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Melatonin and its Relationships with Diabetes and Obesity: A Literature Review
Abstract
Significance
Obesity is a multifactorial disease with many risks to public health, affecting 39.6% of American adults and 18.5% of young people. Brazil ranks fifth in the world ranking, with about 18 million obese people. It is estimated that 415 million people live with diabetes in the world, which is roughly 1 in 11 of the world's adult population. This is expected to rise to 642 million people living with diabetes worldwide by 2040. In this scenario, Melatonin has evidenced an important function in the regulation of energy metabolism.
Objective
to carry out a broad narrative review of the literature on the main aspects of the influence of melatonin on Diabetes Mellitus and obesity.
Methods
Article reviews, systematic reviews, prospective studies, retrospective studies, randomized, double-blind, placebo-controlled trials in humans recently published were selected and analyzed. A total of 368 articles were collated and submitted to the eligibility analysis. Subsequently, 215 studies were selected to compose the textual part of the manuscript and 153 to compose the Narrative Review.
Results and final considerations
Studies suggest a possible role of melatonin in metabolic diseases such as obesity, T2DM and metabolic syndrome. Intervention studies using this hormone in metabolic diseases are still unclear regarding a possible benefit of it. There is so far no consensus about a possible role of melatonin as an adjuvant in the treatment of metabolic diseases. More studies are necessary to define possible risks and benefits of melatonin as a therapeutic agent.
Objective: To explore the effects and the possible mechanism of electroacupuncture (EA) on diabetic bladder dysfunction (DBD) in streptozotocin-high fat diet (STZ-HFD) induced type 2 diabetes mellitus (T2DM) rats.
Methods: The experiment was divided into Control, diabetic bladder dysfunction, electroacupuncture, and Sham electroacupuncture group. After 8 weeks of electroacupuncture intervention, the body mass, 24 h urine volume, intraperitoneal glucose tolerance test (IPGTT), and urodynamics were detected. After the wet weight of the bladder was detected, the hematoxylin-eosin (HE), Masson’s trichrome, and TUNEL were used to analyze histological changes. The PACAP38 expressions in the bladder were detected by Real-time PCR and Western blot.
Results: Compared to the Control group, the bladder wet weight, 24 h urine volume, blood glucose, maximum bladder capacity, bladder compliance, bladder wall thickness, the smooth muscle/collagen ratio, and apoptosis rate of the diabetic bladder dysfunction group were significantly increased. Moreover, the body mass and leak point pressure were significantly reduced. Compared with the Sham electroacupuncture group, the bladder wet weight, maximum bladder capacity, bladder compliance, bladder wall thickness, and apoptosis rate of the electroacupuncture group were significantly reduced. In contrast, the leak point pressure was increased. The PACAP38 mRNA and PACAP38 protein expression of the diabetic bladder dysfunction group were significantly lower than the Control group, while electroacupuncture treatment could upregulate PACAP38 mRNA levels and PACAP38 protein expression of diabetic bladder dysfunction model rats.
Conclusion: electroacupuncture could ameliorate bladder dysfunction in the diabetic bladder dysfunction model rats by reversing bladder remodeling, which might be mainly mediated by regulating the PACAP38 level.
In recent days, the hike in obesity mediated epidemic across the globe and prevalence of obesity induced cardiovascular disease (CVD) has become one of the chief grounds of morbidity and mortality. This epidemic driven detrimental events in the cardiac tissues starts with the altered distribution and metabolism pattern of high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) leading to cholesterol (oxidized LDL) deposition on arterial wall and atherosclerotic plaque generation, followed by vascular spasm and infarction. Subsequently, obesity triggered metabolic malfunction induce free radical generation which may further trigger pro‐inflammatory signalling and nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) transcriptional factor, thus inducing interferon‐gamma (IFN‐γ), tumour necrosis factor‐alpha (TNF‐α), and inducible nitric oxide synthase (iNOS). This terrifying cardiomyopathy can be further aggravated in type 2 diabetes mellitus, thereby turning the obese diabetic patients prone towards the development of myocardial infarction or stroke in comparison to their non diabetic counterparts. The accelerated oxidative stress and pro‐inflammatory response induced cardiomyocyte hypertrophy, followed by apoptosis in obese diabetic individuals causes progression of athero‐thrombotic vascular disease. Being an efficient antioxidative and anti‐inflammatory indolamine, melatonin effectively inhibits lipid peroxidation (LPO), pro‐inflammatory reactions, thereby resolving free radical induced myocardial damages along with maintaining antioxidant reservoir to preserve cardiovascular integrity. Prolonged melatonin treatment maintains balanced body weight and serum total cholesterol (TC) concentration by inhibiting cholesterol synthesis and promoting cholesterol catabolism. Additionally, melatonin promotes macrophage polarization toward the anti‐inflammatory state, providing a proper shield during the recovery period. Therefore, the protective role of melatonin in maintaining the lipid metabolism homeostasis and blocking the atherosclerotic plaque rupture could be targeted as the possible therapeutic strategy for the management of obesity induced acute myocardial infarction (AMI). This review aimed at orchestrating the efficacy of melatonin in ameliorating irrevocable oxidative cardiovascular damage induced by the obesity‐ diabetes correlation. This article is protected by copyright. All rights reserved.
Melatonin (MT) has been reported to control and prevent Alzheimer's disease (AD) in the clinic; however, the effect and mechanism of MT on AD have not been specifically described. Therefore, the main purpose of this meta-analysis was to explore the effect and mechanism of MT on AD models by studying behavioural indicators and pathological features. Seven databases were searched and 583 articles were retrieved. Finally, nine studies (13 analyses, 294 animals) were included according to pre-set criteria. Three authors independently judged the selected literature and the methodological quality. Meta-analysis showed that MT markedly ameliorated the learning ability by reducing the escape latency (EL), and the memory deficit was significantly corrected by increasing the dwell time in the target quadrant and crossings over the platform location in the Morris Water Maze (MWM). Among the pathological features, subgroup analysis found that MT may ease the symptoms of AD mainly by reducing the deposition of Aβ40 and Aβ42 in the cortex. In addition, MT exerted a superior effect on ameliorating the learning ability of senescence-related and metabolic AD models, and corrected the memory deficit of the toxin-induced AD model. The study was registered at PROSPERO (CRD42021226594).
Objective: chronic sleep disturbance is a comorbid condition with arterial hypertension, often combined with affective disorders, anxiety, depression. Forced sleep deprivation in patients with hypertension indicates a high activity of the renin‑angiotensin‑aldosterone system (RAAS) and desynchronosis of biological rhythms caused by a probable deficit in melatonin secretion during the night. Timely elimination of any pathological process associated with insomnia and arterial hypertension (AH) in the early stages of its development is a prerequisite for the effectiveness of therapy. Therefore, initial therapy should help neutralize the adverse effects of RAAS and improve the 24‑hour blood pressure (BP) profile. The aim of this study was to determine the therapeutic effect of monotherapy with an angiotensin converting enzyme (ACE) inhibitor, As well as in combination with a synthetic analogue of melatonin, on the course of hypertension and parameters of systemic hemodynamics in patients with first degree hypertension with insomnia at the onset of the disease. Combined therapy with an ACE inhibitor and a synthetic analogue of MT in patients with hypertension and insomnia was accompanied by an improvement in the clinical state, achievement of the target blood pressure level in most patients, positive dynamics of central blood pressure parameters and indicators reflecting the rigidity of peripheral arteries.
Obesity is defined as a condition of abnormal or excessive fat accumulation in white adipose tissue that results from the exacerbated consumption of calories associated with low energy expenditure. Fat accumulation in both adipose tissue and other organs contributes to a systemic inflammation leading to the development of metabolic disorders such as type 2 diabetes, hypertension, and dyslipidemia. Melatonin is a potent antioxidant and improves inflammatory processes and energy metabolism. Using male mice fed a high-fat diet (HFD—59% fat from lard and soybean oil; 9:1) as an obesity model, we investigated the effects of melatonin supplementation on the prevention of obesity-associated complications through an analysis of plasma biochemical profile, body and fat depots mass, adipocytes size and inflammatory cytokines expression in epididymal (EPI) adipose depot. Melatonin prevented a gain of body weight and fat depot mass as well as adipocyte hypertrophy. Melatonin also reversed the increase of total cholesterol, triglycerides and LDL-cholesterol. In addition, this neurohormone was effective in completely decreasing the inflammatory cytokines leptin and resistin in plasma. In the EPI depot, melatonin reversed the increase of leptin, Il-6, Mcp-1 and Tnf-α triggered by obesity. These data allow us to infer that melatonin presents an anti-obesity effect since it acts to prevent the progression of pro-inflammatory markers in the epididymal adipose tissue together with a reduction in adiposity.
The human MT1 and MT2 melatonin receptors1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns³. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer³, and MT2 has also been implicated in type 2 diabetes4,5. Here we report X-ray free electron laser (XFEL) structures of the human MT2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon⁶ at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H2085.46A (superscripts represent the Ballesteros–Weinstein residue numbering nomenclature⁷) and N862.50D, obtained in complex with 2-PMT. Comparison of the structures of MT2 with a published structure⁸ of MT1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [³H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT1 and MT2, but in addition the MT2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT2. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.
Melatonin, a pineal hormone synthesized at night, is critical for the synchronization of circadian and seasonal rhythms, being a key regulator of energy metabolism in many animal species. Although studies in humans are lacking, several reports, mainly on hibernating animals, demonstrate that melatonin supplementation and short photoperiod increase brown adipose tissue (BAT) mass. The present proof-of-concept study is the first, to our knowledge, to evaluate BAT in melatonin non-proficient patients (radiotherapy or surgical removal of pineal gland) before and after daily melatonin (3 mg) replacement for three months. All four studied patients presented increased BAT volume and activity measured by PET-MRI. We also found an improvement in total cholesterol and triglycerides blood levels, without significant effects on body weight, liver fat, HDL and LDL levels. Albeit not statistically significant, fasting insulin levels and HOMA-IR decreased in all four patients. In conclusion, the present results show that oral melatonin replacement increases BAT volume and activity and improves blood lipids levels in melatonin non-proficient patients, being suggested as a possible BAT activator.
Future studies are warranted as hypomelatoninemia is usually present in aging and appears as a result of light-at-night exposure and/or the use of beta blocker drugs.
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 specie, pineal hormone melatonin is always produced during the night and its production and secretory episode duration is 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 focus on the above considerations, proposes a putative classification of clinical melatonin dysfunctions and discuss general guidelines to the therapeutic use of melatonin.
Background
Metabolic syndrome (MetS) is a cluster of metabolic risk factors which increases the chances for future cardiovascular diseases, as well as diabetes. The underlying causes of MetS include overweight and obesity, physical inactivity and genetic factors. Our intension here was to focus in this study on the importance of the chronobiology, represented by melatonin (MT) and cryptochrome 2 (CRY2), in developing MetS and type 2 diabetes mellitus (T2DM). Thus, we aimed to compare MT and CRY2 plasma levels and correlate both biomarkers with adiposity, atherogenicity and hematological indices in MetS and T2DM cohorts.
Methods
In a cross-sectional study, 28 normoglycemic lean subjects (controls), 29 normoglycemic MetS subjects and 30 MetS (pre-diabetic/diabetic) were recruited.
Results
MT (pg/mL) was elevated significantly in MetS arm p-value < 0.05, whereas CRY2 levels (ng/mL) were markedly higher in both MetS groups (non-diabetic and pre-diabetic/diabetic) (all with p-value < 0.001). A reciprocal MT-CRY2 relationship was observed in the MetS (non-diabetic) group (p-value = 0.003). Of note in the total study population, both MT and CRY2 proportionally correlated with each of the following: atherogenicity index of plasma (AIP), waist circumference (WC) and systolic blood pressure (SBP) (all with p-value < 0.05) for MT and CRY2, respectively). Whereas MT correlated inversely with high-density lipoprotein-cholesterol (HDL-C) (p-value < 0.05). Additionally, CRY2 correlated directly with each of the following: diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein (LDL-C), hip circumference (HC), body adiposity index (BAI), weight-to-height (WHtR) ratio, mean platelet volume (MPV) and platelet/lymphocyte ratio (PLR) (p-value < 0.05).
Conclusion
These findings substantiate that both metabolic risk biomarkers can be prognostic tools and pharmacotherapeutic targets to slowdown the accelerated nature of T2DM.
Melatonin (Mel), a molecule that conveys photoperiodic information to the organisms, is also involved in the regulation of energy homeostasis. Mechanisms of action of Mel in the energy balance remain unclear; herein we investigated how Mel regulates energy intake and expenditure to promote a proper energy balance. Male Wistar rats were assigned to control, control + Mel, pinealectomized (PINX) and PINX + Mel groups. To restore a 24-h rhythm, Mel (1 mg/kg) was added to the drinking water exclusively during the dark phase for 13 weeks. After this treatment period, rats were subjected to a 24-h fasting test, an acute leptin responsiveness test and cold challenge. Mel treatment reduced food intake, body weight, and adiposity. When challenged to 24-h fasting, Mel-treated rats also showed reduced hyperphagia when the food was replaced. Remarkably, PINX rats exhibited leptin resistance; this was likely related to the capacity of leptin to affect body weight, food intake, and hypothalamic signal-transducer and activator of transcription 3 phosphorylation, all of which were reduced. Mel treatment restored leptin sensitivity in PINX rats. An increased hypothalamic expression of agouti-related peptide (Agrp), neuropeptide Y, and Orexin was observed in the PINX group while Mel treatment reduced the expression of Agrp and Orexin. In addition, PINX rats presented lower UCP1 protein levels in the brown adipose tissue and required higher tail vasoconstriction to get a proper thermogenic response to cold challenge. Our findings reveal a previously unrecognized interaction of Mel and leptin in the hypothalamus to regulate the energy balance. These findings may help to explain the high incidence of metabolic diseases in individuals exposed to light at night.
PurposeA common variant of the melatonin receptor 1B (MTNR1B) gene has been related to increased signaling of melatonin, a hormone previously associated with body fatness mainly through effects on energy metabolism. We examined whether the MTNR1B variant affects changes of body fatness and composition in response to a dietary weight loss intervention. Methods
The MTNR1B rs10830963 variant was genotyped for 722 overweight and obese individuals, who were randomly assigned to one of four diets varying in macronutrient composition. Anthropometric and body composition measurements (DXA scan) were collected at baseline and at 6 and 24 months of follow-up. ResultsStatistically significant interactions were observed between the MTNR1B genotype and low-/high-fat diet on changes in weight, body mass index (BMI), waist circumference (WC) and total body fat (p interaction = 0.01, 0.02, 0.002 and 0.04, respectively), at 6 months of dietary intervention. In the low-fat diet group, increasing number of the sleep disruption-related G allele was significantly associated with a decrease in weight (p = 0.004), BMI (p = 0.005) and WC (p = 0.001). In the high-fat diet group, carrying the G allele was positively associated with changes in body fat (p = 0.03). At 2 years, the associations remained statistically significant for changes in body weight (p = 0.02), BMI (p = 0.02) and WC (p = 0.048) in the low-fat diet group, although the gene–diet interaction became less significant. Conclusions
The results suggest that carriers of the G allele of the MTNR1B rs10830963 may have a greater improvement in body adiposity and fat distribution when eating a low-fat diet.
The objective of our study was to determine the effect of melatonin administration on atypical antipsychotic-induced metabolic adverse effects in patients with psychiatric disorders. A systematic search was performed in PUBMED, Cochrane Library, Scopus, Web of Science, and EBSCOhost electronic databases. Randomized controlled trials studying the effect of melatonin on antipsychotic-induced metabolic adverse effects were identified and subjected to meta-analysis. Four studies were included in the meta-analysis, including 57 patients on melatonin and 61 patients on placebo. Melatonin produced a significant decrease in the diastolic blood pressure compared with placebo (mean difference = −4.44 [95% CI, −7.00 to −1.88]; p=0.0007 ; I2 = 13%), but not the systolic blood pressure (mean difference = −4.23 [95% CI, −8.11 to −0.36]; p=0.03 ; I2 = 0%). Although a decrease in the body mass index was seen in the melatonin group, the difference was not significant in the random-effects analysis model. To conclude, in patients on atypical antipsychotics, melatonin at a dose of up to 5 mg/day for a treatment duration of up to 12 weeks attenuated the rise in diastolic blood pressure compared with placebo but had no significant effects on other metabolic parameters.
Background:
Our aims were to evaluate critically the evidence from systematic reviews as well as narrative reviews of the effects of melatonin (MLT) on health and to identify the potential mechanisms of action involved.
Methods:
An umbrella review of the evidence across systematic reviews and narrative reviews of endogenous and exogenous (supplementation) MLT was undertaken. The Oxman checklist for assessing the methodological quality of the included systematic reviews was utilised. The following databases were searched: MEDLINE, EMBASE, Web of Science, CENTRAL, PsycINFO and CINAHL. In addition, reference lists were screened. We included reviews of the effects of MLT on any type of health-related outcome measure.
Results:
Altogether, 195 reviews met the inclusion criteria. Most were of low methodological quality (mean -4.5, standard deviation 6.7). Of those, 164 did not pool the data and were synthesised narratively (qualitatively) whereas the remaining 31 used meta-analytic techniques and were synthesised quantitatively. Seven meta-analyses were significant with P values less than 0.001 under the random-effects model. These pertained to sleep latency, pre-operative anxiety, prevention of agitation and risk of breast cancer.
Conclusions:
There is an abundance of reviews evaluating the effects of exogenous and endogenous MLT on health. In general, MLT has been shown to be associated with a wide variety of health outcomes in clinically and methodologically heterogeneous populations. Many reviews stressed the need for more high-quality randomised clinical trials to reduce the existing uncertainties.
Recent genetic studies have highlighted the potential involvement of melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) in the pathogenesis of type 2 diabetes. Here we report that mice lacking MT1 (MT1 KO) tend to accumulate more fat mass than WT mice and exhibit marked systemic insulin resistance. Additional experiments revealed that the main insulin signaling pathway affected by the loss of MT1 was the activation of phosphatidylinositol-3-kinase (PI3K). Transcripts of both catalytic and regulatory subunits of PI3K were strongly down-regulated within MT1 KO mice. Moreover, the suppression of nocturnal melatonin levels within WT mice, by exposing mice to constant light, resulted in impaired PI3K activity and insulin resistance during the day, similar to what was observed in MT1 KO mice. Inversely, administration of melatonin to WT mice exposed to constant light, was sufficient and necessary to restore insulin mediated PI3K activity and insulin sensitivity. Hence our data demonstrate that the activation of MT1 signaling at night modulates insulin sensitivity during the day via the regulation of the PI3K transcription and activity. Lastly we provide evidence that decreased expression of MTNR1A (MT1) in the liver of diabetic individuals is associated with poorly controlled diabetes.
Purpose of review:
Type 2 diabetes (T2D) is a complex genetic metabolic disorder. T2D heritability has been estimated around 40-70%. In the last decade, exponential progress has been made in identifying T2D genetic determinants, through genome-wide association studies (GWAS). Among single-nucleotide polymorphisms mostly associated with T2D risk, rs10830963 is located in the MTNR1B gene, encoding one of the two receptors of melatonin, a neurohormone involved in circadian rhythms. Subsequent studies aiming to disentangle the role of MTNR1B in T2D pathophysiology led to controversies. In this review, we will tackle them and will try to give some directions to get a better view of MTNR1B contribution to T2D pathophysiology.
Recent findings:
Recent studies either based on genetic/genomic analyses, clinical/epidemiology data, functional analyses at rs10830963 locus, insulin secretion assays in response to melatonin (involving or not MTNR1B) or animal model analyses have led to strong controversies at each level of interpretation. We discuss possible caveats in these studies and present ways to go beyond these issues, towards a better understanding of T2D molecular mechanisms, keeping in mind that melatonin is a versatile hormone and regulates many functions via its primary role in the body clock.
Significance
This paper describes the finding that mitochondria synthesize and release melatonin and have their selective G protein-coupled receptor (GPCR) in the outer membrane. We further demonstrate that mitochondrial melatonin type 1 receptors respond to melatonin by activating heterotrimeric G proteins located in the intermembrane space and inhibit stress-mediated cytochrome c release. This remarkable insight changes our classical understanding of biological GPCR function by showing that a cellular organelle both synthesizes and has a signaling receptor for a specific ligand. Implicit with our original work is the existence of an automitocrine signaling pathway by which melatonin prevents neurodegeneration associated with mitochondrial cytochrome c release and downstream caspase activation.
A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed.
Alzheimer’s disease (AD) is defined by the excessive accumulation of toxic peptides, such as beta amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFT). The risk factors associated with AD include genetic mutations, aging, insulin resistance, and oxidative stress. To date, several studies that have demonstrated an association between AD and diabetes have revealed that the common risk factors include insulin resistance, sleep disturbances, blood brain barrier (BBB) disruption, and altered glucose homeostasis. Many researchers have discovered that there are mechanisms common to both diabetes and AD. AD that results from insulin resistance in the brain is termed “type 3 diabetes”. Melatonin synthesized by the pineal gland is known to contribute to circadian rhythms, insulin resistance, protection of the BBB, and cell survival mechanisms. Here, we review the relationship between melatonin and type 3 diabetes, and suggest that melatonin might regulate the risk factors for type 3 diabetes. We suggest that melatonin is crucial for attenuating the onset of type 3 diabetes by intervening in Aβ accumulation, insulin resistance, glucose metabolism, and BBB permeability.
Background:
Melatonin is a molecule with numerous properties applicable to the treatment of neurological diseases. Among these properties are the following: potent scavenger of oxygen and nitrogen reactive species, anti-inflammatory features, immuno-enhancing nature, and modulation of circadian rhythmicity. Furthermore, low concentrations of melatonin are usually found in patients with neurological diseases and mental disorders. The positive results obtained in experimental models of diverse pathologies, including diseases of the nervous system (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, epilepsy, headaches, etc.) as well as mental and behavioural disordes (e.g., autism spectrum disorders, attention-deficit hyperactivity disorders, etc.), have served as a basis for the design of clinical trials to study melatonin's possible usefulness in human pathology, although the satisfactory results obtained from the laboratory "bench" are not always applicable to the patient's "bedside".
Objective:
In this article, we review those papers describing the results of the administration of melatonin to humans for various therapeutic purposes in the field of neuropathology.
Conclusion:
Clinical trials with strong methodologies and appropriate doses of melatonin are necessary to support or reject the usefulness of melatonin in neurological diseases.
Mammals receive light information through the eyes, which perform two major functions: image forming vision to see objects and non-image forming adaptation of physiology and behavior to light. Cone and rod photoreceptors form images and send the information via retinal ganglion cells to the brain for image reconstruction. In contrast, nonimage-forming photoresponses vary widely from adjustment of pupil diameter to adaptation of the circadian clock. nonimage-forming responses are mediated by retinal ganglion cells expressing the photopigment melanopsin. Melanopsin-expressing cells constitute 1–2% of retinal ganglion cells in the adult mammalian retina, are intrinsically photosensitive, and integrate photic information from rods and cones to control nonimage-forming adaptation. Action spectra of ipRGCs and of melanopsin photopigment peak around 480 nm blue light. Understanding melanopsin function lets us recognize considerable physiological effects of blue light, which is increasingly important in our modern society that uses light-emitting diode. Misalignment of circadian rhythmicity is observed in numerous conditions, including aging, and is thought to be involved in the development of age-related disorders, such as depression, diabetes, hypertension, obesity, and cancer. The appropriate regulation of circadian rhythmicity by proper lighting is therefore essential. This perspective introduces the potential risks of excessive blue light for human health through circadian rhythm disruption and sleep deprivation. Knowing the positive and negative aspects, this study claims the importance of being exposed to light at optimal times and intensities during the day, based on the concept of the circadian clock, ultimately to improve quality of life to have a healthy and longer life.
Insomnia is a serious worldwide health threat, affecting nearly one third of the general population. Melatonin has been reported to improve sleep efficiency and it was found that eating melatonin-rich foods could assist sleep. During the last decades, melatonin has been widely identified and qualified in various foods from fungi to animals and plants. Eggs and fish are higher melatonin-containing food groups in animal foods, whereas in plant foods, nuts are with the highest content of melatonin. Some kinds of mushrooms, cereals and germinated legumes or seeds are also good dietary sources of melatonin. It has been proved that the melatonin concentration in human serum could significantly increase after the consumption of melatonin containing food. Furthermore, studies show that melatonin exhibits many bioactivities, such as antioxidant activity, anti-inflammatory characteristics, boosting immunity, anticancer activity, cardiovascular protection, anti-diabetic, anti-obese, neuroprotective and anti-aging activity. This review summaries the dietary sources and bioactivities of melatonin, with special attention paid to the mechanisms of action.
Introduction
Brown adipose tissue (BAT) is a thermogenic organ with substantial metabolic capacity and has important roles in the maintenance of body weight and metabolism. Regulation of BAT is primarily mediated through the β-adrenoceptor (β-AR) pathway. The in vivo endocrine regulation of this pathway in humans is unknown. The objective of our study was to assess the in vivo BAT temperature responses to acute glucocorticoid administration.
Methods
We studied 8 healthy male volunteers, not pre-selected for BAT presence or activity and without prior BAT cold-activation, on two occasions, following an infusion with hydrocortisone (0.2 mg.kg− 1.min− 1 for 14 h) and saline, respectively. Infusions were given in a randomized double-blind order. They underwent assessment of supraclavicular BAT temperature using infrared thermography following a mixed meal, and during β-AR stimulation with isoprenaline (25 ng.kg fat-free mass− 1.min− 1 for 60 min) in the fasting state.
Results
During hydrocortisone infusion, BAT temperature increased both under fasting basal conditions and during β-AR stimulation. We observed a BAT temperature threshold, which was not exceeded despite maximal β-AR activation. We conclude that BAT thermogenesis is present in humans under near-normal conditions. Glucocorticoids modulate BAT function, representing important physiological endocrine regulation of body temperature at times of acute stress.
In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management.
Background:
Seasonal variations in physiology and behavior have frequently been reported. Light is the major zeitgeber for synchronizing internal circadian rhythms with the external solar day. Non-image forming effects of light radiation, for example, phase resetting of the circadian rhythms, melatonin suppression, and acute alerting effects, depend on several characteristics of the light exposure including intensity, timing and duration, spectral composition and previous light exposure, or light history. The aim of the present study was to report on the natural pattern of diurnal and seasonal light exposure and to examine seasonal variations in the circadian change of melatonin and cortisol concentrations for a group of Swedish office workers.
Methods:
Fifteen subjects participated in a field study that was carried out in the south of Sweden. Ambulatory equipment was used for monthly measurements of the daily exposure to light radiation across the year. The measurements included illuminance and irradiance. The subjects collected saliva samples every 4 h during 1 day of the monthly measuring period.
Results:
The results showed that there were large seasonal differences in daily amount of light exposure across the year. Seasonal differences were observed during the time periods 04:00-08:00, 08:00-12:00, 12:00-16:00, 16:00-20:00, and 20:00-24:00. Moreover, there were seasonal differences regarding the exposure pattern. The subjects were to a larger extent exposed to light in the afternoon/evening in the summer. During the winter, spring, and autumn, the subjects received much of the daily light exposure in the morning and early afternoon. Regarding melatonin, a seasonal variation was observed with a larger peak level during the winter and higher levels in the morning at 07:00.
Conclusions:
This study adds to the results from other naturalistic studies by reporting on the diurnal and seasonal light exposure patterns for a group living at a northern latitude of 56° N, with large annual variations in photoperiod length. It seems to be seasonal variation in the lighting conditions, both concerning intensities as well as regarding the pattern of the light exposure to which people living at high latitudes are exposed which may result in seasonal variation in the circadian profile of melatonin.
The discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased 18fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C–17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health.
Background & aims:
The risk allele (G) of rs10830963 in the melatonin receptor 1 B (MTNR1B) gene presents an association with biochemical parameters and obesity. We study the effect of this SNP on insulin resistance and weight loss secondary to two hypocaloric diets.
Methods:
270 obese subjects were randomly allocated during 9 months (Diet HP: a high protein/low carbohydrate vs. Diet S: a standard severe hypocaloric diets). Anthropometric parameters, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipid profile and adipocytokines levels were measured. Genotype of MTNR1B gene polymorphism (rs10830963) was evaluated.
Results:
All adiposity parameters, systolic blood pressure and leptin levels decreased in all subjects after both diets. This improvement of adiposity parameters was higher in non-G allele carriers than G allele carriers. After weight loss with Diet HP, (CC vs. CG + GG at 9 months); total cholesterol (delta: -9.9 ± 2.4 mg/dl vs. -4.8 ± 2.2 mg/dl:p < 0.05), LDL-cholesterol (delta: -8.3 ± 1.9 mg/dl vs. -5.1 ± 2.2 mg/dl: p < 0.05), insulin (delta: -4.7 ± 0.8 UI/L vs. -0.9 ± 1.0 UI/L: p < 0.05), triglycerides (delta: -17.7 ± 3.9 mg/dl vs. -6.1 ± 2.8 mg/dl: p < 0.05) and HOMA IR (delta: -0.8 ± 0.2 units vs. -0.2 ± 0.1 units: p < 0.05) improved only in no G allele carriers. After weight loss with Diet S in non G allele carriers, insulin levels (delta (CC vs. CG + GG): -3.4 ± 0.6 UI/L vs. -1.2 ± 0.4 UI/L: p < 0.05), triglycerides (delta: -29.2 ± 3.4 mg/dl vs. -8.2 ± 3.8 mg/dl: p < 0.05), HOMA-IR (delta (CC vs. CG + GG): -1.1 ± 0.2 units vs. -0.1 ± 0.1 units: p < 0.05), total cholesterol (delta: -15.9 ± 7.4 mg/dl vs. -5.8 ± 2.9 mg/dl:ns) and LDL-cholesterol (delta: -13.7 ± 5.9 mg/dl vs. -6.0 ± 2.9 mg/dl: ns) decreased, too.
Conclusions:
our study detected a relationship of rs10830963 variant of MTNR1B gene with adiposity changes, cholesterol changes and insulin resistance modification induced by two different hypocaloric during 9 months.
Background:
Epidemiological evidence suggests that melatonin has some effects on the serum lipid. However, these results are controversial. The aim of this systematic review and meta-analysis is to examine the effect of melatonin supplement on dyslipidemia and anthropometric indices.
Methods:
We searched electronic databases including Medline, Embase, Scopus, Web of Science and Cochrane Library up to Des 2018 without any language restriction. To compare the effects of melatonin with placebo, differences in standardized means difference (SMD) with 95% confidence intervals (95% CI) were pooled using random effects model.
Results:
Twelve trials including 641 participants included in meta-analysis finally. The dose of melatonin was reported at 0.8-30 mg. Comparing with the control group, melatonin may improve low density lipoprotein cholesterol (LDL-C) (-0.31 mmol/L, 95% CI (-0.61, 0.01), P = 0.049, I2 = 42%) and triglyceride (TG) level (SMD = -0.45 mmol/L; 95% CI, -0.77, -0.13, P = 0.006, I2 = 47%). No significant effect of melatonin on high density lipoprotein cholesterol (HDL-C) and anthropometric indices was found.
Conclusions:
The results of our systematic review and Meta-analyzes showed that supplementation of melatonin could be effective in improving lipid parameters and should be considered in the prevention of cardiovascular disease, although the effect of this supplement on anthropometric indices needs further investigation.
Despite considerable advances in the past few years, obesity and type 2 diabetes mellitus (T2DM) remain two major challenges for public health systems globally. In the past 9 years, genome-wide association studies (GWAS) have established a major role for genetic variation within the MTNR1B locus in regulating fasting plasma levels of glucose and in affecting the risk of T2DM. This discovery generated a major interest in the melatonergic system, in particular the melatonin MT2 receptor (which is encoded by MTNR1B). In this Review, we discuss the effect of melatonin and its receptors on glucose homeostasis, obesity and T2DM. Preclinical and clinical post-GWAS evidence of frequent and rare variants of the MTNR1B locus confirmed its importance in regulating glucose homeostasis and T2DM risk with minor effects on obesity. However, these studies did not solve the question of whether melatonin is beneficial or detrimental, an issue that will be discussed in the context of the peculiarities of the melatonergic system. Melatonin receptors might have therapeutic potential as they belong to the highly druggable G protein-coupled receptor superfamily. Clarifying the precise role of melatonin and its receptors on glucose homeostasis is urgent, as melatonin is widely used for other indications, either as a prescribed medication or as a supplement without medical prescription, in many countries in Europe and in the USA.
This systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to clarify the effect of melatonin supplementation on glycemic control. Databases including PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched until July 30th, 2018. Two reviewers independently assessed study eligibility, extracted data, and evaluated the risk of bias for included trials. Heterogeneity among included studies was assessed using Cochran’s Q test and I-square (I2) statistic. Data were pooled using random-effect models and standardized mean difference (SMD) was considered as the overall effect size. Twelve trials out of 292 selected reports were identified eligible to be included in current meta-analysis. The pooled findings indicated that melatonin supplementation significantly reduced fasting glucose (SMD=–6.34; 95% CI, –12.28, –0.40; p=0.04; I2: 65.0) and increased the quantitative insulin sensitivity check index (QUICKI) (SMD=0.01; 95% CI, 0.00, 0.02; p=0.01; I2: 0.0). However, melatonin administration did not significantly influence insulin levels (SMD=–1.03; 95% CI, –3.82, 1.77; p=0.47; I2: 0.53), homeostasis model assessment of insulin resistance (HOMA-IR) (SMD=–0.34; 95% CI, –1.25, 0.58; p=0.37; I2: 0.37) or HbA1c levels (SMD=–0.22; 95% CI, –0.47, 0.03; p=0.08; I2: 0.0). In summary, the current meta-analysis showed a promising effect of melatonin supplementation on glycemic control through reducing fasting glucose and increasing QUICKI, yet additional prospective studies are recommended, using higher supplementation doses and longer intervention period, to confirm the impact of melatonin on insulin levels, HOMA-IR and HbA1c.
There are several pathologies, syndromes and physiological processes in which autophagy is involved. This process of self‐digestion that cells trigger as a survival mechanism is complex and tightly regulated, according to the homeostatic conditions of the organ. However, in all cases, its relationship with oxidative stress alterations is evident, following a pathway that suggests endoplasmic reticulum stress and/or mitochondrial changes. There is accumulating evidence of the beneficial role that melatonin has in the regulation and restoration of damaged autophagic processes. In this review, we focus on major physiological changes such as aging and essential pathologies including cancer, neurodegenerative diseases, viral infections and obesity, and document the essential role of melatonin in the regulation of autophagy in each of these different situations.
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Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in MTNR1B, which encodes the melatonin receptor MT2, a G protein–coupled receptor (GPCR), are associated with an increased risk of type 2 diabetes (T2D). To identify specific T2D-associated signaling pathway(s), we profiled the signaling output of 40 MT2 variants by monitoring spontaneous (ligand-independent) and melatonin-induced activation of multiple signaling effectors. Genetic association analysis showed that defects in the melatonin-induced activation of Gαi1 and Gαz proteins and in spontaneous β-arrestin2 recruitment to MT2 were the most statistically significantly associated with an increased T2D risk. Computational variant impact prediction by in silico evolutionary lineage analysis strongly correlated with the measured phenotypic effect of each variant, providing a predictive tool for future studies on GPCR variants. Together, this large-scale functional study provides an operational framework for the postgenomic analysis of the multiple GPCR variants present in the human population. The association of T2D risk with signaling pathway–specific defects opens avenues for pathway-specific personalized therapeutic intervention and reveals the potential relevance of MT2 function during the day, when melatonin is undetectable, but spontaneous activity of the receptor occurs.
The review presents data on the dependence of endogenous melatonin synthesis on the time of day, age, pineal gland size, lighting conditions, administration of beta-blockers and a number of other medications. The results of studies on parasecretion and efficacy of exogenous melatonin use in sleep-wake cycle disturbances, insomnia, neurodegeneration, diabetes mellitus and oncological diseases are discussed.
Circadian rhythms are ubiquitous in biological systems and control metabolic processes throughout the body. Misalignment of these circadian rhythms increases risk of developing metabolic diseases. Thus, disruption of the circadian system has been proven to affect onset of type 2 diabetes mellitus (T2DM). In this context, the pineal indoleamine melatonin is a signaling molecule able to entrain circadian rhythms. There is mounting evidence that suggests a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Besides, several genetic association studies have causally associated various single nucleotide polymorphysms (SNPs) of human MT2 receptor with increased risk of developing T2DM. Taken together, these data suggest that endogenous as well as exogenous melatonin may influence diabetes and associated metabolic disturbances not only by regulating insulin secretion, but also by providing protection against reactive oxygen species (ROS), since pancreatic β-cells are very susceptible to oxidative stress due to their low antioxidant capacity.
Brown adipose tissue (BAT) plays a critical role in cold- and diet-induced thermogenesis. Although BAT is densely innervated by the sympathetic nervous system (SNS), little is known about the central nervous system (CNS) origins of this innervation. The purpose of the present experiment was to determine the neuroanatomic chain of functionally connected neurons from the CNS to BAT. A transneuronal viral tract tracer, Bartha's K strain of the pseudorabies virus (PRV), was injected into the interscapular BAT of Siberian hamsters. The animals were killed 4 and 6 days postinjection, and the infected neurons were visualized by immunocytochemistry. PRV-infected neurons were found in the spinal cord, brain stem, midbrain, and forebrain. The intensity of labeled neurons in the forebrain varied from heavy infections in the medial preoptic area and paraventricular hypothalamic nucleus to few infections in the ventromedial hypothalamic nucleus, with moderate infections in the suprachiasmatic and lateral hypothalamic nuclei. These results define the SNS outflow from the brain to BAT for the first time in any species.
Circadian misalignment is hypothesized to contribute to increased diabetes and obesity among shift workers and individuals with late sleep timing. Accordingly, the goal of our study was to identify-among normal and overweight/obese adults-associations between circadian timing (dim light melatonin onset; DLMO) and circadian misalignment (the interval between DLMO and sleep onset) with metabolic disease risk. This was a secondary analysis of data from a larger study. Participants ages 18 to 50 years without depression, diabetes, or shift work, with sleep duration 6.5 h or more, completed the following evaluations: 7 days of wrist actigraphy, circadian timing assessment (DLMO), and a fasting blood draw to measure glucose and insulin and calculate the Homeostatic Model of Assessment-Insulin Resistance (HOMA-IR). Data were analyzed using correlation and regression analyses controlling for age, sex, DLMO, and sleep duration. Analyses were conducted for the entire sample ( n = 54) and stratified by normal weight ( n = 36) and overweight/obese groups ( n = 18). Mean age was 26.4 years (SD = 7.1 years). Average sleep duration was 436.2 min (SD = 55.1 min), DLMO was 2250h (SD = 01:31), and interval between DLMO and sleep onset was 2 h 18 min (SD = 53 min). Average BMI was 24.3 kg/m2 (SD = 4.5 kg/m2). Circadian timing and interval between DLMO and sleep onset were not associated with glucose, insulin, or HOMA-IR in the main analyses. Among overweight/obese participants, a shorter interval between DLMO and sleep onset was associated with higher insulin ( B[SE] = -5.12 [2.24], p = 0.04) and HOMA-IR ( B[SE] = -1.32 [0.57], p = 0.04). Results of our multivariable model indicated that among overweight/obese participants, insulin was 5.1 pmol/L higher and HOMA was 1.3 µU/mL higher for every hour closer that sleep onset was to DLMO. The strengths of this study include the use of objective measures of circadian timing, but results should be considered hypothesis generating due to the small sample size and use of subgroup analyses.
Diabetic retinopathy (DR), a microvascular complication of diabetes mellitus (DM), remains as one of the major causes of vision loss worldwide. The release of pro-inflammatory cytokines and the adhesion of leukocytes to retinal capillaries are initial events in DR development. Inflammation, ER stress, oxidative stress and autophagy are major causative factors involved in the pathogenesis of DR. Diabetes associated hyperglycemia leads to mitochondrial electron transport chain dysfunction culminating in a rise in ROS generation. Since mitochondria are the major source of ROS production, oxidative stress induced by mitochondrial dysfunction also contributes to the development of diabetic retinopathy. Autophagy increases in the retina of diabetic patients and is regulated by ER stress, oxidative stress and inflammation-related pathways. Autophagy functions as a double-edged sword in DR. Under mild stress, autophagic activity can lead to cell survival while during severe stress, dysregulated autophagy results in massive cell death and may have a role in initiation and exacerbation of DR. Melatonin and its metabolites play protective roles against inflammation, ER stress and oxidative stress due to their direct free radical scavenger activities and indirect antioxidant activity via the stimulation antioxidant enzymes including glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase. Melatonin also acts as a cell survival agent by modulating autophagy in various cell types and under different conditions through amelioration of oxidative stress, ER stress and inflammation. Herein, we review the possible effects of melatonin on diabetic retinopathy, focusing on its ability to regulate autophagy processes.
Background & aims:
Melatonin supplementation may be associated with blood lipids improvement; however, the current evidence from randomized controlled trials (RCTs) is inconsistent. The present study aimed to systematically review and analyze RCTs assessing the effects of melatonin supplementation on blood lipids.
Methods:
A comprehensive literature search in several database was performed up to January 2017. Quantitative data synthesis was performed using a fixed or random-effects model, with weight mean difference (WMD) and 95% confidence intervals (CI). Standard methods were used for assessment of heterogeneity, meta-regression, sensitivity analysis and publication bias.
Results:
A total of 8 RCTs were eligible. Meta-analysis suggested a significant association between melatonin supplementation and a reduction in triglycerides (WMD: -31.54 mg/dL, 95% CI: -50.71, -12.38, p = 0.001), and total cholesterol levels (WMD: -18.48 mg/dL, 95% CI: -35.33, -1.63, p = 0.032), while no significant effect on LDL-C (WMD: -2.37 mg/dL, 95% CI: -11.61, -6.86, p = 0.615) and HDL-C (WMD: 1.28 mg/dL, 95% CI: -0.66, 3.23, p = 0.197) was found. In sub-group analysis, a significant decrease in triglycerides was found at doses ≥8 mg/d and when trials last ≥8 weeks. In addition, a significant decrease of total cholesterol was found at doses ≥8 mg/d and when total cholesterol baseline levels were ≥200 mg/dL.
Conclusions:
Melatonin supplementation has significant effects on triglycerides and total cholesterol levels, which was more evident in higher dose and longer duration and also in a higher concentration of cholesterol levels. Further studies are required to determine the benefits of melatonin on lipid profile.
Aim:
To investigate the effect of glucocorticoids on BAT function in humans MATERIALS & METHODS: In a randomised double-blind cross-over design, 13 healthy adults underwent 1 week of oral prednisolone (15mg/day) and placebo treatment with an intervening 2-week wash-out period. BAT function was assessed in response to cooling (19(0) C) and to a standardised meal, by measuring fluoro-deoxyglucose (FDG) uptake using Positron Emission Tomography-Computed Tomography and skin temperatures overlying the supraclavicular (SCL) BAT depots using infrared thermography. Postprandial energy and substrate metabolism was assessed by indirect calorimetry.
Results:
During cooling, prednisolone significantly reduced BAT FDG uptake (standardised uptake value, SUVmax, 6.1±2.2 vs 3.7±1.2; P<0.05) and SCL temperature (-0.45±0.1 vs -1.0±0.1(0) C; P<0.01) compared to placebo. Postprandially, prednisolone significantly blunted the rise in SCL temperature (+0.2±0.1 vs -0.3±0.1(0) C; P<0.05), enhanced energy production (+221±17 vs +283±27 kcal/day; P<0.01) and lipid synthesis (+16.3±3.2 vs +23.6±4.9 mg/min; P<0.05). The prednisolone-induced reduction in SCL temperature significantly correlated with the reduction in FDG uptake (r=0.65, P<0.05), while the increase in energy production significantly correlated with the increase in lipogenesis (r=0.6, P<0.05).
Conclusion:
Prolonged glucocorticoid suppresses the function of human BAT. The enhancement of energy production and lipogenesis in the face of reduced dissipation of energy as heat suggests that glucocorticoids channel energy towards fat storage after nutrient intake. This is a novel mechanism of glucocorticoid-induced obesity.
Physiological levels of glucocorticoids are required for proper metabolic control, and excessive glucocorticoid action has been linked to a variety of pandemic metabolic diseases. microRNA (miRNA)-19b plays a critical role in the pathogenesis of glucocorticoid-induced metabolic diseases. This study sought to explore the potential of miRNA-based therapeutics targeting adipose tissue. Our results showed that overexpressed miR-19b in stromal vascular fraction cells derived from subcutaneous adipose tissue had the same effects as dexamethasone treatment on the inhibition of adipose browning and oxygen consumption rate. The inhibition of miR-19b blocked dexamethasone -mediated suppression of the expression of browning marker genes as well as the oxygen consumption rate in differentiated stromal vascular fraction cells derived from subcutaneous and brown adipose tissue. While overexpressed miR-19b in stromal vascular fraction cells derived from brown adipose tissue also had the same effects as dexamethasone treatment on the inhibition of brown adipose differentiation and energy expenditure. Glucocorticoids transcriptionally regulate the expression of miR-19b via a glucocorticoid receptor-mediated direct DNA binding mechanism. This study confirmed that miR-19b is an essential target for glucocorticoid-mediated control of adipose tissue browning. It is hoped that the plasticity of the adipose organ can be exploited in the next generation of therapeutic strategies to combat the increasing incidence of metabolic diseases, including obesity and diabetes.
Introduction:
The use of second-generation atypical antipsychotics has an increasing role in the development of metabolic syndrome. However, these medications due to metabolic disorders can lead to an increased risk of cardiovascular disease and subsequently mortality as well as reduced adherence to treatment. The main objective of current study was to determine the ability of melatonin to reduce the metabolic effects of second-generation antipsychotics.
Methods:
This double blind controlled clinical trial was conducted on 100 patients aged 18-64 years old were treated with the second-generation antipsychotics for the first time. The patients were divided randomly into two groups of 50. The case group received slow-release melatonin at a dose of 3mg and the control group was given oral placebo at 8 p.m.
Results:
The findings in melatonin group indicated significantly increase of HDL and decreased fasting blood sugar and systolic blood pressure, as well as had statistically significant increase in waist circumference, weight and BMI compared with placebo group.
Conclusion:
According to the findings, it can be claimed that the addition of melatonin to atypical antipsychotics has led to a reduction in some of the metabolic effects of these drugs. In this study, HDL level was increased, and the mean systolic blood pressure and FBS were decreased in the melatonin group. Considering that these factors are contributing to cardiovascular disease as a leading cause of mortality in psychiatric patients, so the use of melatonin can reduce some of the medical effects of long-term treatment of atypical antipsychotics.
Changes in photoperiod length are transduced into neuroendocrine signals by melatonin (MEL) secreted by the pineal gland triggering seasonally adaptive responses in many animal species. Siberian hamsters, transferred from a long-day ‘summer-like’ photoperiod (LD) to a short-day ‘winter-like’ photoperiod (SD), exhibit a naturally-occurring reversal in obesity. Photoperiod-induced changes in adiposity are mediated by the duration of MEL secretion and can be mimicked by exogenously administered MEL into animals housed in LD. Evidence suggests that MEL increases the sympathetic nervous system (SNS) drive to white adipose tissue (WAT). Here, we investigated whether MEL-driven seasonally adaptive losses in body fat are associated with WAT lipolysis and browning. Hamsters were subcutaneously administered vehicle (LD + VEH) or 0.4 mg/kg MEL (LD + MEL) daily for 10 weeks while animals housed in SD served as a positive control. MEL and SD exposure significantly decreased the retroperitoneal (RWAT), inguinal (IWAT), epididymal (EWAT) WAT, food intake and caused testicular regression compared with the LD + VEH group. MEL/SD induced lipolysis in the IWAT and EWAT, browning of the RWAT, IWAT, and EWAT, and increased UCP1 expression in the IBAT. Additionally, MEL/SD significantly increased the number of shared MEL receptor 1a and dopamine beta-hydroxylase-immunoreactive neurons in discrete brain sites, notably the paraventricular hypothalamic nucleus, dorsomedial hypothalamic nucleus, arcuate nucleus, locus coeruleus and dorsal motor nucleus of vagus. Collectively, these findings support our hypothesis that SD-exposed Siberian hamsters undergo adaptive decreases in body adiposity due to SNS-stimulated lipid mobilization and generalized WAT browning.
Objective:
Melatonin has been widely studied in the treatment of sleep disorders and evidence is accumulating on a possible role for melatonin influencing mood. Our aim was to determine the efficacy and acceptability of melatonin for mood disorders.
Method:
We conducted a comprehensive systematic review of randomized clinical trials on patients with mood disorders, comparing melatonin to placebo.
Results:
Eight clinical trials were included; one study in bipolar, three in unipolar depression and four in seasonal affective disorder. We have only a small study on patients with bipolar disorder, while we have more studies testing melatonin as an augmentation strategy for depressive episodes in major depressive disorder and seasonal affective disorder. The acceptability and tolerability were good. We analyzed data from three trials on depressive episodes and found that the evidence for an effect of melatonin in improving mood symptoms is not significant (SMD = 0.37; 95% CI [-0.05, 0.37]; P = 0.09). The small sample size and the differences in methodology of the trials suggest that our results are based on data deriving from investigations occurring early in this field of study.
Conclusion:
There is no evidence for an effect of melatonin on mood disorders, but the results are not conclusive and justify further research.
DNA repair is responsible for maintaining the integrity of the genome. Perturbations in the DNA repair pathways have been identified in several human cancers. Thus, compounds targeting DNA damage response (DDR) hold great promise in cancer therapy. A great deal of effort, in pursuit of new anticancer drugs, has been devoted to understanding the basic mechanisms and functions of the cellular DNA repair machinery. Melatonin, a widely-produced indoleamine in all organisms is associated with a reduced risk of cancer and has multiple regulatory roles on the different aspects of the DDR and DNA repair. Herein, we have mainly discussed how defective components in different DNA repair machineries, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), nucleotide excision repair (NER) and finally DNA mismatch repair (MMR) can contribute to the risk of cancer. Melatonin biosynthesis, mode of action and antioxidant effects are reviewed along with the means by which the indoleamine regulates DDR at the transduction, mediation and functional levels. Finally, we summarize recent studies which illustrate how melatonin can be combined with DNA damaging agents to improve their efficacy in cancer therapy. This article is protected by copyright. All rights reserved.
Objectives:
We aimed to evaluate melatonin effectiveness in weight gain reduction following olanzapine use for 11-17-year-old bipolar disorder patients.
Experimental design:
Seventy-seven adolescent outpatients, subsequent to their initial diagnosis of bipolar I disorder by a psychiatrist, entered this study. After assessing inclusion and exclusion criteria, 48 patients consented to participate. Twenty-four patients were allocated to receive olanzapine, lithium carbonate, and melatonin, and 24 patients were allocated to receive olanzapine, lithium carbonate, and placebo by simple randomization. The Young Mania Rating Scale (YMRS) was performed at baseline. Before treatment and after 6 and 12 weeks of treatment, weight, height, and body mass index (BMI) were measured. Analysis of variance (ANOVA) with repeated measure and t-test were used to analyze data.
Principal observations:
Nineteen patients in each group finished the study and their data were entered for analysis. Mean rise in BMI in the melatonin group compared with placebo (2.45 vs. 3.25 respectively) was marginally significant (t = 1.936; df = 36; p = 0.061). ANOVA with repeated measure also showed a marginally significant difference (F = 3.74; df = 1; p = 0.061) between groups and across time in regard to BMI. Mean body weight rise in the melatonin group compared with the placebo group (5.8 kg vs. 8.2 kg respectively) was marginally significant (t = 1.923; df = 28; p = 0.065). ANOVA with repeated measure also showed a marginally significant difference (F = 3.73; df = 1.1; p = 0.056) between groups and across time for body weight.
Conclusions:
Coadministration of melatonin with olanzapine and lithium carbonate in adolescents with bipolar disorder could reduce the sharp weight gain side effect of these drugs to near significance.
Genome-wide association studies have detected an association between type 2 diabetes risk and a non-coding SNP located in MTNR1B, the gene encoding melatonin receptor 2 (MT2). Melatonin regulates circadian rhythms and sleep and associates with metabolic disorders. However, the mechanisms underlying these actions are still unclear. Functional genomic, animal and clinical studies have not reached the same conclusions: while some studies have reported that decreased melatonin signalling increases type 2 diabetes risk, others have found the opposite. In this commentary, we have tried to provide an explanation for these contradictions and we suggest how the community may progress to reach a unified picture of the effect of melatonin and its signalling on type 2 diabetes.
Of the associations of genetic variants with type 2 diabetes, the one of an SNP in an intron of the gene encoding the melatonin receptor 1B (MTNR1B) has been remarkably robust. Work from our group and others has provided support for a model where carriers of this risk G allele exhibit increased MTNR1B expression in islets of Langerhans. Most published studies to date favour that melatonin’s action on the beta cell is inhibition of insulin secretion. Hence, our model proposes that this inhibitory effect of melatonin is exaggerated in carriers of the MTNR1B risk G allele. This would explain why this genetic association causes reduced insulin secretion and greater risk of future type 2 diabetes, as has been observed in numerous studies. Concurrently, another body of work has shown that rare MTNR1B alleles, which could perturb receptor function, also associate with type 2 diabetes. In this commentary, it is suggested that such apparently conflicting observations can be reconciled by the fact that non-coding (intronic; frequent) and coding (exonic; rare) alleles of MTNR1B give rise to different phenotypes. Thus, altered gene transcription may explain why SNPs, which do not alter coding sequences, exhibit cell-specific effects. In contrast, SNPs that change protein sequences are more likely to exert generalised effects since an altered protein will appear in all cells expressing the gene.
Pineal melatonin secretion declines with aging, whereas visceral fat, plasma insulin, and plasma leptin tend to increase. We have previously demonstrated that daily melatonin administration at middle age suppressed male rat intraabdominal visceral fat, plasma leptin, and plasma insulin to youthful levels; the current study was designed to begin investigating mechanisms that mediate these responses. Melatonin (0.4 μg/ml) or vehicle was administered in the drinking water of 10-month-old male Sprague Dawley rats (18/treatment) for 12 weeks. Half (9/treatment) were then killed, and the other half were submitted to cross-over treatment for an additional 12 weeks. Twelve weeks of melatonin treatment decreased (P < 0.05) body weight (BW; by 7% relative to controls), relative intraabdominal adiposity (by 16%), plasma leptin (by 33%), and plasma insulin (by 25%) while increasing (P < 0.05) locomotor activity (by 19%), core body temperature (by 0.5 C), and morning plasma corticosterone (by 154%), restoring each of ...
Exposure to Artificial Light At Night (ALAN) results in a disruption of the circadian system, which is deleterious to health. In industrialized countries, 75% of the total workforce is estimated to have been involved in shift work and night work. Epidemiologic studies, mainly of nurses, have revealed an association between sustained night work and a 50–100% higher incidence of breast cancer. The potential and multifactorial mechanisms of the effects include the suppression of melatonin secretion by ALAN, sleep deprivation, and circadian disruption.
Epigenetic modifications, including methylation or acetylation as well as posttranscriptional modifications are mechanisms used by eukaryotic cells to increase the genome diversity in terms of differential gene expression and protein diversity. Among these modifying enzymes, sirtuins, a class III histone deacetylase (HDAC) enzymes are of particular importance. Sirtuins regulate the cell cycle, DNA repair, cell survival and apoptosis, thus having important roles in normal and cancer cells. Sirtuins can also regulate metabolic pathways by changing preference for glycolysis under aerobic conditions as well as glutaminolysis. These actions make sirtuins a major target in numerous physiological processes as well as in other contexts such as calorie restriction-induced antiaging, cancer or neurodegenerative disease. Interestingly melatonin, a nighttime-produced indole synthesized by pineal gland and many other organs, have important cytoprotective effects in many tissues including aging, neurodegerative diseases, immunomodulation and cancer. The pleiotropic actions of melatonin in different physiological and pathological conditions indicate that may be basic cellular targetd for the indole. Thus, much research has focused attention on the potential mechanisms of the indole in modulating expression and/or activity of sirtuins. Numerous findings report a rise in activity, especially on SIRT1, in a diversity of cells and animal models after melatonin treatment. This contrasts, however, with data reporting an inhibitory effect of melatonin on this sirtuin in some tumor cells. This review tabulates and discusses the recent findings relating melatonin with sirtuins, particularly SIRT1 and mitochondrial SIRT3, showing the apparent dichotomy with the differential actions documented in normal and in cancer cells. This article is protected by copyright. All rights reserved.
Gestational diabetes mellitus (GDM) is glucose intolerance detected during pregnancy. The MTNR1B gene is the genetic locus associated with type 2 diabetes, that may affect insulin secretion and pancreatic glucose sensing. In this study, we examined the association between MTNR1A (rs2119882) and MTNR1B (rs10830963, rs4753426) gene polymorphisms and the risk of GDM. According to the results of their oral glucose tolerance test (OGTT), the women were divided into two groups: 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance (NGT). There were no statistically significant differences in the distribution of MTNR1A rs2119882 and MTNR1B rs4753426 genotypes and alleles between women with GDM and healthy pregnant women. With regard to the MTNR1B rs10830963 polymorphism, we observed a statistically significant prevalence of GG and CG genotypes and the G allele among pregnant women with GDM (GG + CG vs CC, OR 1.50, 95% CI 1.02-2.22, p = 0.04; G vs C, OR 1.43, 95% CI 1.07-1.90, p = 0.016). In a multivariate logistic regression analysis, a higher number of MTNR1B rs10830963 G alleles was an independent significant predictor of a higher risk of GDM. The results of our study indicate that MTNR1B rs10830963 polymorphism is associated with GDM susceptibility, and women with a higher number of G alleles have an increased risk of GDM development.
Background
Disturbance of the circadian rhythm has been associated with disease states, such as metabolic disorders, depression and cancer. Quantification of the circadian markers such as melatonin and cortisol critically depend on reliable and reproducible analytical methods. Previously, melatonin and cortisol were primarily analyzed separately, mainly using immunoassays.
Methods
Here we describe the validation and application of a high-throughput liquid chromatography in combination with mass spectrometry (LC-MS/MS) method for the combined analysis of melatonin and cortisol in plasma and saliva. The LC-MS/MS method was validated according to international validation guidelines. We used this method to analyze total plasma, free plasma (as obtained by equilibrium dialysis) and saliva melatonin and cortisol in healthy adults.
Results
Validation results for plasma and saliva melatonin and cortisol were well within the international validation criteria. We observed no difference between saliva collected by passive drooling or Salivette. Moreover, we noted a significant difference in saliva vs. free plasma melatonin. We observed on average 36% (95% CI: 4%–60%) higher salivary melatonin levels in comparison to free plasma melatonin, suggestive of local production of melatonin in the salivary glands.
Conclusions
The novel outcome of this study is probably due to the high precision of our LC-MS/MS assay. These outcomes illustrate the added value of accurate and sensitive mass spectrometry based methods for the quantification of neuroendocrine biomarkers.
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