLOCK, NR1D1, and DBP[8], are integral to the transcriptional and translational feedback loops that generate circadian rhythms[9]. In the liver, seven of these canonical clock genes – CLOCK, BMAL1, PER1, PER2, PER3, CRY1, AND CRY2 – exhibit circadian rhythms under normal conditions[10]. CLOCK and BMAL1 serve as the primary activators of molecular clocks. CLOCK, a transcription factor, interacts with BMAL1 to initiate the expression of other clock genes, such as PER and CRY. The proteins produced by PER and CRY accumulate within the cell and eventually inhibit the activity of CLOCK and BMAL1, establishing a feedback loop that results in the rhythmic expression of clock genes. These clock genes regulate the expression of approximately 40% of the transcriptome, including key metabolic genes[11]. Notably, liver clock genes are subject to both spatial and temporal regulation. Single-cell RNA-seq analysis has revealed that many liver genes exhibit both zonation and rhythmicity, with combined spatiotemporal effects[12]. However, core circadian clock genes are expressed uniformly, indicating that the liver clock is resistant to zonation[12]. Furthermore, the liver clock can rapidly adapt to new feeding cycles within a few days, demonstrating responsiveness to nutritional signals[13]. Figure 1 illustrates the regulation of liver clock genes.

Figure 1 Interaction of liver clock with central clock and entraining factors. Central clock regulates liver clock by signaling through hormones. Liver clock regulates metabolism. Lack of synchronisation can lead to metabolic disorders. HPA: Hypothalamic pituitary adrenal; SCN: Suprachiasmatic nucleus.

The liver clock is particularly sensitive to feeding rhythms and can be synchronized by food timing, even when it conflicts with the central clock[13]. Interestingly, the liver clock appears to play a crucial role in buffering the effects of feeding-related signals on the rhythmicity of other peripheral tissues, acting as a mediator between nutrient-related signals and other peripheral clocks, thereby underscoring its importance in maintaining systemic metabolic balance. Restricted feeding (RF) can induce a 12-hour shift in peripheral circadian clocks (PCCs) without affecting the SCN clock, resulting in misalignment[14]. This occurs because the SCN does not express peroxisome proliferator-activated receptor alpha (PPARα) and glucagon receptors[14]. Consequently, the liver clock shifts without corresponding changes in the central clock, leading to misalignment. Additionally, a reduction in insulin during the RF period activates the nuclear receptor RevErbα through downstream phosphorylation, resulting in the repression of BMAL1 and CRY, which is critical for PCCs shifting. Feeding time influences clock rhythmicity in a tissue-specific manner. While the clocks of some tissues, such as the liver and white adipose tissue, are strongly phase-shifted, other tissues, like the kidney, respond only partially, and some, such as the lungs, show no response.

Irregular sleep patterns can cause a desynchronization between central and peripheral clocks, leading to the misalignment of circadian genes[15]. Timed sleep restriction triggers significant transcriptional reprogramming in white adipose tissue, which is indicative of increased lipogenesis, elevated secretion of the adipokine leptin, and heightened food intake, all associated with leptin resistance. Some of these changes persist for at least a week after timed sleep restriction ends, suggesting that even short episodes of sleep disruption can result in prolonged physiological impairment. Numerous studies have identified epigenetic DNA modifications linked with shift work. One study involving 117 female participants from Denmark revealed that long-term shift work correlates with promoter hypomethylation of CLOCK and hypermethylation of CRY216[16]. Research on sleep deprivation has confirmed that the distribution of sleep and wakefulness influences the expression of most clock genes in tissues outside the SCN[17]. Six hours of sleep deprivation increased PER2 expression in the brain, liver, and kidney, with the effects in the liver persisting longer than those in the brain[18]. Retinohypothalamic signals may be transmitted to the adrenal clock during the subjective day through a retinal pathway or cellular mechanism, independent of light's effect on the SCN neural clock network. This process may be crucial for the temporal integration of physiology and metabolism, impacting hepatocytes and the liver clock. Consequently, sleep disruption affects not only the central SCN clock but also peripheral clocks, including the liver clock. Prolonged exposure to artificial light is linked to human obesity. In animal studies, mice exposed to extended periods of light (16 hours or 24 hours) show increased adiposity without changes in food intake or activity levels[18]. The underlying mechanism involves decreased sympathetic input to the brown adipose tissue, reducing its activity and energy expenditure. This impairment in brown adipose tissue activity may significantly mediate the connection between disturbed circadian rhythms and increased adiposity. Acute temperature challenges dampen body temperature (BT) oscillations and lead to an advanced liver circadian phase. SCN-driven BT oscillations regulate hepatic SIRT7 expression, which affects the liver clock. Disruption of the BT-SIRT7-CRY1 axis can result in an advanced liver circadian phase due to asynchrony[19] as liver’s high expression of SIRT7 (compared to the kidney) makes it more vulnerable to temperature-induced CRY1 dysregulation. Mechanism of liver clock malalignment are tabulated in Table 1.

Table 1 Mechanism of liver clock misalignment and its mechanisms.

Causes of misalignment of central and liver clock	Underlying mechanisms
Feeding time	Suprachiasmatic nucleus lacks expression of PPARα and glucagon receptors due to which it can’t respond to feeding cues; activation of liver PPARα combined with reduced insulin leads to RevErbα-mediated repression of BMAL1 and CRY, resulting in circadian clock misalignment
Irregular sleep timing	Transcriptional reprogramming of adipose tissue with increased lipogenesis and altered adipokine secretion
Night time light exposure	Decreased sympathetic output to brown adipose tissue
Temperature changes	Advanced liver circadian phase

PPARα: Peroxisome proliferator-activated receptor alpha.

CONSEQUENCES OF MALALIGNMENT OF LIVER CLOCK

The circadian clock machinery is integral to the regulation of hormonal and metabolic homeostasis, exerting a significant influence on the development and progression of Metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis and potentially hepatocellular carcinoma[20]. Circadian misalignment disrupts the delicate equilibrium of lipid metabolism in the liver, resulting in steatosis. This disruption is mediated through alterations in clock gene expression, modifications in triglyceride and cholesterol synthesis, and interference with autonomic nervous system regulation. The liver's biological clock functions as a network-level hub, coordinating various metabolic pathways, bile acid synthesis, autophagy, and inflammatory processes[21]. High-fat diets can disrupt circadian rhythms by altering the expression of core circadian genes, such as CLOCK and BMAL1, leading to metabolic abnormalities via the INSIG2-SREBP pathway[22]. This disruption culminates in increased liver lipid accumulation. Notably, the circadian clock regulates energy homeostasis by modulating the expression and activity of enzymes involved in metabolism. CLOCKΔ19 mice with disrupted circadian rhythms spontaneously develop obesity and metabolic syndrome, paralleling MASLD progression[23]. This disruption primes hepatic stellate cells to accelerate the fibrotic response, exacerbating liver diseases[24]. Intriguingly, the genomic recruitment of histone deacetylase 3 by RevErbα orchestrates the circadian rhythm of histone acetylation and gene expression, both of which are crucial for maintaining normal hepatic lipid homeostasis. The deletion of histone deacetylase 3 or RevErbα in the mouse liver leads to hepatic steatosis, highlighting the vital role these circadian regulators play in liver health[25]. Circadian misalignment has a significant impact on glucose metabolism, resulting in insulin resistance and an elevated risk of developing diabetes. Research has shown that disruptions in the circadian timing system can impair glucose homeostasis and reduce whole-body insulin sensitivity[26,27]. Short-term circadian misalignment of the liver clock can cause a significant decrease in muscle insulin sensitivity due to reduced skeletal muscle non-oxidative glucose disposal[28,29]. Additionally, circadian misalignment has been found to lower insulin sensitivity rather than affecting β-cell function[30]. Analysis of muscle biopsies suggests that the molecular liver clock was not aligned with the inverted behavioral cycle, with the PPAR pathway being a key player in altered energy metabolism upon circadian misalignment[28]. Circadian disruption in the liver can affect appetite regulation and energy expenditure, thereby contributing to obesity. Research has shown that resting energy expenditure varies with the circadian phase, being lowest in the late biological night and highest in the biological afternoon and evening[31]. Additionally, the respiratory quotient, which reflects macronutrient utilization, varies by circadian phase, with implications for carbohydrate and lipid oxidation patterns throughout the day[32]. Chronic inflammation, oxidative stress, and epigenetic changes increase the risk of developing liver cancer. Gene misalignment can have significant health consequences and predispose individuals to various diseases, including cancer.

Insufficient sleep and alteration in circadian rhythms are correlates with an increased body mass index, obesity, and diminished insulin sensitivity[32,33]. Also, sleep deprivation is linked to decreased levels of leptin and ghrelin, increased hunger, and reduced insulin sensitivity[34]. Individuals having morning chronotype (early risers) consume more energy earlier in the day, and those with an evening chronotype delay their meals till late evening, and often skip breakfast. These individuals may experience reduced insulin sensitivity and increased adiposity with subsequent elevated postprandial glucose levels. Studies indicate that insulin sensitivity naturally increases throughout the day, peaking in the morning[35,36]. Individuals with a morning chronotype often take advantage of their natural energy boost by having breakfast, which helps keep their glucose levels steady throughout the day[37]. On the other hand, those with an evening chronotype might experience higher ghrelin levels at night, leading to increased hunger and more frequent eating, which can contribute to weight gain[38]. Cortisol imbalance can impact glucose metabolism and heighten the risk of metabolic issues like insulin resistance and type 2 diabetes mellitus[39].

REALIGNMENT OF CIRCADIAN CLOCK

Adjusting circadian genes can be accomplished through lifestyle and behavioral changes. These methods help reset internal clocks, enhancing the alignment between central and peripheral clocks, such as the hepatocyte clock. The following measures can be considered for realignment of liver clock with peripheral and central clock (Table 2).

Table 2 Therapeutic and life style measures for realignment of liver clock.

Management options	Mechanism	Remarks
Time restricted eating	Entrains liver clock with peripheral rhythms independent of central clock regulating key genes in lipid and glucose homeostasis	Aligns feeding to circadian phase; restricts intake to 6-10 hours
Morning light exposure	Entrains central clock with peripheral rhytms by neural and hormonal signals	Regulates SCN entrainment via melatonin and cortisol
Melatonin	Improves liver rhythm, especially during circadian disruption	Acts via MT1/MT2 receptors to influence peripheral clocks
Exercise timing (chrono-exercise)	Amplifies expression of liver clock genes like BMAL1, PER2	Time-of-day dependent AMPK/SIRT1 modulation
Nutrient timing (macronutrient scheduling)	Enhances clock-gene synchrony with metabolic cycles	Aligns insulin/glucose peaks with liver sensitivity. Prioritize protein breakfasts to leverage morning insulin sensitivity and aligning carbohydrate intake with afternoon liver glucose sensitivity reduces steatosis
Avoidance of night eating/shift work	Helps resynchronize liver rhythms	Prevents desynchrony of SCN and liver via feeding timing

SCN: Suprachiasmatic nucleus.

Both intermittent fasting (IF) and time RF create consistent eating schedules that act as powerful zeitgebers, or time cues, for regulating the body's peripheral biological clocks. By aligning eating habits with the body's natural circadian rhythm, these methods can help restore the rhythmic expression of circadian genes. Time restricted eating (TRE) adjusts the liver clock by realigning peripheral circadian rhythms, especially the expression of genes related to the clock and lipid metabolism in the liver. This realignment results in better lipid balance, decreased liver fat accumulation, and improved overall metabolic health. These benefits seem to be facilitated through various pathways involving circadian proteins, metabolic regulators like SIRT1, SREBP, and PPARα, as well as changes in the gut microbiota composition. These findings underscore the potential of TRE as a promising strategy for preventing and treating MASLD. TRE significantly influences the expression of circadian clock genes in the liver, even when the SCN clock is not functioning[40]. This realignment of peripheral circadian rhythms can help prevent or manage metabolic syndrome and hepatic steatosis. TRE shifts the circadian patterns of the hepatic clock and genes involved in de novo fatty acid synthesis by 2-4 hours, supporting the regulation of lipid metabolism[41]. These positive effects of TRE can occur without the need for calorie restriction. A 30-day fasting regimen from dawn to dusk in humans increased key regulatory proteins for glucose and lipid metabolism, including the circadian clock, and led to a serum proteome that protects against metabolic syndrome[42]. IF influences the expression of essential clock genes, such as CLOCK, BMAL1, PER, and CRY. By restricting eating to certain periods, IF strengthens the natural fluctuations of these genes, thereby enhancing the circadian rhythm[43]. This gene expression interaction ensures that various biological activities occur at optimal times, aligning biological functions with the external environment. IF affects the rhythmic expression of genes linked to metabolic pathways, especially those involved in glucose and lipid metabolism, by realigning key genes like PPARα and SREBP-1c[44]. Moreover, IF decreases inflammation and oxidative stress, which help stabilize the circadian clock and can lead to beneficial epigenetic modifications, such as DNA methylation and histone changes[45]. These modifications encourage the rhythmic expression of circadian genes, thus restoring normal circadian rhythms.

Eating earlier, (from 7 AM to 3 PM), is typically more effective than late eating windows, (from 12 PM to 8 PM), for liver clock entrainment and various metabolic outcomes. This effect is due, in part, to greater insulin sensitivity and improved glucose metabolism in the morning. Human studies consistently indicate that eating the bulk of calories earlier in the day optimizes food intake schedules with endogenous circadian rhythms, enhances insulin sensitivity following a meal, improves postprandial glucose response, expands appetite regulation, and results in better overall metabolic health when measured against late eating windows[46]. In general, it is best to limit caloric intake after 6 PM for individuals, especially those at risk for metabolic syndrome or MASLD, because insulin sensitivity is decreasing and cortisol is often elevated later in the day. Early and late time RF will likely reduce total energy intake and improve glycemic control compared to unfettered eating patterns, but benefiting from early TRE conditions (e.g. from 8 AM to 2 PM, from 8 AM to 3 PM) will likely produce more robust improvements in fasting glucose, insulin sensitivity, and overall β-cell function than late TRE conditions (e.g. from 12 PM to 8 PM)[47-49].

Adjusting TRE for shift workers is a challenge due to circadian misalignment due to sleeping and waking and light and dark cycles. Some research has shown shift workers can still benefit from TRE by reducing caloric intake on night shift workdays; preferably, workers would not eat overnight and eat at home during the day between night shifts, avoiding eating between 1 AM and 6 AM[50]. This adjusted method of TRE would reduce circadian disruption while improving metabolic markers such as insulin resistance and managing weight. However, the feasibility of individual membership remains an important consideration for the shift work population. Flexible but individualized eating windows that are regularly followed - even when those hours aren't in the expected daytime - could help reduce overall health risks as they relate to circadian misalignment[51].

Light is one of the most potent external cues influencing circadian rhythms. Exposure to bright light in the morning reinforces circadian signals, promoting alertness and improving mood[52,53]. Conversely, minimizing light exposure in the evening, particularly the blue light emitted by screens, can promote the release of melatonin, which is responsible for delayed sleep onset. In the absence of light melatonin is secreted and is inhibited in its presence, but in either case it serves as hormonal signal of night. It also acts on MT1 and MT2 receptor. Melatonin affects circadian requlation expressive of various processes beyond sleep. Melatonin’s rhythmic release prompts tissues to shift into night mode when it influences patterns of expression of genes regulated by the clock genes PER1, PER2 and CRY1, whose protein products gene are involved in transcriptional-translational feedback loops that drive circadian timing. In addition to melatonin’s action on clock-controlled genes, it also interacts with neurotransmitter systems to create a drive for sleep and neuroprotection and is an antioxidant action, further modifying cellular and systemic homeostatsis and their alignment with circadian rhythm[54]. From clinical perspective, the administration of melatonin has distinct utility for realigning circadian misalignment due to delayed sleep phase syndrome, jetlag, shift work sleep disorder, and also neurodegenerative disease. The timing of melatonin is important, taking melatonin in evening is likely to advance circadian phase and might reduce sleep latency, whereas taking melatonin in the morning has been shown to delay the phase. A regular sleep-wake schedule can have positive effects on diabetes, cholesterol, obesity, and metabolic disorders. Morning light exposure is the most effective signal for the SCN, which governs the timing of circadian rhythms throughout the body by influencing peripheral clocks through neural and hormonal signals[55]. Light impacts the expression of key clock genes (CLOCK, BMAL1, PER, and CRY) that are vital for maintaining circadian rhythms. Exposure to morning light can advance these rhythms, aiding in the realignment of the liver and central clocks. Additionally, light suppresses melatonin, a hormone that promotes sleep, thereby facilitating the advancement of the sleep-wake cycle. This suppression of melatonin enhances the synchronization of the clocks in hepatocytes.

Clinical studies of MASLD commonly provide melatonin in a 6 mg/day dosage; with robust evidence indicating significant decreases in liver enzymes (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase) and markers of inflammation, and only a limited rate of adverse effects. Lower dosages of melatonin (such as 3 mg/day) have been trialed in MASLD cohorts, yet we do not know the data comparing the effects of available doses on hepatic outcomes, nor the potential of individuals to respond to lower doses with favorable results[56]. Nevertheless, available evidence suggests higher doses (6 mg/day) are more favorable to hepatic outcome measures. Overall, findings indicate individuals receiving melatonin are not much different from placebo users, with reported adverse effects including headache, daytime sleepiness, or dizziness, expectedly rare and mild. Caution should be prescribed to individuals who are often drowsy or have impaired alertness, and machinery is best avoided. Melatonin did not produce significant severe adverse events in MASLD research, signalling potential short-term safety of the supplementation, lucent to not generate serious adverse events associated with giving melatonin among MASLD droves upon assessments of rare and mild adverse events[57].

Interventions targeting sleep quality and duration have demonstrated significant potential in addressing MASLD. Melatonin supplementation, particularly at a dosage of 6 mg/day, has been shown to positively impact various MASLD-related factors. These include improvements in liver enzyme levels, high-sensitivity C-reactive protein, anthropometric measurements, blood pressure, serum leptin levels, and overall fatty liver grade[58]. The efficacy of melatonin in managing MASLD symptoms highlights the importance of circadian rhythm regulation in liver health. Additionally, the development of novel melatonin agonists, such as NEU-P11, has shown promise in animal studies, improving body weight, insulin sensitivity, and overall metabolic profile in obese rats[59]. The relationship between sleep and liver health extends beyond melatonin supplementation. Maintaining a consistent sleep-wake schedule plays a crucial role in reinforcing natural circadian rhythms, which are intricately linked to metabolic processes and liver function. Regular sleep patterns help synchronize the body's internal clock, potentially improving insulin sensitivity, glucose metabolism, and lipid regulation. This synchronization may contribute to better liver health by reducing the risk of fat accumulation and inflammation associated with MASLD. Furthermore, adequate sleep duration and quality may help regulate appetite hormones, reducing the likelihood of overeating and subsequent weight gain, which are known risk factors for MASLD progression. It is advisable to limit screen time before sleep and establish a consistent bedtime routine. This can include engaging in relaxing activities, dimming lights, and creating a sleep-conducive environment to support the body's natural circadian rhythm and promote better sleep quality[59].

Regular physical activity serves as a powerful zeitgeber, or time-giver, for PCCs, particularly in skeletal muscles and the liver[60,61]. This synchronization occurs through the modulation of gene expression patterns in these tissues, aligning them with the body's overall circadian rhythm. The timing of exercise plays a crucial role in this process, with morning or early afternoon sessions proving especially effective in resetting and regulating these peripheral clocks. The impact of exercise on circadian rhythms extends beyond local tissue effects, influencing systemic metabolic processes and overall physiological function. By engaging in consistent, timed physical activity, individuals can enhance the coordination between central and peripheral clocks, potentially improving metabolic health, sleep quality, and overall well-being[62]. This temporal regulation of exercise underscores the importance of not just what type of physical activity is performed, but also when it is undertaken, highlighting the intricate relationship between circadian biology and exercise physiology. Chronic stress can interfere with circadian rhythms by impacting the hypothalamic pituitary adrenal axis. Techniques for managing stress, such as mindfulness, meditation, and getting enough rest, can help maintain a stable circadian rhythm[63].

BT exhibits a distinct circadian pattern, with fluctuations occurring over a 24-hour cycle[64]. These variations are regulated by the body's internal biological clock, which is synchronized with external environmental cues such as light and dark cycles. Typically, BT reaches its lowest point in the early morning hours, around 2-4 AM, and gradually rises throughout the day, peaking in the late afternoon or early evening[65]. This natural rhythm plays a crucial role in various physiological processes, including sleep-wake cycles, hormone secretion, and metabolic functions. The amplitude of these temperature fluctuations can vary between individuals and may be influenced by factors such as age, sex, physical activity, and environmental conditions[66]. Creating a comfortable sleep environment and controlling room temperature can improve sleep quality, thereby supporting regular circadian rhythms. Cooler temperatures are generally more favorable for sleep, while slightly warmer temperatures during waking hours can boost alertness and daytime cognitive performance[65,66].

Acute temperature change particularly acute cold exposure has shown to pose a significat physiological challenge that has direct impact on the alignment and function of the liver circardian clock. A study has shown that when the surrounding temperature was decreased, liver activates antioxidant defense[67] that might alter the expression of core clock genes such as PER2, BMAL1 and CRY1 adjust the metabolic process. It has also been observed that acute cold stress not only upregulates ferroptosis related pathways that leads to oxidative stress and lipid peroxidation but also leads to misaligned activity of certain enzymes like superoxide dismutase, serum glutamate oxaloacetate transaminases and serum glutamate pyruvate transaminases that protects hepatic cells from damage. Another study by Zhang et al[67] had shown that chronic cold exposure perturbed rhythmic expression of PER2, MESOR and also reduction in the protein content of liver PER2. Despite unaltered expression of the liver clock genes, Masri et al[68] in his study showed alteration in the expression of the liver clock control genes.

Social cues play a crucial role in regulating the circadian rhythm, which is the body's internal clock that governs various physiological processes[68]. Regular social activities and structured routines can significantly strengthen this internal clock, helping to maintain a consistent sleep-wake cycle and optimize overall health. Engaging in social interactions at consistent times throughout the day can act as zeitgebers, or time cues, that help synchronize behavioral patterns and reinforce the body's natural rhythms. Maintaining this synchronization also requires avoiding disruptive habits, such as alcohol consumption, which not only interfere with the circadian cycle but also contribute to serious health problems such as severe alcoholic hepatitis[69,70]. This synchronization is particularly effective when individuals within a social group follow similar schedules, creating a collective rhythm that reinforces individual circadian patterns[71].

CONCLUSION

An unhealthy lifestyle, including poor eating and sleeping patterns, along with genetic and work-related factors, can disrupt the circadian synchronization of the central and liver clocks. Realignment can be achieved by modifying triggering behaviors or through short-term medication use. By considering various factors, such as sleep-wake schedules, exercise timing, nutrient intake, light exposure, temperature regulation, social interactions, technology use, and dietary considerations, individuals can effectively support and optimize their circadian rhythm. This comprehensive approach not only improves overall well-being but also reduces the risk of circadian-related disorders, ensuring a harmonious balance between biological processes and external environmental cues.