Melatonin has been implicated in improving insulin sensitivity through multiple molecular pathways. A key mechanism involves the activation of insulin receptor substrate (IRS) proteins, which enhance insulin signaling cascades and promote glucose uptake in target tissues [9,19]. In addition, melatonin affects the Akt/glycogen synthase kinase-3β (GSK-3β) signaling pathway, which is a pivotal regulator of glucose metabolism (Table 1). Activation of Akt results in the phosphorylation and inhibition of GSK-3β. This promotes glycogen synthesis and glucose utilization [9,10,19]. Melatonin has been shown to have beneficial effects on both insulin secretion and sensitivity through both receptor-dependent and independent mechanisms. At the level of the pancreatic beta cells, melatonin activates its specific membrane receptors MT1 and MT2. This activation directly enhances insulin production and glucose-stimulated insulin secretion via increased insulin gene expression [12,20]. At the same time, melatonin exerts protective effects against apoptosis and oxidative stress-mediated damage in the beta cells [14,21]. In peripheral insulin-responsive tissues including skeletal muscle and adipocytes, melatonin facilitates cellular glucose uptake in an insulin-independent manner by upregulating the expression and translocation of glucose transporters and insulin receptor substrates [11,17]. This effectively alleviates insulin resistance, particularly in obesity and diabetes.

Taken together, the collective effects of melatonin on insulin secretion dynamics, binding affinity, signal transduction activation, and glucose metabolism underscore its potential as an adjuvant therapeutic agent [12,22]. Supplementation with melatonin or synthetic analogs may benefit patients with diabetes or insulin-resistant states by ameliorating beta-cell dysfunction and improving glycemic control [12]. Further research should aim to confirm the clinical translation of these preclinical findings by optimizing melatonin dosage, timing of administration, and selection of appropriate cohorts to derive maximal synergistic benefits from the melatonin-insulin interplay [22].

Recent studies suggest that melatonin may regulate glucose homeostasis by modulating key regulatory proteins involved in cellular glucose uptake and subsequent metabolism (Table 1) [9,10]. Melatonin has been found to increase the expression of mRNA and protein expression of the prominent glucose transporters GLUT1, GLUT3, and GLUT4 in various tissues [10,17]. The increased glucose influx via GLUT4 has been linked to the insulin-sensitizing effects of melatonin under metabolic conditions [23]. Melatonin increases glucose uptake into cells by activating receptor-mediated IRS-PI3k-Akt signaling and inducing translocation of GLUT transporters to the plasma membrane [10]. In addition, melatonin upregulates rate-limiting glycolytic enzymes such as hexokinase, phosphofructokinase, and pyruvate kinase to further enhance downstream glucose metabolism. Melatonin has the potential to improve cellular glucose utilization and reduce excessive postprandial glucose spikes by affecting proteins that regulate glucose uptake and glycolysis [9,10,20]. This is particularly relevant in diabetes, where glycolytic defects and impaired GLUT functionality may accelerate glycemic dysregulation [13]. Overall, the synergistic effects of indoleamine on proteins that support glucose influx and glycolysis make it an attractive adjunctive strategy for optimizing glycemic control in metabolic disease [10]. Ongoing research should continue to determine the optimal melatonin doses for clinical translation of these mechanistic benefits.

Mitochondria are essential for energy production through oxidative phosphorylation [14]. Melatonin may play a protective role in maintaining cellular energy homeostasis [14,24], as well as inhibiting oxidative stress, a pathological condition that may contribute to the onset of mitochondrial dysfunction (Table 1) [14,19]. In addition to its antioxidant properties, it appears to affect the dynamics of mitochondrial biogenesis and autophagy [14,25]. It has been associated with the upregulation of critical regulators of mitochondrial biogenesis, such as the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which promote the formation of new mitochondria [24,26]. Concurrently, melatonin may also enhance mitophagy, the selective autophagic turnover of damaged mitochondria, thereby maintaining a healthy population of mitochondria in cells [27,28]. The interaction between the hormone and mitochondrial function extends to the regulation of the mitochondrial membrane potential, which is an indicator of mitochondrial health and function. Melatonin helps maintain this potential by ensuring efficient adenosine triphosphate (ATP) production, which is essential for various cellular processes that require energy [23,24]. In addition, melatonin stabilizes the inner mitochondrial membrane, preventing the release of cytochrome c, a pro-apoptotic factor, and thereby inhibiting cell death pathways [24,29]. Through these effects, melatonin is implicated in the regulation of cellular energy metabolism [23]. It affects enzymes involved in the glycolytic pathway, which impacts metabolic flux and energy yield [13]. This modulation is crucial under conditions of metabolic stress, where the presence of melatonin can shift cellular metabolism to a more protective state, ensuring energy conservation and reducing the generation of potentially harmful by-products [17]. The association of melatonin with mitochondrial function has potential therapeutic implications for a wide range of diseases in which mitochondrial dysfunction is a contributing factor, such as metabolic disorders [9,10], neurodegenerative diseases [13], and aging [16]. The hormone’s ability to increase mitochondrial efficiency and protect against oxidative damage may provide a basis for novel interventions aimed at restoring energy balance in diseased or aging cells [24,26]. In summary, the association between melatonin and mitochondrial function is an important aspect of its biological activity. Protective effects of melatonin on mitochondrial integrity and function contribute to its role in maintaining cellular energy balance. This relationship holds promise for the development of therapeutic strategies targeting mitochondrialrelated diseases and conditions characterized by altered energy homeostasis. However, further research is needed to fully understand these interactions and their implications for clinical practice.

Adipocyte differentiation, or adipogenesis, is the process by which pre-adipocytes, or undifferentiated fibroblast-like cells, become mature adipocytes [11,18]. These cells specialize in storing energy as fat and are essential for maintaining energy homeostasis in the body [31,32]. Adipogenesis plays an important role in obesity and related metabolic disorders [31]. Recent studies have implicated melatonin in adipocyte differentiation and fat accumulation (Table 1) [29,33]. This association is particularly relevant in the context of the global rise in obesity rates and metabolic syndrome, which are conditions characterized by increased adiposity [1-3]. Moreover, studies suggest that melatonin may modulate adipogenesis by interacting with melatonin receptors present on preadipocytes and triggering a cascade of intracellular signals that influence cell differentiation [11,23,34]. In vitro studies have shown that melatonin can inhibit the differentiation of preadipocytes by downregulating the expression of key adipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein alpha (C/EBPα), which are critical for the initiation and maintenance of the adipogenic program (Table 1) [11,23,30,34]. The antiadipogenic effect of melatonin is also thought to involve the modulation of the signaling pathways such as the Wnt/β-catenin pathway, which plays a pivotal role in maintaining preadipocytes in an undifferentiated state [34,35]. By activating this pathway, melatonin may contribute to the inhibition of adipocyte differentiation.

Melatonin affects lipid metabolism within adipocytes, including the enzymes responsible for lipogenesis and lipolysis [22,23], the processes of fat formation and breakdown, respectively. Studies suggest that melatonin may reduce the activity of lipogenic enzymes, resulting in decreased triglyceride uptake and synthesis within adipocytes [22]. In addition, the role of melatonin as a regulator of circadian rhythms is also relevant to adiposity [30,33]. By maintaining proper circadian function, melatonin helps synchronize metabolic processes, including those related to energy expenditure and fat storage. Further human studies are necessary to confirm the efficacy and safety of melatonin in modulating adipocyte differentiation and fat accumulation. Additionally, it is important to understand the appropriate dosage and timing of administration.

Adipose-derived mesenchymal stem cells (AMSCs) are multipotent stem cells derived from adipose tissue, the body’s storage of fat. They have gained attention in the scientific community for their potential in regenerative medicine. Under certain conditions, AMSCs can differentiate into various cell types, including adipocytes, osteoblasts, chondrocytes, myocytes, and potentially other cell types [32]. The important role of AMSCs in tissue regeneration has been emphasized by a significant amount of evidence, positioning them as a promising therapeutic option [31,32].

Melatonin has been found to enhance the adipogenic differentiation of mesenchymal stem cells (MSCs) by increasing key transcription factors such as PPARγ and C/EBPα [11,17]. It influences adipogenesis by regulating the expression of key adipocyte marker genes such as adiponectin and leptin, which are important for the terminal differentiation and functional maturation of adipocytes derived from MSCs [36]. Additionally, it exhibits anti-proliferative effects on adipose MSCs, modulating cell cycle progression [35].

Melatonin has been shown to reduce cellular senescence in MSCs and preserve their functionality and regenerative potential. It also has anti-inflammatory effects on adipose MSCs by suppressing the release of pro-inflammatory cytokines, which is important for creating a conducive microenvironment for regenerative processes [16,37,38]. Melatonin affects signaling pathways such as nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), by inhibiting their activation and reducing inflammation within the MSC niche [29,34]. Additionally, melatonin enhances the angiogenic potential of adipose MSCs by upregulating genes associated with angiogenesis, which contributes to improved vascularization in regenerating tissues [39]. It influences the signaling pathways of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2), promoting angiogenesis and facilitating the integration of transplanted MSCs into damaged tissues [39].

The cellular responses to melatonin are mediated by the presence of melatonin receptors, particularly MT1 and MT2, on adipose MSCs [12,29]. The observed effects are orchestrated by intracellular signaling cascades by receptor activation. These findings not only enhance our understanding of cellular dynamics but also provide opportunities for improving the therapeutic potential of adipose MSCs in regenerative medicine. This highlights the significance of melatonin as a crucial regulator in cellular therapy [11].

Melatonin has been increasingly implicated in the modulation of lipid metabolism enzymes and transport proteins in humans [34,36]. This association is of great interest due to the critical role that lipid metabolism plays in overall metabolic health and disease [9,16]. The effect of melatonin on lipid metabolism can be observed through its interaction with various enzymes and transport proteins that are essential to lipid homeostasis. The hormone has been found to exert influence both directly and indirectly, through various signaling pathways and receptor-mediated mechanisms [33]. One of the primary enzymes in cholesterol biosynthesis is hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase). Melatonin inhibits the activity of this enzyme, possibly through its antioxidant properties or through melatonin receptors expressed in the liver [40]. It may lower the synthesis of cholesterol by reducing the activity of HMG-CoA reductase, which can have a favorable impact on lipid profiles [40,41]. Additionally, melatonin targets lipoprotein lipase (LPL), a key enzyme responsible for the hydrolysis of triglycerides in the bloodstream, facilitating their uptake by fat and muscle tissue [29,42]. Previous studies have suggested that melatonin may enhance LPL activity, which potentially reduces the risk of atherosclerosis and cardiovascular disease by accelerating the clearance of triglycerides from the plasma [10,26,43].

Melatonin is thought to interact with adipocytes, affecting the expression and function of proteins involved in fatty acid uptake and storage along the lipid metabolism pathway [19,23]. This passage discusses the downregulation of transport proteins such as fatty acid transport protein (FATP), and the promotion of pathways that favor lipid mobilization over storage, thereby possibly contributing to a reduction in visceral fat accumulation [42,44,45]. It may encourage the use of fatty acids as an energy source by influencing these enzymes, rather than storing them as body fat. The role of melatonin as an antioxidant is well-documented, providing protection against lipid peroxidation. This process occurs when free radicals attack lipids, leading to cell damage and contributing to the development of atherosclerosis [19,40,43]. Through its ability to scavenge free radicals, melatonin may help maintain the lipid integrity and reduce oxidative stress on the cardiovascular system.

In summary, the influence of melatonin on lipid metabolism enzymes and transport proteins suggests its potential role in regulating lipid homeostasis in humans. Although the underlying mechanisms are becoming clearer, further investigation is required to translate these effects into clinical practice. Further research, particularly randomized controlled trials, is necessary to gain a better understanding of the therapeutic potential of melatonin in lipid metabolism and its potential benefits for metabolic health.

It has been suggested that melatonin plays a role in regulating body weight and obesity. Extensive research has been conducted into potential regulatory mechanisms and treatments for obesity, with melatonin emerging as an area of particular interest. The regulation of body weight is primarily determined by energy balance, which may be influenced by melatonin through its effects on both energy intake and expenditure. Melatonin is thought to activate brown adipose tissue (BAT), which is responsible for thermogenesis, the process of heat production in organisms (Table 2) [11,23]. This activation is thought to stimulate energy expenditure by increasing the expression of uncoupling proteins, such as UCP1 (Table 1), which enhances the thermogenic capacity of BAT [24,46]. This increased thermogenesis has the potential to counteract obesity. Recently, interesting studies also suggest that melatonin may enhance BAT activity, promoting thermogenesis and energy expenditure [18,46]. These findings open exciting avenues for exploring the potential role of melatonin in managing obesity and associated metabolic disorders. Nevertheless, melatonin induces hypothermia by modulating thermoregulatory centers in the brain during sleep. These contrasting effects may arise from different mechanisms and contexts (acute exposure versus circadian rhythms), reflecting the multifaced roles of melatonin. Consequently, further mechanistic data is required to elucidate these conflicting functions.

Appetite regulation is a complex process that involves multiple hormones signaling hunger and fullness to the brain [36,47]. Melatonin interacts with hormonal pathways, including those involving leptin and ghrelin [47]. By modulating the secretion and action of these hormones, melatonin could influence appe-tite and food intake, playing a role in controlling body weight. However, the findings are heterogeneous and do not allow for a robust conclusion [47].

The role of melatonin in maintaining circadian rhythms is also crucial for metabolic processes, which follow a diurnal pattern [33]. Circadian misalignment, which is often observed in shift workers and individuals with irregular sleep patterns, has been linked to metabolic dysregulation and obesity [30,33,47]. By realigning disrupted circadian rhythms, melatonin may help normalize metabolic rates and support weight regulation. Multiple population studies have shown that there is a negative correlation between circulating blood melatonin concentrations and measures of adiposity, such as body mass index (BMI) and abdominal obesity [48,49]. Additionally, obese individuals were also found to have lower levels of melatonin compared to nonobese matched controls [10,49,50]. Disruption of melatonin circadian rhythms, such as in nighttime shift work and social jet lag, has also been associated with increased adiposity [51,52]. These epidemiological data link impaired melatonin status to the development of an obese phenotype. Based on the correlational data presented above, the potential of melatonin supplementation to combat obesity has been extensively studied in rodent models over the past two decades [19,41,45]. In various studies conducted on mice and rats with diet-induced obesity, melatonin administration consistently prevented a 15%–30% increase in body weight and completely inhibited visceral fat accumulation, even when a high-fat diet was consumed [17,45,53]. Although animal studies have shown that exogenous melatonin is effective against obesity, its translation to human clinical trials has been limited so far. Several preliminary studies have examined the effects of oral melatonin supplements on body weight and composition in overweight adults or various obese phenotypes [17,23,36]. However, it is important to note that these studies are preliminary, and further research is needed to determine the efficacy of melatonin supplementation in treating obesity in humans. Moreover, future studies should focus on the long-term effects of melatonin, exploring individual variability in response to melatonin, and examining its potential use in combination with lifestyle interventions for the prevention and management of obesity.

Melatonin has been shown to have multiple effects on inflammation, oxidative stress caused by reactive oxygen species (ROS), and metabolic disorders in humans (Table 1) [10,23]. Its significant antioxidant capabilities are demonstrated by its ability to directly scavenge ROS and increase the expression of antioxidant enzymes, thereby reducing oxidative stress, which is a contributing factor in the development of various metabolic disorders [16,24,33]. Inflammation is a common factor that links several metabolic disorders, such as obesity, diabetes, and cardiovascular diseases [3,17,54]. Melatonin’s anti-inflammatory effects are mediated by inhibiting the NF-κB pathway, which is central to the inflammatory response [16]. By modulating this pathway, melatonin can reduce the secretion of pro-inflammatory cytokines, thereby mitigating the inflammatory state associated with metabolic dysregulation. Oxidative stress and chronic inflammation are widely recognized as key contributors to the pathogenesis of metabolic disorders [3]. Therefore, potential therapeutic interventions have gained increased attention [3,13,54]. Melatonin is widely known for its potent antioxidant properties, which play a crucial role in the body’s defense against oxidative stress [22,24]. This state is characterized by an imbalance between the production of harmful free radicals and the ability to counteract their harmful effects in the human body. The antioxidant function of melatonin is attributed to its chemical structure, specifically the indole ring [22,26], which enables direct scavenging of a wide range of reactive oxygen and nitrogen species. Melatonin is unique among other antioxidants because of its ability to easily cross physiological barriers, such as the blood-brain barrier, due to its amphiphilic nature. This property allows it to reach all cells and protect them from oxidative damage [26]. Furthermore, melatonin acts as a free radical scavenger. It also exerts antioxidant effects indirectly by stimulating the expression of antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase [15]. To improve cellular defense mechanisms against oxidative stress, it is important to maintain mitochondrial function [14]. Melatonin present in mitochondria can help reduce oxidative harm, stabilize the electron transport chain, and maintain cellular energy balance [17,33]. The potent antioxidant properties of melatonin make it a crucial defender against oxidative stress in metabolic disorders such as type 2 diabetes and obesity, where elevated oxidative stress contributes to insulin resistance and impaired metabolic function [23,45,53].

Melatonin regulates various signaling pathways, including NF-κB, transforming growth factor-β (TGF-β), and MAPK, which are pivotal players in inflammation [16,55]. By inhibiting their activation, melatonin downregulates the expression of various pro-inflammatory cytokines [16]. Furthermore, recent studies have shown that melatonin also suppresses inflammasome activation, a crucial mediator of inflammation, by downregulating NLRP3 inflammasome components, thereby reducing the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18) [16,56].

Metabolic inflammation, also known as meta-inflammation, is a chronic low-grade inflammation that is associated with metabolic dysregulation and obesity in the human body [4,54]. Melatonin, a hormone that influences various cellular and molecular pathways, plays a significant role in regulating metabolic inflammation (Table 3) [23,33,56]. At the cellular level, melatonin influences the behavior of immune cells central to the inflammatory response. It regulates adhesion molecules to impede leukocyte adhesion to vascular endothelial cells [39,57]. This inhibits the recruitment of immune cells to sites of inflammation, mitigating the inflammatory response. Additionally, it downregulates the expression of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukins, which mitigates the chronic low-grade inflammation observed in metabolic disorders. This anti-inflammatory action is crucial for addressing the systemic inflammation linked to insulin resistance and metabolic dysfunction. Macrophages have a crucial role in controlling immune and inflammatory reactions [58]. They can polarize into two types: the classically pro-inflammatory M1 phenotype or the alternatively anti-inflammatory M2 phenotype. The imbalance between these M1/M2 activation states is often the cause of many chronic inflammatory diseases [16,59]. Melatonin has the potential to modulate macrophage polarization, which could have therapeutic implications. Recent studies suggest that melatonin may inhibit the activation of M1 macrophages and promote the M2 phenotype [56,59]. In lipopolysaccharide (LPS)-stimulated macrophages, melatonin suppresses the expression of M1 marker genes, including TNF-α, IL-1β, iNOS, and COX-2. This is achieved through the inhibition of NF-kB signaling, a key pathway driving M1 activation [59,60]. Additionally, melatonin upregulates M2 macrophage markers such as Arg-1, IL-10, and CD206 [59,61] and also activates STAT6 to induce M2 polarization and inhibits STAT1 involved in M1 progression [59]. Thus, as described above, these immunomodulatory effects of melatonin on macrophage phenotypes have generated interest in its potential therapeutic use for inflammatory diseases. For example, melatonin treatment has been shown to suppress endothelial inflammation and atherosclerosis development in animal models, which is associated with an increase in anti-inflammatory M2 macrophages in plaques [62,63].

Melatonin also modulates T-cell responses in the context of metabolic disorders [64]. T cells are a crucial component of the adaptive immune system and can be classified into subsets, including Th1, Th2, Th17, and regulatory T cells (Tregs), each with unique functions and cytokine production profiles. Th1 cells produce pro-inflammatory cytokines, such as interferon-gamma (IFN-γ), while Th2 cells produce anti-inflammatory cytokines, such as interleukin-4 (IL-4). Th17 cells are recognized to participate in autoimmune responses, while Tregs play a crucial role in maintaining immune tolerance and preventing autoimmunity. The balance of T helper cells, a type of T-cell crucial to immune response, can be specifically influenced by Th1 and Th2 cells. Th1 cells activate macrophages and promote cellular immunity, which is associated with inflammation. In contrast, Th2 cells promote humoral immunity, which is characterized by the production of antibodies and associated with anti-inflammatory responses. Metabolic disorders often involve an imbalance between Th1 and Th2 responses, with Th1 responses being overly dominant. Therefore, this imbalance results in increased metabolic inflammation, which can exacerbate the disorder. In the context of obesity and its associated metabolic dysfunction, melatonin has been found to have a beneficial effect on dampening inflammatory T cell responses. Studies on mouse models of dietinduced obesity have shown that melatonin inhibits the activation and proliferative capacity of both CD4+ and CD8+ T cells, resulting in an overall reduction in T cell-mediated inflammation in adipose tissue and circulation [54,65]. In addition, melatonin reduces the production of proinflammatory cytokines IFNγ and IL-17 from CD4+ T helper cell subsets Th1 and Th17. These cytokines are responsible for the inflammatory responses that lead to insulin resistance in metabolic disease [16,54,66]. On the other hand, melatonin promotes the production of the antiinflammatory cytokine IL-10 by regulatory T cells, which helps to suppress excessive inflammation [16,59]. Melatonin may modulate T lymphocytes by interfering with their signaling pathways, particularly the metabolic sensor mammalian target of rapamycin (mTOR) kinase [66]. The effect of melatonin on metabolic inflammation has produced inconsistent results in clinical studies. Several studies have shown beneficial effects on inflammatory markers, while others have shown minimal impact [66]. Further research is needed to optimize the dosage, timing, and understand the long-term effects of melatonin supplementation. Melatonin has potential therapeutic applications in managing metabolic inflammation due to its effects on immune cells, inflammatory pathways, antioxidant defense, and mitochondrial protection. However, translating these findings into clinical practice requires a more comprehensive and targeted approach.