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1
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Fehsel K, Bouvier ML. Sex-Specific Effects of Long-Term Antipsychotic Drug Treatment on Adipocyte Tissue and the Crosstalk to Liver and Brain in Rats. Int J Mol Sci 2024; 25:2188. [PMID: 38396865 PMCID: PMC10889281 DOI: 10.3390/ijms25042188] [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: 01/17/2024] [Revised: 02/01/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Antipsychotic drug (APD) medication can lead to metabolic dysfunctions and weight gain, which together increase morbidity and mortality. Metabolically active visceral adipose tissue (VAT) in particular plays a crucial role in the etiopathology of these metabolic dysregulations. Here, we studied the effect of 12 weeks of drug medication by daily oral feeding of clozapine and haloperidol on the perirenal fat tissue as part of VAT of male and female Sprague Dawley rats in the context of complex former investigations on brain, liver, and blood. Adipocyte area values were determined, as well as triglycerides, non-esterified fatty acids (NEFAs), glucose, glycogen, lactate, malondialdehyde equivalents, ferric iron and protein levels of Perilipin-A, hormone-sensitive-lipase (HSL), hepcidin, glucose transporter-4 (Glut-4) and insulin receptor-ß (IR-ß). We found increased adipocyte mass in males, with slightly higher adipocyte area values in both males and females under clozapine treatment. Triglycerides, NEFAs, glucose and oxidative stress in the medicated groups were unchanged or slightly decreased. In contrast to controls and haloperidol-medicated rats, perirenal adipocyte mass and serum leptin levels were not correlated under clozapine. Protein expressions of perilipin-A, Glut-4 and HSL were decreased under clozapine treatment. IR-ß expression changed sex-specifically in the clozapine-medicated groups associated with higher hepcidin levels in the perirenal adipose tissue of clozapine-treated females. Taken together, clozapine and haloperidol had a smaller effect than expected on perirenal adipose tissue. The perirenal adipose tissue shows only weak changes in lipid and glucose metabolism. The main changes can be seen in the proteins examined, and probably in their effect on liver metabolism.
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Affiliation(s)
- Karin Fehsel
- Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Bergische Landstraße 2, 40629 Düsseldorf, Germany;
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2
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Campaña M, Davis TR, Novak SX, Cleverdon ER, Bates M, Krishnan N, Curtis ER, Childs MD, Pierce MR, Morales-Rodriguez Y, Sieburg MA, Hehnly H, Luyt LG, Hougland JL. Cellular Uptake of a Fluorescent Ligand Reveals Ghrelin O-Acyltransferase Interacts with Extracellular Peptides and Exhibits Unexpected Localization for a Secretory Pathway Enzyme. ACS Chem Biol 2023; 18:1880-1890. [PMID: 37494676 PMCID: PMC10442857 DOI: 10.1021/acschembio.3c00334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/17/2023] [Indexed: 07/28/2023]
Abstract
Ghrelin O-acyltransferase (GOAT) plays a central role in the maturation and activation of the peptide hormone ghrelin, which performs a wide range of endocrinological signaling roles. Using a tight-binding fluorescent ghrelin-derived peptide designed for high selectivity for GOAT over the ghrelin receptor GHSR, we demonstrate that GOAT interacts with extracellular ghrelin and facilitates ligand cell internalization in both transfected cells and prostate cancer cells endogenously expressing GOAT. Coupled with enzyme mutagenesis, ligand uptake studies support the interaction of the putative histidine general base within GOAT with the ghrelin peptide acylation site. Our work provides a new understanding of GOAT's catalytic mechanism, establishes that GOAT can interact with ghrelin and other peptides located outside the cell, and raises the possibility that other peptide hormones may exhibit similar complexity in their intercellular and organismal-level signaling pathways.
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Affiliation(s)
- Maria
B. Campaña
- Department
of Chemistry, Syracuse University, Syracuse, New York 13244, United States
| | - Tasha R. Davis
- Department
of Chemistry, Syracuse University, Syracuse, New York 13244, United States
| | - Sadie X. Novak
- Department
of Chemistry, Syracuse University, Syracuse, New York 13244, United States
| | | | - Michael Bates
- Department
of Biology, Syracuse University, Syracuse, New York 13244, United States
| | - Nikhila Krishnan
- Department
of Biology, Syracuse University, Syracuse, New York 13244, United States
| | - Erin R. Curtis
- Department
of Biology, Syracuse University, Syracuse, New York 13244, United States
| | - Marina D. Childs
- Department
of Chemistry, University of Western Ontario, London, Ontario N6A 2K7, Canada
| | - Mariah R. Pierce
- Department
of Chemistry, Syracuse University, Syracuse, New York 13244, United States
| | | | - Michelle A. Sieburg
- Department
of Chemistry, Syracuse University, Syracuse, New York 13244, United States
| | - Heidi Hehnly
- Department
of Biology, Syracuse University, Syracuse, New York 13244, United States
- BioInspired
Syracuse, Syracuse University, Syracuse, New York 13244, United States
| | - Leonard G. Luyt
- Department
of Chemistry, University of Western Ontario, London, Ontario N6A 2K7, Canada
- Department
of Oncology and Department of Medical Imaging, London Regional Cancer
Program, Lawson Health Research Institute, 800 Commissioners Road East, London, Ontario N6A 5W9, Canada
| | - James L. Hougland
- Department
of Chemistry, Syracuse University, Syracuse, New York 13244, United States
- Department
of Biology, Syracuse University, Syracuse, New York 13244, United States
- BioInspired
Syracuse, Syracuse University, Syracuse, New York 13244, United States
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3
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Rees D, Beynon AL, Lelos MJ, Smith GA, Roberts LD, Phelps L, Dunnett SB, Morgan AH, Brown RM, Wells T, Davies JS. Acyl-Ghrelin Attenuates Neurochemical and Motor Deficits in the 6-OHDA Model of Parkinson's Disease. Cell Mol Neurobiol 2023; 43:2377-2384. [PMID: 36107359 PMCID: PMC10287784 DOI: 10.1007/s10571-022-01282-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 08/30/2022] [Indexed: 11/24/2022]
Abstract
The feeding-related hormone, acyl-ghrelin, protects dopamine neurones in murine 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-based models of experimental Parkinson's disease (PD). However, the potential protective effect of acyl-ghrelin on substantia nigra pars compacta (SNpc) dopaminergic neurones and consequent behavioural correlates in the more widely used 6-hydroxydopamine (6-OHDA) rat medial forebrain bundle (MFB) lesion model of PD are unknown. To address this question, acyl-ghrelin levels were raised directly by mini-pump infusion for 7 days prior to unilateral injection of 6-OHDA into the MFB with assessment of amphetamine-induced rotations on days 27 and 35, and immunohistochemical analysis of dopaminergic neurone survival. Whilst acyl-ghrelin treatment was insufficient to elevate food intake or body weight, it attenuated amphetamine-induced circling behaviour and SNpc dopamine neurone loss induced by 6-OHDA. These data support the notion that elevating circulating acyl-ghrelin may be a valuable approach to slow or impair progression of neurone loss in PD.
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Affiliation(s)
- Daniel Rees
- Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, SA28PP, UK
| | - Amy L Beynon
- Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, SA28PP, UK
| | - Mariah J Lelos
- School of Biosciences, Cardiff University, Cardiff, CF103AT, UK
| | - Gaynor A Smith
- School of Biosciences, Cardiff University, Cardiff, CF103AT, UK
| | - Luke D Roberts
- Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, SA28PP, UK
| | - Lyndsey Phelps
- School of Biosciences, Cardiff University, Cardiff, CF103AT, UK
| | | | - Alwena H Morgan
- Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, SA28PP, UK
| | - Rowan M Brown
- College of Engineering, Swansea University, Swansea, SA28PP, UK
| | - Timothy Wells
- School of Biosciences, Cardiff University, Cardiff, CF103AT, UK
| | - Jeffrey S Davies
- Molecular Neurobiology, Institute of Life Sciences, School of Medicine, Swansea University, Swansea, SA28PP, UK.
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4
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Abstract
Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are essential to normal growth, metabolism, and body composition, but in acromegaly, excesses of these hormones strikingly alter them. In recent years, the use of modern methodologies to assess body composition in patients with acromegaly has revealed novel aspects of the acromegaly phenotype. In particular, acromegaly presents a unique pattern of body composition changes in the setting of insulin resistance that we propose herein to be considered an acromegaly-specific lipodystrophy. The lipodystrophy, initiated by a distinctive GH-driven adipose tissue dysregulation, features insulin resistance in the setting of reduced visceral adipose tissue (VAT) mass and intra-hepatic lipid (IHL) but with lipid redistribution, resulting in ectopic lipid deposition in muscle. With recovery of the lipodystrophy, adipose tissue mass, especially that of VAT and IHL, rises, but insulin resistance is lessened. Abnormalities of adipose tissue adipokines may play a role in the disordered adipose tissue metabolism and insulin resistance of the lipodystrophy. The orexigenic hormone ghrelin and peptide Agouti-related peptide may also be affected by active acromegaly as well as variably by acromegaly therapies, which may contribute to the lipodystrophy. Understanding the pathophysiology of the lipodystrophy and how acromegaly therapies differentially reverse its features may be important to optimizing the long-term outcome for patients with this disease. This perspective describes evidence in support of this acromegaly lipodystrophy model and its relevance to acromegaly pathophysiology and the treatment of patients with acromegaly.
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Affiliation(s)
- Pamela U. Freda
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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5
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Piper NBC, Whitfield EA, Stewart GD, Xu X, Furness SGB. Targeting appetite and satiety in diabetes and obesity, via G protein-coupled receptors. Biochem Pharmacol 2022; 202:115115. [PMID: 35671790 DOI: 10.1016/j.bcp.2022.115115] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 11/17/2022]
Abstract
Type 2 diabetes and obesity have reached pandemic proportions throughout the world, so much so that the World Health Organisation coined the term "Globesity" to help encapsulate the magnitude of the problem. G protein-coupled receptors (GPCRs) are highly tractable drug targets due to their wide involvement in all aspects of physiology and pathophysiology, indeed, GPCRs are the targets of approximately 30% of the currently approved drugs. GPCRs are also broadly involved in key physiologies that underlie type 2 diabetes and obesity including feeding reward, appetite and satiety, regulation of blood glucose levels, energy homeostasis and adipose function. Despite this, only two GPCRs are the target of approved pharmaceuticals for treatment of type 2 diabetes and obesity. In this review we discuss the role of these, and select other candidate GPCRs, involved in various facets of type 2 diabetic or obese pathophysiology, how they might be targeted and the potential reasons why pharmaceuticals against these targets have not progressed to clinical use. Finally, we provide a perspective on the current development pipeline of anti-obesity drugs that target GPCRs.
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Affiliation(s)
- Noah B C Piper
- Receptor Transducer Coupling Laboratory, School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, QLD 4072, Australia
| | - Emily A Whitfield
- Receptor Transducer Coupling Laboratory, School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, QLD 4072, Australia
| | - Gregory D Stewart
- Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology Monash University, Parkville, VIC 3052, Australia
| | - Xiaomeng Xu
- Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology Monash University, Parkville, VIC 3052, Australia
| | - Sebastian G B Furness
- Receptor Transducer Coupling Laboratory, School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, QLD 4072, Australia; Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology Monash University, Parkville, VIC 3052, Australia.
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6
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Bukhari SNA. An insight into the multifunctional role of ghrelin and structure activity relationship studies of ghrelin receptor ligands with clinical trials. Eur J Med Chem 2022; 235:114308. [PMID: 35344905 DOI: 10.1016/j.ejmech.2022.114308] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/06/2022] [Accepted: 03/18/2022] [Indexed: 11/30/2022]
Abstract
Ghrelin is a multifunctional gastrointestinal acylated peptide, primarily synthesized in the stomach and regulates the secretion of growth hormone and energy homeostasis. It plays a central role in modulating the diverse biological, physiological and pathological functions in vertebrates. The synthesis of ghrelin receptor ligands after the finding of growth hormone secretagogue developed from Met-enkephalin led to reveal the endogenous ligand ghrelin and the receptors. Subsequently, many peptides, small molecules and peptidomimetics focusing on the ghrelin receptor, GHS-R1a, were derived. In this review, the key features of ghrelin's structure, forms, its bio-physiological functions, pathological roles and therapeutic potential have been highlighted. A few peptidomimetics and pseudo peptide synthetic perspectives have also been discussed to make ghrelin receptor ligands, clinical trials and their success.
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Affiliation(s)
- Syed Nasir Abbas Bukhari
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 2014, Saudi Arabia.
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7
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Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets. Biomolecules 2022; 12:biom12030407. [PMID: 35327599 PMCID: PMC8945998 DOI: 10.3390/biom12030407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/19/2022] [Accepted: 02/27/2022] [Indexed: 02/07/2023] Open
Abstract
Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global Ghsr−/− mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr−/− mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr−/− mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr−/− mice, but the ATP/ADP ratio in Ghsr−/− islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in Ghsr−/− islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of Ghsr−/− mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.
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8
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Miralpeix C, Reguera AC, Fosch A, Zagmutt S, Casals N, Cota D, Rodríguez-Rodríguez R. Hypothalamic endocannabinoids in obesity: an old story with new challenges. Cell Mol Life Sci 2021; 78:7469-7490. [PMID: 34718828 PMCID: PMC8557709 DOI: 10.1007/s00018-021-04002-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/28/2021] [Accepted: 10/19/2021] [Indexed: 11/20/2022]
Abstract
The crucial role of the hypothalamus in the pathogenesis of obesity is widely recognized, while the precise molecular and cellular mechanisms involved are the focus of intense research. A disrupted endocannabinoid system, which critically modulates feeding and metabolic functions, through central and peripheral mechanisms, is a landmark indicator of obesity, as corroborated by investigations centered on the cannabinoid receptor CB1, considered to offer promise in terms of pharmacologically targeted treatment for obesity. In recent years, novel insights have been obtained, not only into relation to the mode of action of CB receptors, but also CB ligands, non-CB receptors, and metabolizing enzymes considered to be part of the endocannabinoid system (particularly the hypothalamus). The outcome has been a substantial expansion in knowledge of this complex signaling system and in drug development. Here we review recent literature, providing further evidence on the role of hypothalamic endocannabinoids in regulating energy balance and the implication for the pathophysiology of obesity. We discuss how these lipids are dynamically regulated in obesity onset, by diet and metabolic hormones in specific hypothalamic neurons, the impact of gender, and the role of endocannabinoid metabolizing enzymes as promising targets for tackling obesity and related diseases.
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Affiliation(s)
- Cristina Miralpeix
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 3300, Bordeaux, France.
| | - Ana Cristina Reguera
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain
| | - Anna Fosch
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain
| | - Sebastian Zagmutt
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain
| | - Núria Casals
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de La Obesidad Y La Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Daniela Cota
- University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 3300, Bordeaux, France
| | - Rosalía Rodríguez-Rodríguez
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Josep Trueta S/N, 08195, Sant Cugat del Vallès, Spain.
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9
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Yadegari M, Zare-Feyzabadi R, Zakariaeiseraji M, Sahebi R, Shabani N, Khedmatgozar H, Ferns GA, Ghazizadeh H, Mohammadi-Bajgiran M, Jalalian M, Zoghi M, Darban RA, Mohammadian-Ghosooni M, Esmaily H, Avan A, Ghayour-Mobarhan M. Interaction between the genetic variant of rs696217-ghrelin and food intake and obesity and dyslipidemia. Ann Hum Genet 2021; 86:14-23. [PMID: 34437712 DOI: 10.1111/ahg.12443] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 07/15/2021] [Accepted: 08/09/2021] [Indexed: 11/28/2022]
Abstract
In this study, we aimed to investigate the relationship between the genetic variant of rs696217-ghrelin and fasted lipid profile, indices of obesity, and environmental parameters. Amplification refractory mutation system-polymerase chain reaction (ARMs-PCR) was used for genotyping 1118 individuals recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorder (MASHAD) cohort study. The interaction between the presence of the genetic variant of rs696217-ghrelin and nutritional intake and other major determinants of obesity and lipid profile was examined in the MASHAD study population. Individuals with the TT genotype at the locus had the lowest prevalence of obesity compared to other genotypes among the individuals. No significant relationship was found between the two groups regarding the lipid profile and TT genotype. Furthermore, no significant association was found between dietary intake and the genetic variant of rs696217-ghrelin in the population under study. Individuals with a TT or GT genotype appear to be at a higher risk of obesity, compared to those with a GG genotype. The results of the current study revealed a significant association between the genetic variant of rs696217-ghrelin and obesity; however, this gene did not correlate with the risk factors of cardiovascular diseases and dyslipidemia in the Iranian population.
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Affiliation(s)
- Mehran Yadegari
- Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Zare-Feyzabadi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Reza Sahebi
- Department of Molecular Medicine, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Niloofar Shabani
- Department of Biostatistics & Epidemiology, School of Health, Management, & Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Khedmatgozar
- Center for Biotechnology and Genomics, Texas Tech University, Lubbock, TX, USA
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, UK
| | - Hamideh Ghazizadeh
- International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Mohammadi-Bajgiran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Melika Jalalian
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Mohadese Zoghi
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | - Reza Assaran Darban
- Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
| | | | - Habibollah Esmaily
- Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran
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10
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Spiridon IA, Ciobanu DGA, Giușcă SE, Căruntu ID. Ghrelin and its role in gastrointestinal tract tumors (Review). Mol Med Rep 2021; 24:663. [PMID: 34296307 PMCID: PMC8335721 DOI: 10.3892/mmr.2021.12302] [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] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Accepted: 06/23/2021] [Indexed: 12/13/2022] Open
Abstract
Ghrelin, an orexigenic hormone, is a peptide that binds to the growth hormone secretagogue receptor; it is secreted mainly by enteroendocrine cells in the oxyntic glands of the stomach. Ghrelin serves a role in both local and systemic physiological processes, and is implicated in various pathologies, including neoplasia, with tissue expression in several types of malignancies in both in vitro and in vivo studies. However, the precise implications of the ghrelin axis in metastasis, invasion and cancer progression regulation has yet to be established. In the case of gastrointestinal (GI) tract malignancies, ghrelin has shown potential to become a prognostic factor or even a therapeutic target, although data in the literature are inconsistent and unsystematic, with reports untailored to a specific histological subtype of cancer or a particular localization. The evaluation of immunohistochemical expression shows a limited outlook owing to the low number of cases analyzed, and in vivo analyses have conflicting data regarding differences in ghrelin serum levels in patients with cancer. The aim of this review was to examine the relationship between ghrelin and GI tract malignancies to demonstrate the inconsistencies in current results and to highlight its clinical significance in the outcome of these patients.
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Affiliation(s)
- Irene Alexandra Spiridon
- Department of Pathology, 'Grigore T. Popa' University of Medicine and Pharmacy, Iași 700115, Romania
| | | | - Simona Eliza Giușcă
- Department of Pathology, 'Grigore T. Popa' University of Medicine and Pharmacy, Iași 700115, Romania
| | - Irina Draga Căruntu
- Department of Histology, 'Grigore T. Popa' University of Medicine and Pharmacy, Iași 700115, Romania
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11
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Fazeli PK, Bredella MA, Pachon-Peña G, Zhao W, Zhang X, Faje AT, Resulaj M, Polineni SP, Holmes TM, Lee H, O'Donnell EK, MacDougald OA, Horowitz MC, Rosen CJ, Klibanski A. The dynamics of human bone marrow adipose tissue in response to feeding and fasting. JCI Insight 2021; 6:138636. [PMID: 33974568 PMCID: PMC8262500 DOI: 10.1172/jci.insight.138636] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 05/06/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Adipocytes were long considered inert components of the bone marrow niche, but mouse and human models suggest bone marrow adipose tissue (BMAT) is dynamic and responsive to hormonal and nutrient cues. METHODS In this study of healthy volunteers, we investigated how BMAT responds to acute nutrient changes, including analyses of endocrine determinants and paracrine factors from marrow aspirates. Study participants underwent a 10-day high-calorie protocol, followed by a 10-day fast. RESULTS We demonstrate (a) vertebral BMAT increased significantly during high-calorie feeding and fasting, suggesting BMAT may have different functions in states of caloric excess compared with caloric deprivation; (b) ghrelin, which decreased in response to high-calorie feeding and fasting, was inversely associated with changes in BMAT; and (c) in response to high-calorie feeding, resistin levels in the marrow sera, but not the circulation, rose significantly. In addition, TNF-α expression in marrow adipocytes increased with high-calorie feeding and decreased upon fasting. CONCLUSION High-calorie feeding, but not fasting, induces an immune response in bone marrow similar to what has been reported in peripheral adipose tissue. Understanding the immunomodulatory regulators in the marrow may provide further insight into the homeostatic function of this unique adipose tissue depot. FUNDING NIH grant R24 DK084970, Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH, award UL 1TR002541), and NIH grants P30 DK040561 and U19 AG060917S1.
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Affiliation(s)
- Pouneh K Fazeli
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA.,Neuroendocrinology Unit, Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Miriam A Bredella
- Harvard Medical School, Boston, Massachusetts, USA.,Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Wenxiu Zhao
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Xun Zhang
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Alexander T Faje
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Megi Resulaj
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Sai P Polineni
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | | | - Hang Lee
- Harvard Medical School, Boston, Massachusetts, USA.,Biostatistics Center, and
| | - Elizabeth K O'Donnell
- Harvard Medical School, Boston, Massachusetts, USA.,Division of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ormond A MacDougald
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Mark C Horowitz
- Department of Orthopaedics and Rehabilitation, Yale School of Medicine, New Haven, Connecticut, USA
| | - Clifford J Rosen
- Maine Medical Center Research Institute, Scarborough, Maine, USA
| | - Anne Klibanski
- Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
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12
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Kopp T, Codipilly C, Potak D, Fishbein J, Lamport L, Kurepa D, Weinberger B. Serum ghrelin is associated with early feeding readiness but not growth in premature infants. J Neonatal Perinatal Med 2021; 15:147-154. [PMID: 33935112 DOI: 10.3233/npm-200664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Feeding tolerance among premature infants is unpredictable using clinical parameters. Ghrelin, a peptide hormone, acts on the hypothalamus to increase hunger and gut motility. It is present in fetal tissues, promotes intestinal maturation, and is secreted in milk. We hypothesized that higher serum ghrelin levels on days 0-7 are associated with improved feeding tolerance and growth in premature infants. METHODS Infants (< 1500 g birth weight, n = 36) were recruited on day (D) 0-7. Serum ghrelin was measured by ELISA on D 0-7, D 10-14, and D 24-32, and milk ghrelin in a feeding concurrent with each serum sample. Feeding tolerance was assessed as days to first and full enteral feeds. Growth was quantified as both weight and adipose and muscle deposition by ultrasound. RESULTS Mean serum ghrelin levels decreased from D 0-7 to D 24-32. Higher ghrelin levels on D 0-7 were correlated with shorter time to first enteral feeding, but not with time to full enteral feeds, rate of weight gain, or rate of accretion of muscle or adipose tissue. Milk ghrelin was not related to serum ghrelin or growth. Abdominal and suprascapular muscle and adipose increased during the first month, but weight gain correlated only with the rate of accretion of abdominal adipose. CONCLUSIONS Elevated serum ghrelin in the first days of life may contribute to gut motility and readiness to feed. Weight gain in premature infants may primarily indicate abdominal fat accumulation, suggesting that ultrasound measurement of muscle accretion is a better marker for lean body growth.
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Affiliation(s)
- T Kopp
- Neonatal-Perinatal Medicine, Cohen Children's Medical Center, Lilling Family Neonatal Research Lab, Feinstein Institutes for Medical Research, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, USA
| | - C Codipilly
- Neonatal-Perinatal Medicine, Cohen Children's Medical Center, Lilling Family Neonatal Research Lab, Feinstein Institutes for Medical Research, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, USA
| | - D Potak
- Neonatal-Perinatal Medicine, Cohen Children's Medical Center, Lilling Family Neonatal Research Lab, Feinstein Institutes for Medical Research, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, USA
| | - J Fishbein
- Division of Biostatistics, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - L Lamport
- Neonatal-Perinatal Medicine, Cohen Children's Medical Center, Lilling Family Neonatal Research Lab, Feinstein Institutes for Medical Research, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, USA
| | - D Kurepa
- Neonatal-Perinatal Medicine, Cohen Children's Medical Center, Lilling Family Neonatal Research Lab, Feinstein Institutes for Medical Research, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, USA
| | - B Weinberger
- Neonatal-Perinatal Medicine, Cohen Children's Medical Center, Lilling Family Neonatal Research Lab, Feinstein Institutes for Medical Research, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, USA
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13
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β Cell GHS-R Regulates Insulin Secretion and Sensitivity. Int J Mol Sci 2021; 22:ijms22083950. [PMID: 33920473 PMCID: PMC8069226 DOI: 10.3390/ijms22083950] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/09/2021] [Accepted: 04/09/2021] [Indexed: 12/14/2022] Open
Abstract
Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in β and α cells. We then generated β-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic β and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, β cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.
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14
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Stoyanova I, Lutz D. Ghrelin-Mediated Regeneration and Plasticity After Nervous System Injury. Front Cell Dev Biol 2021; 9:595914. [PMID: 33869167 PMCID: PMC8046019 DOI: 10.3389/fcell.2021.595914] [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: 08/17/2020] [Accepted: 02/24/2021] [Indexed: 12/17/2022] Open
Abstract
The nervous system is highly vulnerable to different factors which may cause injury followed by an acute or chronic neurodegeneration. Injury involves a loss of extracellular matrix integrity, neuronal circuitry disintegration, and impairment of synaptic activity and plasticity. Application of pleiotropic molecules initiating extracellular matrix reorganization and stimulating neuronal plasticity could prevent propagation of the degeneration into the tissue surrounding the injury. To find an omnipotent therapeutic molecule, however, seems to be a fairly ambitious task, given the complex demands of the regenerating nervous system that need to be fulfilled. Among the vast number of candidates examined so far, the neuropeptide and hormone ghrelin holds within a very promising therapeutic potential with its ability to cross the blood-brain barrier, to balance metabolic processes, and to stimulate neurorepair and neuroactivity. Compared with its well-established systemic effects in treatment of metabolism-related disorders, the therapeutic potential of ghrelin on neuroregeneration upon injury has received lesser appreciation though. Here, we discuss emerging concepts of ghrelin as an omnipotent player unleashing developmentally related molecular cues and morphogenic cascades, which could attenuate and/or counteract acute and chronic neurodegeneration.
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Affiliation(s)
- Irina Stoyanova
- Department of Anatomy and Cell Biology, Medical University Varna, Varna, Bulgaria
| | - David Lutz
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Bochum, Germany
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15
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Biased signaling: A viable strategy to drug ghrelin receptors for the treatment of obesity. Cell Signal 2021; 83:109976. [PMID: 33713808 DOI: 10.1016/j.cellsig.2021.109976] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 02/23/2021] [Accepted: 03/08/2021] [Indexed: 02/07/2023]
Abstract
Obesity is a global burden and a chronic ailment with damaging overall health effects. Ghrelin, an octanoylated 28 amino acid peptide hormone, is secreted from the oxyntic mucosa of the stomach. Ghrelin acts on regions of the hypothalamus to regulate feeding behavior and glucose homeostasis through its G protein-coupled receptor. Recently, several central pathways modulating the metabolic actions of ghrelin have been reported. While these signaling pathways can be inhibited or activated by antagonists or agonists, they can also be discriminatingly activated in a "biased" response to impart different degrees of activation in distinct pathways downstream of the receptor. Here, we review recent ghrelin biased signaling findings as well as characteristics of ghrelin hormone and its receptors pertinent for biased signaling. We then evaluate the feasibility for ghrelin receptor biased signaling as a strategy for the development of effective pharmacotherapy in obesity treatment.
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16
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Jamshidi M, Mohammadi Pour S, Bahadoram M, Mahmoudian-Sani MR, Saeedi Boroujeni A. Genetic polymorphisms associated with polycystic ovary syndrome among Iranian women. Int J Gynaecol Obstet 2020; 153:33-44. [PMID: 33314055 DOI: 10.1002/ijgo.13534] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 09/05/2020] [Accepted: 12/09/2020] [Indexed: 12/27/2022]
Abstract
Polycystic ovary syndrome (PCOS) involves abnormalities in ovarian, reproductive, and metabolic systems. Genetic polymorphisms associated with individual differences and variations might be related to complex disorders with unknown causes, including PCOS. Several leading genetic markers with known cellular functions have been identified among Iranian women presenting with PCOS. In particular, the existing evidence shows a significant relationship between PCOS and the following genetic polymorphisms: rs2275913 (interleukin-17A), rs9927163 (interleukin-32), Pro12Ala (peroxisome proliferator-activated receptor-γ), rs17173608 (chemerin), rs2236242 (vaspin), ApaI (vitamin D receptor), and rs7895833 (sirtuin 1). In addition, a higher risk of PCOS is associated with the rs2910164 (microRNA 146a), rs2241766 (adiponectin), -34 T/C (cytochrome 17), and rs1800682 (Fas) polymorphisms. Furthermore, protective effects against PCOS have been reported for the A4223C polymorphism of adenosine deaminase 1. Overall, the available data indicate that Iranian women with PCOS have a higher prevalence of polymorphisms in inflammation- and metabolism-related genes, but not in insulin-related genes. More extensive studies are needed to identify the ethnicity-related genetic associations in PCOS.
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Affiliation(s)
- Mohammad Jamshidi
- Department of Laboratory Sciences, School of Allied Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Somayeh Mohammadi Pour
- Department of Obstetrics and Gynecology, School of Medicine Lorestan, University of Medical Sciences, Khorramabad, Iran
| | - Mohammad Bahadoram
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Saeedi Boroujeni
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,ImmunologyToday, Universal Scientific Education and Research Network, Tehran, Iran
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17
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Gulubova MV, Tolekova AN, Ivanova K, Hamza S, Hadzhi M, Chonov D, Ananiev J. Fructose-induced metabolic disturbances in rats and its impact on stomach endocrine cell number and smooth muscle contractility. Arch Physiol Biochem 2020; 126:440-448. [PMID: 30633582 DOI: 10.1080/13813455.2018.1555601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Context: Gastric ghrelin-positive endocrine cells (GHR + EC) were most dense in the oxyntic mucosa.Objective: We evaluated ECs and contractile activity in rat stomach with metabolic disorders.Materials and methods: Male Wistar rats were divided into two groups: Control (n = 9) received tap water and Fructose (n = 9) drank 15% fructose solution for 12 weeks. Streptozotocin was applied in a dose of 20 mg/kg b.w. two weeks after the beginning of the experiment on Fructose group. Smooth-muscle strips from the stomach were influenced by Angiotensin II for analysis of parameters of contractions. Stomach samples were elaborated with immunohistochemistry for ghrelin, somatostatin, gastrin antibodies and with double immunofluorescence.Results: In treated animals, GHR + EC were significantly increased in the corpus where somatostatin-positive cells were decreased. Contractile activity was decreased.Conclusions: The increase number of GHR + EC was discussed in the context of Somatostatin and Gastrin-positive ECs variations and correlated with the decrease of smooth muscle contraction.
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Affiliation(s)
- Maya V Gulubova
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
| | - Anna N Tolekova
- Department of Physiology, Pathophysiology and Pharmacology, Trakia University, Stara Zagora, Bulgaria
| | - Koni Ivanova
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
| | - Sevinch Hamza
- Department of Anatomy, Trakia University, Stara Zagora, Bulgaria
| | - Mehmed Hadzhi
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
| | - Dimitar Chonov
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
| | - Julian Ananiev
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
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18
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Gupta S, Mitra A. Heal the heart through gut (hormone) ghrelin: a potential player to combat heart failure. Heart Fail Rev 2020; 26:417-435. [PMID: 33025414 DOI: 10.1007/s10741-020-10032-2] [Citation(s) in RCA: 5] [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] [Accepted: 09/21/2020] [Indexed: 12/17/2022]
Abstract
Ghrelin, a small peptide hormone (28 aa), secreted mainly by X/A-like cells of gastric mucosa, is also locally produced in cardiomyocytes. Being an orexigenic factor (appetite stimulant), it promotes release of growth hormone (GH) and exerts diverse physiological functions, viz. regulation of energy balance, glucose, and/or fat metabolism for body weight maintenance. Interestingly, administration of exogenous ghrelin significantly improves cardiac functions in CVD patients as well as experimental animal models of heart failure. Ghrelin ameliorates pathophysiological condition of the heart in myocardial infarction, cardiac hypertrophy, fibrosis, cachexia, and ischemia reperfusion injury. This peptide also exerts significant impact at the level of vasculature leading to lowering high blood pressure and reversal of endothelial dysfunction and atherosclerosis. However, the molecular mechanism of actions elucidating the healing effects of ghrelin on the cardiovascular system is still a matter of conjecture. Some experimental data indicate its beneficial effects via complex cellular cross talks between autonomic nervous system and cardiovascular cells, some other suggest more direct receptor-mediated molecular actions via autophagy or ionotropic regulation and interfering with apoptotic and inflammatory pathways of cardiomyocytes and vascular endothelial cells. Here, in this review, we summarise available recent data to encourage more research to find the missing links of unknown ghrelin receptor-mediated pathways as we see ghrelin as a future novel therapy in cardiovascular protection.
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Affiliation(s)
- Shreyasi Gupta
- Department of Zoology, Triveni Devi Bhalotia College, Raniganj, Paschim Bardhaman, 713347, India
| | - Arkadeep Mitra
- Department of Zoology, City College , 102/1, Raja Rammohan Sarani, Kolkata, 700009, India.
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19
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Karl JP, Berryman CE, Harris MN, Lieberman HR, Gadde KM, Rood JC, Pasiakos SM. Effects of Testosterone Supplementation on Ghrelin and Appetite During and After Severe Energy Deficit in Healthy Men. J Endocr Soc 2020; 4:bvaa024. [PMID: 32258956 PMCID: PMC7101089 DOI: 10.1210/jendso/bvaa024] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/26/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Severe energy deficits cause interrelated reductions in testosterone and fat free mass. Testosterone supplementation may mitigate those decrements, but could also reduce circulating concentrations of the orexigenic hormone ghrelin, thereby exacerbating energy deficit by suppressing appetite. OBJECTIVE To determine whether testosterone supplementation during severe energy deficit influences fasting and postprandial ghrelin concentrations and appetite. DESIGN AND METHODS Secondary analysis of a randomized, double-blind trial that determined the effects of testosterone supplementation on body composition changes during and following severe energy deficit in nonobese, eugonadal men. Phase 1 (PRE-ED): 14-day run-in; phase 2: 28 days, 55% energy deficit with 200 mg testosterone enanthate weekly (TEST; n = 24) or placebo (PLA; n = 26); phase 3: free-living until body mass recovered (end-of-study; EOS). Fasting and postprandial acyl ghrelin and des-acyl ghrelin concentrations and appetite were secondary outcomes measured during the final week of each phase. RESULTS Fasting acyl ghrelin concentrations, and postprandial acyl and des-acyl ghrelin concentrations increased in PLA during energy deficit then returned to PRE-ED values by EOS, but did not change in TEST (phase-by-group, P < 0.05). Correlations between changes in free testosterone and changes in fasting acyl ghrelin concentrations during energy deficit (ρ = -0.42, P = 0.003) and body mass recovery (ρ = -0.38; P = 0.01) were not mediated by changes in body mass or body composition. Transient increases in appetite during energy deficit were not affected by testosterone treatment. CONCLUSIONS Testosterone supplementation during short-term, severe energy deficit in healthy men prevents deficit-induced increases in circulating ghrelin without blunting concomitant increases in appetite. CLINICAL TRIALS REGISTRATION www.clinicaltrials.gov NCT02734238 (registered 12 April 2016).
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Affiliation(s)
- J Philip Karl
- Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Claire E Berryman
- Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA, USA
- Oak Ridge Institute for Science and Education, Belcamp, MD, USA
- Department of Nutrition, Food, and Exercise Sciences, Florida State University, Tallahassee, FL, USA
| | - Melissa N Harris
- Louisiana State University’s Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Harris R Lieberman
- Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA, USA
| | - Kishore M Gadde
- Louisiana State University’s Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Jennifer C Rood
- Louisiana State University’s Pennington Biomedical Research Center, Baton Rouge, LA, USA
| | - Stefan M Pasiakos
- Military Nutrition Division, US Army Research Institute of Environmental Medicine, Natick, MA, USA
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20
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Mak RH, Cheung W, Purnell J. Ghrelin in Chronic Kidney Disease: Too Much or Too Little? Perit Dial Int 2020. [DOI: 10.1177/089686080702700112] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Robert H. Mak
- Department of Pediatrics Oregon Health & Science University Portland, Oregon, USA
| | - Wai Cheung
- Department of Pediatrics Oregon Health & Science University Portland, Oregon, USA
| | - Jonathan Purnell
- Department of Medicine Oregon Health & Science University Portland, Oregon, USA
- Center for the Study of Weight Regulation Oregon Health & Science University Portland, Oregon, USA
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21
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Unacylated ghrelin stimulates fatty acid oxidation to protect skeletal muscle against palmitate-induced impairment of insulin action in lean but not high-fat fed rats. Metabol Open 2020; 5:100026. [PMID: 32812929 PMCID: PMC7424793 DOI: 10.1016/j.metop.2020.100026] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 01/28/2020] [Accepted: 01/29/2020] [Indexed: 11/29/2022] Open
Abstract
Background Ghrelin is a gut hormone that spikes in circulation before mealtime. Recent findings suggest that both ghrelin isoforms stimulate skeletal muscle fatty acid oxidation, lending to the possibility that it may regulate skeletal muscle’s handling of meal-derived substrates. It was hypothesized in the current study that ghrelin may preserve muscle insulin response during conditions of elevated saturated fatty acid (palmitate) availability by promoting its oxidation. Methods and results Soleus muscle strips were isolated from male rats to determine the direct effects of ghrelin isoforms on fatty acid oxidation, glucose uptake and insulin signaling. We demonstrate that unacylated ghrelin (UnAG) is the more potent stimulator of skeletal muscle fatty acid oxidation. Both isoforms of ghrelin generally protected muscle from impaired insulin-mediated phosphorylation of AKT Ser473 and Thr308, as well as downstream phosphorylation of AS160 Ser588 during high palmitate exposure. However, only UnAG was able to preserve insulin-stimulated glucose uptake during exposure to high palmitate concentrations. The use of etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase (CPT-1) abolished this protection, strongly suggesting that UnAG’s stimulation of fatty acid oxidation may be essential to this protection. To our knowledge, we are also the first to investigate the impact of a chronic high-fat diet on ghrelin’s actions in muscle. Following 6 wks of a high-fat diet, UnAG was unable to preserve insulin-stimulated signaling or glucose transport during an acute high palmitate exposure. UnAG was also unable to further stimulate 5′ AMP-activated protein kinase (AMPK) or fatty acid oxidation during high palmitate exposure. Corticotropin-releasing hormone receptor-2 (CRF-2R) content was significantly decreased in muscle from high-fat fed animals, which may partially account for the loss of UnAG’s effects. Conclusions UnAG is able to protect muscle from acute lipid exposure, likely due to its ability to stimulation fatty acid oxidation. This effect is lost in high-fat fed animals, implying a resistance to ghrelin at the level of the muscle. The underlying mechanisms accounting for ghrelin resistance in high fat-fed animals remain to be discovered.
Saturated lipids acutely impair muscle insulin signaling and glucose transport. Ghrelin isoforms consistently protect insulin signaling from lipid detriment. Unacylated ghrelin more potently stimulates fat oxidation, preserving glucose transport. Muscle of chronic high fat-fed rats may be resistant to ghrelin’s metabolic effects.
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22
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Mills JG, Larkin TA, Deng C, Thomas SJ. Weight gain in Major Depressive Disorder: Linking appetite and disordered eating to leptin and ghrelin. Psychiatry Res 2019; 279:244-251. [PMID: 30878306 DOI: 10.1016/j.psychres.2019.03.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/08/2019] [Accepted: 03/09/2019] [Indexed: 01/12/2023]
Abstract
Major Depressive Disorder (MDD) involves changes in appetite and weight, with a subset of individuals at an increased risk of weight gain. Pathways to weight gain may include appetite disturbances, excess eating, and dysregulation of appetite hormones. However, little research has simultaneously examined relationships between hormones, eating behaviours and MDD symptoms. Plasma ghrelin and leptin, biometrics, eating behaviours and psychopathology were compared between depressed (n = 60) and control (n = 60) participants. Depressed participants were subcategorised into those with increased or decreased appetite/weight for comparison by subtype. The Dutch Eating Behaviours Questionnaire and Yale Food Addiction Scale measured eating behaviours. Disordered eating was higher in MDD than controls, in females than males, and in depressed individuals with increased, compared to decreased, appetite/weight. Leptin levels were higher in females only. Leptin levels correlated positively, and ghrelin negatively, with disordered eating. The results provide further evidence for high levels of disordered eating in MDD, particularly in females. The correlations suggest that excessive eating in MDD is significantly linked to appetite hormones, indicating that it involves physiological, rather than purely psychological, factors. Further, longitudinal, research is needed to better understand whether hormonal factors play a causal role in excessive eating in MDD.
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Affiliation(s)
- Jessica G Mills
- Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Australia.
| | - Theresa A Larkin
- Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Australia
| | - Chao Deng
- Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Australia; Antipsychotic Research Laboratory, University of Wollongong, Australia
| | - Susan J Thomas
- Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia; Illawarra Health and Medical Research Institute, University of Wollongong, Australia
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23
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Tilston TW, Brown RD, Wateridge MJ, Arms-Williams B, Walker JJ, Sun Y, Wells T. A Novel Automated System Yields Reproducible Temporal Feeding Patterns in Laboratory Rodents. J Nutr 2019; 149:1674-1684. [PMID: 31287142 PMCID: PMC6736427 DOI: 10.1093/jn/nxz116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 04/23/2019] [Accepted: 05/07/2019] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND The impact of temporal feeding patterns remains a major unanswered question in nutritional science. Progress has been hampered by the absence of a reliable method to impose temporal feeding in laboratory rodents, without the confounding influence of food-hoarding behavior. OBJECTIVE The aim of this study was to develop and validate a reliable method for supplying crushed diets to laboratory rodents in consistent, relevant feeding patterns for prolonged periods. METHODS We programmed our experimental feeding station to deliver a standard diet [StD; Atwater Fuel Energy (AFE) 13.9% fat] or high-fat diet (HFD; AFE 45% fat) during nocturnal grazing [providing 1/24th of the total daily food intake (tdF/I) of ad libitum-fed controls every 30 min] and meal-fed (3 × 1-h periods of ad libitum feeding) patterns in male rats (Sprague-Dawley: 4 wk old, 72-119 g) and mice [C57/Bl6J wild-type (WT): 6 mo old, 29-37 g], and ghrelin-null littermates (Ghr-/-; 27-34 g). RESULTS Grazing yielded accurate, consistent feeding events in rats, with an approximately linear rise in nocturnal cumulative food intake [tdF/I (StD): 97.4 ± 1.5% accurate compared with manual measurement; R2 = 0.86; tdF/I (HFD): 99.0 ± 1.4% accurate; R2 = 0.86]. Meal-feeding produced 3 nocturnal meals of equal size and duration in StD-fed rats (tdF/I: 97.4 ± 0.9% accurate; R2 = 0.90), whereas the second meal size increased progressively in HFD-fed rats (44% higher on day 35 than on day 14; P < 0.01). Importantly, cumulative food intake in grazing and meal-fed rats was identical. Similar results were obtained in WT mice except that less restricted grazing induced hyperphagia (compared with meal-fed WT mice; P < 0.05 from day 1). This difference was abolished in Ghr-/- mice, with meal initiation delayed and meal duration enhanced. Neither pattern elevated corticosterone secretion in rats, but meal-feeding aligned ultradian pulses. CONCLUSIONS We have established a consistent, measurable, researcher-defined, stress-free method for imposing temporal feeding patterns in rats and mice. This approach will facilitate progress in understanding the physiologic impact of feeding patterns.
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Affiliation(s)
- Thomas W Tilston
- Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Richard D Brown
- Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Matthew J Wateridge
- Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Bradley Arms-Williams
- Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | - Jamie J Walker
- College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, United Kingdom
- Wellcome Trust Centre for Biomedical Modelling and Analysis, University of Exeter, Exeter, United Kingdom
- EPSRC Centre for Predictive Modelling in Healthcare, University of Exeter, Exeter, United Kingdom
- Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom
| | - Yuxiang Sun
- Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA
| | - Timothy Wells
- Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff University, Cardiff, United Kingdom
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Tauber M, Coupaye M, Diene G, Molinas C, Valette M, Beauloye V. Prader-Willi syndrome: A model for understanding the ghrelin system. J Neuroendocrinol 2019; 31:e12728. [PMID: 31046160 DOI: 10.1111/jne.12728] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 04/26/2019] [Accepted: 04/29/2019] [Indexed: 02/07/2023]
Abstract
Subsequent to the discovery of ghrelin as the endogenous ligand of growth hormone secretagogue receptor 1a, this unique gut peptide has been found to exert numerous physiological effects, such as appetite stimulation and lipid accumulation via the central regulating mechanisms in the hypothalamus, stimulation of gastric motility, regulation of glucose metabolism and brown fat thermogenesis, and modulation of stress, anxiety, taste sensation, reward-seeking behaviour and the sleep/wake cycle. Prader-Willi syndrome (PWS) has been described as a unique pathological state characterised by severe obesity and high circulating levels of ghrelin. It was hypothesised that hyperghrelinaemia would explain at least a part of the feeding behaviour and body composition of PWS patients, who are characterised by hyperphagia, an obsession with food and food-seeking, and increased adiposity. Initially, the link between hyperghrelinaemia and growth hormone deficiency, which is observed in 90% of the children with PWS, was not fully understood. Over the years, however, the increasing knowledge on ghrelin, PWS features and the natural history of the disease has led to a more comprehensive description of the abnormal ghrelin system and its role in the pathophysiology of this rare and complex neurodevelopmental genetic disease. In the present study, we (a) present the current view of PWS; (b) explain its natural history, including recent data on the ghrelin system in PWS patients; and (c) discuss the therapeutic approach of modulating the ghrelin system in these patients and the first promising results.
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Affiliation(s)
- Maithé Tauber
- Centre de Référence du Syndrome de Prader-Willi, Hôpital des Enfants, CHU Toulouse, Toulouse, France
- Axe Pédiatrique du CIC 9302/INSERM. Hôpital des Enfants, Toulouse, France
- INSERM U1043, Centre de Physiopathologie de Toulouse Purpan, Université Paul Sabatier, Toulouse, France
| | - Muriel Coupaye
- Service de Nutrition, Centre de Référence du Syndrome de Prader-Willi Assistance-Publique Hôpitaux de Paris (AP-HP), CHU Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Gwenaelle Diene
- Centre de Référence du Syndrome de Prader-Willi, Hôpital des Enfants, CHU Toulouse, Toulouse, France
- INSERM, UMR 1027- Université Toulouse III Hôpital Paule de Viguier, Toulouse, France
| | - Catherine Molinas
- Centre de Référence du Syndrome de Prader-Willi, Hôpital des Enfants, CHU Toulouse, Toulouse, France
- Axe Pédiatrique du CIC 9302/INSERM. Hôpital des Enfants, Toulouse, France
- INSERM U1043, Centre de Physiopathologie de Toulouse Purpan, Université Paul Sabatier, Toulouse, France
| | - Marion Valette
- Centre de Référence du Syndrome de Prader-Willi, Hôpital des Enfants, CHU Toulouse, Toulouse, France
- Axe Pédiatrique du CIC 9302/INSERM. Hôpital des Enfants, Toulouse, France
| | - Veronique Beauloye
- Unité d'Endocrinologie Pédiatrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
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25
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Koutouratsas T, Kalli T, Karamanolis G, Gazouli M. Contribution of ghrelin to functional gastrointestinal disorders’ pathogenesis. World J Gastroenterol 2019; 25:539-551. [PMID: 30774270 PMCID: PMC6371003 DOI: 10.3748/wjg.v25.i5.539] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 12/20/2018] [Accepted: 01/15/2019] [Indexed: 02/06/2023] Open
Abstract
Functional gastrointestinal disorders (FGID) are heterogeneous disorders with a variety of clinical manifestations, primarily defined by signs and symptoms rather than a definite underlying cause. Their pathophysiology remains obscure and, although it is expected to differ according to the specific FGID, disruptions in the brain-gut axis are now thought to be a common denominator in their pathogenesis. The hormone ghrelin is an important component of this axis, exerting a wide repertoire of physiological actions, including regulation of gastrointestinal motility and protection of mucosal tissue. Ghrelin’s gene shows genetic polymorphism, while its protein product undergoes complex regulation and metabolism in the human body. Numerous studies have studied ghrelin’s relation to the emergence of FGIDs, its potential value as an index of disease severity and as a predictive marker for symptom relief during attempted treatment. Despite the mixed results currently available in scientific literature, the plethora of statistically significant findings shows that disruptions in ghrelin genetics and expression are plausibly related to FGID pathogenesis. The aim of this paper is to review current literature studying these associations, in an effort to uncover certain patterns of alterations in both genetics and expression, which could delineate its true contribution to FGID emergence, either as a causative agent or as a pathogenetic intermediate.
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Affiliation(s)
- Tilemachos Koutouratsas
- Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens 11527, Greece
| | - Theodora Kalli
- Gastroenterology Department, Larnaca General Hospital, Larnaca 6301, Cyprus
| | - Georgios Karamanolis
- Gastroenterology Unit, 2nd Department of Surgery, “Aretaieio” University Hospital, School of Medicine, University of Athens, Athens 11527, Greece
| | - Maria Gazouli
- Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens 11527, Greece
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26
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Hawkes CP, Mostoufi-Moab S. Fat-bone interaction within the bone marrow milieu: Impact on hematopoiesis and systemic energy metabolism. Bone 2019; 119:57-64. [PMID: 29550266 PMCID: PMC6139083 DOI: 10.1016/j.bone.2018.03.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 03/13/2018] [Indexed: 12/23/2022]
Abstract
The relationship between fat, bone and systemic metabolism is a growing area of scientific interest. Marrow adipose tissue is a well-recognized component of the bone marrow milieu and is metabolically distinct from current established subtypes of adipose tissue. Despite recent advances, the functional significance of marrow adipose tissue is still not clearly delineated. Bone and fat cells share a common mesenchymal stem cell (MSC) within the bone marrow, and hormones and transcription factors such as growth hormone, leptin, and peroxisomal proliferator-activated receptor γ influence MSC differentiation into osteoblasts or adipocytes. MSC osteogenic potential is more vulnerable than adipogenic potential to radiation and chemotherapy, and this confers a risk for an abnormal fat-bone axis in survivors following cancer therapy and bone marrow transplantation. This review provides a summary of data from animal and human studies describing the relationship between marrow adipose tissue and hematopoiesis, bone mineral density, bone strength, and metabolic function. The significance of marrow adiposity in other metabolic disorders such as osteoporosis, diabetes mellitus, and estrogen and growth hormone deficiency are also discussed. We conclude that marrow adipose tissue is an active endocrine organ with important metabolic functions contributing to bone energy maintenance, osteogenesis, bone remodeling, and hematopoiesis. Future studies on the metabolic role of marrow adipose tissue may provide the critical insight necessary for selecting targeted therapeutic interventions to improve altered hematopoiesis and augment skeletal remodeling in cancer survivors.
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Affiliation(s)
- C P Hawkes
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, USA
| | - S Mostoufi-Moab
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, USA; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, USA; Perelman School of Medicine, Department of Pediatrics, University of Pennsylvania, Philadelphia, USA.
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27
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Li Y, Meng Y, Yu X. The Unique Metabolic Characteristics of Bone Marrow Adipose Tissue. Front Endocrinol (Lausanne) 2019; 10:69. [PMID: 30800100 PMCID: PMC6375842 DOI: 10.3389/fendo.2019.00069] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 01/24/2019] [Indexed: 02/05/2023] Open
Abstract
Bone marrow adipose tissue (MAT) is distinct from white adipose tissue (WAT) or brown adipose tissue (BAT) for its location, feature and function. As a largely ignored adipose depot, it is situated in bone marrow space and resided with bone tissue side-by-side. MAT is considered not only as a regulator of bone metabolism through paracrine, but also as a functionally particular adipose tissue that may contribute to global metabolism. Adipokines, inflammatory factors and other molecules derived from bone marrow adipocytes may exert systematic effects. In this review, we summary the evidence from several aspects including development, distribution, histological features and phenotype to elaborate the basic characteristics of MAT. We discuss the association between bone metabolism and MAT, and highlight our current understanding of this special adipose tissue. We further demonstrate the probable relationship between MAT and energy metabolism, as well as glucose metabolism. On the basis of preliminary results from animal model and clinical studies, we propose that MAT has its unique secretory and metabolic function, although there is no in-depth study at present.
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Affiliation(s)
- Yujue Li
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Meng
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China
| | - Xijie Yu
- Laboratory of Endocrinology and Metabolism, Department of Endocrinology and Metabolism and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Xijie Yu ;
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28
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Fazeli PK, Klibanski A. The paradox of marrow adipose tissue in anorexia nervosa. Bone 2019; 118:47-52. [PMID: 29458121 PMCID: PMC6095826 DOI: 10.1016/j.bone.2018.02.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 02/13/2018] [Accepted: 02/14/2018] [Indexed: 12/19/2022]
Abstract
Anorexia nervosa (AN) is a psychiatric disorder characterized by inappropriate nutrient intake resulting in low body weight. Multiple hormonal adaptations facilitate decreased energy expenditure in this state of caloric deprivation including non-thyroidal illness syndrome, growth hormone resistance, and hypogonadotropic hypogonadism. Although these hormonal adaptations confer a survival advantage during periods of negative energy balance, they contribute to the long-term medical complications associated with AN, the most common of which is significant bone loss and an increased risk of fracture. In recent years, marrow adipose tissue (MAT) has emerged as an important potential determinant of the low bone mass state characteristic of AN. Unlike subcutaneous and visceral adipose tissue depots which are low in AN, MAT levels are paradoxically elevated and are inversely associated with BMD. In this review, we discuss what is known about MAT in AN and the proposed hormonal determinants of this adipose tissue depot.
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Affiliation(s)
- Pouneh K Fazeli
- Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.
| | - Anne Klibanski
- Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
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29
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Franco Machado J, Silva RD, Melo R, G Correia JD. Less Exploited GPCRs in Precision Medicine: Targets for Molecular Imaging and Theranostics. Molecules 2018; 24:E49. [PMID: 30583594 PMCID: PMC6337414 DOI: 10.3390/molecules24010049] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 12/07/2018] [Accepted: 12/09/2018] [Indexed: 12/18/2022] Open
Abstract
Precision medicine relies on individually tailored therapeutic intervention taking into account individual variability. It is strongly dependent on the availability of target-specific drugs and/or imaging agents that recognize molecular targets and patient-specific disease mechanisms. The most sensitive molecular imaging modalities, Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET), rely on the interaction between an imaging radioprobe and a target. Moreover, the use of target-specific molecular tools for both diagnostics and therapy, theranostic agents, represent an established methodology in nuclear medicine that is assuming an increasingly important role in precision medicine. The design of innovative imaging and/or theranostic agents is key for further accomplishments in the field. G-protein-coupled receptors (GPCRs), apart from being highly relevant drug targets, have also been largely exploited as molecular targets for non-invasive imaging and/or systemic radiotherapy of various diseases. Herein, we will discuss recent efforts towards the development of innovative imaging and/or theranostic agents targeting selected emergent GPCRs, namely the Frizzled receptor (FZD), Ghrelin receptor (GHSR-1a), G protein-coupled estrogen receptor (GPER), and Sphingosine-1-phosphate receptor (S1PR). The pharmacological and clinical relevance will be highlighted, giving particular attention to the studies on the synthesis and characterization of targeted molecular imaging agents, biological evaluation, and potential clinical applications in oncology and non-oncology diseases. Whenever relevant, supporting computational studies will be also discussed.
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Affiliation(s)
- João Franco Machado
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
- Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
| | - Rúben D Silva
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
| | - Rita Melo
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
- Center for Neuroscience and Cell Biology; Rua Larga, Faculdade de Medicina, Polo I, 1ºandar, Universidade de Coimbra, 3004-504 Coimbra, Portugal.
| | - João D G Correia
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, CTN, Estrada Nacional 10 (km 139,7), 2695-066 Bobadela LRS, Portugal.
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30
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Dallak M. Unacylated ghrelin stimulates steroidogenesis in lean rats and reverses reproductive dysfunction in high fat diet-fed rats. Syst Biol Reprod Med 2018; 65:129-146. [DOI: 10.1080/19396368.2018.1523971] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Mohammad Dallak
- Department of Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia
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31
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Maréchal L, Laviolette M, Rodrigue-Way A, Sow B, Brochu M, Caron V, Tremblay A. The CD36-PPARγ Pathway in Metabolic Disorders. Int J Mol Sci 2018; 19:1529. [PMID: 29883404 PMCID: PMC5983591 DOI: 10.3390/ijms19051529] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 05/08/2018] [Accepted: 05/16/2018] [Indexed: 12/21/2022] Open
Abstract
Uncovering the biological role of nuclear receptor peroxisome proliferator-activated receptors (PPARs) has greatly advanced our knowledge of the transcriptional control of glucose and energy metabolism. As such, pharmacological activation of PPARγ has emerged as an efficient approach for treating metabolic disorders with the current use of thiazolidinediones to improve insulin resistance in diabetic patients. The recent identification of growth hormone releasing peptides (GHRP) as potent inducers of PPARγ through activation of the scavenger receptor CD36 has defined a novel alternative to regulate essential aspects of lipid and energy metabolism. Recent advances on the emerging role of CD36 and GHRP hexarelin in regulating PPARγ downstream actions with benefits on atherosclerosis, hepatic cholesterol biosynthesis and fat mitochondrial biogenesis are summarized here. The response of PPARγ coactivator PGC-1 is also discussed in these effects. The identification of the GHRP-CD36-PPARγ pathway in controlling various tissue metabolic functions provides an interesting option for metabolic disorders.
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Affiliation(s)
- Loïze Maréchal
- Research Center, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada.
- Department of Physiology, Faculty of Medicine, University of Montreal, Montréal, QC H3T 1J4, Canada.
| | - Maximilien Laviolette
- Research Center, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada.
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, QC H3T 1J4, Canada.
| | - Amélie Rodrigue-Way
- Research Center, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada.
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, QC H3T 1J4, Canada.
| | - Baly Sow
- Research Center, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada.
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, QC H3T 1J4, Canada.
| | - Michèle Brochu
- Department of Physiology, Faculty of Medicine, University of Montreal, Montréal, QC H3T 1J4, Canada.
| | - Véronique Caron
- Research Center, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada.
| | - André Tremblay
- Research Center, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada.
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montréal, QC H3T 1J4, Canada.
- Centre de Recherche en Reproduction et Fertilité, University of Montreal, Saint Hyacinthe, QC J2S 7C6, Canada.
- Department of Obstetrics & Gynecology, Faculty of Medicine, University of Montreal, Montréal, QC H3T 1C5, Canada.
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32
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Bahrami-Nejad Z, Zhao ML, Tholen S, Hunerdosse D, Tkach KE, van Schie S, Chung M, Teruel MN. A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation. Cell Metab 2018; 27:854-868.e8. [PMID: 29617644 PMCID: PMC5889123 DOI: 10.1016/j.cmet.2018.03.012] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 01/26/2018] [Accepted: 03/17/2018] [Indexed: 12/12/2022]
Abstract
Glucocorticoid and other adipogenic hormones are secreted in mammals in circadian oscillations. Loss of this circadian oscillation pattern correlates with obesity in humans, raising the intriguing question of how hormone secretion dynamics affect adipocyte differentiation. Using live, single-cell imaging of the key adipogenic transcription factors CEBPB and PPARG, endogenously tagged with fluorescent proteins, we show that pulsatile circadian hormone stimuli are rejected by the adipocyte differentiation control system. In striking contrast, equally strong persistent signals trigger maximal differentiation. We identify the mechanism of how hormone oscillations are filtered as a combination of slow and fast positive feedback centered on PPARG. Furthermore, we confirm in mice that flattening of daily glucocorticoid oscillations significantly increases the mass of subcutaneous and visceral fat pads. Together, our study provides a molecular mechanism for why stress, Cushing's disease, and other conditions for which glucocorticoid secretion loses its pulsatility may lead to obesity.
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Affiliation(s)
- Zahra Bahrami-Nejad
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Michael L Zhao
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Stefan Tholen
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Devon Hunerdosse
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Karen E Tkach
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Sabine van Schie
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Mingyu Chung
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
| | - Mary N Teruel
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
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33
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Poher AL, Tschöp MH, Müller TD. Ghrelin regulation of glucose metabolism. Peptides 2018; 100:236-242. [PMID: 29412824 PMCID: PMC5805851 DOI: 10.1016/j.peptides.2017.12.015] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/15/2017] [Accepted: 12/16/2017] [Indexed: 02/07/2023]
Abstract
The a 28-amino acid peptide ghrelin was discovered in 1999 as a growth hormone (GH) releasing peptide. Soon after its discovery, ghrelin was found to increase body weight and adiposity by acting on the hypothalamic melanocortinergic system. Subsequently, ghrelin was found to exert a series of metabolic effects, overall testifying ghrelin a pleiotropic nature of broad pharmacological interest. Ghrelin acts through the growth hormone secretagogue-receptor (GHS-R), a seven transmembrane G protein-coupled receptor with high expression in the anterior pituitary, pancreatic islets, thyroid gland, heart and various regions of the brain. Among ghrelins numerous metabolic effects are the most prominent the stimulation of appetite via activation of orexigenic hypothalamic neurocircuits and the food-intake independent stimulation of lipogenesis, which both together lead to an increase in body weight and adiposity. Ghrelin effects beyond the regulation of appetite and GH secretion include the regulation of gut motility, sleep-wake rhythm, taste sensation, reward seeking behaviour, and the regulation of glucose metabolism. The latter received recently increasing recognition because pharmacological inhibition of ghrelin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes. In this review we highlight the multifaceted nature of ghrelin and summarize its glucoregulatory action and discuss the pharmacological value of ghrelin pathway inhibition for the treatment of glucose intolerance and type 2 diabetes.
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Affiliation(s)
- Anne-Laure Poher
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany.
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34
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Auclair N, Melbouci L, St-Pierre D, Levy E. Gastrointestinal factors regulating lipid droplet formation in the intestine. Exp Cell Res 2018; 363:1-14. [PMID: 29305172 DOI: 10.1016/j.yexcr.2017.12.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/28/2017] [Accepted: 12/29/2017] [Indexed: 12/22/2022]
Abstract
Cytoplasmic lipid droplets (CLD) are considered as neutral lipid reservoirs, which protect cells from lipotoxicity. It became clear that these fascinating dynamic organelles play a role not only in energy storage and metabolism, but also in cellular lipid and protein handling, inter-organelle communication, and signaling among diverse functions. Their dysregulation is associated with multiple disorders, including obesity, liver steatosis and cardiovascular diseases. The central aim of this review is to highlight the link between intra-enterocyte CLD dynamics and the formation of chylomicrons, the main intestinal dietary lipid vehicle, after overviewing the morphology, molecular composition, biogenesis and functions of CLD.
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Affiliation(s)
- N Auclair
- Research Centre, CHU Sainte-Justine and Department of Montreal, Quebec, Canada H3T 1C5; Nutrition, Université de Montréal, Montreal, Quebec, Canada H3T 1C5
| | - L Melbouci
- Research Centre, CHU Sainte-Justine and Department of Montreal, Quebec, Canada H3T 1C5; Department of Sciences and Physical Activities, UQAM, Quebec, Canada H2X 1Y4
| | - D St-Pierre
- Research Centre, CHU Sainte-Justine and Department of Montreal, Quebec, Canada H3T 1C5; Department of Sciences and Physical Activities, UQAM, Quebec, Canada H2X 1Y4
| | - E Levy
- Research Centre, CHU Sainte-Justine and Department of Montreal, Quebec, Canada H3T 1C5; Nutrition, Université de Montréal, Montreal, Quebec, Canada H3T 1C5; Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec, Quebec, Canada G1V 0A6.
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35
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Mahbod P, Smith EP, Fitzgerald ME, Morano RL, Packard BA, Ghosal S, Scheimann JR, Perez-Tilve D, Herman JP, Tong J. Desacyl Ghrelin Decreases Anxiety-like Behavior in Male Mice. Endocrinology 2018; 159:388-399. [PMID: 29155981 PMCID: PMC5761608 DOI: 10.1210/en.2017-00540] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 11/10/2017] [Indexed: 11/19/2022]
Abstract
Ghrelin is a 28-amino acid polypeptide that regulates feeding, glucose metabolism, and emotionality (stress, anxiety, and depression). Plasma ghrelin circulates as desacyl ghrelin (DAG) or, in an acylated form, acyl ghrelin (AG), through the actions of ghrelin O-acyltransferase (GOAT), exhibiting low or high affinity, respectively, for the growth hormone secretagogue receptor (GHSR) 1a. We investigated the role of endogenous AG, DAG, and GHSR1a signaling on anxiety and stress responses using ghrelin knockout (Ghr KO), GOAT KO, and Ghsr stop-floxed (Ghsr null) mice. Behavioral and hormonal responses were tested in the elevated plus maze and light/dark (LD) box. Mice lacking both AG and DAG (Ghr KO) increased anxiety-like behaviors across tests, whereas anxiety reactions were attenuated in DAG-treated Ghr KO mice and in mice lacking AG (GOAT KO). Notably, loss of GHSR1a (Ghsr null) did not affect anxiety-like behavior in any test. Administration of AG and DAG to Ghr KO mice with lifelong ghrelin deficiency reduced anxiety-like behavior and decreased phospho-extracellular signal-regulated kinase phosphorylation in the Edinger-Westphal nucleus in wild-type mice, a site normally expressing GHSR1a and involved in stress- and anxiety-related behavior. Collectively, our data demonstrate distinct roles for endogenous AG and DAG in regulation of anxiety responses and suggest that the behavioral impact of ghrelin may be context dependent.
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Affiliation(s)
- Parinaz Mahbod
- Department of Psychiatry and Behavioral Neuroscience,
University of Cincinnati, Cincinnati, Ohio 45267
| | - Eric P. Smith
- Department of Medicine, University of Cincinnati,
Cincinnati, Ohio 45267
| | - Maureen E. Fitzgerald
- Department of Psychiatry and Behavioral Neuroscience,
University of Cincinnati, Cincinnati, Ohio 45267
| | - Rachel L. Morano
- Department of Psychiatry and Behavioral Neuroscience,
University of Cincinnati, Cincinnati, Ohio 45267
| | - Benjamin A. Packard
- Department of Psychiatry and Behavioral Neuroscience,
University of Cincinnati, Cincinnati, Ohio 45267
| | - Sriparna Ghosal
- Department of Psychiatry and Behavioral Neuroscience,
University of Cincinnati, Cincinnati, Ohio 45267
| | - Jessie R. Scheimann
- Department of Psychiatry and Behavioral Neuroscience,
University of Cincinnati, Cincinnati, Ohio 45267
| | - Diego Perez-Tilve
- Department of Medicine, University of Cincinnati,
Cincinnati, Ohio 45267
| | - James P. Herman
- Department of Psychiatry and Behavioral Neuroscience,
University of Cincinnati, Cincinnati, Ohio 45267
| | - Jenny Tong
- Division of Endocrinology, Metabolism and Nutrition,
Department of Medicine, Duke University, Durham, North Carolina 27708
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Association of −604G/A and −501A/C Ghrelin and Obestatin Prepropeptide Gene Polymorphisms with Polycystic Ovary Syndrome. Biochem Genet 2017; 56:116-127. [DOI: 10.1007/s10528-017-9834-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 11/25/2017] [Indexed: 02/01/2023]
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Bresciani E, Rizzi L, Molteni L, Ravelli M, Liantonio A, Ben Haj Salah K, Fehrentz JA, Martinez J, Omeljaniuk RJ, Biagini G, Locatelli V, Torsello A. JMV2894, a novel growth hormone secretagogue, accelerates body mass recovery in an experimental model of cachexia. Endocrine 2017; 58:106-114. [PMID: 27896546 DOI: 10.1007/s12020-016-1184-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 11/15/2016] [Indexed: 10/20/2022]
Abstract
Oncologic patients subjected to chemotherapy frequently present aphagia, malnutrition, and cachexia. The purpose of this study was to investigate whether selected growth hormone secretagogues including hexarelin, JMV2894 and JMV2951 could antagonize body weight loss and wasting induced by cisplatin administration in rats. The three growth hormone secretagogues behaved as full agonists of the growth hormone secretagogues receptor both in terms of ability to stimulate calcium mobilization in Chinese hamster ovary cells and stimulation of growth hormone release in neonatal rats. Adult rats were (i) treated with vehicle throughout (controls), or (ii) treated with cisplatin (days 1-3) and a growth hormone secretagogues or vehicle, (days 1-12). Body weight and food consumption were measured daily. Although all growth hormone secretagogues caused initial transient acute increases in food intake, the total amount of food eaten by controls and growth hormone secretagogues treated groups over the 12 experimental days was not significantly different. All groups pre-treated with cisplatin lost up to 5-10 % body weight in the first 4 days; they subsequently gained weight at a rate comparable with controls. Interestingly, rats which received JMV2894 demonstrated a faster gain in body weight than any other growth hormone secretagogues treated group and at the end of the protocol reached a weight similar to that of controls. JMV2894 did not stimulate perirenal and epididymal fat accumulation but reduced MuRF mRNA levels in skeletal muscles. In conclusion, our findings demonstrate that JMV2894 antagonizes cisplatin induced weight loss in rats and may prove useful in antagonizing cachexia associated with cancer and chemotherapy in humans.
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Affiliation(s)
- Elena Bresciani
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Rizzi
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Laura Molteni
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Monica Ravelli
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | | | - Khoubaib Ben Haj Salah
- Max Mousseron Institute of Biomolecules UMR5247, CNRS, University of Montpellier, ENSCM, Montpellier, France
| | - Jean-Alain Fehrentz
- Max Mousseron Institute of Biomolecules UMR5247, CNRS, University of Montpellier, ENSCM, Montpellier, France
| | - Jean Martinez
- Max Mousseron Institute of Biomolecules UMR5247, CNRS, University of Montpellier, ENSCM, Montpellier, France
| | - Robert J Omeljaniuk
- Department of Biology, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada
| | - Giuseppe Biagini
- Department of Biomedical, Metabolic and Neural Sciences, Laboratory of Experimental Epileptology, University of Modena and Reggio Emilia, Modena, Italy
| | - Vittorio Locatelli
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Antonio Torsello
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
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Huang HH, Chen LY, Doong ML, Chang SC, Chen CY. α-melanocyte stimulating hormone modulates the central acyl ghrelin-induced stimulation of feeding, gastrointestinal motility, and colonic secretion. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:2377-2386. [PMID: 28860709 PMCID: PMC5566386 DOI: 10.2147/dddt.s143749] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Background Acyl ghrelin-induced intake depends on hypothalamic neuropeptide Y and agouti-related protein (AgRP) neurotransmitters. Intracerebroventricular (ICV) injection of AgRP increases feeding through competitive antagonism at melanocortin receptors. ICV administration of α-melanocyte stimulating hormone (α-MSH), a natural antagonist of AgRP, may modulate the acyl ghrelin-induced orexigenic effect. Objective This study aimed to investigate the modulating effect of α-MSH on the central acyl ghrelin-induced food intake, gastrointestinal motility, and colonic secretion in rats. Methods and procedures We examined the effects of α-MSH and acyl ghrelin on food intake, gastric emptying, small intestinal transit, colonic motility, and secretion in conscious rats with a chronic implant of ICV catheters. Results ICV injection of O-n-octanoylated ghrelin (0.1 nmol/rat) significantly increased the cumulative food intake up to 8 h (P<0.01), enhanced non-nutrient semi-liquid gastric emptying (P<0.001), increased the geometric center and running percentage of small intestinal transit (P<0.001), accelerated colonic transit time (P<0.05), and increased fecal pellet output (P<0.01) and total fecal weight (P<0.01). Pretreatment with ICV injection of α-MSH (1.0 and 2.0 nmol/rat) attenuated the acyl ghrelin-induced hyperphagic effect, fecal pellet output, and total fecal weight, while higher dose of α-MSH (2.0 nmol/rat) attenuated the increase in the geometric center of small intestinal transit (P<0.01). However, neither dose of α-MSH altered acyl ghrelin-stimulated gastroprokinetic effect, increase in the running percentage of small intestinal transit, nor accelerated colonic transit time. Conclusion α-MSH is involved in central acyl ghrelin-elicited feeding, small intestinal transit, fecal pellet output, and fecal weight. α-MSH does not affect central acyl ghrelin-induced acceleration of gastric emptying and colonic transit time in rats.
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Affiliation(s)
- Hsien-Hao Huang
- Institute of Clinical Medicine, National Yang-Ming University of Medicine.,Department of Emergency Medicine, Taipei Veterans General Hospital
| | - Liang-Yu Chen
- Aging and Health Research Center, National Yang-Ming University.,Center for Geriatrics and Gerontology, Taipei Veterans General Hospital
| | - Ming-Luen Doong
- Institute of Physiology, National Yang-Ming University School of Medicine
| | - Shi-Chuan Chang
- Institute of Emergency and Critical Medicine, National Yang-Ming University School of Medicine.,Department of Chest Medicine, Taipei Veterans General Hospital
| | - Chih-Yen Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital.,Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei.,Taiwan Association for the Study of Small Intestinal Diseases, Guishan, Taiwan
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Impact of ghrelin on body composition and muscle function in a long-term rodent model of critical illness. PLoS One 2017; 12:e0182659. [PMID: 28796827 PMCID: PMC5552127 DOI: 10.1371/journal.pone.0182659] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 07/22/2017] [Indexed: 01/14/2023] Open
Abstract
Background Patients with multiple injuries or sepsis requiring intensive care treatment invariably develop a catabolic state with resultant loss of lean body mass, for which there are currently no effective treatments. Recovery can take months and mortality is high. We hypothesise that treatment with the orexigenic and anti-inflammatory gastric hormone, ghrelin may attenuate the loss of body mass following critical illness and improve recovery. Methods Male Wistar rats received an intraperitoneal injection of the fungal cell wall derivative zymosan to induce a prolonged peritonitis and consequent critical illness. Commencing at 48h after zymosan, animals were randomised to receive a continuous infusion of ghrelin or vehicle control using a pre-implanted subcutaneous osmotic mini-pump, and continued for 10 days. Results Zymosan peritonitis induced significant weight loss and reduced food intake with a nadir at Day 2 and gradual recovery thereafter. Supra-physiologic plasma ghrelin levels were achieved in the treated animals. Ghrelin-treated rats ate more food and gained more body mass than controls. Ghrelin increased adiposity and promoted carbohydrate over fat metabolism, but did not alter total body protein, muscle strength nor muscle morphology. Muscle mass and strength remained significantly reduced in all zymosan-treated animals, even at ten days post-insult. Conclusions Continuous infusion of ghrelin increased body mass and food intake, but did not increase muscle mass nor improve muscle function, in a long-term critical illness recovery model. Further studies with pulsatile ghrelin delivery or additional anabolic stimuli may further clarify the utility of ghrelin in survivors of critical illness.
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Suchacki KJ, Roberts F, Lovdel A, Farquharson C, Morton NM, MacRae VE, Cawthorn WP. Skeletal energy homeostasis: a paradigm of endocrine discovery. J Endocrinol 2017; 234:R67-R79. [PMID: 28455432 DOI: 10.1530/joe-17-0147] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 04/28/2017] [Indexed: 12/15/2022]
Abstract
Throughout the last decade, significant developments in cellular, molecular and mouse models have revealed major endocrine functions of the skeleton. More recent studies have evolved the interplay between bone-specific hormones, the skeleton, marrow adipose tissue, muscle and the brain. This review focuses on literature from the last decade, addressing the endocrine regulation of global energy metabolism via the skeleton. In addition, we will highlight several recent studies that further our knowledge of new endocrine functions of some organs; explore remaining unanswered questions; and, finally, we will discuss future directions for this more complex era of bone biology research.
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Affiliation(s)
- Karla J Suchacki
- The Queen's Medical Research InstituteThe University of Edinburgh, Edinburgh, UK
| | - Fiona Roberts
- The Roslin InstituteThe University of Edinburgh, Easter Bush, Midltohian, UK
| | - Andrea Lovdel
- The Queen's Medical Research InstituteThe University of Edinburgh, Edinburgh, UK
| | - Colin Farquharson
- The Roslin InstituteThe University of Edinburgh, Easter Bush, Midltohian, UK
| | - Nik M Morton
- The Queen's Medical Research InstituteThe University of Edinburgh, Edinburgh, UK
| | - Vicky E MacRae
- The Roslin InstituteThe University of Edinburgh, Easter Bush, Midltohian, UK
| | - William P Cawthorn
- The Queen's Medical Research InstituteThe University of Edinburgh, Edinburgh, UK
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41
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Chen SR, Chen H, Zhou JJ, Pradhan G, Sun Y, Pan HL, Li DP. Ghrelin receptors mediate ghrelin-induced excitation of agouti-related protein/neuropeptide Y but not pro-opiomelanocortin neurons. J Neurochem 2017; 142:512-520. [DOI: 10.1111/jnc.14080] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 05/19/2017] [Accepted: 05/22/2017] [Indexed: 12/21/2022]
Affiliation(s)
- Shao-Rui Chen
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - Hong Chen
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - Jing-Jing Zhou
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - Geetali Pradhan
- Department of Pediatrics; USDA/ARS Children's Nutrition Research Center; Baylor College of Medicine; Houston Texas USA
| | - Yuxiang Sun
- Department of Pediatrics; USDA/ARS Children's Nutrition Research Center; Baylor College of Medicine; Houston Texas USA
- Department of Nutrition and Food Science (NFSC); Texas A&M University; College Station Texas USA
| | - Hui-Lin Pan
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - De-Pei Li
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
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Abnormal Growth and Feeding Behavior Persist After Removal of Upper Airway Obstruction in Juvenile Rats. Sci Rep 2017; 7:2730. [PMID: 28577340 PMCID: PMC5457418 DOI: 10.1038/s41598-017-02843-5] [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: 01/24/2017] [Accepted: 04/19/2017] [Indexed: 02/06/2023] Open
Abstract
Pediatric obstructive sleep-disordered breathing is associated with growth retardation, but also with obesity that has a tendency to persist following treatment. We investigated the effect of upper airways obstruction (AO) and of obstruction removal (OR) in juvenile rats on gut-derived ghrelin and related hypothalamic factors, feeding, and growth hormone (GH) homeostasis. Here, we show that after seven weeks of AO, animals gained less weight compared to controls, despite an increase in food intake due to elevated ghrelin and hypothalamic feeding factors. OR rats who had complete restoration of tracheal diameter, consumed more food due to increased ghrelin and exhibited growth retardation due to deregulation of GH homeostasis. This study is the first to show dysregulation of the hormonal axes controlling feeding behavior and growth that are not fully restored following OR. Thus, surgical treatment by itself may not be sufficient to prevent post-surgical increased food intake and growth retardation.
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43
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Colldén G, Tschöp MH, Müller TD. Therapeutic Potential of Targeting the Ghrelin Pathway. Int J Mol Sci 2017; 18:ijms18040798. [PMID: 28398233 PMCID: PMC5412382 DOI: 10.3390/ijms18040798] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 02/07/2023] Open
Abstract
Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.
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Affiliation(s)
- Gustav Colldén
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
| | - Timo D Müller
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Institute for Diabetes and Obesity (IDO), Business Campus Garching-Hochbrück, Parkring 13, 85748 Garching, Germany.
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Hopkins AL, Nelson TAS, Guschina IA, Parsons LC, Lewis CL, Brown RC, Christian HC, Davies JS, Wells T. Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R 1a activity: evidence for target cell-induced acylation. Sci Rep 2017; 7:45541. [PMID: 28361877 PMCID: PMC5374529 DOI: 10.1038/srep45541] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 02/21/2017] [Indexed: 11/09/2022] Open
Abstract
Despite being unable to activate the cognate ghrelin receptor (GHS-R), unacylated ghrelin (UAG) possesses a unique activity spectrum that includes promoting bone marrow adipogenesis. Since a receptor mediating this action has not been identified, we re-appraised the potential interaction of UAG with GHS-R in the regulation of bone marrow adiposity. Surprisingly, the adipogenic effects of intra-bone marrow (ibm)-infused acylated ghrelin (AG) and UAG were abolished in male GHS-R-null mice. Gas chromatography showed that isolated tibial marrow adipocytes contain the medium-chain fatty acids utilised in the acylation of UAG, including octanoic acid. Additionally, immunohistochemistry and immunogold electron microscopy revealed that tibial marrow adipocytes show prominent expression of the UAG-activating enzyme ghrelin O-acyl transferase (GOAT), which is located in the membranes of lipid trafficking vesicles and in the plasma membrane. Finally, the adipogenic effect of ibm-infused UAG was completely abolished in GOAT-KO mice. Thus, the adipogenic action of exogenous UAG in tibial marrow is dependent upon acylation by GOAT and activation of GHS-R. This suggests that UAG is subject to target cell-mediated activation – a novel mechanism for manipulating hormone activity.
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Affiliation(s)
- Anna L Hopkins
- Neuroscience &Mental Health Research Institute, and School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Timothy A S Nelson
- Neuroscience &Mental Health Research Institute, and School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Irina A Guschina
- Neuroscience &Mental Health Research Institute, and School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Lydia C Parsons
- Neuroscience &Mental Health Research Institute, and School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Charlotte L Lewis
- Neuroscience &Mental Health Research Institute, and School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Richard C Brown
- Neuroscience &Mental Health Research Institute, and School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Helen C Christian
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3QX, UK
| | - Jeffrey S Davies
- Institute of Life Science, School of Medicine, Swansea University, Swansea, SA2 8PP, UK
| | - Timothy Wells
- Neuroscience &Mental Health Research Institute, and School of Biosciences, Cardiff University, Museum Avenue, Cardiff, CF10 3AX, UK
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45
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Ghrelin affects stopover decisions and food intake in a long-distance migrant. Proc Natl Acad Sci U S A 2017; 114:1946-1951. [PMID: 28167792 DOI: 10.1073/pnas.1619565114] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Billions of birds migrate long distances to either reach breeding areas or to spend the winter at more benign places. On migration, most passerines frequently stop over to rest and replenish their fuel reserves. To date, we know little regarding how they decide that they are ready to continue their journey. What physiological signals tell a bird's brain that its fuel reserves are sufficient to resume migration? A network of hormones regulates food intake and body mass in vertebrates, including the recently discovered peptide hormone, ghrelin. Here, we show that ghrelin reflects body condition and influences migratory behavior of wild birds. We measured ghrelin levels of wild garden warblers (Sylvia borin) captured at a stopover site. Further, we manipulated blood concentrations of ghrelin to test its effects on food intake and migratory restlessness. We found that acylated ghrelin concentrations of garden warblers with larger fat scores were higher than those of birds without fat stores. Further, injections of unacylated ghrelin decreased food intake and increased migratory restlessness. These results represent experimental evidence that appetite-regulating hormones control migratory behavior. Our study lays a milestone in migration physiology because it provides the missing link between ecologically dependent factors such as condition and timing of migration. In addition, it offers insights in the regulation of the hormonal system controlling food intake and energy stores in vertebrates, whose disruption causes eating disorders and obesity.
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46
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Stievenard A, Méquinion M, Andrews ZB, Destée A, Chartier-Harlin MC, Viltart O, Vanbesien-Mailliot CC. Is there a role for ghrelin in central dopaminergic systems? Focus on nigrostriatal and mesocorticolimbic pathways. Neurosci Biobehav Rev 2017; 73:255-275. [DOI: 10.1016/j.neubiorev.2016.11.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 11/23/2016] [Accepted: 11/25/2016] [Indexed: 12/21/2022]
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47
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Sominsky L, Ziko I, Nguyen TX, Andrews ZB, Spencer SJ. Early life disruption to the ghrelin system with over-eating is resolved in adulthood in male rats. Neuropharmacology 2017; 113:21-30. [DOI: 10.1016/j.neuropharm.2016.09.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 09/21/2016] [Accepted: 09/22/2016] [Indexed: 12/11/2022]
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48
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Golding DM, Rees DJ, Davies JR, Relkovic D, Furby HV, Guschina IA, Hopkins AL, Davies JS, Resnick JL, Isles AR, Wells T. Paradoxical leanness in the imprinting-centre deletion mouse model for Prader-Willi syndrome. J Endocrinol 2017; 232:123-135. [PMID: 27799465 PMCID: PMC5118940 DOI: 10.1530/joe-16-0367] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 10/31/2016] [Indexed: 01/09/2023]
Abstract
Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 15q11-q13, is characterised by growth retardation, hyperphagia and obesity. However, as single gene mutation mouse models for this condition display an incomplete spectrum of the PWS phenotype, we have characterised the metabolic impairment in a mouse model for 'full' PWS, in which deletion of the imprinting centre (IC) abolishes paternal gene expression from the entire PWS cluster. We show that PWS-ICdel mice displayed postnatal growth retardation, with reduced body weight, hyperghrelinaemia and marked abdominal leanness; proportionate retroperitoneal, epididymal/omental and inguinal white adipose tissue (WAT) weights being reduced by 82%, 84% and 67%, respectively. PWS-ICdel mice also displayed a 48% reduction in proportionate interscapular brown adipose tissue (isBAT) weight with significant 'beiging' of abdominal WAT, and a 2°C increase in interscapular surface body temperature. Maintenance of PWS-ICdel mice under thermoneutral conditions (30°C) suppressed the thermogenic activity in PWS-ICdel males, but failed to elevate the abdominal WAT weight, possibly due to a normalisation of caloric intake. Interestingly, PWS-ICdel mice also showed exaggerated food hoarding behaviour with standard and high-fat diets, but despite becoming hyperphagic when switched to a high-fat diet, PWS-ICdel mice failed to gain weight. This evidence indicates that, unlike humans with PWS, loss of paternal gene expression from the PWS cluster in mice results in abdominal leanness. Although reduced subcutaneous insulation may lead to exaggerated heat loss and thermogenesis, abdominal leanness is likely to arise from a reduced lipid storage capacity rather than increased energy utilisation in BAT.
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Affiliation(s)
| | - Daniel J Rees
- Institute of Life SciencesCollege of Medicine, Swansea University, Swansea, UK
| | - Jennifer R Davies
- Behavioural Genetics GroupMRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine & Psychology, Cardiff University, Cardiff, UK
| | - Dinko Relkovic
- Behavioural Genetics GroupMRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine & Psychology, Cardiff University, Cardiff, UK
| | - Hannah V Furby
- Behavioural Genetics GroupMRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine & Psychology, Cardiff University, Cardiff, UK
| | | | | | - Jeffrey S Davies
- Institute of Life SciencesCollege of Medicine, Swansea University, Swansea, UK
| | - James L Resnick
- Center for Mammalian GeneticsUniversity of Florida, College of Medicine, Gainesville, Florida, USA
| | - Anthony R Isles
- Behavioural Genetics GroupMRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine & Psychology, Cardiff University, Cardiff, UK
| | - Timothy Wells
- School of BiosciencesCardiff University, Cardiff, UK
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49
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Kocher C, Christiansen M, Martin S, Adams C, Wehner P, Gress T, Santanam N. Sexual dimorphism in obesity-related genes in the epicardial fat during aging. J Physiol Biochem 2016; 73:215-224. [PMID: 28012156 DOI: 10.1007/s13105-016-0542-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 12/06/2016] [Indexed: 01/07/2023]
Abstract
Aging increases the risk of cardiovascular disease and metabolic syndrome. Alterations in epicardial fat play an important pathophysiological role in coronary artery disease and hypertension. We investigated the impact of normal aging on obesity-related genes in epicardial fat. Sex-specific changes in obesity-related genes with aging in epicardial fat (EF) were determined in young (6 months) and old (30/36 months) female and male, Fischer 344 × Brown Norway hybrid (FBN) rats, using a rat obesity RT2 PCR Array. Circulating sex hormone levels, body and heart weights were determined. Statistical significance was determined using two-tailed Student's t test and Pearson's correlation. Our results revealed sex-specific differences in obesity-related genes with aging. Dramatic changes in the expression profile of obesity-related genes in EF with aging in female, but not in male, FBN rats were observed. The older (30 months) female rats had more significant variations in the abundance of obesity-related genes in the EF compared to that seen in younger female rats or both age groups in male rats. A correlation of changes in obesity-related genes in EF to heart weights was observed in female rats, but not in male rats with aging. No correlation was observed to circulating sex hormone levels. Our findings indicate a dysfunctional EF in female rats with aging compared to male rats. These findings, with further functional validation, might help explain the sex differences in cardiovascular risk and mortality associated with aging observed in humans.
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Affiliation(s)
- Caitlin Kocher
- Department of Pharmacology, Physiology, & Toxicology, Joan C Edwards School of Medicine, Marshall University, One John Marshall Dr, Huntington, WV, 25755, USA
| | - Matthew Christiansen
- Department of Pharmacology, Physiology, & Toxicology, Joan C Edwards School of Medicine, Marshall University, One John Marshall Dr, Huntington, WV, 25755, USA
| | - Sarah Martin
- Department of Pharmacology, Physiology, & Toxicology, Joan C Edwards School of Medicine, Marshall University, One John Marshall Dr, Huntington, WV, 25755, USA
| | - Christopher Adams
- Department of Medicine and Cardiology, Joan C Edwards School of Medicine, Marshall University, One John Marshall Dr, Huntington, WV, 25755, USA
| | - Paulette Wehner
- Department of Medicine and Cardiology, Joan C Edwards School of Medicine, Marshall University, One John Marshall Dr, Huntington, WV, 25755, USA
| | - Todd Gress
- Department of Medicine and Cardiology, Joan C Edwards School of Medicine, Marshall University, One John Marshall Dr, Huntington, WV, 25755, USA
| | - Nalini Santanam
- Department of Pharmacology, Physiology, & Toxicology, Joan C Edwards School of Medicine, Marshall University, One John Marshall Dr, Huntington, WV, 25755, USA.
- Department of Medicine and Cardiology, Joan C Edwards School of Medicine, Marshall University, One John Marshall Dr, Huntington, WV, 25755, USA.
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Hassouna R, Labarthe A, Tolle V. Hypothalamic regulation of body growth and appetite by ghrelin-derived peptides during balanced nutrition or undernutrition. Mol Cell Endocrinol 2016; 438:42-51. [PMID: 27693419 DOI: 10.1016/j.mce.2016.09.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 09/25/2016] [Accepted: 09/26/2016] [Indexed: 12/16/2022]
Abstract
Among the gastrointestinal hormones that regulate food intake and energy homeostasis, ghrelin plays a unique role as the first one identified to increases appetite and stimulate GH secretion. This review highlights the latest mechanism by which ghrelin modulates body growth, appetite and energy metabolism by exploring pharmacological actions of the hormone and consequences of genetic or pharmacological blockade of the ghrelin/GHS-R (Growth Hormone Secretagogue Receptor) system on physiological responses in specific nutritional situations. Within the hypothalamus, novel mechanisms of action of this hormone involve its interaction with other ghrelin-derived peptides, such as desacyl ghrelin and obestatin, which are thought to act as functional ghrelin antagonists, and possible modulation of the GHS-R with other G-protein coupled receptors. During chronic undernutrition such as anorexia nervosa, variations of ghrelin-derived peptides may be an adaptative metabolic response to maintain normal glycemic control. Interestingly, some of ghrelin's metabolic actions are thought to be relayed through modulation of GH, an anabolic and hyperglycemic agent.
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Affiliation(s)
- Rim Hassouna
- UMR-S 894 INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, 2 ter rue d'Alésia, 75014, Paris, France; Naomi Berrie Diabetes Center, Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA
| | - Alexandra Labarthe
- UMR-S 894 INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, 2 ter rue d'Alésia, 75014, Paris, France
| | - Virginie Tolle
- UMR-S 894 INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, 2 ter rue d'Alésia, 75014, Paris, France.
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