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Sheibani M, Hosseinzadeh A, Fatemi I, Naeini AJ, Mehrzadi S. Practical application of melatonin for pancreas disorders: protective roles against inflammation, malignancy, and dysfunctions. Pharmacol Rep 2025; 77:315-332. [PMID: 39604705 DOI: 10.1007/s43440-024-00683-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 11/22/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024]
Abstract
Melatonin, a hormone primarily produced by the pineal gland, exhibits a range of physiological functions that extend beyond its well-known role in regulating circadian rhythms. This hormone influences energy metabolism, modulates insulin sensitivity, and plays a significant role in controlling sleep patterns and food intake. Notably, melatonin is also synthesized in various peripheral organs, including the gastrointestinal system and pancreas, suggesting its function as a local hormone. The presence of melatonin receptors in the pancreas underscores its relevance in pancreatic physiology. Pancreatic disorders, such as diabetes mellitus (DM), pancreatitis, and pancreatic cancer, often stem from inflammatory processes. The majority of these conditions are characterized by dysregulated immune responses and oxidative stress. Melatonin's anti-inflammatory properties are mediated through the inhibition of pro-inflammatory cytokines and the activation of antioxidant enzymes, which help to mitigate cellular damage. Furthermore, melatonin has demonstrated pro-apoptotic effects on cancer cells, promoting cell death in malignant tissues while preserving healthy cells. Thus, melatonin emerges as a multifaceted agent with significant therapeutic potential for pancreatic disorders. Its ability to reduce inflammation and oxidative stress positions it as a promising adjunct therapy for conditions such as diabetes mellitus, pancreatitis, and pancreatic cancer. By modulating immune responses and enhancing cellular resilience through antioxidant mechanisms, melatonin not only addresses the symptoms but also targets the underlying pathophysiological processes associated with these disorders. This review aims to categorize and summarize the impacts of melatonin on pancreatic functions and disorders, emphasizing its potential as a therapeutic agent for managing pancreatic dysfunctions. Future research should focus on elucidating the precise mechanisms by which melatonin exerts its protective effects on pancreatic tissues and exploring optimal dosing strategies for clinical applications. The integration of melatonin into treatment regimens may enhance existing therapies and offer new hope for individuals suffering from pancreatic dysfunctions.
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Affiliation(s)
- Mohammad Sheibani
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Iman Fatemi
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Islamic Republic of Iran
| | - Ali Jamshidi Naeini
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Wang S, Cheng X, Liang Z, Chen Z, Zhang J, Xu Q. Nocturnal Light Pollution Synergistically Impairs Glucose Metabolism With Age and Weight in Monkeys. J Diabetes Res 2024; 2024:5112055. [PMID: 39950097 PMCID: PMC11824604 DOI: 10.1155/2024/5112055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/14/2024] [Indexed: 02/16/2025] Open
Abstract
Over the past decades, the global prevalence of Type 2 diabetes mellitus (T2D) and impaired glucose tolerance (IGT) has been increasing at an epidemic rate, yet the exact cause remains unknown. It is widely accepted that glucose metabolism can be impaired by circadian rhythms and sleep disturbances. Concurrently, exposures to light at night have been closely linked to circadian and sleep disturbances. However, there is no direct experiment on primates to demonstrate the precise extent of how serious light pollution impairs glucose metabolism, whether people will eventually become accustomed to this environment, and whether the pollution has synergistic impairing effects with aging and weight on glucose metabolism. To quantitatively address these questions, 137 cynomolgus were exposed to three distinct nocturnal light intensities for consecutive 10 months. Monthly glucose metabolism assessments were conducted. Data pertaining to the mortality rate of preexisting diabetes, incidence of light-induced diabetes and IGT, and alterations in insulin secretion were collected and analyzed. The results show that nocturnal light (1) caused premature deaths in individuals with preexisting diabetes; (2) intensity-dependently induced diabetes and IGT in previous healthy monkeys; (3) intensity-dependently reduced melatonin secretion; (4) had a synergistic impairing effect on glucose metabolism with aging and weight; and (5) although monkeys would eventually adapt to the environment, the disrupted glucose metabolism would not fully recover in most individuals. In conclusion, nocturnal light is associated with the global high prevalence of T2D and IGT. The harmful effects of light pollution on glucose metabolism are synergistic with age and weight.
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Affiliation(s)
- Shuxing Wang
- Department of Anatomy, Medical School, Foshan University, Foshan, Guangdong Province, China
| | - Xuange Cheng
- Department of Food and Pharmaceutical Sciences, Qingyuan Polytechnic, Panlong Park, Qingcheng District, Qingyuan City 511510, Guangdong Province, China
| | - Zihao Liang
- Qingyuan Hospital of Traditional Chinese Medicine, Qingyuan City, China
| | - Zhenyi Chen
- Primate Research Center, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
| | - Jiankai Zhang
- Department of Anatomy, Guangdong University, Dongguan, China
| | - Qiang Xu
- Primate Research Center, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, China
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Goyal V, Tosini G. Disruption of Melatonin Signaling Leads to Lipids Accumulation in the Liver of Melatonin Proficient Mice. J Pineal Res 2024; 76:e70007. [PMID: 39539075 DOI: 10.1111/jpi.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 11/01/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024]
Abstract
Melatonin signaling via melatonin receptor type 1 (MT1) and type 2 (MT2) plays an important role in the regulation of several physiological functions. Studies in rodents and humans have demonstrated that disruption of melatonin signaling may affect glucose metabolism, insulin sensitivity, and leptin levels. Accumulating experimental evidence also indicates that in rodents the administration of exogenous melatonin has a beneficial effect on the blood lipid levels. However, the molecular mechanism by which melatonin signaling may regulate lipids is still unclear. In addition, most of the studies with mice have been performed in melatonin-deficient mice by administering exogenous melatonin at supraphysiological doses. Hence the results of these studies may be greatly affected by these two factors. In this study, we report the effects of melatonin signaling removal on the liver biology and transcriptome using melatonin-proficient mice (C3H-f+/f+) in which MT1 or MT2 have been genetically ablated. Our data indicate that the absence of MT1 or MT2 signaling leads to disruption of the blood lipids profile and an increase in lipids deposition in the liver. These effects were more pronounced in the mice lacking MT1 than MT2. The gene expression profiles obtained with RNA-seq from the livers of the three genotypes revealed that removal of MT1 affected the transcription of 4255 genes (i.e., 40.6%). Conversely, the removal of MT2 affected the transcription of 1864 transcripts (i.e., 17.2%). Finally, we identified a group of 13 genes involved in lipids biology that may play a key role in the accumulation of lipids in the liver when melatonin signaling is disrupted. In conclusion, our study indicates that melatonin signaling is an important modulator of liver physiology and metabolism. Our study also indicated that the removal of MT1 signaling is more deleterious than MT2 removal.
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Affiliation(s)
- Varunika Goyal
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Neuroscience Institute, Atlanta, Georgia, USA
| | - Gianluca Tosini
- Department of Pharmacology and Toxicology, Morehouse School of Medicine, Neuroscience Institute, Atlanta, Georgia, USA
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Toledano A, Rodríguez-Casado A, Älvarez MI, Toledano-Díaz A. Alzheimer's Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models). Brain Sci 2024; 14:1101. [PMID: 39595866 PMCID: PMC11591712 DOI: 10.3390/brainsci14111101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND/OBJECTIVES Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy and are difficult to prevent and control when they develop. It has been known for many years that these diseases have many pathogenic aspects in common. We highlight in this review that neuroglial cells (astroglia, oligodendroglia, and microglia) play a vital role in the origin, clinical-pathological development, and course of brain neurodegeneration. Moreover, we include the new results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we are investigating. METHODS Critical bibliographic revision and biochemical neuropathological study of neuroglia in a T2D-AD model. RESULTS T2D and AD are not only "connected" by producing complex pathologies in the same individual (obesity, T2D, and AD), but they also have many common pathogenic mechanisms. These include insulin resistance, hyperinsulinemia, hyperglycemia, oxidative stress, mitochondrial dysfunction, and inflammation (both peripheral and central-or neuroinflammation). Cognitive impairment and AD are the maximum exponents of brain neurodegeneration in these pathological processes. both due to the dysfunctions induced by metabolic changes in peripheral tissues and inadequate neurotoxic responses to changes in the brain. In this review, we first analyze the common pathogenic mechanisms of obesity, T2D, and AD (and/or cerebral vascular dementia) that induce transcendental changes and responses in neuroglia. The relationships between T2D and AD discussed mainly focus on neuroglial responses. Next, we present neuroglial changes within their neuropathological context in diverse scenarios: (a) aging involution and neurodegenerative disorders, (b) human obesity and diabetes and obesity/diabetes models, (c) human AD and in AD models, and (d) human AD-T2D and AD-T2D models. An important part of the data presented comes from our own studies on humans and experimental models over the past few years. In the T2D-AD section, we included the results of a T2D-AD mouse model (APP+PS1 mice on a high-calorie diet) that we investigated, which showed that neuroglial dysfunctions (astrocytosis and microgliosis) manifest before the appearance of amyloid neuropathology, and that the amyloid pathology is greater than that presented by mice fed a normal, non-high-caloric diet A broad review is finally included on pharmacological, cellular, genic, and non-pharmacological (especially diet and lifestyle) neuroglial-related treatments, as well as clinical trials in a comparative way between T2D and AD. These neuroglial treatments need to be included in the multimodal/integral treatments of T2D and AD to achieve greater therapeutic efficacy in many millions of patients. CONCLUSIONS Neuroglial alterations (especially in astroglia and microglia, cornerstones of neuroinflammation) are markedly defining brain neurodegeneration in T2D and A, although there are some not significant differences between each of the studied pathologies. Neuroglial therapies are a very important and p. promising tool that are being developed to prevent and/or treat brain dysfunction in T2D-AD. The need for further research in two very different directions is evident: (a) characterization of the phenotypic changes of astrocytes and microglial cells in each region of the brain and in each phase of development of each isolated and associated pathology (single-cell studies are mandatory) to better understand the pathologies and define new therapeutic targets; (b) studying new therapeutic avenues to normalize the function of neuroglial cells (preventing neurotoxic responses and/or reversing them) in these pathologies, as well as the phenotypic characteristics in each moment of the course and place of the neurodegenerative process.
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Affiliation(s)
- Adolfo Toledano
- Instituto Cajal, CSIC, 28002 Madrid, Spain; (A.R.-C.); (M.I.Ä.)
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Jameson AN, Siemann JK, Grueter CA, Grueter B, McMahon DG. Effects of age and sex on photoperiod modulation of nucleus accumbens monoamine content and release in adolescence and adulthood. Neurobiol Sleep Circadian Rhythms 2024; 16:100103. [PMID: 38585223 PMCID: PMC10990739 DOI: 10.1016/j.nbscr.2024.100103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/22/2024] [Accepted: 03/22/2024] [Indexed: 04/09/2024] Open
Abstract
Day length, or photoperiod, is a reliable environmental cue encoded by the brain's circadian clock that indicates changing seasons and induces seasonal biological processes. In humans, photoperiod, age, and sex have been linked to seasonality in neuropsychiatric disorders, as seen in Seasonal Affective Disorder, Major Depressive Disorder, and Bipolar Disorder. The nucleus accumbens is a key locus for the regulation of motivated behaviors and neuropsychiatric disorders. Using periadolescent and young adult male and female mice, here we assessed photoperiod's effect on serotonin and dopamine tissue content in the nucleus accumbens core, as well as on accumbal synaptic dopamine release and uptake. We found greater serotonin and dopamine tissue content in the nucleus accumbens from young adult mice raised in a Short winter-like photoperiod. In addition, dopamine release and clearance were greater in the nucleus accumbens from young adult mice raised in a Long summer-like photoperiod. Importantly, we found that photoperiod's effects on accumbal dopamine tissue content and release were sex-specific to young adult females. These findings support that in mice there are interactions across age, sex, and photoperiod that impact critical monoamine neuromodulators in the nucleus accumbens which may provide mechanistic insight into the age and sex dependencies in seasonality of neuropsychiatric disorders in humans.
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Affiliation(s)
- Alexis N. Jameson
- Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, 37232, USA
| | - Justin K. Siemann
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA
- Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, 37232, USA
| | - Carrie A. Grueter
- Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, 37232, USA
- Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN 37232, USA
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, 37232, USA
- Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA
| | - BradA. Grueter
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA
| | - Douglas G. McMahon
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, 37232, USA
- Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37232, USA
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McPartland M, Stevens S, Bartosova Z, Vardeberg IG, Völker J, Wagner M. Beyond the Nucleus: Plastic Chemicals Activate G Protein-Coupled Receptors. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:4872-4883. [PMID: 38440973 PMCID: PMC10956435 DOI: 10.1021/acs.est.3c08392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 02/05/2024] [Accepted: 02/16/2024] [Indexed: 03/06/2024]
Abstract
G protein-coupled receptors (GPCRs) are central mediators of cell signaling and physiological function. Despite their biological significance, GPCRs have not been widely studied in the field of toxicology. Herein, we investigated these receptors as novel targets of plastic chemicals using a high-throughput drug screening assay with 126 human non-olfactory GPCRs. In a first-pass screen, we tested the activity of triphenol phosphate, bisphenol A, and diethyl phthalate, as well as three real-world mixtures of chemicals extracted from plastic food packaging covering all major polymer types. We found 11 GPCR-chemical interactions, of which the chemical mixtures exhibited the most robust activity at adenosine receptor 1 (ADORA1) and melatonin receptor 1 (MTNR1A). We further confirm that polyvinyl chloride and polyurethane products contain ADORA1 or MTNRA1 agonists using a confirmatory secondary screen and pharmacological knockdown experiments. Finally, an analysis of the associated gene ontology terms suggests that ADORA1 and MTNR1A activation may be linked to downstream effects on circadian and metabolic processes. This work highlights that signaling disruption caused by plastic chemicals is broader than that previously believed and demonstrates the relevance of nongenomic pathways, which have, thus far, remained unexplored.
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Affiliation(s)
- Molly McPartland
- Department of Biology, Norwegian University of Science and Technology (NTNU), Trondheim 7491, Norway
| | - Sarah Stevens
- Department of Biology, Norwegian University of Science and Technology (NTNU), Trondheim 7491, Norway
| | - Zdenka Bartosova
- Department of Biology, Norwegian University of Science and Technology (NTNU), Trondheim 7491, Norway
| | - Ingrid Gisnås Vardeberg
- Department of Biology, Norwegian University of Science and Technology (NTNU), Trondheim 7491, Norway
| | | | - Martin Wagner
- Department of Biology, Norwegian University of Science and Technology (NTNU), Trondheim 7491, Norway
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Cardinali DP, Pandi-Perumal SR, Brown GM. Melatonin as a Chronobiotic and Cytoprotector in Non-communicable Diseases: More than an Antioxidant. Subcell Biochem 2024; 107:217-244. [PMID: 39693027 DOI: 10.1007/978-3-031-66768-8_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
A circadian disruption, manifested by disturbed sleep and low-grade inflammation, is commonly seen in noncommunicable diseases (NCDs). Cardiovascular, respiratory and renal disorders, diabetes and the metabolic syndrome, cancer, and neurodegenerative diseases are among the most common NCDs prevalent in today's 24-h/7 days Society. The decline in plasma melatonin, which is a conserved phylogenetic molecule across all known aerobic creatures, is a constant feature in NCDs. The daily evening melatonin surge synchronizes both the central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN) and myriads of cellular clocks in the periphery ("chronobiotic effect"). Melatonin is the prototypical endogenous chronobiotic agent. Several meta-analyses and consensus studies support the use of melatonin to treat sleep/wake cycle disturbances associated with NCDs. Melatonin also has cytoprotective properties, acting primarily not only as an antioxidant by buffering free radicals, but also by regulating inflammation, down-regulating pro-inflammatory cytokines, suppressing low-grade inflammation, and preventing insulin resistance, among other effects. Melatonin's phylogenetic conservation is explained by its versatility of effects. In animal models of NCDs, melatonin treatment prevents a wide range of low-inflammation-linked alterations. As a result, the therapeutic efficacy of melatonin as a chronobiotic/cytoprotective drug has been proposed. Sirtuins 1 and 3 are at the heart of melatonin's chronobiotic and cytoprotective function, acting as accessory components or downstream elements of circadian oscillators and exhibiting properties such as mitochondrial protection. Allometric calculations based on animal research show that melatonin's cytoprotective benefits may require high doses in humans (in the 100 mg/day range). If melatonin is expected to improve health in NCDs, the low doses currently used in clinical trials (i.e., 2-10 mg) are unlikely to be beneficial. Multicentre double-blind studies are required to determine the potential utility of melatonin in health promotion. Moreover, melatonin dosage and levels used should be re-evaluated based on preclinical research information.
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Affiliation(s)
- Daniel P Cardinali
- Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina.
| | - Seithikurippu R Pandi-Perumal
- Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
| | - Gregory M Brown
- Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
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Qin X, Fu Y, Fan J, Liu B, Liu P, Zhang Y, Jiang T, Zheng Q. Melatonin increases susceptibility to atrial fibrillation in obesity via Akt signaling impairment in response to lipid overload. J Pineal Res 2023; 74:e12851. [PMID: 36639364 DOI: 10.1111/jpi.12851] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 12/22/2022] [Accepted: 01/12/2023] [Indexed: 01/15/2023]
Abstract
Melatonin has been proven to have antiarrhythmic potential; however, several studies have recently challenged this view. Herein, using a mouse model of obesity-induced atrial fibrillation (AF), we tentatively explored whether exogenous melatonin supplementation could increase AF susceptibility in the context of obesity. We observed that an 8-week drinking administration of melatonin (60 µg/ml in water) induced a greater susceptibility to AF in obese mice, although obesity-induced structural remodeling was alleviated. An investigation of systemic insulin sensitivity showed that melatonin treatment improved insulin sensitivity in obese mice, whereas it inhibited glucose-stimulated insulin secretion. Notably, melatonin treatment inhibited protein kinase B (Akt) signaling in the atria of obese mice and palmitate-treated neonatal rat cardiomyocytes, thereby providing an AF substrate. Melatonin increased lipid stress in obesity, as evidenced by elevated lipid accumulation and lipolysis-related gene expression, thus contributing to the impairment in atrial Akt signaling. Taken together, our results demonstrated that melatonin could increase AF susceptibility in obesity, probably due to increased lipid stress and resultant impairment of atrial Akt signaling. Our findings suggest that special precautions should be taken when administering melatonin to obese subjects.
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Affiliation(s)
- Xinghua Qin
- Xi'an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Beilin District, Xi'an, Shaanxi, China
| | - Yuping Fu
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xincheng District, Xi'an, Shaanxi, China
| | - Jiali Fan
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xincheng District, Xi'an, Shaanxi, China
| | - Binghua Liu
- Xi'an Key Laboratory of Special Medicine and Health Engineering, School of Life Sciences, Northwestern Polytechnical University, Beilin District, Xi'an, Shaanxi, China
| | - Peng Liu
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xincheng District, Xi'an, Shaanxi, China
| | - Yudi Zhang
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xincheng District, Xi'an, Shaanxi, China
| | - Tiannan Jiang
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Qiangsun Zheng
- Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xincheng District, Xi'an, Shaanxi, China
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Obstructive Sleep Apnea, Circadian Clock Disruption, and Metabolic Consequences. Metabolites 2022; 13:metabo13010060. [PMID: 36676985 PMCID: PMC9863434 DOI: 10.3390/metabo13010060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Obstructive sleep apnea (OSA) is a chronic disorder characterized by recurrent episodes of apnea and hypopnea during sleep. It is associated with various cardiovascular and metabolic complications, including type 2 diabetes mellitus (T2DM) and obesity. Many pathways can be responsible for T2DM development in OSA patients, e.g., those related to HIF-1 and SIRT1 expression. Moreover, epigenetic mechanisms, such as miRNA181a or miRNA199, are postulated to play a pivotal role in this link. It has been proven that OSA increases the occurrence of circadian clock disruption, which is also a risk factor for metabolic disease development. Circadian clock disruption impairs the metabolism of glucose, lipids, and the secretion of bile acids. Therefore, OSA-induced circadian clock disruption may be a potential, complex, underlying pathway involved in developing and exacerbating metabolic diseases among OSA patients. The current paper summarizes the available information pertaining to the relationship between OSA and circadian clock disruption in the context of potential mechanisms leading to metabolic disorders.
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10
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Pfeffer M, von Gall C, Wicht H, Korf HW. The Role of the Melatoninergic System in Circadian and Seasonal Rhythms—Insights From Different Mouse Strains. Front Physiol 2022; 13:883637. [PMID: 35492605 PMCID: PMC9039042 DOI: 10.3389/fphys.2022.883637] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/22/2022] [Indexed: 01/01/2023] Open
Abstract
The melatoninergic system comprises the neurohormone melatonin and its molecular targets. The major source of melatonin is the pineal organ where melatonin is rhythmically produced during darkness. In mammals, melatonin biosynthesis is controlled by the central circadian rhythm generator in the suprachiasmatic nucleus (SCN) and photoreceptors in the retina. Melatonin elicits its function principally through two specific receptors called MT1 and MT2. MT1 is highly expressed in the SCN and the hypophysial pars tuberalis (PT), an important interface for control of seasonal functions. The expression of the MT2 is more widespread. The role of the melatoninergic system in the control of seasonal functions, such as reproduction, has been known for more than 4 decades, but investigations on its impact on the circadian system under normal (entrained) conditions started 2 decades later by comparing mouse strains with a fully functional melatoninergic system with mouse strains which either produce insufficient amounts of melatonin or lack the melatonin receptors MT1 and MT2. These studies revealed that an intact melatoninergic system is not required for the generation or maintenance of rhythmic behavior under physiological entrained conditions. As shown by jet lag experiments, the melatoninergic system facilitated faster re-entrainment of locomotor activity accompanied by a more rapid adaptation of the molecular clock work in the SCN. This action depended on MT2. Further studies indicated that the endogenous melatoninergic system stabilizes the locomotor activity under entrained conditions. Notably, these effects of the endogenous melatoninergic system are subtle, suggesting that other signals such as corticosterone or temperature contribute to the synchronization of locomotor activity. Outdoor experiments lasting for a whole year indicate a seasonal plasticity of the chronotype which depends on the melatoninergic system. The comparison between mice with an intact or a compromised melatoninergic system also points toward an impact of this system on sleep, memory and metabolism.
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Affiliation(s)
- Martina Pfeffer
- Institute of Anatomy II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
- *Correspondence: Martina Pfeffer,
| | - Charlotte von Gall
- Institute of Anatomy II, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Helmut Wicht
- Dr. Senckenbergische Anatomie II, Fachbereich Medizin der Goethe-Universität, Frankfurt am Main, Germany
| | - Horst-Werner Korf
- Institute of Anatomy I, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
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Miola A, Fornaro M, Sambataro F, Solmi M. Melatonin and melatonin-agonists for metabolic syndrome components in patients treated with antipsychotics: A systematic review and meta-analysis. Hum Psychopharmacol 2022; 37:e2821. [PMID: 34687076 DOI: 10.1002/hup.2821] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 09/27/2021] [Accepted: 09/28/2021] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Metabolic side effects are a limiting factor in the use of antipsychotics, which remain the cornerstone of long-term management of patients with severe mental illness. There is contrasting evidence on a possible role of melatonin and melatonin-agonists in attenuating antipsychotic-induced metabolic abnormalities. DESIGN We conducted a systematic review (PubMed, PsycInfo, Cochrane databases, up to August 2020) and a random-effect meta-analysis of double-blind, randomized placebo-controlled trials (RCTs) involving melatonin and melatonin-agonists in the treatment of antipsychotic-induced metabolic changes. The primary outcome was the standardized mean difference (SMD) of composite metabolic outcomes built with metabolic syndrome components. Secondary outcomes were individual metabolic syndrome components, and other anthropometric, glucose metabolism, lipid profile, and psychopathology measures. RESULTS Out of the initial 41 studies, six documented five separate RCTs randomizing 248 patients (126 to melatonin/ramelteon, 122 to placebo) affected by schizophrenia-spectrum disorders and bipolar disorder. Melatonin/ramelteon outperformed placebo on the primary outcome (SMD -0.28, 95% CI = -0.39 ÷ -0.168), as well as on all individual components of metabolic syndrome (systolic blood pressure MD -3.266, 95% CI = -6.020 ÷ -0.511; fasting glucose MD -3.766, 95% CI = -5.938 ÷ -1.593; triglycerides MD -9.800, 95% CI = -19.431 ÷ -0.169; HDL MD 2.995, 95% CI = 0.567 ÷ 5.423), except waist circumference. CONCLUSIONS Melatonin/ramelteon augmentation may be beneficial for non-anthropometric metabolic syndrome components in patients treated with antipsychotics.
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Affiliation(s)
- Alessandro Miola
- Department of Neuroscience, University of Padova, Padua, Italy.,Padua Neuroscience Center, University of Padova, Padua, Italy
| | - Michele Fornaro
- Section of Psychiatry, Department of Neuroscience, Reproductive Sciences and Dentistry, Federico II University, Naples, Italy
| | - Fabio Sambataro
- Department of Neuroscience, University of Padova, Padua, Italy.,Padua Neuroscience Center, University of Padova, Padua, Italy
| | - Marco Solmi
- Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada.,Department of Mental Health, The Ottawa Hospital, Ottawa, Ontario, Canada.,Clinical Epidemiology Program, Ottawa Hospital Research Institute (OHRI), University of Ottawa, Ottawa, Ontario, Canada
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12
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Interactions between nocturnal melatonin secretion, metabolism, and sleeping behavior in adolescents with obesity. Int J Obes (Lond) 2022; 46:1051-1058. [PMID: 35140394 PMCID: PMC9050511 DOI: 10.1038/s41366-022-01077-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 12/17/2021] [Accepted: 01/12/2022] [Indexed: 02/06/2023]
Abstract
Background/objectives Sleeping behavior and individual prospensity in sleep timing during a 24 h period, known as chronotypes, are underestimated factors, which may favor the development of obesity and metabolic diseases. Furthermore, melatonin is known to play an important role in circadian rhythm, but was also suggested to directly influence metabolism and bodyweight regulation. Since disturbed and shifted sleep rhythms have been observed in adolescents with obesity, this study aimed to investigate potential interactions between melatonin secretion, chronobiology, and metabolism. In addition, the influence of artificial light especially emitted by electronic devices on these parameters was of further interest. Subjects/methods We performed a cross-sectional study including 149 adolescents (mean age 14.7 ± 2.1 years) with obesity. Metabolic blood parameters (e.g., cholesterol, triglycerides, uric acid, and insulin) were obtained from patients and correlated with nocturnal melatonin secretion. Melatonin secretion was determined by measuring 6-sulfatoxymelatonin (MT6s), the major metabolite of melatonin in the first-morning urine, and normalized to urinary creatinine levels to account for the urinary concentration. Chronobiologic parameters were further assessed using the Munich ChronoType Questionnaire. Results Subjects with insulin resistance (n = 101) showed significantly lower nocturnal melatonin levels compared to those with unimpaired insulin secretion (p = 0.006). Furthermore, triglyceride (p = 0.012) and elevated uric acid levels (p = 0.029) showed significant associations with melatonin secretion. Patients with late chronotype showed a higher incidence of insulin resistance (p = 0.018). Moreover, late chronotype and social jetlag were associated with the time and duration of media consumption. Conclusion We identified an association of impaired energy metabolism and lower nocturnal melatonin secretion in addition to late chronotype and increased social jetlag (misalignment of biological and social clocks) in adolescents with obesity. This might point towards a crucial role of chronotype and melatonin secretion as risk factors for the development of pediatric and adolescent obesity.
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13
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Tse LH, Wong YH. Modeling the Heterodimer Interfaces of Melatonin Receptors. Front Cell Neurosci 2021; 15:725296. [PMID: 34690701 PMCID: PMC8529217 DOI: 10.3389/fncel.2021.725296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/16/2021] [Indexed: 11/16/2022] Open
Abstract
Melatonin receptors are Class A G protein-coupled receptors (GPCRs) that regulate a plethora of physiological activities in response to the rhythmic secretion of melatonin from the pineal gland. Melatonin is a key regulator in the control of circadian rhythm and has multiple functional roles in retinal physiology, memory, immunomodulation and tumorigenesis. The two subtypes of human melatonin receptors, termed MT1 and MT2, utilize overlapping signaling pathways although biased signaling properties have been reported in some cellular systems. With the emerging concept of GPCR dimerization, melatonin receptor heterodimers have been proposed to participate in system-biased signaling. Here, we used computational approaches to map the dimerization interfaces of known heterodimers of melatonin receptors, including MT1/MT2, MT1/GPR50, MT2/GPR50, and MT2/5-HT2C. By homology modeling and membrane protein docking analyses, we have identified putative preferred interface interactions within the different pairs of melatonin receptor dimers and provided plausible structural explanations for some of the unique pharmacological features of specific heterodimers previously reported. A thorough understanding of the molecular basis of melatonin receptor heterodimers may enable the development of new therapeutic approaches against aliments involving these heterodimeric receptors.
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Affiliation(s)
- Lap Hang Tse
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, SAR China
| | - Yung Hou Wong
- Division of Life Science and the Biotechnology Research Institute, Hong Kong University of Science and Technology, Hong Kong, SAR China.,State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, Hong Kong University of Science and Technology, Hong Kong, SAR China.,Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, SAR China
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14
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Hegron A, Huh E, Deupi X, Sokrat B, Gao W, Le Gouill C, Canouil M, Boissel M, Charpentier G, Roussel R, Balkau B, Froguel P, Plouffe B, Bonnefond A, Lichtarge O, Jockers R, Bouvier M. Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants. ACS Pharmacol Transl Sci 2021; 4:1614-1627. [PMID: 34661078 PMCID: PMC8507577 DOI: 10.1021/acsptsci.1c00157] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Indexed: 11/30/2022]
Abstract
Melatonin is a hormone mainly produced by the pineal gland and MT1 is one of the two G protein-coupled receptors (GPCRs) mediating its action. Despite an increasing number of available GPCR crystal structures, the molecular mechanism of activation of a large number of receptors, including MT1, remains poorly understood. The purpose of this study is to elucidate the structural elements involved in the process of MT1's activation using naturally occurring variants affecting its function. Thirty-six nonsynonymous variants, including 34 rare ones, were identified in MTNR1A (encoding MT1) from a cohort of 8687 individuals and their signaling profiles were characterized using Bioluminescence Resonance Energy Transfer-based sensors probing 11 different signaling pathways. Computational analysis of the experimental data allowed us to group the variants in clusters according to their signaling profiles and to analyze the position of each variant in the context of the three-dimensional structure of MT1 to link functional selectivity to structure. MT1 variant signaling profiles revealed three clusters characterized by (1) wild-type-like variants, (2) variants with selective defect of βarrestin-2 recruitment, and (3) severely defective variants on all pathways. Our structural analysis allows us to identify important regions for βarrestin-2 recruitment as well as for Gα12 and Gα15 activation. In addition to identifying MT1 domains differentially controlling the activation of the various signaling effectors, this study illustrates how natural variants can be used as tools to study the molecular mechanisms of receptor activation.
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Affiliation(s)
- Alan Hegron
- Université
de Paris, Institut Cochin, CNRS, INSERM, F-75014 Paris, France
- Department
of Biochemistry and Molecular Medicine, University de Montréal, Montreal, Quebec, H3T 1J4 Canada
- Institute
for Research in Immunology and Cancer, University
of Montreal, Montreal, Quebec, H3T 1J4 Canada
| | - Eunna Huh
- Department
of Pharmacology and Chemical Biology, Baylor
College of Medicine, Houston, Texas 77030, United States of America
| | - Xavier Deupi
- Laboratory
of Biomolecular Research, Paul Scherrer
Institute (PSI), 5232 Villigen, Switzerland
- Condensed
Matter Theory group, Paul Scherrer Institute
(PSI), 5232 Villigen, Switzerland
| | - Badr Sokrat
- Department
of Biochemistry and Molecular Medicine, University de Montréal, Montreal, Quebec, H3T 1J4 Canada
- Institute
for Research in Immunology and Cancer, University
of Montreal, Montreal, Quebec, H3T 1J4 Canada
| | - Wenwen Gao
- Université
de Paris, Institut Cochin, CNRS, INSERM, F-75014 Paris, France
| | - Christian Le Gouill
- Institute
for Research in Immunology and Cancer, University
of Montreal, Montreal, Quebec, H3T 1J4 Canada
| | - Mickaël Canouil
- Inserm
UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, 59000, France
- University
of Lille, Lille University
Hospital, Lille, 59000, France
| | - Mathilde Boissel
- Inserm
UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, 59000, France
- University
of Lille, Lille University
Hospital, Lille, 59000, France
| | - Guillaume Charpentier
- Centre d’Étude et de Recherche pour l’Intensification
du Traitement du Diabète, 91000, Evry, France
| | - Ronan Roussel
- Department
of Diabetology Endocrinology Nutrition, Hôpital Bichat, DHU FIRE, Assistance Publique Hôpitaux
de Paris, 75004 Paris, France
- Inserm U1138, Centre de Recherche des Cordeliers, 75006 Paris, France
- UFR de Médecine, University Paris
Diderot, Sorbonne Paris Cité, 75006 Paris, France
| | - Beverley Balkau
- Inserm U1018, Center for Research in Epidemiology and Population
Health, 94805 Villejuif, France
- University
Paris-Saclay, University Paris-Sud, 94270 Villejuif, France
| | - Philippe Froguel
- Inserm
UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, 59000, France
- University
of Lille, Lille University
Hospital, Lille, 59000, France
- Department
of Metabolism, Imperial College London, London, W12 0NN, United Kingdom
| | - Bianca Plouffe
- Department
of Biochemistry and Molecular Medicine, University de Montréal, Montreal, Quebec, H3T 1J4 Canada
- Institute
for Research in Immunology and Cancer, University
of Montreal, Montreal, Quebec, H3T 1J4 Canada
| | - Amélie Bonnefond
- Inserm
UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, 59000, France
- University
of Lille, Lille University
Hospital, Lille, 59000, France
- Department
of Metabolism, Imperial College London, London, W12 0NN, United Kingdom
| | - Olivier Lichtarge
- Department
of Pharmacology and Chemical Biology, Baylor
College of Medicine, Houston, Texas 77030, United States of America
- Department
of Molecular and Human Genetics, Baylor
College of Medicine, Houston, Texas 77030, United States
| | - Ralf Jockers
- Université
de Paris, Institut Cochin, CNRS, INSERM, F-75014 Paris, France
| | - Michel Bouvier
- Department
of Biochemistry and Molecular Medicine, University de Montréal, Montreal, Quebec, H3T 1J4 Canada
- Institute
for Research in Immunology and Cancer, University
of Montreal, Montreal, Quebec, H3T 1J4 Canada
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15
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Shah N, Abdalla MA, Deshmukh H, Sathyapalan T. Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice. Ther Adv Endocrinol Metab 2021; 12:20420188211042145. [PMID: 34589201 PMCID: PMC8474306 DOI: 10.1177/20420188211042145] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic, progressive, and multifaceted illness resulting in significant physical and psychological detriment to patients. As of 2019, 463 million people are estimated to be living with DM worldwide, out of which 90% have type-2 diabetes mellitus (T2DM). Over the years, significant progress has been made in identifying the risk factors for developing T2DM, understanding its pathophysiology and uncovering various metabolic pathways implicated in the disease process. This has culminated in the implementation of robust prevention programmes and the development of effective pharmacological agents, which have had a favourable impact on the management of T2DM in recent times. Despite these advances, the incidence and prevalence of T2DM continue to rise. Continuing research in improving efficacy, potency, delivery and reducing the adverse effect profile of currently available formulations is required to keep pace with this growing health challenge. Moreover, new metabolic pathways need to be targeted to produce novel pharmacotherapy to restore glucose homeostasis and address metabolic sequelae in patients with T2DM. We searched PubMed, MEDLINE, and Google Scholar databases for recently included agents and novel medication under development for treatment of T2DM. We discuss the pathophysiology of T2DM and review how the emerging anti-diabetic agents target the metabolic pathways involved. We also look at some of the limiting factors to developing new medication and the introduction of unique methods, including facilitating drug delivery to bypass some of these obstacles. However, despite the advances in the therapeutic options for the treatment of T2DM in recent years, the industry still lacks a curative agent.
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Affiliation(s)
- Najeeb Shah
- Hull University Teaching Hospitals NHS Trust,
Hull, UK
- Department of Academic Diabetes, Endocrinology
& Metabolism, Hull York Medical School, University of Hull, Brocklehurst
Building, 220-236 Anlaby Road, Hull, HU3 2RW, UK
| | - Mohammed Altigani Abdalla
- Department of Academic Diabetes, Endocrinology
& Metabolism, Hull York Medical School, University of Hull, Hull,
UK
| | - Harshal Deshmukh
- University Teaching Hospitals NHS Trust and
Department of Academic Diabetes, Endocrinology & Metabolism, Hull York
Medical School, University of Hull, Hull, UK
| | - Thozhukat Sathyapalan
- University Teaching Hospitals NHS Trust and
Department of Academic Diabetes, Endocrinology & Metabolism, Hull York
Medical School, University of Hull, Hull, UK
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16
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Veronesi VB, Pioli MR, de Souza DN, Teixeira CJ, Murata GM, Santos-Silva JC, Hecht FB, Vicente JM, Bordin S, Anhê GF. Agomelatine reduces circulating triacylglycerides and hepatic steatosis in fructose-treated rats. Biomed Pharmacother 2021; 141:111807. [PMID: 34120066 DOI: 10.1016/j.biopha.2021.111807] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/28/2021] [Accepted: 06/07/2021] [Indexed: 11/16/2022] Open
Abstract
Agomelatine (AGO) is an antidepressant drug with agonistic activity at melatonin receptor 1 (MT1) and MT2 and with neutral antagonistic activity at serotonin receptor 5-HT2C. Although experimental studies show that melatonin reduces hypertriglyceridemia and hepatic steatosis induced by excessive fructose intake, no studies have tested if AGO exerts similar actions. To address this issue we have treated male Wistar rats with fructose (15% in the drinking water) and/or AGO (40 mg/kg/day) for two weeks. AGO reduced body weight gain, feeding efficiency and hepatic lipid levels without affecting caloric intake in fructose-treated rats. AGO has also decreased very low-density lipoprotein (VLDL) production and circulating TAG levels after an oral load with olive oil. Accordingly, treatment with AGO reduced the hepatic expression of fatty acid synthase (Fasn), a limiting step for hepatic de novo lipogenesis (DNLG). The expression of apolipoprotein B (Apob) and microsomal triglyceride transfer protein (Mttp) in the ileum, two crucial proteins for intestinal lipoprotein production, were also downregulated by treatment with AGO. Altogether, the present data show that AGO mimics the metabolic benefits of melatonin when used in fructose-treated rats. This study also suggests that it is relevant to evaluate the potential of AGO to treat metabolic disorders in future clinical trials.
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Affiliation(s)
- Vanessa Barbosa Veronesi
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, 105 Alexander Flemming St., Zip Code: 13083-881, Campinas, SP, Brazil
| | - Mariana Rodrigues Pioli
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, 105 Alexander Flemming St., Zip Code: 13083-881, Campinas, SP, Brazil
| | - Dailson Nogueira de Souza
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, 105 Alexander Flemming St., Zip Code: 13083-881, Campinas, SP, Brazil
| | - Caio Jordão Teixeira
- Department of Physiology and Biophysics, Institute of Biomedical Science, University of Sao Paulo, 1524 Prof. Lineu Prestes Ave., ICB 1, Zip Code: 05508-000, Sao Paulo, SP, Brazil
| | - Gilson Masahiro Murata
- Department of Physiology and Biophysics, Institute of Biomedical Science, University of Sao Paulo, 1524 Prof. Lineu Prestes Ave., ICB 1, Zip Code: 05508-000, Sao Paulo, SP, Brazil
| | - Junia Carolina Santos-Silva
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, 105 Alexander Flemming St., Zip Code: 13083-881, Campinas, SP, Brazil
| | - Fernanda Ballerini Hecht
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, 105 Alexander Flemming St., Zip Code: 13083-881, Campinas, SP, Brazil
| | - Julia Modesto Vicente
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, 105 Alexander Flemming St., Zip Code: 13083-881, Campinas, SP, Brazil
| | - Silvana Bordin
- Department of Physiology and Biophysics, Institute of Biomedical Science, University of Sao Paulo, 1524 Prof. Lineu Prestes Ave., ICB 1, Zip Code: 05508-000, Sao Paulo, SP, Brazil
| | - Gabriel Forato Anhê
- Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, 105 Alexander Flemming St., Zip Code: 13083-881, Campinas, SP, Brazil.
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17
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Han SJ, Lee SH. Nontraditional Risk Factors for Obesity in Modern Society. J Obes Metab Syndr 2021; 30:93-103. [PMID: 34011693 PMCID: PMC8277595 DOI: 10.7570/jomes21004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/10/2021] [Accepted: 02/18/2021] [Indexed: 01/01/2023] Open
Abstract
Overweight and obesity, which have rapidly increased around the world in recent years, are significant health problems. They can lead to various morbidities, including cardiovascular diseases, cerebrovascular diseases, type 2 diabetes, some types of cancer, and even death. Obesity is caused by an energy imbalance due to excessive calorie intake and insufficient energy consumption, and genetic factors and individual behavioral problems are also known to be major contributing factors. However, these are insufficient to explain the surge in obesity that has occurred in recent decades. Recent studies have suggested that environmental factors arising from the process of socioeconomic development and modernization contribute to this phenomenon. These environmental factors include light pollution due to artificial lighting, air pollution, endocrine-disrupting chemicals, and reduced exposure to green spaces due to urbanization of residential areas. In this manuscript, the findings and mechanisms of these novel risk factors causing overweight and obesity are reviewed.
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Affiliation(s)
- Su-Jin Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Hwan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea
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18
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Li Z, Zheng M, Mo J, Li K, Yang X, Guo L, Zhang X, Abdalla BA, Nie Q. Single-cell RNA sequencing of preadipocytes reveals the cell fate heterogeneity induced by melatonin. J Pineal Res 2021; 70:e12725. [PMID: 33621367 DOI: 10.1111/jpi.12725] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 01/01/2021] [Accepted: 02/12/2021] [Indexed: 12/18/2022]
Abstract
Obesity is a global epidemic health disorder and associated with several diseases. Body weight-reducing effects of melatonin have been reported; however, no investigation toward examining whether the beneficial effects of melatonin are associated with preadipocyte heterogeneity has been reported. In this study, we profiled 25 071 transcriptomes of normal and melatonin-treated preadipocytes using scRNA-seq. By tSNE analysis, we present a cellular-state landscape for melatonin-treated preadipocytes that covers multiple-cell subpopulations, defined as cluster 0 to cluster 13. Cluster 0 and cluster 1 were the largest components of normal and melatonin-treated preadipocytes, respectively. G0S2, an inhibitor of adipose triglyceride lipase (ATGL), was significantly upregulated in cluster 0 and downregulated in cluster 1. We redefined cluster 0 as the G0S2-positive cluster (G0S2+ ) and cluster 1 as the G0S2-negative cluster (G0S2- ). Through pseudotime analysis, the G0S2- cluster cell differentiation trajectory was divided into three major structures, that is, the prebranch, the lipid catabolism branch, and the cell fate 2 branch. In vitro, G0S2 knockdown enhanced the expression levels of ATGL, BAT markers and fatty acid oxidation-related genes, but inhibited C/EBPα and PPARγ expression. In vivo, knockdown of G0S2 reduced the body weight gain in high-fat-fed mice. The beneficial effects of the G0S2- cell cluster in promoting lipolysis and inhibiting adipogenesis are dependent on two major aspects: first, downregulation of the G0S2 gene in the G0S2- cluster, resulting in activation of ATGL, which is responsible for the bulk of triacylglycerol hydrolase activity; and second, upregulation of FABP4 in the G0S2- cluster, resulting in inhibition of PPARγ and further reducing adipogenesis.
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Affiliation(s)
- Zhenhui Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, USA
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
| | - Ming Zheng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
| | - Jiawei Mo
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
| | - Kan Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
| | - Xin Yang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
| | - Lijin Guo
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
| | - Xiquan Zhang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
| | - Bahareldin Ali Abdalla
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
| | - Qinghua Nie
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Lingnan Guangdong Laboratory of Agriculture, College of Animal Science, South China Agricultural University, Guangzhou, China
- Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, China
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19
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Ferreira MA, Azevedo H, Mascarello A, Segretti ND, Russo E, Russo V, Guimarães CRW. Discovery of ACH-000143: A Novel Potent and Peripherally Preferred Melatonin Receptor Agonist that Reduces Liver Triglycerides and Steatosis in Diet-Induced Obese Rats. J Med Chem 2021; 64:1904-1929. [PMID: 33626870 DOI: 10.1021/acs.jmedchem.0c00627] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.
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Affiliation(s)
| | - Hatylas Azevedo
- Aché Laboratórios Farmacêuticos, Guarulhos, São Paulo 07034-904, Brazil
| | | | | | - Elisa Russo
- Zirkon Ind. Com de Insumos Químicos, Itapira, São Paulo 13977-105, Brazil
| | - Valter Russo
- Zirkon Ind. Com de Insumos Químicos, Itapira, São Paulo 13977-105, Brazil
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20
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Tchio C, Baba K, Piccione G, Tosini G. Removal of melatonin receptor type 1 signalling induces dyslipidaemia and hormonal changes in mice subjected to environmental circadian disruption. Endocrinol Diabetes Metab 2021; 4:e00171. [PMID: 33532613 PMCID: PMC7831213 DOI: 10.1002/edm2.171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/02/2020] [Accepted: 07/05/2020] [Indexed: 11/26/2022] Open
Abstract
Background Melatonin is a hormone secreted by the pineal gland in a circadian rhythmic manner with peak synthesis at night. Melatonin signalling was suggested to play a critical role in metabolism during the circadian disruption. Methods Melatonin-proficient (C3H-f+/+ or WT) and melatonin receptor type 1 knockout (MT1 KO) male and female mice were phase-advanced (6 hours) once a week for 6 weeks. Every week, we measured weight, food intake and basal glucose levels. At the end of the experiment, we sacrificed the animals and measured the blood's plasma for lipids profile (total lipids, phospholipids, triglycerides and total cholesterol), metabolic hormones profiles (ghrelin, leptin, insulin, glucagon, glucagon-like-peptide and resistin) and the body composition. Results Environmental circadian disruption (ECD) did not produce any significant effects in C3H-f+/+, while it increased lipids profile in MT1 KO with the significant increase observed in total lipids and triglycerides. For metabolic hormones profile, ECD decreased plasma ghrelin and increased plasma insulin in MT1 KO females. Under control condition, MT1 KO females have significantly different body weight, fat mass, total lipids and total cholesterol than the control C3H-f+/+ females. Conclusion Our data show that melatonin-proficient mice are not affected by ECD. When the MT1 receptors are removed, ECD induced dyslipidaemia in males and females with females experiencing the most adverse effect. Overall, our data demonstrate that MT1 signalling is an essential modulator of lipid and metabolic homeostasis during ECD.
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Affiliation(s)
- Cynthia Tchio
- Circadian Rhythms and Sleep Disorders ProgramNeuroscience InstituteAtlantaGAUSA
- Department of Pharmacology and ToxicologyMorehouse School of MedicineNeuroscience InstituteAtlantaGAUSA
| | - Kenkichi Baba
- Circadian Rhythms and Sleep Disorders ProgramNeuroscience InstituteAtlantaGAUSA
- Department of Pharmacology and ToxicologyMorehouse School of MedicineNeuroscience InstituteAtlantaGAUSA
| | - Giuseppe Piccione
- Dipartimento di Medicine VeterinariaUniversita di MessinaMessinaItaly
| | - Gianluca Tosini
- Circadian Rhythms and Sleep Disorders ProgramNeuroscience InstituteAtlantaGAUSA
- Department of Pharmacology and ToxicologyMorehouse School of MedicineNeuroscience InstituteAtlantaGAUSA
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Li Y, Ma J, Yao K, Su W, Tan B, Wu X, Huang X, Li T, Yin Y, Tosini G, Yin J. Circadian rhythms and obesity: Timekeeping governs lipid metabolism. J Pineal Res 2020; 69:e12682. [PMID: 32656907 DOI: 10.1111/jpi.12682] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/02/2020] [Accepted: 07/07/2020] [Indexed: 12/29/2022]
Abstract
Almost all living organisms have evolved autoregulatory transcriptional-translational feedback loops that produce oscillations with a period of approximately 24-h. These endogenous time keeping mechanisms are called circadian clocks. The main function of these circadian clocks is to drive overt circadian rhythms in the physiology of the organisms to ensure that main physiological functions are in synchrony with the external environment. Disruption of circadian rhythms caused by genetic or environmental factors has long-term consequences for metabolic health. Of relevance, host circadian rhythmicity and lipid metabolism are increasingly recognized to cross-regulate and the circadian clock-lipid metabolism interplay may involve in the development of obesity. Multiple systemic and molecular mechanisms, such as hormones (ie, melatonin, leptin, and glucocorticoid), the gut microbiome, and energy metabolism, link the circadian clock and lipid metabolism, and predictably, the deregulation of circadian clock-lipid metabolism interplay can increase the risk of obesity, which in turn may exacerbate circadian disorganization. Feeding time and dietary nutrients are two of key environmental Zeitgebers affecting the circadian rhythm-lipid metabolism interplay, and the influencing mechanisms in obesity development are highlighted in this review. Together, the characterization of the clock machinery in lipid metabolism aimed at producing a healthy circadian lifestyle may improve obesity care.
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Affiliation(s)
- Yuying Li
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Jie Ma
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Kang Yao
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Wenxuan Su
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Bie Tan
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Xin Wu
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Xingguo Huang
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Tiejun Li
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Yulong Yin
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
- Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China
| | - Gianluca Tosini
- Department of Pharmacology and Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA
| | - Jie Yin
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
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Abstract
Circadian clocks are cell-autonomous self-sustaining oscillators that allow organisms to anticipate environmental changes throughout the solar day and persist in nearly every cell examined. Environmental or genetic disruption of circadian rhythms increases the risk of several types of cancer, but the underlying mechanisms are not well understood. Here, we discuss evidence connecting circadian rhythms-with emphasis on the cryptochrome proteins (CRY1/2)-to cancer through in vivo models, mechanisms involving known tumor suppressors and oncogenes, chemotherapeutic efficacy, and human cancer risk.
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Affiliation(s)
- Alanna B Chan
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
| | - Katja A Lamia
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
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Daneshvar Kakhaki R, Ostadmohammadi V, Kouchaki E, Aghadavod E, Bahmani F, Tamtaji OR, J Reiter R, Mansournia MA, Asemi Z. Melatonin supplementation and the effects on clinical and metabolic status in Parkinson's disease: A randomized, double-blind, placebo-controlled trial. Clin Neurol Neurosurg 2020; 195:105878. [PMID: 32417629 DOI: 10.1016/j.clineuro.2020.105878] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 04/25/2020] [Accepted: 04/27/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This study was performed to evaluate the impact of melatonin supplementation on clinical and metabolic profiles in people with Parkinson's disease (PD). METHODS This randomized, double-blind, placebo-controlled clinical trial was conducted among 60 patients with PD. Participants were randomly divided into two groups to intake either 10 mg melatonin (two melatonin capsules, 5 mg each) (n = 30) or placebo (n = 30) once a day, 1 h before bedtime for 12 weeks. RESULTS Melatonin supplementation significantly reduced the Unified Parkinson's Disease Rating Scale (UPDRS) part I score (β -2.33; 95% CI, -3.57, -1.09; P < 0.001), Pittsburgh Sleep Quality Index (PSQI) (β -1.82; 95% CI, -3.36, -0.27; P = 0.02), Beck Depression Inventory (BDI) (β -3.32; 95% CI, -5.23, -1.41; P = 0.001) and Beck Anxiety Inventory (BAI) (β -2.22; 95% CI, -3.84, -0.60; P = 0.008) compared with the placebo treatment. Compared with the placebo, melatonin supplementation resulted in a significant reduction in serum high sensitivity C-reactive protein (hs-CRP) (β -0.94 mg/L; 95% CI, -1.55, -0.32; P = 0.003) and a significant elevation in plasma total antioxidant capacity (TAC) (β 108.09 mmol/L; 95% CI, 78.21, 137.97; P < 0.001) and total glutathione (GSH) levels (β 77.08 μmol/L; 95% CI, 44.29, 109.86; P < 0.001). Additionally, consuming melatonin significantly decreased serum insulin levels (β -1.79 μIU/mL; 95% CI, -3.12, -0.46; P = 0.009), homeostasis model of assessment-insulin resistance (HOMA-IR) (β -0.47; 95% CI, -0.80, -0.13; P = 0.007), total- (β -13.16 mg/dL; 95% CI, -25.14, -1.17; P = 0.03) and LDL- (β -10.44 mg/dL; 95% CI, -20.55, -0.34; P = 0.04) compared with the placebo. CONCLUSIONS Overall, melatonin supplementation for 12 weeks to patients with PD had favorable effects on the UPDRS part I score, PSQI, BDI, BAI, hs-CRP, TAC, GSH, insulin levels, HOMA-IR, total-, LDL-cholesterol, and gene expression of TNF-α, PPAR-γ and LDLR, but did not affect other metabolic profiles.
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Affiliation(s)
- Reza Daneshvar Kakhaki
- Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Vahidreza Ostadmohammadi
- Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran; Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Ebrahim Kouchaki
- Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran; Department of Neurology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Esmat Aghadavod
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Fereshteh Bahmani
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Omid Reza Tamtaji
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science, Center, San Antonio, TX, USA
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
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24
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Effects of melatonin on cardiovascular risk factors and metabolic syndrome: a comprehensive review. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:521-536. [DOI: 10.1007/s00210-020-01822-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/10/2020] [Indexed: 12/13/2022]
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Ostadmohammadi V, Soleimani A, Bahmani F, Aghadavod E, Ramezani R, Reiter RJ, Mansournia MA, Banikazemi Z, Soleimani M, Zaroudi M, Asemi Z. The Effects of Melatonin Supplementation on Parameters of Mental Health, Glycemic Control, Markers of Cardiometabolic Risk, and Oxidative Stress in Diabetic Hemodialysis Patients: A Randomized, Double-Blind, Placebo-Controlled Trial. J Ren Nutr 2019; 30:242-250. [PMID: 31597622 DOI: 10.1053/j.jrn.2019.08.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 07/22/2019] [Accepted: 08/10/2019] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE This study evaluated the effects of melatonin supplementation on parameters of mental health, glycemic control, markers of cardiometabolic risk, and oxidative stress in diabetic hemodialysis (HD) patients. DESIGN A randomized, double-blind, placebo-controlled clinical trial was conducted in 60 diabetic HD patients, 18-80 years of age. Participants were randomly divided into 2 groups to take either melatonin (2 x 5mg/day) (n = 30) or placebo (n = 30) 1 hour before bedtime for 12 weeks. The effects of melatonin on mental health, metabolic status, and gene expression related to metabolic status were assessed using multiple linear regression adjusting for age and BMI. RESULTS Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (P = .007), Beck Depression Inventory index (P = .001), and Beck Anxiety Inventory index (P = .01) compared with the placebo. Additionally, melatonin administration significantly reduced fasting plasma glucose (β = -21.77 mg/dL, 95% CI -33.22 to -10.33, P < .001), serum insulin levels (β = -1.89 μIU/mL, 95% CI -3.34 to -0.45, P = .01), and homeostasis model of assessment-insulin resistance (β = -1.45, 95% CI -2.10 to -0.80, P < .001), and significantly increased the quantitative insulin sensitivity check index (β = 0.01, 95% CI 0.007-0.02, P < .001) compared with placebo treated subjects. In addition, melatonin administration resulted in a significant reduction in serum high sensitivity C-reactive protein (β = -1.92 mg/L, 95% CI -3.02 to -0.83, P = .001) and plasma malondialdehyde (β = -0.21 μmol/L, 95% CI -0.36 to -0.06, P = .005); also, significant rises in plasma total antioxidant capacity (β = 253.87 mmol/L, 95% CI 189.18-318.56, P < .001) and nitric oxide levels (β = 2.99 μmol/L, 95% CI 0.71-5.28, P = .01) were observed compared with the placebo. CONCLUSION Overall, melatonin supplementation for 12 weeks to diabetic HD patients had beneficial effects on mental health, glycemic control, inflammatory markers, and oxidative stress.
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Affiliation(s)
- Vahidreza Ostadmohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Soleimani
- Department of Internal Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Fereshteh Bahmani
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Esmat Aghadavod
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Reza Ramezani
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health San Antonio, San Antonio, Texas
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Zarrin Banikazemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Soleimani
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Marsa Zaroudi
- Student Research Committee, Faculty of Public Health Branch, Iran University of Medical Sciences, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
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Buonfiglio D, Tchio C, Furigo I, Donato J, Baba K, Cipolla-Neto J, Tosini G. Removing melatonin receptor type 1 signaling leads to selective leptin resistance in the arcuate nucleus. J Pineal Res 2019; 67:e12580. [PMID: 30968433 PMCID: PMC6687516 DOI: 10.1111/jpi.12580] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 03/28/2019] [Accepted: 04/04/2019] [Indexed: 12/15/2022]
Abstract
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 (MT1 KO) 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, MT1 KO 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 MT1 KO mice beyond levels observed in mice injected with phosphate-buffered saline (PBS). Furthermore, STAT3 phosphorylation within the arcuate nucleus (ARH) was decreased in MT1 KO mice. Leptin receptor mRNA levels in the hypothalamus of MT1 KO 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.
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Affiliation(s)
- Daniella Buonfiglio
- Department of Physiology and Biophysics, Institute of Biomedical Sciences-I, University of São Paulo (USP), São Paulo, Brazil
- Department of Pharmacology and Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia
| | - Cynthia Tchio
- Department of Pharmacology and Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia
| | - Isadora Furigo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences-I, University of São Paulo (USP), São Paulo, Brazil
| | - José Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences-I, University of São Paulo (USP), São Paulo, Brazil
| | - Kenkichi Baba
- Department of Pharmacology and Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia
| | - José Cipolla-Neto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences-I, University of São Paulo (USP), São Paulo, Brazil
| | - Gianluca Tosini
- Department of Pharmacology and Toxicology and Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia
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Owino S, Buonfiglio DDC, Tchio C, Tosini G. Melatonin Signaling a Key Regulator of Glucose Homeostasis and Energy Metabolism. Front Endocrinol (Lausanne) 2019; 10:488. [PMID: 31379753 PMCID: PMC6651071 DOI: 10.3389/fendo.2019.00488] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 07/04/2019] [Indexed: 12/29/2022] Open
Abstract
Melatonin, a hormone synthesized by both the pineal gland and retina, functions as an important modulator of a number of physiological functions. In addition to its rather well-established roles in the regulation of circadian rhythms, sleep, and reproduction, melatonin has also been identified as an important regulator of glucose metabolism. Recent genomic studies have also shown that disruption of melatonin receptors signaling may contribute to the pathogenesis of type 2 diabetes, although the exact mechanisms underlying its action remain unclear. Additionally, a large number of animal studies have highlighted a role for melatonin in the regulation of both glucose metabolism and energy balance. This review summarizes the current knowledge on the role that melatonin and its associated receptors play in the regulation of metabolism.
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Affiliation(s)
- Sharon Owino
- Department of Pharmacology and Toxicology Morehouse School of Medicine, Neuroscience Institute, Atlanta, GA, United States
- Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, United States
| | - Daniella D. C. Buonfiglio
- Department of Pharmacology and Toxicology Morehouse School of Medicine, Neuroscience Institute, Atlanta, GA, United States
- Department of Physiology and Biophysics, Institute of Biomedical Sciences-I, University of São Paulo (USP), São Paulo, Brazil
| | - Cynthia Tchio
- Department of Pharmacology and Toxicology Morehouse School of Medicine, Neuroscience Institute, Atlanta, GA, United States
| | - Gianluca Tosini
- Department of Pharmacology and Toxicology Morehouse School of Medicine, Neuroscience Institute, Atlanta, GA, United States
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28
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Ghaderi A, Banafshe HR, Mirhosseini N, Motmaen M, Mehrzad F, Bahmani F, Aghadavod E, Mansournia MA, Reiter RJ, Karimi MA, Asemi Z. The effects of melatonin supplementation on mental health, metabolic and genetic profiles in patients under methadone maintenance treatment. Addict Biol 2019; 24:754-764. [PMID: 29949232 DOI: 10.1111/adb.12650] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 04/24/2018] [Accepted: 05/21/2018] [Indexed: 12/11/2022]
Abstract
This investigation was designed to determine the effect of melatonin supplementation on mental health parameters, metabolic and genetic profiles in patients under methadone maintenance treatment (MMT). This randomized, double-blind, placebo-controlled, clinical trial was conducted among 54 patients under MMT. Participants were randomly allocated to receive either 10 mg melatonin (2 melatonin capsules, 5 mg each) (n = 26) or placebo (n = 28) once a day, 1 hour before bedtime for 12 weeks. Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (β -4.08; 95 percent CI, -5.51, -2.65; P < 0.001), Beck Depression Inventory index (β -5.46; 95% CI, -8.92, -2.00; P = 0.003) and Beck Anxiety Inventory index (β -3.87; 95% CI, -5.96, -1.77; P = 0.001) and significantly increased International Index of Erectile Functions (β 5.59; 95% CI, 1.76, 9.42; P = 0.005) compared with the placebo. Subjects who received melatonin supplements had significantly lower serum insulin levels (β -2.53; 95% CI, -4.48, -0.59; P = 0.01), homeostasis model of assessment-insulin resistance (β -0.56; 95% CI, -1.03, -0.09; P = 0.01) and higher quantitative insulin sensitivity check index (β 0.01; 95% CI, 0.004, 0.02; P = 0.009) and HDL-cholesterol levels (β 3.71; 95% CI, 1.77, 5.64; P = 0.002) compared to placebo. Additionally, melatonin intake resulted in a significant reduction in serum high sensitivity C-reactive protein (β -0.15; 95% CI, -0.27, -0.02; P = 0.02), malondialdehyde (β -0.31; 95% CI, -0.57, -0.05; P = 0.02) and protein carbonyl (β -0.06; 95% CI, -0.09, -0.04; P < 0.001). This trial indicated that taking melatonin supplements for 12 weeks by patients under MMT had beneficial effects on their mental health metabolic profiles.
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Affiliation(s)
- Amir Ghaderi
- Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamid Reza Banafshe
- Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Department of Pharmacology, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Maryam Motmaen
- Department of Psychiatry, School of Medicine, Kashan University of Medical Science, Kashan, Iran
| | - Fatemeh Mehrzad
- Department of Psychiatry, School of Medicine, Kashan University of Medical Science, Kashan, Iran
| | - Fereshteh Bahmani
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Esmat Aghadavod
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Russel J Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science, Center, San Antonio, TX, USA
| | - Mohammad-Amin Karimi
- Department of Educational Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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Shabani A, Foroozanfard F, Kavossian E, Aghadavod E, Ostadmohammadi V, Reiter RJ, Eftekhar T, Asemi Z. Effects of melatonin administration on mental health parameters, metabolic and genetic profiles in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial. J Affect Disord 2019; 250:51-56. [PMID: 30831541 DOI: 10.1016/j.jad.2019.02.066] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/22/2019] [Accepted: 02/25/2019] [Indexed: 12/14/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the effect of melatonin supplementation on mental health parameters, metabolic and genetic parameters in women suffering from polycystic ovary syndrome (PCOS). METHODS This randomized, double-blinded, placebo-controlled clinical trial was performed on 58 subjects, aged 18-40 years old. Subjects were randomly allocated to take either 10 mg melatonin (2 melatonin capsules, 5 mg each) (n = 29) or placebo (n = 29) once a day 1 h before bedtime for 12 weeks. Glycemic control and lipid profiles were measured at baseline and after the 12-week intervention. Using RT-PCR method, gene expression related to insulin and lipid metabolism was conducted on peripheral blood mononuclear cells (PBMCs) of PCOS women. RESULTS Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (β -2.15; 95% CI, -3.62, -0.68; P = 0.005), Beck Depression Inventory index (β -3.62; 95% CI, -5.53, -1.78; P<0.001) and Beck Anxiety Inventory index (β -1.95; 95% CI, -3.41, -0.48; P = 0.01) compared with the placebo. In addition, melatonin administration, compared with the placebo, significantly reduced serum insulin (β -1.20 µIU/mL; 95% CI, -2.14, -0.26; P = 0.01), homeostasis model of assessment-insulin resistance (HOMA-IR) (β -0.28; 95% CI, -0.50, -0.05; P = 0.01), serum total- (β -7.96 mg/dL; 95% CI, -13.75, -2.17; P = 0.008) and LDL-cholesterol levels (β -5.88 mg/dL; 95% CI, -11.42, -0.33; P = 0.03), and significantly increased the quantitative insulin sensitivity check index (QUICKI) (β 0.008; 95% CI, 0.002, 0.014; P = 0.007). Moreover, melatonin supplementation upregulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.004) and low-density lipoprotein receptor (LDLR) (P = 0.01) compared with the placebo. CONCLUSIONS Overall, melatonin administration for 12 weeks had beneficial effects on mental health parameters, insulin levels, HOMA-IR, QUICKI, total- and LDL-cholesterol levels, and gene expression of PPAR-γ and LDLR among women with PCOS.
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Affiliation(s)
- Azade Shabani
- Department of Gynecology and Obstetrics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Foroozanfard
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Elham Kavossian
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Esmat Aghadavod
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Vahidreza Ostadmohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health San Antonio, TX, USA
| | - Tahereh Eftekhar
- Reproductive Health Research Center, Tehran University of Medical Science, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
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Abstract
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.
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Affiliation(s)
- Angeliki Karamitri
- Inserm, U1016, Institut Cochin, Paris, France
- CNRS UMR 8104, Paris, France
- Université Paris Descartes, Université Sorbonne Paris Cité, Paris, France
| | - Ralf Jockers
- Inserm, U1016, Institut Cochin, Paris, France.
- CNRS UMR 8104, Paris, France.
- Université Paris Descartes, Université Sorbonne Paris Cité, Paris, France.
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Dadvar S, Ferreira DMS, Cervenka I, Ruas JL. The weight of nutrients: kynurenine metabolites in obesity and exercise. J Intern Med 2018; 284:519-533. [PMID: 30141532 DOI: 10.1111/joim.12830] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Obesity ultimately results from an imbalance between energy intake and expenditure. However, in addition to their bioenergetic value, nutrients and their metabolites can function as important signalling molecules in energy homeostasis. Indeed, macronutrients and their metabolites can be direct regulators of metabolism through their actions on different organs. In turn, target organs can decide to use, store or transform the incoming nutrients depending on their physiological context and in coordination with other cell types. Tryptophan-kynurenine metabolites are an example of a family of compounds that can serve as systemic integrators of energy metabolism by signalling to different cell types. These include adipocytes, immune cells and muscle fibres, in addition to the well-known effects of kynurenine metabolites on the central nervous system. In the context of energy metabolism, several of the effects elicited by kynurenic acid are mediated by the G-protein-coupled receptor, GPR35. As GPR35 is expressed in tissues such as the adipose tissue, immune cells and the gastrointestinal tract, this receptor could be a potential therapeutic target for the treatment of obesity, diabetes and other metabolic diseases. In addition, metabolic disorders often coincide with states of chronic inflammation, which further highlights GPR35 as an integration node in conditions where inflammation skews metabolism. Defining the molecular interplay between different tissues in the regulation of energy homeostasis can help us understand interindividual variability in the response to nutrient intake and develop safe and efficient therapies to fight obesity and metabolic disease.
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Affiliation(s)
- S Dadvar
- Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology, Karolinska Institutet, Biomedicum, Stockholm, Sweden
| | - D M S Ferreira
- Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology, Karolinska Institutet, Biomedicum, Stockholm, Sweden
| | - I Cervenka
- Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology, Karolinska Institutet, Biomedicum, Stockholm, Sweden
| | - J L Ruas
- Department of Physiology and Pharmacology, Molecular & Cellular Exercise Physiology, Karolinska Institutet, Biomedicum, Stockholm, Sweden
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Dantas‐Ferreira RF, Raingard H, Dumont S, Schuster‐Klein C, Guardiola‐Lemaitre B, Pevet P, Challet E. Melatonin potentiates the effects of metformin on glucose metabolism and food intake in high-fat-fed rats. Endocrinol Diabetes Metab 2018; 1:e00039. [PMID: 30815567 PMCID: PMC6354841 DOI: 10.1002/edm2.39] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 08/01/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Melatonin is a hormone synthesized mainly by the pineal gland, and secreted only at night. Melatonin has been proposed as a modulator of glucose metabolism. METHODS Here we studied the metabolic effects of melatonin administration alone (s.c. 10 mg/kg) or in combination with metformin (p.o. 300 mg/kg), a widely used anti-diabetic drug. These treatments were tested on glucose tolerance, insulin sensitivity and food intake in Zucker fatty rats (i.e., bearing a missense mutation in the leptin receptor gene) and high-fat fed Sprague-Dawley rats. RESULTS Melatonin alone or in combination did not significantly modify glucose tolerance in either model. Melatonin alone in high-fat fed Sprague-Dawley improved insulin sensitivity to the level of metformin. In addition, combined treatment further ameliorated insulin sensitivity (+13%), especially during the late phase of rising glycemia. The lack of similar effects in Zucker rats suggests an involvement of leptin signaling in mediating the positive effects of melatonin. Body mass gain in Sprague-Dawley rats was decreased by both metformin, and combined metformin and melatonin. While melatonin alone did not markedly affect food intake, its combination with metformin led to a more pronounced anorexia (-17% food intake during the last week), as compared to metformin alone. CONCLUSIONS Melatonin improves the beneficial effects of metformin on insulin sensitivity and body mass gain in high-fat fed Sprague-Dawley rats. Therefore, the combination of melatonin and metformin could be beneficial to develop dual therapies to treat or delay type 2 diabetes associated with obesity.
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Affiliation(s)
- Rosana F. Dantas‐Ferreira
- Circadian Clocks & Metabolism teamInstitute of Cellular and Integrative NeurosciencesCentre National de la Recherche Scientifique (CNRS)University of StrasbourgStrasbourgFrance
| | - Helene Raingard
- Circadian Clocks & Metabolism teamInstitute of Cellular and Integrative NeurosciencesCentre National de la Recherche Scientifique (CNRS)University of StrasbourgStrasbourgFrance
| | - Stephanie Dumont
- Circadian Clocks & Metabolism teamInstitute of Cellular and Integrative NeurosciencesCentre National de la Recherche Scientifique (CNRS)University of StrasbourgStrasbourgFrance
| | | | | | - Paul Pevet
- Circadian Clocks & Metabolism teamInstitute of Cellular and Integrative NeurosciencesCentre National de la Recherche Scientifique (CNRS)University of StrasbourgStrasbourgFrance
| | - Etienne Challet
- Circadian Clocks & Metabolism teamInstitute of Cellular and Integrative NeurosciencesCentre National de la Recherche Scientifique (CNRS)University of StrasbourgStrasbourgFrance
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Simultaneous quantification of urinary 6‑sulfatoxymelatonin and 8‑hydroxy‑2′‑deoxyguanosine using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1095:119-126. [DOI: 10.1016/j.jchromb.2018.07.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/25/2018] [Accepted: 07/26/2018] [Indexed: 01/10/2023]
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Napso T, Yong HEJ, Lopez-Tello J, Sferruzzi-Perri AN. The Role of Placental Hormones in Mediating Maternal Adaptations to Support Pregnancy and Lactation. Front Physiol 2018; 9:1091. [PMID: 30174608 PMCID: PMC6108594 DOI: 10.3389/fphys.2018.01091] [Citation(s) in RCA: 273] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 07/23/2018] [Indexed: 12/12/2022] Open
Abstract
During pregnancy, the mother must adapt her body systems to support nutrient and oxygen supply for growth of the baby in utero and during the subsequent lactation. These include changes in the cardiovascular, pulmonary, immune and metabolic systems of the mother. Failure to appropriately adjust maternal physiology to the pregnant state may result in pregnancy complications, including gestational diabetes and abnormal birth weight, which can further lead to a range of medically significant complications for the mother and baby. The placenta, which forms the functional interface separating the maternal and fetal circulations, is important for mediating adaptations in maternal physiology. It secretes a plethora of hormones into the maternal circulation which modulate her physiology and transfers the oxygen and nutrients available to the fetus for growth. Among these placental hormones, the prolactin-growth hormone family, steroids and neuropeptides play critical roles in driving maternal physiological adaptations during pregnancy. This review examines the changes that occur in maternal physiology in response to pregnancy and the significance of placental hormone production in mediating such changes.
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Affiliation(s)
- Tina Napso
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
| | - Hannah E J Yong
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
| | - Jorge Lopez-Tello
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
| | - Amanda N Sferruzzi-Perri
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
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Owino S, Sánchez-Bretaño A, Tchio C, Cecon E, Karamitri A, Dam J, Jockers R, Piccione G, Noh HL, Kim T, Kim JK, Baba K, Tosini G. Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity. J Pineal Res 2018; 64:10.1111/jpi.12462. [PMID: 29247541 PMCID: PMC5843510 DOI: 10.1111/jpi.12462] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 11/27/2017] [Indexed: 12/26/2022]
Abstract
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 downregulated 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.
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Affiliation(s)
- Sharon Owino
- Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute and Department of Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Aida Sánchez-Bretaño
- Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute and Department of Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Cynthia Tchio
- Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute and Department of Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Erika Cecon
- Inserm, U1016, Institut Cochin, Paris, France
| | | | - Julie Dam
- Inserm, U1016, Institut Cochin, Paris, France
| | | | | | - Hye Lim Noh
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Taekyoon Kim
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Jason K. Kim
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
- Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Massachusetts Medical School, Worcester, MA
| | - Kenkichi Baba
- Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute and Department of Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Gianluca Tosini
- Circadian Rhythms and Sleep Disorders Program, Neuroscience Institute and Department of Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, GA, USA
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Melatonin administration lowers biomarkers of oxidative stress and cardio-metabolic risk in type 2 diabetic patients with coronary heart disease: A randomized, double-blind, placebo-controlled trial. Clin Nutr 2017; 38:191-196. [PMID: 29275919 DOI: 10.1016/j.clnu.2017.12.004] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Revised: 11/21/2017] [Accepted: 12/05/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Melatonin may benefit diabetic people with coronary heart disease (CHD) through its beneficial effects on biomarkers of oxidative stress and cardio-metabolic risk. This investigation evaluated the effects of melatonin administration on metabolic status in diabetic patients with CHD. METHODS This randomized, double-blind, placebo-controlled trial was conducted and involved 60 diabetic patients with CHD. Subjects were randomly allocated into two groups to receive either 10 mg melatonin (2 melatonin capsules, 5 mg each) (n = 30) or placebo (n = 30) once a day for 12 weeks. RESULTS Compared with the placebo, melatonin supplementation resulted in significant increases in plasma glutathione (GSH) (+64.7 ± 105.7 vs. -11.1 ± 137.6 μmol/L, P = 0.02) and nitric oxide (NO) (+0.9 ± 4.7 vs. -3.3 ± 9.6 μmol/L, P = 0.03), and significant decreases in malondialdehyde (MDA) (-0.2 ± 0.3 vs. +0.1 ± 0.5 μmol/L, P = 0.007), protein carbonyl (PCO) (-0.12 ± 0.08 vs. +0.03 ± 0.07 mmol/mg protein, P < 0.001) and serum high sensitivity C-reactive protein (hs-CRP) levels (-1463.3 ± 2153.8 vs. +122.9 ± 1230.4 ng/mL, P = 0.001). In addition, taking melatonin, compared with the placebo, significantly reduced fasting plasma glucose (-29.4 ± 49.0 vs. -5.5 ± 32.4 mg/dL, P = 0.03), serum insulin concentrations (-2.2 ± 4.1 vs. +0.7 ± 4.2 μIU/mL, P = 0.008), homeostasis model of assessment-estimated insulin resistance (-1.0 ± 2.2 vs. +0.01 ± 1.6, P = 0.04), total-/HDL-cholesterol ratio (-0.18 ± 0.38 vs. +0.03 ± 0.35, P = 0.02) and systolic (-4.3 ± 9.6 vs. +1.0 ± 7.5 mmHg, P = 0.01) and diastolic blood pressure (-2.8 ± 7.3 vs. +0.1 ± 3.6 mmHg, P = 0.04). Melatonin treatment also significantly increased quantitative insulin sensitivity check index (+0.006 ± 0.01 vs. -0.004 ± 0.01, P = 0.01) and serum HDL-cholesterol (+2.6 ± 5.5 vs. -0.01 ± 4.4 mg/dL, P = 0.04). Supplementation with melatonin had no significant effect on other metabolic parameters. CONCLUSIONS Overall, melatonin intake for 12 weeks to diabetic patients with CHD had beneficial effects on plasma GSH, NO, MDA, PCO, serum hs-CRP levels, glycemic control, HDL-cholesterol, total-/HDL-cholesterol ratio, blood pressures and parameters of mental health. Registered under ClinicalTrials.gov Identifier no. http://www.irct.ir: IRCT2017051333941N1.
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Varcoe TJ, Gatford KL, Kennaway DJ. Maternal circadian rhythms and the programming of adult health and disease. Am J Physiol Regul Integr Comp Physiol 2017; 314:R231-R241. [PMID: 29141950 DOI: 10.1152/ajpregu.00248.2017] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The in utero environment is inherently rhythmic, with the fetus subjected to circadian changes in temperature, substrates, and various maternal hormones. Meanwhile, the fetus is developing an endogenous circadian timing system, preparing for life in an external environment where light, food availability, and other environmental factors change predictably and repeatedly every 24 h. In humans, there are many situations that can disrupt circadian rhythms, including shift work, international travel, insomnias, and circadian rhythm disorders (e.g., advanced/delayed sleep phase disorder), with a growing consensus that this chronodisruption can have deleterious consequences for an individual's health and well-being. However, the impact of chronodisruption during pregnancy on the health of both the mother and fetus is not well understood. In this review, we outline circadian timing system ontogeny in mammals and examine emerging research from animal models demonstrating long-term negative implications for progeny health following maternal chronodisruption during pregnancy.
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Affiliation(s)
- Tamara J Varcoe
- Robinson Research Institute, Adelaide Medical School, University of Adelaide , Adelaide, South Australia , Australia
| | - Kathryn L Gatford
- Robinson Research Institute, Adelaide Medical School, University of Adelaide , Adelaide, South Australia , Australia
| | - David J Kennaway
- Robinson Research Institute, Adelaide Medical School, University of Adelaide , Adelaide, South Australia , Australia
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Mayo JC, Sainz RM, González-Menéndez P, Hevia D, Cernuda-Cernuda R. Melatonin transport into mitochondria. Cell Mol Life Sci 2017; 74:3927-3940. [PMID: 28828619 PMCID: PMC11107582 DOI: 10.1007/s00018-017-2616-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/03/2017] [Indexed: 12/15/2022]
Abstract
Melatonin is a well-known, nighttime-produced indole found in bacteria, eukaryotic unicellulars, animals or vascular plants. In vertebrates, melatonin is the major product of the pineal gland, which accounts for its increase in serum during the dark phase, but it is also produced by many other organs and cell types. Such a wide distribution is consistent with its multiple and well-described functions which include from the circadian regulation and adaptation to seasonal variations to immunomodulatory and oncostatic actions in different types of tumors. The discovery of its antioxidant properties in the early 1990s opened a new field of potential protective functions in multiple tissues. A special mention should be made regarding the nervous system, where the indole is considered a major neuroprotector. Furthermore, mitochondria appear as one of the most important targets for the indole's protective actions. Melatonin's mechanisms of action vary from the direct molecular interaction with free radicals (free radical scavenger) to the binding to membrane (MLT1A and MLT1B) or nuclear receptors (RZR/RORα). Receptor binding has been associated with some, but not all of the indole functions reported to date. Recently, two new mechanisms of cellular uptake involving the facilitative glucose transporters GLUT/SLC2A and the proton-driven oligopeptide transporter PEPT1/2 have been reported. Here we discuss the potential importance that these newly discovered transport systems could have in determining the actions of melatonin, particularly in the mitochondria. We also argue the relative importance of passive diffusion vs active transport in different parts of the cell.
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Affiliation(s)
- Juan C Mayo
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain.
- Instituto Universitario Oncológico del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
| | - Rosa M Sainz
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain
- Instituto Universitario Oncológico del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - Pedro González-Menéndez
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain
- Instituto Universitario Oncológico del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - David Hevia
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain
- Instituto Universitario Oncológico del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - Rafael Cernuda-Cernuda
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/Julián Clavería, 6, 33006, Oviedo, Asturias, Spain
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Song J, Whitcomb DJ, Kim BC. The role of melatonin in the onset and progression of type 3 diabetes. Mol Brain 2017; 10:35. [PMID: 28764741 PMCID: PMC5539639 DOI: 10.1186/s13041-017-0315-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
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.
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Affiliation(s)
- Juhyun Song
- Department of Biomedical Sciences, Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, 61469, South Korea
| | - Daniel J Whitcomb
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Healthy Sciences, University of Bristol, Whitson street, Bristol, BS1 3NY, UK
| | - Byeong C Kim
- Department of Neurology, Chonnam National University Medical School, Gwangju, 61469, South Korea.
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Nduhirabandi F, Huisamen B, Strijdom H, Lochner A. Role of melatonin in glucose uptake by cardiomyocytes from insulin-resistant Wistar rats. Cardiovasc J Afr 2017; 28:362-369. [PMID: 28556852 PMCID: PMC5885054 DOI: 10.5830/cvja-2017-018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 04/04/2017] [Indexed: 12/31/2022] Open
Abstract
Aim Melatonin supplementation reduces insulin resistance and protects the heart in obese rats. However, its role in myocardial glucose uptake remains unknown. This study investigated the effect of short-term melatonin treatment on glucose uptake by cardiomyocytes isolated from obese and insulin-resistant rats. Methods Cardiomyocytes were isolated from obese rats fed a high-calorie diet for 16 to 23 weeks, their age-matched controls, as well as young control rats aged four to eight weeks. After incubation with melatonin with or without insulin, glucose uptake was initiated by the addition of 2-deoxy-D-[3H] glucose and measured after 30 minutes. Additional control and obese rats received melatonin in the drinking water (4 mg/kg/day) for the last six weeks of feeding (20 weeks) and glucose uptake was determined in isolated cardiomyocytes after incubation with insulin. Intraperitoneal glucose tolerance and biometric parameters were also measured. Results Obese rats (fed for more than 20 weeks) developed glucose intolerance. Cardiomyocytes isolated from these obese rats had a reduced response to insulin-stimulated glucose uptake (ISGU) (p < 0.05). Melatonin administration in vitro had no effect on glucose uptake per se. However, it increased ISGU by cardiomyocytes from the young rats (p < 0.05), while having no effect on ISGU by cardiomyocytes from the older control and obese groups. Melatonin in vivo had no significant effect on glucose tolerance, but it increased basal (p < 0.05) and ISGU by cardiomyocytes from the obese rats (50.1 ± 1.7 vs 32.1 ± 5.1 pmol/mg protein/30 min, p < 0.01). Conclusion These data suggest that short-term melatonin treatment in vivo but not in vitro improved glucose uptake and insulin responsiveness of cardiomyocytes in obesity and insulin-resistance states.
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Affiliation(s)
- Frederic Nduhirabandi
- Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.
| | - Barbara Huisamen
- Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa; Biotechnology, Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa
| | - Hans Strijdom
- Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
| | - Amanda Lochner
- Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa
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Wongchitrat P, Lansubsakul N, Kamsrijai U, Sae-Ung K, Mukda S, Govitrapong P. Melatonin attenuates the high-fat diet and streptozotocin-induced reduction in rat hippocampal neurogenesis. Neurochem Int 2016; 100:97-109. [PMID: 27620814 DOI: 10.1016/j.neuint.2016.09.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 08/10/2016] [Accepted: 09/06/2016] [Indexed: 12/15/2022]
Abstract
A deviant level of melatonin in blood circulation has been associated with the development of diabetes and with learning and memory deficiencies. Melatonin might have an important function in diabetes control; however, the mechanism of melatonin in diabetes remains unknown. The present study aimed to investigate the hyperglycemic condition induced by high-fat diet (HFD) feeding and streptozotocin (STZ) injection and to examine the effect of melatonin on adult hippocampal functions. HFD-fed and STZ-treated rats significantly increased blood glucose level. The present study showed that HFD-fed and STZ-treated rats significantly impaired memory in the Morris Water Maze task, reduced neurogenesis in the hippocampus shown by a reduction in nestin, doublecortin (DCX) and β-III tubulin immunoreactivities, reduced axon terminal markers, synaptophysin, reduced dendritic marker including postsynaptic density 95 (PSD-95) and the glutamate receptor subunit NR2A. Moreover, a significant downregulation of melatonin receptor, insulin receptor-β (IR-β) and both p-IR-β and phosphorylated extracellular signal-regulated kinase (p-ERK) occurred in HFD-fed and STZ-treated rats, while the level of glial fibrillary acidic protein (GFAP) increased. Treatment of melatonin, rats had shorter escape latencies and remained in the target quadrant longer compared to the HFD-fed and STZ-treated rats. Melatonin attenuated the reduction of neurogenesis, synaptogenesis and the induction of astrogliosis. Moreover, melatonin countered the reduction of melatonin receptor, insulin receptor and downstream signaling pathway for insulin. Our data suggested that the dysfunction of insulin signaling pathway occurred in the diabetes may provide a convergent mechanism of hippocampal impaired neurogenesis and synaptogenesis lead to impair memory while melatonin reverses these effects, suggesting that melatonin may reduce the pathogenesis of diabetes.
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Affiliation(s)
- Prapimpun Wongchitrat
- Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Salaya, Nakon Pathom, 73170, Thailand
| | - Niyada Lansubsakul
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakon Pathom, 73170, Thailand; Department of Anatomy, Faculty of Veterinary Medicine, Kasetsart University, Bangkok, 10900, Thailand
| | - Utcharaporn Kamsrijai
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakon Pathom, 73170, Thailand
| | - Kwankanit Sae-Ung
- Innovative Learning Center, Srinakharinwirot University, Bangkok, 10110, Thailand
| | - Sujira Mukda
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakon Pathom, 73170, Thailand
| | - Piyarat Govitrapong
- Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakon Pathom, 73170, Thailand; Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
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Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol 2016; 173:2702-25. [PMID: 27314810 DOI: 10.1111/bph.13536] [Citation(s) in RCA: 302] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 05/15/2016] [Accepted: 05/19/2016] [Indexed: 02/06/2023] Open
Abstract
Melatonin receptors are seven transmembrane-spanning proteins belonging to the GPCR superfamily. In mammals, two melatonin receptor subtypes exist - MT1 and MT2 - encoded by the MTNR1A and MTNR1B genes respectively. The current review provides an update on melatonin receptors by the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands, and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by their functions in the immune system and the CNS. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.
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Affiliation(s)
- Ralf Jockers
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,University Paris Descartes, Paris, France
| | | | - Margarita L Dubocovich
- Department Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Science, University at Buffalo (SUNY), Buffalo, USA
| | - Regina P Markus
- Institute of Biosciences, University of São Paulo, São Paulo, Brazil
| | | | - Gianluca Tosini
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Erika Cecon
- Inserm, U1016, Institut Cochin, Paris, France.,CNRS UMR 8104, Paris, France.,University Paris Descartes, Paris, France
| | - Darius P Zlotos
- Department of Pharmaceutical Chemistry, The German University in Cairo, New Cairo City, Cairo, Egypt
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43
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Owino S, Contreras-Alcantara S, Baba K, Tosini G. Melatonin Signaling Controls the Daily Rhythm in Blood Glucose Levels Independent of Peripheral Clocks. PLoS One 2016; 11:e0148214. [PMID: 26824606 PMCID: PMC4732609 DOI: 10.1371/journal.pone.0148214] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 01/14/2016] [Indexed: 01/01/2023] Open
Abstract
Melatonin is rhythmically secreted by both the pineal gland and retina in a circadian fashion, with its peak synthesis occurring during the night. Once synthesized, melatonin exerts its effects by binding to two specific G-protein coupled receptors-melatonin receptor type 1(MT1) and melatonin receptor type 2(MT2). Recent studies suggest the involvement of MT1 and MT2 in the regulation of glucose homeostasis; however the ability of melatonin signaling to impart timing cues on glucose metabolism remains poorly understood. Here we report that the removal of MT1 or MT2 in mice abolishes the daily rhythm in blood glucose levels. Interestingly, removal of melatonin receptors produced small effects on the rhythmic expression patterns of clock genes within skeletal muscle, liver, and adipose tissue. Taken together, our data suggest that the loss of the daily rhythm in blood glucose observed in MT1(-/-) and MT2(-/-) mice does not occur as a consequence of 'disrupted' clocks within insulin sensitive tissues. Finally our results highlight a diurnal contribution of melatonin receptor signaling in the daily regulation of blood glucose levels.
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MESH Headings
- Adipose Tissue/metabolism
- Animals
- Blood Glucose/metabolism
- CLOCK Proteins/genetics
- CLOCK Proteins/metabolism
- Circadian Rhythm/genetics
- Gene Expression Regulation
- Homeostasis
- Liver/metabolism
- Male
- Melatonin/metabolism
- Mice
- Mice, Knockout
- Muscle, Skeletal/metabolism
- Pineal Gland/metabolism
- Receptor, Melatonin, MT1/deficiency
- Receptor, Melatonin, MT1/genetics
- Receptor, Melatonin, MT2/deficiency
- Receptor, Melatonin, MT2/genetics
- Retina/metabolism
- Signal Transduction
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Affiliation(s)
- Sharon Owino
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Susana Contreras-Alcantara
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Kenkichi Baba
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
- * E-mail: (KB); (GT)
| | - Gianluca Tosini
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States of America
- * E-mail: (KB); (GT)
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44
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Kunst S, Wolloscheck T, Kelleher DK, Wolfrum U, Sargsyan SA, Iuvone PM, Baba K, Tosini G, Spessert R. Pgc-1α and Nr4a1 Are Target Genes of Circadian Melatonin and Dopamine Release in Murine Retina. Invest Ophthalmol Vis Sci 2016; 56:6084-94. [PMID: 26393668 DOI: 10.1167/iovs.15-17503] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
PURPOSE The neurohormones melatonin and dopamine mediate clock-dependent/circadian regulation of inner retinal neurons and photoreceptor cells and in this way promote their functional adaptation to time of day and their survival. To fulfill this function they act on melatonin receptor type 1 (MT1 receptors) and dopamine D4 receptors (D4 receptors), respectively. The aim of the present study was to screen transcriptional regulators important for retinal physiology and/or pathology (Dbp, Egr-1, Fos, Nr1d1, Nr2e3, Nr4a1, Pgc-1α, Rorβ) for circadian regulation and dependence on melatonin signaling/MT1 receptors or dopamine signaling/D4 receptors. METHODS This was done by gene profiling using quantitative polymerase chain reaction in mice deficient in MT1 or D4 receptors. RESULTS The data obtained determined Pgc-1α and Nr4a1 as transcriptional targets of circadian melatonin and dopamine signaling, respectively. CONCLUSIONS The results suggest that Pgc-1α and Nr4a1 represent candidate genes for linking circadian neurohormone release with functional adaptation and healthiness of retina and photoreceptor cells.
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Affiliation(s)
- Stefanie Kunst
- Institute of Functional and Clinical Anatomy University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany 2Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University, Mainz, Germany
| | - Tanja Wolloscheck
- Institute of Functional and Clinical Anatomy University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Debra K Kelleher
- Institute of Functional and Clinical Anatomy University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Uwe Wolfrum
- Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University, Mainz, Germany
| | - S Anna Sargsyan
- Departments of Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, Georgia, United States
| | - P Michael Iuvone
- Departments of Ophthalmology and Pharmacology, Emory University School of Medicine, Atlanta, Georgia, United States
| | - Kenkichi Baba
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States
| | - Gianluca Tosini
- Neuroscience Institute and Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia, United States
| | - Rainer Spessert
- Institute of Functional and Clinical Anatomy University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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45
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Rong PJ, Zhao JJ, Li YQ, Litscher D, Li SY, Gaischek I, Zhai X, Wang L, Luo M, Litscher G. Auricular acupuncture and biomedical research—A promising Sino-Austrian research cooperation. Chin J Integr Med 2015; 21:887-894. [DOI: 10.1007/s11655-015-2090-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Indexed: 11/28/2022]
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46
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Sharma S, Singh H, Ahmad N, Mishra P, Tiwari A. The role of melatonin in diabetes: therapeutic implications. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2015; 59:391-9. [PMID: 26331226 DOI: 10.1590/2359-3997000000098] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 07/06/2015] [Indexed: 01/27/2023]
Abstract
Melatonin referred as the hormone of darkness is mainly secreted by pineal gland, its levels being elevated during night and low during the day. The effects of melatonin on insulin secretion are mediated through the melatonin receptors (MT1 and MT2). It decreases insulin secretion by inhibiting cAMP and cGMP pathways but activates the phospholipaseC/IP3 pathway, which mobilizes Ca2+from organelles and, consequently increases insulin secretion. Both in vivo and in vitro, insulin secretion by the pancreatic islets in a circadian manner, is due to the melatonin action on the melatonin receptors inducing a phase shift in the cells. Melatonin may be involved in the genesis of diabetes as a reduction in melatonin levels and a functional interrelationship between melatonin and insulin was observed in diabetic patients. Evidences from experimental studies proved that melatonin induces production of insulin growth factor and promotes insulin receptor tyrosine phosphorylation. The disturbance of internal circadian system induces glucose intolerance and insulin resistance, which could be restored by melatonin supplementation. Therefore, the presence of melatonin receptors on human pancreatic islets may have an impact on pharmacotherapy of type 2 diabetes.
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Affiliation(s)
- Shweta Sharma
- School of Biotechnology, Rajiv Gandhi Technical University, Bhopal, Madhya Pradesh, India
| | - Hemant Singh
- School of Biotechnology, Rajiv Gandhi Technical University, Bhopal, Madhya Pradesh, India
| | - Nabeel Ahmad
- School of Biotechnology, IFTM University, Uttar Pradesh, India
| | - Priyanka Mishra
- School of Biotechnology, Rajiv Gandhi Technical University, Bhopal, Madhya Pradesh, India
| | - Archana Tiwari
- School of Biotechnology, Rajiv Gandhi Technical University, Bhopal, Madhya Pradesh, India
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47
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Green NH, Jackson CR, Iwamoto H, Tackenberg MC, McMahon DG. Photoperiod programs dorsal raphe serotonergic neurons and affective behaviors. Curr Biol 2015; 25:1389-94. [PMID: 25959961 DOI: 10.1016/j.cub.2015.03.050] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 02/20/2015] [Accepted: 03/24/2015] [Indexed: 11/27/2022]
Abstract
The serotonergic raphe nuclei of the midbrain are principal centers from which serotonin neurons project to innervate cortical and sub-cortical structures. The dorsal raphe nuclei receive light input from the circadian visual system and indirect input from the biological clock nuclei. Dysregulation of serotonin neurotransmission is implicated in neurobehavioral disorders, such as depression and anxiety, and alterations in the serotonergic phenotype of raphe neurons have dramatic effects on affective behaviors in rodents. Here, we demonstrate that day length (photoperiod) during development induces enduring changes in mouse dorsal raphe serotonin neurons—programming their firing rate, responsiveness to noradrenergic stimulation, intrinsic electrical properties, serotonin and norepinephrine content in the midbrain, and depression/anxiety-related behavior in a melatonin receptor 1 (MT1)-dependent manner. Our results establish mechanisms by which seasonal photoperiods may dramatically and persistently alter the function of serotonin neurons.
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Affiliation(s)
- Noah H Green
- Department of Biological Sciences, Vanderbilt University School of Medicine, Nashville, TN 37235, USA; Silvio O. Conte Center for Neuroscience Research, Vanderbilt University School of Medicine, Nashville, TN 37235, USA
| | - Chad R Jackson
- Department of Biological Sciences, Vanderbilt University School of Medicine, Nashville, TN 37235, USA; Silvio O. Conte Center for Neuroscience Research, Vanderbilt University School of Medicine, Nashville, TN 37235, USA
| | - Hideki Iwamoto
- Department of Biological Sciences, Vanderbilt University School of Medicine, Nashville, TN 37235, USA; Silvio O. Conte Center for Neuroscience Research, Vanderbilt University School of Medicine, Nashville, TN 37235, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37235, USA
| | - Michael C Tackenberg
- Neuroscience Graduate Program, Vanderbilt University School of Medicine, Nashville, TN 37235, USA
| | - Douglas G McMahon
- Department of Biological Sciences, Vanderbilt University School of Medicine, Nashville, TN 37235, USA; Silvio O. Conte Center for Neuroscience Research, Vanderbilt University School of Medicine, Nashville, TN 37235, USA; Neuroscience Graduate Program, Vanderbilt University School of Medicine, Nashville, TN 37235, USA.
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48
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Wang S, Zhai X, Li S, McCabe MF, Wang X, Rong P. Transcutaneous vagus nerve stimulation induces tidal melatonin secretion and has an antidiabetic effect in Zucker fatty rats. PLoS One 2015; 10:e0124195. [PMID: 25880500 PMCID: PMC4400163 DOI: 10.1371/journal.pone.0124195] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Accepted: 02/26/2015] [Indexed: 01/29/2023] Open
Abstract
Melatonin plays a protective role in type 2 diabetes (T2D) through regulation of glucose metabolism. Whether transcutaneous vagus nerve stimulation (taVNS) is antidiabetic and whether a modulated melatonin production is involved in the antidiabetic mechanism of taVNS is unknown. In this study, once daily 30min noninvasive taVNS was administered in Zucker diabetic fatty (ZDF, fa/fa) and Zucker lean (ZL, +/fa) littermates under anesthesia for 5 consecutive weeks. The acute and chronic influences of taVNS on the secretion of melatonin were studied as well as the effects of taVNS on blood glucose metabolism. We found that naïve ZDF rats develop hyperglycemia naturally with age. Each taVNS session would trigger a tidal secretion of melatonin both during and after the taVNS procedure and induce an acute two-phase glycemic change, a steep increase followed by a gradual decrease. Once daily taVNS sessions eventually reduced the glucose concentration to a normal level in seven days and effectively maintained the normal glycemic and plasma glycosylated hemoglobin (HbAlc) levels when applied for five consecutive weeks. These beneficial effects of taVNS also exist in pinealectomized rats, which otherwise would show overt and continuous hyperglycemia, hyperinsulinemia, and high HbAlc levels. We concluded that multiple taVNS sessions are antidiabetic in T2D through triggering of tidal secretion of melatonin. This finding may have potential importance in developing new approaches to the treatment of T2D, which is highly prevalent, incurable with any current approaches, and very costly to the world.
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Affiliation(s)
- Shuxing Wang
- Department of Anatomy, Xinxiang Medical University, Xinxiang, Henan Province, China
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
- MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
- Guangdong Landau Biotechnology Inc. Ltd., Guangzhou, Guangdong, China
- * E-mail: (SW); (PR)
| | - Xu Zhai
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Shaoyuan Li
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
| | - Michael F. McCabe
- MGH Center for Translational Pain Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Xing Wang
- Department of Anatomy, Xinxiang Medical University, Xinxiang, Henan Province, China
| | - Peijing Rong
- Department of Physiology, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, China
- * E-mail: (SW); (PR)
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49
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Briançon-Marjollet A, Weiszenstein M, Henri M, Thomas A, Godin-Ribuot D, Polak J. The impact of sleep disorders on glucose metabolism: endocrine and molecular mechanisms. Diabetol Metab Syndr 2015. [PMID: 25834642 DOI: 10.1186/s13098- 015-0018-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Modern lifestyle has profoundly modified human sleep habits. Sleep duration has shortened over recent decades from 8 to 6.5 hours resulting in chronic sleep deprivation. Additionally, irregular sleep, shift work and travelling across time zones lead to disruption of circadian rhythms and asynchrony between the master hypothalamic clock and pacemakers in peripheral tissues. Furthermore, obstructive sleep apnea syndrome (OSA), which affects 4 - 15% of the population, is not only characterized by impaired sleep architecture but also by repetitive hemoglobin desaturations during sleep. Epidemiological studies have identified impaired sleep as an independent risk factor for all cause of-, as well as for cardiovascular, mortality/morbidity. More recently, sleep abnormalities were causally linked to impairments in glucose homeostasis, metabolic syndrome and Type 2 Diabetes Mellitus (T2DM). This review summarized current knowledge on the metabolic alterations associated with the most prevalent sleep disturbances, i.e. short sleep duration, shift work and OSA. We have focused on various endocrine and molecular mechanisms underlying the associations between inadequate sleep quality, quantity and timing with impaired glucose tolerance, insulin resistance and pancreatic β-cell dysfunction. Of these mechanisms, the role of the hypothalamic-pituitary-adrenal axis, circadian pacemakers in peripheral tissues, adipose tissue metabolism, sympathetic nervous system activation, oxidative stress and whole-body inflammation are discussed. Additionally, the impact of intermittent hypoxia and sleep fragmentation (key components of OSA) on intracellular signaling and metabolism in muscle, liver, fat and pancreas are also examined. In summary, this review provides endocrine and molecular explanations for the associations between common sleep disturbances and the pathogenesis of T2DM.
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Affiliation(s)
- Anne Briançon-Marjollet
- Université Grenoble Alpes, HP2, F-38041 Grenoble, Cedex France.,INSERM U1042, F-38041 Grenoble, Cedex France
| | - Martin Weiszenstein
- Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Marion Henri
- Université Grenoble Alpes, HP2, F-38041 Grenoble, Cedex France.,INSERM U1042, F-38041 Grenoble, Cedex France
| | - Amandine Thomas
- Université Grenoble Alpes, HP2, F-38041 Grenoble, Cedex France.,INSERM U1042, F-38041 Grenoble, Cedex France
| | - Diane Godin-Ribuot
- Université Grenoble Alpes, HP2, F-38041 Grenoble, Cedex France.,INSERM U1042, F-38041 Grenoble, Cedex France
| | - Jan Polak
- Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University, Prague, Czech Republic.,2nd Internal Medicine Department, University Hospital Kralovske Vinohrady, Prague, Czech Republic.,Sports Medicine Department, Third Faculty of Medicine, Charles University in Prague, Ruska 87, Praha 10, 100 00 Czech Republic
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50
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Sleep habits and diabetes. DIABETES & METABOLISM 2015; 41:263-271. [PMID: 25623152 DOI: 10.1016/j.diabet.2014.12.004] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 12/09/2014] [Accepted: 12/29/2014] [Indexed: 01/07/2023]
Abstract
Sleep duration has been constantly decreasing over the past 50 years. Short sleep duration, sleep quality and, recently, long sleep duration have all been linked to poor health outcomes, increasing the risk of developing metabolic diseases and cardiovascular events. Beyond the duration of sleep, the timing of sleep may also have consequences. Having a tendency to go early to bed (early chronotype) compared with the habit of going to bed later (late chronotype) can interfere considerably with social schedules (school, work). Eventually, a misalignment arises in sleep timing between work days and free days that has been described as 'social jet lag'. The present review looks at how different sleep habits can interfere with diabetes, excluding sleep breathing disorders, and successively looks at the effects of sleep duration, chronotype and social jet lag on the risk of developing diabetes as well as on the metabolic control of both type 1 and type 2 diabetes. Finally, this review addresses the current state of knowledge of physiological mechanisms that could be linking sleep habits and metabolic health.
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