Abstract
Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and ...paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain-acting molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and discusses general guidelines to the therapeutic use of melatonin.
Melatonin is a ubiquitous molecule in nature, being locally synthesized in several cells and tissues, besides being a hormone that is centrally produced in the pineal gland of vertebrates, ...particularly in mammals. Its pineal synthesis is timed by the suprachiasmatic nucleus, that is synchronized to the light-dark cycle via the retinohypothalamic tract, placing melatonin synthesis at night, provided its dark. This unique trait turns melatonin into an internal synchronizer that adequately times the organism's physiology to the daily and seasonal demands. Besides being amphiphilic, melatonin presents specific mechanisms and ways of action devoted to its role as a time-giving agent, being widely spread in the organism. The present review aims to focus on melatonin as a pineal hormone with specific mechanisms and ways of action, besides presenting the clinical syndromes related to its synthesis and/or function disruptions.
Recent studies have highlighted the involvement of melatonin in the regulation of energy homeostasis. In this study, we report that mice lacking melatonin receptor 1 (MT1KO) gained more weight, had a ...higher cumulative food intake, and were more hyperphagic after fasting compared to controls (WT). In response to a leptin injection, MT1KO mice showed a diminished reduction in body weight and food intake. To evaluate hypothalamic leptin signaling, we tested leptin‐induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3). Leptin failed to induce STAT3 phosphorylation in MT1KO mice beyond levels observed in mice injected with phosphate‐buffered saline (PBS). Furthermore, STAT3 phosphorylation within the arcuate nucleus (ARH) was decreased in MT1KO mice. Leptin receptor mRNA levels in the hypothalamus of MT1KO were significantly reduced (about 50%) compared to WT. This study shows that: (a) MT1 deficiency causes weight gain and increased food intake; (b) a lack of MT1 signaling induces leptin resistance; (c) leptin resistance is ARH region‐specific; and (d) leptin resistance is likely due to down‐regulation of the leptin receptor. Our data demonstrate that MT1 signaling is an important modulator of leptin signaling.
In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the ...melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists' actions as cardioprotective therapeutic agents.
Diabetes mellitus (DM) leads to complications, the majority of which are nephropathy, retinopathy, and neuropathy. Redox imbalance and inflammation are important components of the pathophysiology of ...these complications. Many studies have been conducted to find a specific treatment for these neural complications, and some of them have investigated the therapeutic potential of melatonin (MEL), an anti-inflammatory agent and powerful antioxidant. In the present article, we review studies published over the past 21 years on the therapeutic efficacy of MEL in the treatment of DM-induced neural complications. Reports suggest that there is a real prospect of using MEL as an adjuvant treatment for hypoglycemic agents. However, analysis shows that there is a wide range of approaches regarding the doses used, duration of treatment, and treatment times in relation to the temporal course of DM. This wide range hinders an objective analysis of advances and prospective vision of the paths to be followed for the unequivocal establishment of parameters to be used in an eventual therapeutic validation of MEL in neural complications of DM.
The cerebrospinal fluid melatonin is released from the pineal gland, directly into the third ventricle, or produced de novo in the brain from extrapineal melatonin sources leading to a melatonin ...concentration gradient in the cerebrospinal fluid. Despite the interest on this topic, the brain areas capable of producing melatonin are not yet clear. Bearing this in mind, we hypothesized that the choroid plexus (CP) could be one of these melatonin sources. We analyzed and confirmed the presence of the four enzymes required for melatonin synthesis in rat CP and demonstrated that arylalkylamine N‐acetyltransferase shows a circadian expression in female and male rat CP. Specifically, this enzyme colocalizes with mitochondria in rat CP epithelial cells, an organelle known to be involved in melatonin function and synthesis. Then, we demonstrated that melatonin is synthesized by porcine CP explants, although without a circadian pattern. In conclusion, our data show that the CP is a local source of melatonin to the central nervous system, probably contributing to its high levels in the cerebrospinal fluid. We believe that in the CP, melatonin might be regulated by its endogenous clock machinery and by the hormonal background.
Shift workers experience chronic circadian misalignment, which can manifest itself in reduced melatonin production, and has been associated with metabolic disorders. In addition, chronotype modulates ...the effect of night shift work, with early types presenting greater circadian misalignment when working night shift as compared to late types. Melatonin supplementation has shown positive results reducing weight gain in animal models, but the effect of exogenous melatonin in humans on body weight in the context of shift work remains inconsistent. The aim of this study was thus to evaluate the effects of exogenous melatonin on circadian misalignment and body weight among overweight night shift workers, according to chronotype, under real‐life conditions. We conducted a double‐blind, randomized, placebo‐controlled, crossover trial where melatonin (3 mg) or placebo was administered on non‐night shift nights for 12 weeks in 27 female nurses (37.1 yo, ±5.9 yo; BMI 29.9 kg/m2, ±3.3 kg/m2). Melatonin (or placebo) was only taken on nights when the participants did not work night shifts, that is, on nights when they slept (between night shifts and on days off). Composite Phase Deviations (CPD) of actigraphy‐based mid‐sleep timing were calculated to measure circadian misalignment. The analyses were performed for the whole group and by chronotype. We found approximately 20% reduction in circadian misalignment after exogenous melatonin administration considering all chronotypes. Moreover, melatonin supplementation in those who presented high circadian misalignment, as observed in early chronotypes, reduced body weight, BMI, waist circumference, and hip circumference, without any change in the participants’ calorie intake or physical activity levels.
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Despite the evolving advances in clinical approaches to obesity and its inherent comorbidities, the therapeutic challenge persists. Among several pharmacological tools already ...investigated, recent studies suggest that melatonin supplementation could be an efficient therapeutic approach in the context of obesity. In the present review, we have amalgamated the evidence so far available on physiological effects of melatonin supplementation in obesity therapies, addressing its effects upon neuroendocrine systems, cardiometabolic biomarkers and body composition. Most studies herein appraised employed melatonin supplementation at dosages ranging from 1 to 20 mg/day, and most studies followed up participants for periods from 3 weeks to 12 months. Overall, it was observed that melatonin plays an important role in glycaemic homeostasis, in addition to modulation of white adipose tissue activity and lipid metabolism, and mitochondrial activity. Additionally, melatonin increases brown adipose tissue volume and activity, and its antioxidant and anti-inflammatory properties have also been demonstrated. There appears to be a role for melatonin in adiposity reduction; however, several questions remain unanswered, for example melatonin baseline levels in obesity, and whether any seeming hypomelatonaemia or melatonin irresponsiveness could be clarifying factors. Supplementation dosage studies and more thorough clinical trials are needed to ascertain not only the relevance of such findings but also the efficacy of melatonin supplementation.
Melatonin has a number of beneficial metabolic actions and reduced levels of melatonin may contribute to type 2 diabetes. The present study investigated the metabolic pathways involved in the effects ...of melatonin on mitochondrial function and insulin resistance in rat skeletal muscle. The effect of melatonin was tested both in vitro in isolated rats skeletal muscle cells and in vivo using pinealectomized rats (PNX). Insulin resistance was induced in vitro by treating primary rat skeletal muscle cells with palmitic acid for 24 hr. Insulin‐stimulated glucose uptake was reduced by palmitic acid followed by decreased phosphorylation of AKT which was prevented my melatonin. Palmitic acid reduced mitochondrial respiration, genes involved in mitochondrial biogenesis and the levels of tricarboxylic acid cycle intermediates whereas melatonin counteracted all these parameters in insulin‐resistant cells. Melatonin treatment increases CAMKII and p‐CREB but had no effect on p‐AMPK. Silencing of CREB protein by siRNA reduced mitochondrial respiration mimicking the effect of palmitic acid and prevented melatonin‐induced increase in p‐AKT in palmitic acid‐treated cells. PNX rats exhibited mild glucose intolerance, decreased energy expenditure and decreased p‐AKT, mitochondrial respiration, and p‐CREB and PGC‐1 alpha levels in skeletal muscle which were restored by melatonin treatment in PNX rats. In summary, we showed that melatonin could prevent mitochondrial dysfunction and insulin resistance via activation of CREB‐PGC‐1 alpha pathway. Thus, the present work shows that melatonin play an important role in skeletal muscle mitochondrial function which could explain some of the beneficial effects of melatonin in insulin resistance states.
Brown adipose tissue (BAT) influences energy balance through nonshivering thermogenesis, and its metabolism daily and seasonal variations are regulated by melatonin through partially known ...mechanisms. We evaluated the role of melatonin in BAT molecular machinery of male Control, pinealectomized (PINX), and melatonin‐treated pinealectomized (PINX/Mel) adult rats. BAT was collected either every 3 hours over 24 hours or after cold or high‐fat diet (HFD) acute exposure. HFD PINX animals presented decreased Dio2 expression, while HFD PINX/Mel animals showed increased Dio2, Ucp1, and Cidea expression. Cold‐exposed PINX rats showed decreased Dio2 and Lhs expression, and melatonin treatment augmented Adrβ3, Dio2, Ucp1, and Cidea expression. Daily profiles analyses showed altered Dio2, Lhs, Ucp1, Pgc1α, and Cidea gene and UCP1 protein expression in PINX animals, leading to altered rhythmicity under sub‐thermoneutral conditions, which was partially restored by melatonin treatment. The same was observed for mitochondrial complexes I, II, and IV protein expression and enzyme activity. Melatonin absence seems to impair BAT responses to metabolic challenges, and melatonin replacement reverses this effect, with additional increase in the expression of crucial genes, suggesting that melatonin plays an important role in several key points of the thermogenic activation pathway, influencing both the rhythmic profile of the tissue and its ability to respond to metabolic challenges, which is crucial for the organism homeostasis.
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