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Abassi W, Ouerghi N, Muscella A, Marsigliante S, Feki M, Bouassida A. Systematic Review: Does Exercise Training Influence Ghrelin Levels? Int J Mol Sci 2025; 26:4753. [PMID: 40429895 PMCID: PMC12112022 DOI: 10.3390/ijms26104753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 05/10/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Ghrelin, a gastric-derived peptide, regulates appetite, food intake, and energy homeostasis. Body weight plays a crucial role in modulating circulating ghrelin levels. Since exercise training is one of the most valuable tools for controlling body weight, it is relevant to consider whether exercise can influence total ghrelin secretion. This study aims to perform a systematic review of the effect of acute/chronic exercise on plasma ghrelin levels. An extensive literature search was carried out on various databases, including PubMed, ScienceDirect, and Google Scholar. The search was conducted using English keywords such as acute-exercise, transient-exercise, exercise, chronic-exercise, training, physical-activity, physical-training, exercise training, and total-ghrelin, ghrelin, appetite-related-peptides, gastrointestinal-peptides, gastrointestinal-hormones, and appetite-regulating-hormone. Initially, 2104 studies were identified. After evaluating study quality, data from 61 relevant studies were extracted for inclusion in this review. Most studies indicated that short-term acute aerobic exercise did not affect total ghrelin levels regardless of exercise intensity, characteristics, or growth hormone (GH) secretion. However, long and very-long aerobic/chronic exercise increased total ghrelin levels, mainly in overweight/obese individuals. Acute/chronic exercise may differentially influence total ghrelin secretion. Short-term acute aerobic exercise induces stable plasma ghrelin concentrations, independent of GH secretion. Long-term aerobic training increased its levels mainly in overweight/obese individuals through body composition and oxidative stress reduction. Additionally, total ghrelin secretion is more sensitive to exercise/training duration than exercise/training intensity.
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Affiliation(s)
- Wissal Abassi
- Research Unit “Sport Sciences, Health and Movement” (UR22JS01), High Institute of Sport and Physical Education of Kef, University of Jendouba, Kef 7100, Tunisia; (W.A.); (N.O.); (A.B.)
| | - Nejmeddine Ouerghi
- Research Unit “Sport Sciences, Health and Movement” (UR22JS01), High Institute of Sport and Physical Education of Kef, University of Jendouba, Kef 7100, Tunisia; (W.A.); (N.O.); (A.B.)
- Faculty of Medicine of Tunis, University of Tunis El Manar, Rabta Hospital, LR99ES11, Tunis 1007, Tunisia;
- High Institute of Sport and Physical Education of Gafsa, University of Gafsa, Gafsa 2100, Tunisia
| | - Antonella Muscella
- Department of Biological and Environmental Science and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy;
| | - Santo Marsigliante
- Department of Biological and Environmental Science and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy;
| | - Moncef Feki
- Faculty of Medicine of Tunis, University of Tunis El Manar, Rabta Hospital, LR99ES11, Tunis 1007, Tunisia;
| | - Anissa Bouassida
- Research Unit “Sport Sciences, Health and Movement” (UR22JS01), High Institute of Sport and Physical Education of Kef, University of Jendouba, Kef 7100, Tunisia; (W.A.); (N.O.); (A.B.)
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Hassanzadeh-Taheri M, Mohammadifard M, Erfanian Z, Hosseini M. The maternal reduced uteroplacental perfusion model of preeclampsia induces sexually dimorphic metabolic responses in rat offspring. Biol Sex Differ 2022; 13:48. [PMID: 36109770 PMCID: PMC9479437 DOI: 10.1186/s13293-022-00458-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 08/31/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Offspring born to preeclamptic mothers are prone to obesity, diabetes and hypertension in later life, but still, studies investigating the underlying mechanism are limited. Here, we aimed to investigate the impact of the reduced uteroplacental perfusion (RUPP) rat preeclampsia model on offspring metabolic outcomes. METHODS Timed pregnant Wistar rats underwent RUPP or sham surgeries on day 14 of gestation. Glucometabolic parameters were evaluated on postnatal days (PND), 14 (childhood), and 60 (young adult). In addition, intraperitoneal glucose tolerance test (IPGTT), homeostatic model assessment of insulin resistance (HOMA-IR), immunohistochemical staining for insulin in pancreatic islets, arterial blood pressure and 24-h urine protein (24hUP) excretion were performed at PND60. RESULTS Male, but not female, young adult rats (PND60) of RUPP dams exhibited an impaired IPGTT, decreased circulatory insulin and weakened pancreatic insulin immunoreactivity. Compared to the male offspring of the sham group, the body mass of male RUPP offspring significantly caught up after PND42, but it was not sex-specific. RUPP pups also exhibited upregulations in glucagon (only males) and ghrelin (both sexes with a more significant increase in males) during PND14-PND60. However, in sham offspring (both sexes), glucagon levels were downregulated and ghrelin levels unchanged during PND14-PND60. The blood pressure, HOMA-IR and 24hUP values did not alter in RUPP pups. CONCLUSIONS The overall results suggest that maternal RUPP has negative and sex-specific impacts on insulin, glucagon and ghrelin regulations in offspring and that, as young adults, male RUPP rats may be more prone to develop obesity and diabetes.
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Affiliation(s)
- Mohammadmehdi Hassanzadeh-Taheri
- Cellular and Molecular Research Center, Department of Anatomical Sciences, Birjand University of Medical Sciences, Birjand, Iran
| | - Mahtab Mohammadifard
- Department of Pathology, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Zahra Erfanian
- Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Mehran Hosseini
- Cellular and Molecular Research Center, Department of Anatomical Sciences, Birjand University of Medical Sciences, Birjand, Iran.
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Villarreal D, Pradhan G, Zhou Y, Xue B, Sun Y. Diverse and Complementary Effects of Ghrelin and Obestatin. Biomolecules 2022; 12:517. [PMID: 35454106 PMCID: PMC9028691 DOI: 10.3390/biom12040517] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/21/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Ghrelin and obestatin are two "sibling proteins" encoded by the same preproghrelin gene but possess an array of diverse and complex functions. While there are ample literature documenting ghrelin's functions, the roles of obestatin are less clear and controversial. Ghrelin and obestatin have been perceived to be antagonistic initially; however, recent studies challenge this dogma. While they have opposing effects in some systems, they function synergistically in other systems, with many functions remaining debatable. In this review, we discuss their functional relationship under three "C" categories, namely complex, complementary, and contradictory. Their functions in food intake, weight regulation, hydration, gastrointestinal motility, inflammation, and insulin secretion are complex. Their functions in pancreatic beta cells, cardiovascular, muscle, neuroprotection, cancer, and digestive system are complementary. Their functions in white adipose tissue, thermogenesis, and sleep regulation are contradictory. Overall, this review accumulates the multifaceted functions of ghrelin and obestatin under both physiological and pathological conditions, with the intent of contributing to a better understanding of these two important gut hormones.
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Affiliation(s)
- Daniel Villarreal
- Department of Nutrition, Texas A & M University, College Station, TX 77843, USA;
| | - Geetali Pradhan
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA;
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yu Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Qingdao University, Qingdao 266071, China;
| | - Bingzhong Xue
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA;
| | - Yuxiang Sun
- Department of Nutrition, Texas A & M University, College Station, TX 77843, USA;
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA;
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Wittekind DA, Kratzsch J, Mergl R, Baber R, Witte V, Villringer A, Kluge M. Free triiodothyronine (T3) is negatively associated with fasting ghrelin serum levels in a population sample of euthyroid subjects. J Endocrinol Invest 2021; 44:2655-2664. [PMID: 33881751 PMCID: PMC8572188 DOI: 10.1007/s40618-021-01578-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 04/10/2021] [Indexed: 11/28/2022]
Abstract
PURPOSE Ghrelin is an orexigenic peptide hormone secreted in times of stress and hunger. It is deeply involved in the regulation of metabolism and energy homeostasis, promoting energy intake and inhibiting energy expenditure on a metabolic level. In this regard, it has in many ways antagonistic effect on the thyroid hormones, which increase metabolism and thus energy expenditure. While there is reasonable evidence of a negative association between ghrelin and hormones of the hypothalamic-pituitary-thyroid (HPT-) axis from studies in patients with thyroid dysfunction and small intervention studies, large-scale studies in healthy subjects are lacking. Therefore, we studied the relationship between total ghrelin serum levels and serum levels of the thyroid hormones in a large sample of euthyroid subjects. METHODS Total ghrelin, thyroid-stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were determined after an overnight fast in 1666 subjects participating in a population-based cross-sectional study ('LIFE') including 10,000 adults. 1012 subjects were included in this analysis. Multiple linear regression analyses were performed. RESULTS FT3 was negatively associated with serum ghrelin; total sample: β = - 0.0001, p < 0.001; men: β = - 0.0002, p = 0.013; women: β = - 0.0001, p = 0.010, adjusted for age, BMI, alcohol consumption, serum levels of TSH and fT4 and smoking status. No associations were found between ghrelin serum levels and serum levels of fT4 or TSH. CONCLUSION This is to date the largest study investigating the relationship between total serum ghrelin and thyroid hormones. The results point to a complex interaction and should initiate further research.
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Affiliation(s)
- D A Wittekind
- Department of Psychiatry and Psychotherapy, University of Leipzig, Semmelweisstrasse 10, 04103, Leipzig, Germany.
| | - J Kratzsch
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
| | - R Mergl
- Institute of Psychology, Universität der Bundeswehr München, Neubiberg, Germany
| | - R Baber
- Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
- LIFE, Leipzig Research Center for Civilization Diseases, University of Leipzig, Philipp-Rosenthal-Strasse 27, 04103, Leipzig, Germany
| | - V Witte
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany
| | - A Villringer
- Department of Neurology, Max Planck Institute for Cognitive and Brain Sciences, Leipzig, Germany
| | - M Kluge
- Department of Psychiatry and Psychotherapy, University of Leipzig, Semmelweisstrasse 10, 04103, Leipzig, Germany
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Barzowska A, Pucelik B, Pustelny K, Matsuda A, Martyniak A, Stępniewski J, Maksymiuk A, Dawidowski M, Rothweiler U, Dulak J, Dubin G, Czarna A. DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis. Cells 2021; 10:2263. [PMID: 34571911 PMCID: PMC8467532 DOI: 10.3390/cells10092263] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 08/26/2021] [Accepted: 08/26/2021] [Indexed: 11/23/2022] Open
Abstract
The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes β-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived β-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing β-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small-molecule-induced human β-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.
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Affiliation(s)
- Agata Barzowska
- Malopolska Center of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (A.B.); (B.P.); (K.P.); (A.M.); (G.D.)
| | - Barbara Pucelik
- Malopolska Center of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (A.B.); (B.P.); (K.P.); (A.M.); (G.D.)
| | - Katarzyna Pustelny
- Malopolska Center of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (A.B.); (B.P.); (K.P.); (A.M.); (G.D.)
| | - Alex Matsuda
- Malopolska Center of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (A.B.); (B.P.); (K.P.); (A.M.); (G.D.)
| | - Alicja Martyniak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; (A.M.); (J.S.); (J.D.)
| | - Jacek Stępniewski
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; (A.M.); (J.S.); (J.D.)
| | - Anna Maksymiuk
- Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland; (A.M.); (M.D.)
| | - Maciej Dawidowski
- Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland; (A.M.); (M.D.)
| | - Ulli Rothweiler
- The Norwegian Structural Biology Centre, Department of Chemistry, UiT, The Arctic University of Norway, N-9037 Tromsø, Norway;
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; (A.M.); (J.S.); (J.D.)
| | - Grzegorz Dubin
- Malopolska Center of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (A.B.); (B.P.); (K.P.); (A.M.); (G.D.)
| | - Anna Czarna
- Malopolska Center of Biotechnology, Jagiellonian University, Gronostajowa 7A, 30-387 Krakow, Poland; (A.B.); (B.P.); (K.P.); (A.M.); (G.D.)
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Verbeure W, van Goor H, Mori H, van Beek AP, Tack J, van Dijk PR. The Role of Gasotransmitters in Gut Peptide Actions. Front Pharmacol 2021; 12:720703. [PMID: 34354597 PMCID: PMC8329365 DOI: 10.3389/fphar.2021.720703] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/07/2021] [Indexed: 12/31/2022] Open
Abstract
Although gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) receive a bad connotation; in low concentrations these play a major governing role in local and systemic blood flow, stomach acid release, smooth muscles relaxations, anti-inflammatory behavior, protective effect and more. Many of these physiological processes are upstream regulated by gut peptides, for instance gastrin, cholecystokinin, secretin, motilin, ghrelin, glucagon-like peptide 1 and 2. The relationship between gasotransmitters and gut hormones is poorly understood. In this review, we discuss the role of NO, CO and H2S on gut peptide release and functioning, and whether manipulation by gasotransmitter substrates or specific blockers leads to physiological alterations.
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Affiliation(s)
- Wout Verbeure
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Harry van Goor
- Departement of Endocrinology, University Medical Center Groningen, Groningen, Netherlands
| | - Hideki Mori
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - André P. van Beek
- Departement of Endocrinology, University Medical Center Groningen, Groningen, Netherlands
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Peter R. van Dijk
- Departement of Endocrinology, University Medical Center Groningen, Groningen, Netherlands
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Skuratovskaia D, Vulf M, Chasovskikh N, Komar A, Kirienkova E, Shunkin E, Zatolokin P, Litvinova L. The Links of Ghrelin to Incretins, Insulin, Glucagon, and Leptin After Bariatric Surgery. Front Genet 2021; 12:612501. [PMID: 33959145 PMCID: PMC8093791 DOI: 10.3389/fgene.2021.612501] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/15/2021] [Indexed: 12/16/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most prominent and socially significant problems. The present study aimed to identify the mechanisms of interaction of critical regulators of carbohydrate metabolism using bioinformatics and experimental methods and to assess their influence on the development of T2DM. We conducted an in silico search for the relationship of hormones and adipokines and performed functional annotation of the receptors for ghrelin and incretins. Hormones and adipokines were assessed in the plasma of obese patients with and without T2DM as well as after laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB) surgeries. Incretin- and ghrelin-associated functions and metabolic processes were discovered. Low ghrelin levels were observed in obese patients without T2DM compared with healthy volunteers and the other groups. The highest ghrelin levels were observed in obese patients with T2DM. This defense mechanism against insulin resistance could be realized through the receptors G-protein-coupled receptor (GPCR), growth hormone secretagogue receptor (GHSR), and growth hormone-releasing hormone receptor (GHRHR). These receptors are associated with proliferative, inflammatory, and neurohumoral signaling pathways and regulate responses to nutrient intake. Signaling through the GPCR class unites ghrelin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide (GLP)-1. Ghrelin impairs carbohydrate and lipid metabolism in obese patients. Ghrelin is associated with elevated plasma levels of insulin, glucagon, and leptin. Specific activation of receptors and modulation by posttranslational modifications of ghrelin can control IR’s development in obesity, which is a promising area for research.
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Affiliation(s)
- Daria Skuratovskaia
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Maria Vulf
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Nataliya Chasovskikh
- Department of Medical and Biological Cybernetics, Siberian State Medical University, Tomsk, Russia
| | - Aleksandra Komar
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Elena Kirienkova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Egor Shunkin
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Pavel Zatolokin
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Larisa Litvinova
- Center for Immunology and Cellular Biotechnology, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
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Taneera J, Mohammed I, Mohammed AK, Hachim M, Dhaiban S, Malek A, Dunér P, Elemam NM, Sulaiman N, Hamad M, Salehi A. Orphan G-protein coupled receptor 183 (GPR183) potentiates insulin secretion and prevents glucotoxicity-induced β-cell dysfunction. Mol Cell Endocrinol 2020; 499:110592. [PMID: 31550518 DOI: 10.1016/j.mce.2019.110592] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 09/15/2019] [Accepted: 09/20/2019] [Indexed: 12/28/2022]
Abstract
The expression and functional impact of most orphan G-protein coupled receptors (GPCRs) in β-cell is not fully understood. Microarray expression indicated that 36 orphan GPCRs are restricted in human islets, while 55 receptors overlapped between human islets and INS-1 cells. GPR183 showed higher expression in diabetic compared to non-diabetic human islets. GPR183 expression co-localized with β-cells while it was lacking in α-cells in human islets. The GPR183 agonist (7α-25-DHC) potentiated insulin secretion and protected against glucotoxicity-induced β-cell damage in human islets. Silencing of GPR183 in INS-1 cells decreased the expression of proinsulin genes, Pdx1, Mafa and impaired insulin secretion with a concomitant decrease in cAMP generation. Cultured INS-1 cells with 7α-25-DHC were associated with increased proliferation and expression of GPR183, INS2, PDX1, NeuroD, and INSR. In conclusion, the beneficial impact of GPR183 activation on β-cell function makes it a potential therapeutic target to prevent or reverse β-cell dysfunction.
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Affiliation(s)
- Jalal Taneera
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
| | - Israa Mohammed
- Department of Clinical Science, UMAS, Clinical Research Center, Lund University, Malmö, Sweden
| | - Abdul Khader Mohammed
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Mahmood Hachim
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Sarah Dhaiban
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Abdullah Malek
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Pontus Dunér
- Department of Clinical Science, UMAS, Clinical Research Center, Lund University, Malmö, Sweden
| | - Noha M Elemam
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Nabil Sulaiman
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Mawieh Hamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates; Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Albert Salehi
- Department of Clinical Science, UMAS, Clinical Research Center, Lund University, Malmö, Sweden; Department of Neuroscience and Physiology, Metabolic Research Unit, University of Gothenburg, Gothenburg, Sweden.
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Abstract
The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the ε-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1α), exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1α receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1α was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats, only, also improved the peak insulin response to glucose in vivo, thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.
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Affiliation(s)
- Carl Johan Drott
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
| | - Petra Franzén
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
| | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
- Department of Medical Sciences, Uppsala University , Uppsala , Sweden
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10
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Adriaenssens AE, Reimann F, Gribble FM. Distribution and Stimulus Secretion Coupling of Enteroendocrine Cells along the Intestinal Tract. Compr Physiol 2018; 8:1603-1638. [DOI: 10.1002/cphy.c170047] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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11
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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: 112] [Impact Index Per Article: 16.0] [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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12
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Papandreou D, Karavolias C, Arvaniti F, Kafeza E, Sidawi F. Fasting Ghrelin Levels Are Decreased in Obese Subjects and Are Significantly Related With Insulin Resistance and Body Mass Index. Open Access Maced J Med Sci 2017; 5:699-702. [PMID: 29104675 PMCID: PMC5661704 DOI: 10.3889/oamjms.2017.182] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 07/20/2017] [Accepted: 08/19/2017] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Ghrelin is a 28-amino acid peptide that predominantly produced by the stomach. Strong evidence indicates the effects of ghrelin in the regulation of metabolic functions and its potential role in the aetiology of obesity. AIM The aim of this study was to investigate the relationship of ghrelin levels with obesity, insulin resistance and glucose in normal and obese subjects. METHODS Thirteen normal (n = 13) and seven (n = 7) obese weight subjects aged 20-22 participated in the study. Fasting plasma ghrelin, insulin and glucose levels were measured after overnight fasting. HOMA-IR was calculated to evaluate insulin resistance. RESULTS Ghrelin and insulin levels were found to be statistically significantly lower and higher in obese subjects (P < 0.001), respectively. Glucose levels were clinically higher in obese subjects but not statistically significant. Fasting plasma ghrelin was negatively correlated with BMI (r = -0.77, P < 0.001), fasting insulin levels (r = -0.55, P < 0.001) and HOMA-IR (r = -0.66, P < 0.001). There was no correlation between ghrelin and glucose. In multiple regression analysis, insulin levels (Beta:-2.66, 95%CI:-2.49, -2.78, P < 0.001) HOMA-IR (Beta:-2.41, 95%CI:-2.33, -2.55, P < 0.001) and BMI (Beta:-1.77, 95%CI:-1.66, -1.89, P < 0.001) were significant independent determinants of fasting ghrelin. CONCLUSION Obese subjects have low fasting ghrelin levels that they are significantly related to insulin resistance and body mass index. More prospective studies are needed to establish the role of ghrelin in the pathogenesis of human obesity.
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Affiliation(s)
- Dimitrios Papandreou
- Department of Health Sciences, CNHS, Zayed University, Abu Dhabi, United Arab Emirates, Greece
| | | | | | - Eleana Kafeza
- College of Technological Innovation, Zayed University, Abu Dhabi, United Arab Emirates
| | - Fatima Sidawi
- Department of Health Sciences, CNHS, Zayed University, Abu Dhabi, United Arab Emirates, Greece
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Adriaenssens AE, Svendsen B, Lam BYH, Yeo GSH, Holst JJ, Reimann F, Gribble FM. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets. Diabetologia 2016; 59:2156-65. [PMID: 27390011 PMCID: PMC5016554 DOI: 10.1007/s00125-016-4033-1] [Citation(s) in RCA: 161] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 06/01/2016] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Intra-islet and gut-islet crosstalk are critical in orchestrating basal and postprandial metabolism. The aim of this study was to identify regulatory proteins and receptors underlying somatostatin secretion though the use of transcriptomic comparison of purified murine alpha, beta and delta cells. METHODS Sst-Cre mice crossed with fluorescent reporters were used to identify delta cells, while Glu-Venus (with Venus reported under the control of the Glu [also known as Gcg] promoter) mice were used to identify alpha and beta cells. Alpha, beta and delta cells were purified using flow cytometry and analysed by RNA sequencing. The role of the ghrelin receptor was validated by imaging delta cell calcium concentrations using islets with delta cell restricted expression of the calcium reporter GCaMP3, and in perfused mouse pancreases. RESULTS A database was constructed of all genes expressed in alpha, beta and delta cells. The gene encoding the ghrelin receptor, Ghsr, was highlighted as being highly expressed and enriched in delta cells. Activation of the ghrelin receptor raised cytosolic calcium levels in primary pancreatic delta cells and enhanced somatostatin secretion in perfused pancreases, correlating with a decrease in insulin and glucagon release. The inhibition of insulin secretion by ghrelin was prevented by somatostatin receptor antagonism. CONCLUSIONS/INTERPRETATION Our transcriptomic database of genes expressed in the principal islet cell populations will facilitate rational drug design to target specific islet cell types. The present study indicates that ghrelin acts specifically on delta cells within pancreatic islets to elicit somatostatin secretion, which in turn inhibits insulin and glucagon release. This highlights a potential role for ghrelin in the control of glucose metabolism.
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Affiliation(s)
- Alice E Adriaenssens
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Berit Svendsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Brian Y H Lam
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Giles S H Yeo
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Frank Reimann
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
| | - Fiona M Gribble
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
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14
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Razzaghy-Azar M, Nourbakhsh M, Pourmoteabed A, Nourbakhsh M, Ilbeigi D, Khosravi M. An Evaluation of Acylated Ghrelin and Obestatin Levels in Childhood Obesity and Their Association with Insulin Resistance, Metabolic Syndrome, and Oxidative Stress. J Clin Med 2016; 5:61. [PMID: 27348010 PMCID: PMC4961992 DOI: 10.3390/jcm5070061] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/16/2016] [Accepted: 06/01/2016] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Ghrelin is a 28-amino acid peptide with an orexigenic property, which is predominantly produced by the stomach. Acylated ghrelin is the active form of this hormone. Obestatin is a 23-amino acid peptide which is produced by post-translational modification of a protein precursor that also produces ghrelin. Obestatin has the opposite effect of ghrelin on food intake. The aim of this study was to evaluate acylated ghrelin and obestatin levels and their ratio in obese and normal-weight children and adolescents, and their association with metabolic syndrome (MetS) parameters. METHODS Serum acyl-ghrelin, obestatin, leptin, insulin, fasting plasma glucose (FPG), lipid profile, and malondialdehyde (MDA) were evaluated in 73 children and adolescents (42 obese and 31 control). Insulin resistance was calculated by a homeostasis model assessment of insulin resistance (HOMA-IR). MetS was determined according to IDF criteria. RESULTS Acyl-ghrelin levels were significantly lower in obese subjects compared to the control group and lower in obese children with MetS compared to obese subjects without MetS. Obestatin was significantly higher in obese subjects compared to that of the control, but it did not differ significantly among those with or without MetS. Acyl-ghrelin to obestatin ratio was significantly lower in obese subjects compared to that in normal subjects. Acyl-ghrelin showed significant negative and obestatin showed significant positive correlations with body mass index (BMI), BMI Z-score, leptin, insulin, and HOMA-IR. Acyl-ghrelin had a significant negative correlation with MDA as an index of oxidative stress. CONCLUSION Ghrelin is decreased and obestatin is elevated in obesity. Both of these hormones are associated with insulin resistance, and ghrelin is associated with oxidative stress. The balance between ghrelin and obestatin seems to be disturbed in obesity.
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Affiliation(s)
- Maryam Razzaghy-Azar
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, 1411715851 Tehran, Iran.
- H. Aliasghar Hospital, Iran University of Medical Sciences, 1449614535 Tehran, Iran.
| | - Mitra Nourbakhsh
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, 1449614535 Tehran, Iran.
| | | | - Mona Nourbakhsh
- H. Aliasghar Hospital, Iran University of Medical Sciences, 1449614535 Tehran, Iran.
| | - Davod Ilbeigi
- Department of Biochemistry, School of Medicine, Tehran University of Medical Sciences, 1417614418 Tehran, Iran.
| | - Mohsen Khosravi
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, 1449614535 Tehran, Iran.
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15
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Wiedemann T, Bielohuby M, Müller TD, Bidlingmaier M, Pellegata NS. Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity. Diabetes 2016; 65:406-20. [PMID: 26512025 DOI: 10.2337/db15-0374] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 10/23/2015] [Indexed: 11/13/2022]
Abstract
Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.
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Affiliation(s)
- Tobias Wiedemann
- Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany
| | - Maximilian Bielohuby
- Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwigs-Maximilians University, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany
| | - Martin Bidlingmaier
- Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwigs-Maximilians University, Munich, Germany
| | - Natalia S Pellegata
- Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany
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16
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Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, Bowers CY, Broglio F, Casanueva FF, D'Alessio D, Depoortere I, Geliebter A, Ghigo E, Cole PA, Cowley M, Cummings DE, Dagher A, Diano S, Dickson SL, Diéguez C, Granata R, Grill HJ, Grove K, Habegger KM, Heppner K, Heiman ML, Holsen L, Holst B, Inui A, Jansson JO, Kirchner H, Korbonits M, Laferrère B, LeRoux CW, Lopez M, Morin S, Nakazato M, Nass R, Perez-Tilve D, Pfluger PT, Schwartz TW, Seeley RJ, Sleeman M, Sun Y, Sussel L, Tong J, Thorner MO, van der Lely AJ, van der Ploeg LHT, Zigman JM, Kojima M, Kangawa K, Smith RG, Horvath T, Tschöp MH. Ghrelin. Mol Metab 2015; 4:437-60. [PMID: 26042199 PMCID: PMC4443295 DOI: 10.1016/j.molmet.2015.03.005] [Citation(s) in RCA: 772] [Impact Index Per Article: 77.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/11/2015] [Accepted: 03/11/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.
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Affiliation(s)
- T D Müller
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - R Nogueiras
- Department of Physiology, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, University of Santiago de Compostela (CIMUS)-Instituto de Investigación Sanitaria (IDIS)-CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - M L Andermann
- Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Z B Andrews
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia
| | - S D Anker
- Applied Cachexia Research, Department of Cardiology, Charité Universitätsmedizin Berlin, Germany
| | - J Argente
- Department of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain ; Department of Pediatrics, Universidad Autónoma de Madrid and CIBER Fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - R L Batterham
- Centre for Obesity Research, University College London, London, United Kingdom
| | - S C Benoit
- Metabolic Disease Institute, Division of Endocrinology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - C Y Bowers
- Tulane University Health Sciences Center, Endocrinology and Metabolism Section, Peptide Research Section, New Orleans, LA, USA
| | - F Broglio
- Division of Endocrinology, Diabetes and Metabolism, Dept. of Medical Sciences, University of Torino, Torino, Italy
| | - F F Casanueva
- Department of Medicine, Santiago de Compostela University, Complejo Hospitalario Universitario de Santiago (CHUS), CIBER de Fisiopatologia Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III, Santiago de Compostela, Spain
| | - D D'Alessio
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - I Depoortere
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - A Geliebter
- New York Obesity Nutrition Research Center, Department of Medicine, St Luke's-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - E Ghigo
- Department of Pharmacology & Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - P A Cole
- Monash Obesity & Diabetes Institute, Monash University, Clayton, Victoria, Australia
| | - M Cowley
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia ; Monash Obesity & Diabetes Institute, Monash University, Clayton, Victoria, Australia
| | - D E Cummings
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - A Dagher
- McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - S Diano
- Dept of Neurobiology, Yale University School of Medicine, New Haven, CT, USA
| | - S L Dickson
- Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - C Diéguez
- Department of Physiology, School of Medicine, Instituto de Investigacion Sanitaria (IDIS), University of Santiago de Compostela, Spain
| | - R Granata
- Division of Endocrinology, Diabetes and Metabolism, Dept. of Medical Sciences, University of Torino, Torino, Italy
| | - H J Grill
- Department of Psychology, Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA, USA
| | - K Grove
- Department of Diabetes, Obesity and Metabolism, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA
| | - K M Habegger
- Comprehensive Diabetes Center, University of Alabama School of Medicine, Birmingham, AL, USA
| | - K Heppner
- Division of Diabetes, Obesity, and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, USA
| | - M L Heiman
- NuMe Health, 1441 Canal Street, New Orleans, LA 70112, USA
| | - L Holsen
- Departments of Psychiatry and Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - B Holst
- Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen N, Denmark
| | - A Inui
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - J O Jansson
- Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - H Kirchner
- Medizinische Klinik I, Universitätsklinikum Schleswig-Holstein Campus Lübeck, Lübeck, Germany
| | - M Korbonits
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary University of London, London, UK
| | - B Laferrère
- New York Obesity Research Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - C W LeRoux
- Diabetes Complications Research Centre, Conway Institute, University College Dublin, Ireland
| | - M Lopez
- Department of Physiology, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, University of Santiago de Compostela (CIMUS)-Instituto de Investigación Sanitaria (IDIS)-CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - S Morin
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - M Nakazato
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki, Japan
| | - R Nass
- Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA
| | - D Perez-Tilve
- Department of Internal Medicine, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - P T Pfluger
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany
| | - T W Schwartz
- Department of Neuroscience and Pharmacology, Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - R J Seeley
- Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA
| | - M Sleeman
- Department of Physiology, Faculty of Medicine, Monash University, Melbourne, Victoria, Australia
| | - Y Sun
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - L Sussel
- Department of Genetics and Development, Columbia University, New York, NY, USA
| | - J Tong
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - M O Thorner
- Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA
| | - A J van der Lely
- Department of Medicine, Erasmus University MC, Rotterdam, The Netherlands
| | | | - J M Zigman
- Departments of Internal Medicine and Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - M Kojima
- Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
| | - K Kangawa
- National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
| | - R G Smith
- The Scripps Research Institute, Florida Department of Metabolism & Aging, Jupiter, FL, USA
| | - T Horvath
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - M H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, München, Germany ; Division of Metabolic Diseases, Department of Medicine, Technical University Munich, Munich, Germany
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Gao B, Wang L, Han S, Pingguan-Murphy B, Zhang X, Xu F. Engineering of microscale three-dimensional pancreatic islet models in vitro and their biomedical applications. Crit Rev Biotechnol 2015; 36:619-29. [PMID: 25669871 DOI: 10.3109/07388551.2014.1002381] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Diabetes now is the most common chronic disease in the world inducing heavy burden for the people's health. Based on this, diabetes research such as islet function has become a hot topic in medical institutes of the world. Today, in medical institutes, the conventional experiment platform in vitro is monolayer cell culture. However, with the development of micro- and nano-technologies, several microengineering methods have been developed to fabricate three-dimensional (3D) islet models in vitro which can better mimic the islet of pancreases in vivo. These in vitro islet models have shown better cell function than monolayer cells, indicating their great potential as better experimental platforms to elucidate islet behaviors under both physiological and pathological conditions, such as the molecular mechanisms of diabetes and clinical islet transplantation. In this review, we present the state-of-the-art advances in the microengineering methods for fabricating microscale islet models in vitro. We hope this will help researchers to better understand the progress in the engineering 3D islet models and their biomedical applications such as drug screening and islet transplantation.
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Affiliation(s)
- Bin Gao
- a The Key Laboratory of Biomedical Information Engineering of Ministry of Education , Xi'an Jiaotong University School of Life Science and Technology , Xi'an , China .,b Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University , Xi'an , China .,c Department of Endocrinology and Metabolism , Xijing Hospital, Fourth Military Medical University , Xi'an , China
| | - Lin Wang
- a The Key Laboratory of Biomedical Information Engineering of Ministry of Education , Xi'an Jiaotong University School of Life Science and Technology , Xi'an , China .,b Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University , Xi'an , China
| | - Shuang Han
- d Institute of Digestive Disease, Xijing Hospital, Fourth Military Medical University , Xi'an , China , and
| | - Belinda Pingguan-Murphy
- e Department of Biomedical Engineering, Faculty of Engineering , University of Malaya , Kuala Lumpur , Malaysia
| | - Xiaohui Zhang
- a The Key Laboratory of Biomedical Information Engineering of Ministry of Education , Xi'an Jiaotong University School of Life Science and Technology , Xi'an , China .,b Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University , Xi'an , China
| | - Feng Xu
- a The Key Laboratory of Biomedical Information Engineering of Ministry of Education , Xi'an Jiaotong University School of Life Science and Technology , Xi'an , China .,b Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University , Xi'an , China
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18
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Heppner KM, Tong J. Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions. Eur J Endocrinol 2014; 171:R21-32. [PMID: 24714083 DOI: 10.1530/eje-14-0183] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Ghrelin is a 28-amino acid peptide secreted mainly from the X/A-like cells of the stomach. Ghrelin is found in circulation in both des-acyl (dAG) and acyl forms (AG). Acylation is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). AG acts on the GH secretagogue receptor (GHSR) in the CNS to promote feeding and adiposity and also acts on GHSR in the pancreas to inhibit glucose-stimulated insulin secretion. These well-described actions of AG have made it a popular target for obesity and type 2 diabetes mellitus pharmacotherapies. However, despite the lack of a cognate receptor, dAG appears to have gluco-regulatory action, which adds an additional layer of complexity to ghrelin's regulation of glucose metabolism. This review discusses the current literature on the gluco-regulatory action of the ghrelin system (dAG, AG, GHSR, and GOAT) with specific emphasis aimed toward distinguishing AG vs dAG action.
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Affiliation(s)
- Kristy M Heppner
- Division of DiabetesObesity and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA andDivision of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, 260 Stetson Street, Suite 4200, Cincinnati, Ohio 45219-0547, USA
| | - Jenny Tong
- Division of DiabetesObesity and Metabolism, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon, USA andDivision of EndocrinologyDiabetes and Metabolism, Department of Medicine, University of Cincinnati, 260 Stetson Street, Suite 4200, Cincinnati, Ohio 45219-0547, USA
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Chabot F, Caron A, Laplante M, St-Pierre DH. Interrelationships between ghrelin, insulin and glucose homeostasis: Physiological relevance. World J Diabetes 2014; 5:328-341. [PMID: 24936254 PMCID: PMC4058737 DOI: 10.4239/wjd.v5.i3.328] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 05/08/2014] [Indexed: 02/05/2023] Open
Abstract
Ghrelin is a 28 amino acid peptide mainly derived from the oxyntic gland of the stomach. Both acylated (AG) and unacylated (UAG) forms of ghrelin are found in the circulation. Initially, AG was considered as the only bioactive form of ghrelin. However, recent advances indicate that both AG and UAG exert distinct and common effects in organisms. Soon after its discovery, ghrelin was shown to promote appetite and adiposity in animal and human models. In response to these anabolic effects, an impressive number of elements have suggested the influence of ghrelin on the regulation of metabolic functions and the development of obesity-related disorders. However, due to the complexity of its biochemical nature and the physiological processes it governs, some of the effects of ghrelin are still debated in the literature. Evidence suggests that ghrelin influences glucose homeostasis through the modulation of insulin secretion and insulin receptor signaling. On the other hand, insulin was also shown to influence circulating levels of ghrelin. Here, we review the relationship between ghrelin and insulin and we describe the impact of this interaction on the modulation of glucose homeostasis.
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Ziegler TE, Colman RJ, Tardif SD, Sosa ME, Wegner FH, Wittwer DJ, Shrestha H. Development of metabolic function biomarkers in the common marmoset, Callithrix jacchus. Am J Primatol 2013; 75:500-8. [PMID: 23447060 DOI: 10.1002/ajp.22126] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Revised: 11/26/2012] [Accepted: 12/19/2012] [Indexed: 11/05/2022]
Abstract
Metabolic assessment of a non-human primate model of metabolic syndrome and obesity requires the necessary biomarkers specific to the species. While the rhesus monkey has a number of specific assays for assessing metabolic syndrome, the marmoset does not. Furthermore, the common marmoset (Callithrix jacchus) has a small blood volume that necessitates using a single blood volume for multiple analyses. The common marmoset holds a great potential as an alternative primate model for the study of human disease but assay methods need to be developed and validated for the biomarkers of metabolic syndrome. Here we report on the adaptation, development, and validation of commercially available immunoassays for common marmoset samples in small volumes. We have performed biological validations for insulin, adiponectin, leptin, and ghrelin to demonstrate the use of these biomarkers in examining metabolic syndrome and other related diseases in the common marmoset.
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Affiliation(s)
- Toni E Ziegler
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA.
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Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release. Proc Natl Acad Sci U S A 2012; 109:19003-8. [PMID: 23112170 DOI: 10.1073/pnas.1209590109] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Both ghrelin and somatostatin (SST) inhibit glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells, but how these independent actions are regulated has been unclear. The mechanism must accommodate noncanonical ghrelin receptor (GHS-R1a)-G-protein coupling to Gα(i/o) instead of Gα(q11) and dependence on energy balance. Here we present evidence for an equilibrium model of receptor heteromerization that fulfills these criteria. We show that GHS-R1a coupling to Gα(i/o) rather than Gα(q11) requires interactions between GHS-R1a and SST receptor subtype 5 (SST5) and that in the absence of SST5 ghrelin enhances GSIS. At concentrations of GHS-R1a and SST5 expressed in islets, time-resolved FRET and bioluminescence resonance energy transfer assays illustrate constitutive formation of GHS-R1a:SST5 heteromers in which ghrelin, but not SST, suppresses GSIS and cAMP accumulation. GHS-R1a-G-protein coupling and the formation of GHS-R1a:SST5 heteromers is dependent on the ratio of ghrelin to SST. A high ratio enhances heteromer formation and Gα(i/o) coupling, whereas a low ratio destabilizes heteromer conformation, restoring GHS-R1a-Gα(q11) coupling. The [ghrelin]/[SST] ratio is dependent on energy balance: Ghrelin levels peak during acute fasting, whereas postprandially ghrelin is at a nadir, and islet SST concentrations increase. Hence, under conditions of low energy balance our model predicts that endogenous ghrelin rather than SST establishes inhibitory tone on the β-cell. Collectively, our data are consistent with physiologically relevant GHS-R1a:SST5 heteromerization that explains differential regulation of islet function by ghrelin and SST. These findings reinforce the concept that signaling by the G-protein receptor is dynamic and dependent on protomer interactions and physiological context.
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Wadden D, Cahill F, Amini P, Randell E, Vasdev S, Yi Y, Zhang W, Sun G. Serum acylated ghrelin concentrations in response to short-term overfeeding in normal weight, overweight, and obese men. PLoS One 2012; 7:e45748. [PMID: 23029221 PMCID: PMC3459950 DOI: 10.1371/journal.pone.0045748] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 08/24/2012] [Indexed: 02/05/2023] Open
Abstract
Background Ghrelin, an orexigenic gut hormone secreted primarily from the stomach, is involved in energy homeostasis. However, little data is available regarding its response to energy surplus and the development of human obesity. Objective The present study investigated the response of circulating acylated ghrelin to a 7-day positive energy challenge. Design A total of 68 healthy young men were overfed 70% more calories than required, for 1-week. Subjects were classified based on percent body fat (measured by dual-energy X-ray absorptiometry) as normal weight, overweight, and obese. Serum acylated ghrelin concentration was measured before and after the positive energy challenge. Additionally, the relationship between acylated ghrelin and obesity-related phenotypes including weight, body mass index, percent body fat, cholesterol, HDL-c, LDL-c, glucose, insulin and homeostasis model assessment of insulin resistance and β-cell function at baseline and change due to overfeeding, were assessed. Results Contrary to our expectations, serum acylated ghrelin was significantly increased in response to overfeeding and the increase was independent of obesity status. There was no significant difference in fasting acylated ghrelin between normal weight, overweight, and obese men at baseline. Acylated ghrelin was negatively correlated with weight and BMI for normal weight and with BMI in overweight men. Also ghrelin was correlated with change in weight and BMI in overweight (negative relationship) and obese (positive relationship) groups. Conclusion Our results showed that circulating acylated ghrelin was increased after a 7-day positive energy challenge regardless of adiposity status. However, acylated ghrelin was correlated with change in weight and BMI in opposing directions, in overweight and obese subjects respectively, thus dependent on obesity status.
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Affiliation(s)
- Danny Wadden
- Division of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Farrell Cahill
- Division of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Peyvand Amini
- Division of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Edward Randell
- Discipline of Laboratory Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Sudesh Vasdev
- Division of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Yanqing Yi
- Division of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
| | - Guang Sun
- Division of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
- * E-mail:
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Amini P, Wadden D, Cahill F, Randell E, Vasdev S, Chen X, Gulliver W, Zhang W, Zhang H, Yi Y, Sun G. Serum acylated ghrelin is negatively correlated with the insulin resistance in the CODING study. PLoS One 2012; 7:e45657. [PMID: 23029165 PMCID: PMC3447757 DOI: 10.1371/journal.pone.0045657] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Accepted: 08/21/2012] [Indexed: 11/19/2022] Open
Abstract
Objective Ghrelin is a 28-amino acid orexigenic peptide synthesized mainly in the stomach. Acute administration of ghrelin has been found to decrease insulin secretion. However, little data is available regarding whether ghrelin contributes to the long-term regulation of insulin resistance at the population level. The aim of this study is to investigate the association between circulating ghrelin and insulin resistance in a large population based study. Design A total of 2082 CODING study (Complex Diseases in the Newfoundland population: Environment and Genetics) subjects were assessed. Subjects were of at least third generation Newfoundland descent, between the ages of 20 and 79 years, and had no serious metabolic, cardiovascular, or endocrine diseases. Ghrelin was measured with an Enzyme Immunoassay method. Insulin and fasting glucose were measured by Immulite 2500 autoanalyzer and Lx20 clinical chemistry analyzer, respectively. Homeostatic Model Assessment of β cell function (HOMA-β) and Insulin Resistance (HOMA-IR) and Quantitative Insulin-sensitivity Check Index (QUICKI) were used for measurement of insulin resistance. Results Partial correlation analyses showed a significant negative correlation between circulating ghrelin and insulin level and insulin resistance in the entire cohort and also in men and women separately. The aforementioned correlation was independent of age, percentage of trunk fat and HDL-cholesterol. According to menopausal status, only pre-menopausal women revealed negative correlations. Conclusion Our results suggest that except for postmenopausal women, high circulating ghrelin level is associated with lower insulin resistance in the general population.
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Affiliation(s)
- Peyvand Amini
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Danny Wadden
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Farrell Cahill
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Edward Randell
- Discipline of Laboratory Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Sudesh Vasdev
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Xihua Chen
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Wayne Gulliver
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, People’s Republic of China
| | - Hongwei Zhang
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Yanqing Yi
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
| | - Guang Sun
- Division of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada
- * E-mail:
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Beléen C, Martínez-Fuentes AJ, Gracia-Navarro F. Role of SST, CORT and ghrelin and its receptors at the endocrine pancreas. Front Endocrinol (Lausanne) 2012; 3:114. [PMID: 23162532 PMCID: PMC3444847 DOI: 10.3389/fendo.2012.00114] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 09/03/2012] [Indexed: 12/21/2022] Open
Abstract
Somatostatin (SST), cortistatin (CORT), and its receptors (sst1-5), and ghrelin and its receptors (GHS-R) are two highly interrelated neuropeptide systems with a broad range of overlapping biological actions at central, cardiovascular, and immune levels among others. Besides their potent regulatory role on GH release, its endocrine actions are highlighted by SST/CORT and ghrelin influence on insulin secretion, glucose homeostasis, and insulin resistance. Interestingly, most components of these systems are expressed at the endocrine pancreas and are actively involved in the modulation of pancreatic islet function and, consequently influence glucose homeostasis. In addition, some of them also participate in islet survival and regeneration. Furthermore, under severe metabolic condition as well as in endocrine pathologies, their expression profile is severely deregulated. These findings suggest that SST/CORT and ghrelin systems could play a relevant role in pancreatic function under metabolic and endocrine pathologies. Accordingly, these systems have been therapeutically targeted for the prevention or amelioration of certain metabolic conditions (obesity) as well as for tumor growth inhibition and/or hormonal regulation in endocrine pathologies (neuroendocrine tumors). This review focuses on the interrelationship between SST/CORT and ghrelin systems and their role in severe metabolic conditions and some endocrine disorders.
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Affiliation(s)
- Chanclón Beléen
- Department of Cell Biology, Physiology and Immunology, University of CórdobaCórdoba, Spain
- Instituto Maimónides de Investigación Biomédica de CórdobaCórdoba, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y NutriciónCórdoba, Spain
| | - Antonio J. Martínez-Fuentes
- Department of Cell Biology, Physiology and Immunology, University of CórdobaCórdoba, Spain
- Instituto Maimónides de Investigación Biomédica de CórdobaCórdoba, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y NutriciónCórdoba, Spain
| | - Francisco Gracia-Navarro
- Department of Cell Biology, Physiology and Immunology, University of CórdobaCórdoba, Spain
- Instituto Maimónides de Investigación Biomédica de CórdobaCórdoba, Spain
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y NutriciónCórdoba, Spain
- *Correspondence: Francisco Gracia-Navarro, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Campus de Rabanales, Edificio Severo-Ochoa, Planta 3, E-14014 Córdoba, Spain. e-mail:
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25
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Baragli A, Lanfranco F, Allasia S, Granata R, Ghigo E. Neuroendocrine and metabolic activities of ghrelin gene products. Peptides 2011; 32:2323-32. [PMID: 22056513 DOI: 10.1016/j.peptides.2011.10.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 10/03/2011] [Accepted: 10/25/2011] [Indexed: 12/15/2022]
Abstract
Acylated ghrelin (AG) is a 28 amino acid gastric peptide a natural ligand for the growth hormone secretagogue (GHS) receptor type 1a (GHS-R1a), endowed with GH-secreting and orexigenic properties. Besides, ghrelin exerts several peripheral metabolic actions, including modulation of glucose homeostasis and stimulation of adipogenesis. Notably, AG administration causes hyperglycemia in rodents as in humans. Ghrelin pleiotropy is supported by a widespread expression of the ghrelin gene, of GHS-R1a and other unknown ghrelin binding sites. The existence of alternative receptors for AG, of several natural ligands for GHS-R1a and of acylation-independent ghrelin non-neuroendocrine activities, suggests that there might be a complex 'ghrelin system' not yet completely explored. Moreover, the patho-physiological implications of unacylated ghrelin (UAG), and obestatin (Ob), the other two ghrelin gene-derived peptides, need to be clarified. Within the next few years, we may better understand the 'ghrelin system', where we might envisage clinical applications.
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Affiliation(s)
- Alessandra Baragli
- Laboratory of Molecular and Cellular Endocrinology, Division of Endocrinology, Department of Internal Medicine, University of Turin, Turin, Italy.
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26
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Kang K, Zmuda E, Sleeman MW. Physiological role of ghrelin as revealed by the ghrelin and GOAT knockout mice. Peptides 2011; 32:2236-41. [PMID: 21600256 DOI: 10.1016/j.peptides.2011.04.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2011] [Revised: 03/26/2011] [Accepted: 04/29/2011] [Indexed: 11/27/2022]
Abstract
Ghrelin is a gastric hormone that has been shown to regulate food intake and energy metabolism. One unique feature of ghrelin is that its activity is regulated post transcriptionally by ghrelin O-acyltransferase (GOAT) through the addition of fatty acid to the serine residue in the N terminal region. Despite much biochemical characterization, to date no other proteins have been shown to be specifically octonylated by GOAT, suggesting a unique matching of the acyl transferase for a single ligand, ghrelin. If this is indeed correct, then genetic deletion of ghrelin or GOAT should produce near identical phenotypes and there should be extensive overlap in expression patterns. This review summarizes the similarities and differences in the phenotypes with the genetic deletion of ghrelin and GOAT in the various knockout mouse lines reported to date. While there is considerable overlap in expression pattern between ghrelin and GOAT, the latter does exhibit some unique tissue expression that could suggest that additional peptides may be acylated and await discovery and characterization.
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Affiliation(s)
- Kihwa Kang
- Regeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
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27
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Chuang JC, Sakata I, Kohno D, Perello M, Osborne-Lawrence S, Repa JJ, Zigman JM. Ghrelin directly stimulates glucagon secretion from pancreatic alpha-cells. Mol Endocrinol 2011; 25:1600-11. [PMID: 21719535 DOI: 10.1210/me.2011-1001] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Previous work has demonstrated that the peptide hormone ghrelin raises blood glucose. Such has been attributed to ghrelin's ability to enhance GH secretion, restrict insulin release, and/or reduce insulin sensitivity. Ghrelin's reported effects on glucagon have been inconsistent. Here, both animal- and cell-based systems were used to determine the role of glucagon in mediating ghrelin's effects on blood glucose. The tissue and cell distribution of ghrelin receptors (GHSR) was evaluated by quantitative PCR and histochemistry. Plasma glucagon levels were determined following acute acyl-ghrelin injections and in pharmacological and/or transgenic mouse models of ghrelin overexpression and GHSR deletion. Isolated mouse islets and the α-cell lines αTC1 and InR1G9 were used to evaluate ghrelin's effects on glucagon secretion and the role of calcium and ERK in this activity. GHSR mRNA was abundantly expressed in mouse islets and colocalized with glucagon in α-cells. Elevation of acyl-ghrelin acutely (after sc administration, such that physiologically relevant plasma ghrelin levels were achieved) and chronically (by slow-releasing osmotic pumps and as observed in transgenic mice harboring ghrelinomas) led to higher plasma glucagon and increased blood glucose. Conversely, genetic GHSR deletion was associated with lower plasma glucagon and reduced fasting blood glucose. Acyl-ghrelin increased glucagon secretion in a dose-dependent manner from mouse islets and α-cell lines, in a manner requiring elevation of intracellular calcium and phosphorylation of ERK. Our study shows that ghrelin's regulation of blood glucose involves direct stimulation of glucagon secretion from α-cells and introduces the ghrelin-glucagon axis as an important mechanism controlling glycemia under fasting conditions.
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Affiliation(s)
- Jen-Chieh Chuang
- Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9077, USA
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28
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Sudar E, Dobutovic B, Soskic S, Mandusic V, Zakula Z, Misirkic M, Vucicevic L, Janjetovic K, Trajkovic V, Mikhailidis DP, Isenovic ER. Regulation of inducible nitric oxide synthase activity/expression in rat hearts from ghrelin-treated rats. J Physiol Biochem 2010; 67:195-204. [PMID: 21107779 DOI: 10.1007/s13105-010-0063-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2010] [Accepted: 11/09/2010] [Indexed: 11/28/2022]
Abstract
The purpose of this study was to examine the effects of ghrelin on protein kinase B (Akt) and mitogen-activated protein kinase p42/44 (ERK1/2) activation as well as ghrelin effects on inducible nitric oxide (NO) synthase (iNOS; for gene Nos2) activity/expression in rat hearts. Male Wistar rats were treated with ghrelin (0.3 nmol/5 μl) or an equal volume of phosphate-buffered saline, injected every 24 h into the lateral cerebral ventricle for 5 days and 2 h after the last treatment the animals were sacrificed. Serum NO, L-arginine (L-Arg), and arginase activity were measured spectrophotometrically. For phosphorylation of Akt, ERK1/2, and iNOS protein expression, Western blot method was used. The expression of Nos2 mRNA was measured by the quantitative real-time polymerase chain reaction (qRT-PCR). Treatment with ghrelin significantly increased NO production in serum by 1.4-fold compared with control. The concentration of L-Arg was significantly higher in ghrelin-treated rats than in control while arginase activity was significantly lower in ghrelin-treated than in control hearts. Ghrelin treatment increased phosphorylation of Akt by 1.9-fold and ERK1/2 by 1.6-fold and increased iNOS expression by 2.5-fold compared with control. In addition, ghrelin treatment increased Nos2 gene expression by 2.2-fold as determined by qRT-PCR. These results indicate that ghrelin regulation of iNOS expression/activity is mediated via Akt/ERK1/2 signaling pathway. These results may be relevant to understanding molecular mechanisms underlying direct cardiovascular actions of ghrelin.
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Affiliation(s)
- Emina Sudar
- Laboratory of Radiobiology and Molecular Genetics, Institute Vinca, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
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Ni H, De Waele K, Walia P, Chanoine JP. In vitro and in vivo effect of acylated and unacylated ghrelin on neonatal glucose homeostasis. Pediatr Res 2010; 67:609-13. [PMID: 20496472 DOI: 10.1203/pdr.0b013e3181da463a] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Maintenance of normal glucose homeostasis is crucial for survival during the perinatal period. Acylated ghrelin (AG) but not unacylated ghrelin (UAG) inhibits insulin release from pancreatic islets in adult rats. Circulating AG concentrations are low in the fetus and progressively increase in the postnatal period. We tested the hypothesis that AG has insulinostatic effects in vitro and in vivo during the perinatal period. In vitro, AG (10(-10)-10(-8) M) caused a 25-53% decrease in insulin secretion by islets from 5-d-old rat pups under normo- and hyperglycemic conditions, an effect that was mediated through the growth hormone secretagogue receptor (GHSR- 1a). Ghrelin (1-5) amide, [Dap3]-octanoyl, a pentapeptide that is resistant to deacylation and binds the GHSR-1a, had similar effects at 10(-8) M. In vivo, AG, UAG, or GHRP-6 [D-Lys3], a GHSR-1a antagonist, did not affect insulin or glucagon concentrations during the first 3 h of life. In 6-d-old pups, AG, UAG, or ghrelin (1-5) amide, [Dap3]-octanoyl did not affect glucose-induced insulin or C-peptide concentrations. In summary, AG has insulinostatic effects in vitro as early as during the perinatal period. These effects could not be confirmed in vivo, possibly due to the short half-life of AG in rat neonates.
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Affiliation(s)
- Hehong Ni
- Endocrinology and Diabetes Unit, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
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30
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Interactions of gastrointestinal peptides: ghrelin and its anorexigenic antagonists. INTERNATIONAL JOURNAL OF PEPTIDES 2010; 2010. [PMID: 20798884 PMCID: PMC2925274 DOI: 10.1155/2010/817457] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Revised: 10/13/2009] [Accepted: 10/19/2009] [Indexed: 12/21/2022]
Abstract
Food intake behaviour and energy homeostasis are strongly regulated by a complex system of humoral factors and nerval structures constituting the brain-gut-axis. To date the only known peripherally produced and centrally acting peptide that stimulates food intake is ghrelin, which is mainly synthesized in the stomach. Recent data indicate that the orexigenic effect of ghrelin might be influenced by other gastrointestinal peptides such as cholecystokinin (CCK), bombesin, desacyl ghrelin, peptide YY (PYY), as well as glucagon-like peptide (GLP). Therefore, we will review on the interactions of ghrelin with several gastrointestinal factors known to be involved in appetite regulation in order to elucidate the interdependency of peripheral orexigenic and anorexigenic peptides in the control of appetite.
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Egido EM, Hernández R, Marco J, Silvestre RA. Effect of obestatin on insulin, glucagon and somatostatin secretion in the perfused rat pancreas. ACTA ACUST UNITED AC 2009; 152:61-6. [DOI: 10.1016/j.regpep.2008.08.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2008] [Revised: 07/08/2008] [Accepted: 08/07/2008] [Indexed: 11/17/2022]
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Broglio F, Prodam F, Riganti F, Gottero C, Destefanis S, Granata R, Muccioli G, Abribat T, van der Lely AJ, Ghigo E. The continuous infusion of acylated ghrelin enhances growth hormone secretion and worsens glucose metabolism in humans. J Endocrinol Invest 2008; 31:788-94. [PMID: 18997491 DOI: 10.1007/bf03349259] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
CONTEXT Acylated ghrelin (AG) has been discovered as a natural ligand of the GH secretagogue receptor type 1a and is now recognized as an important orexigenic factor. Besides stimulation of GH secretion and appetite, it exerts other central and peripheral actions including modulation of insulin secretion, glucose and lipid metabolism. OBJECTIVE To define the effects of the continuous iv infusion of AG in humans with particular attention to metabolic parameters. MATERIALS AND METHODS We studied the effects of 16- h (from 21:00 to 13:00 h) infusion of AG (0.5 microg/kg/h) or saline in 8 young volunteers who were provided with isocaloric balanced meals. GH, cortisol, insulin, glucose, free fatty acid (FFA), and ghrelin levels were assayed every 20 min. RESULTS AG infusion increased circulating total ghrelin to a steady state that was maintained over 16 h infusion of the peptide. With respect to saline, AG infusion significantly modified GH, cortisol, insulin, and glucose profiles and decreased FFA area under the curve (p<0.01). AG increased GH pulse frequency and approximate entropy (p<0.05). AG enhanced the glucose response to both dinner (p<0.02) and breakfast (p<0.03). AG infusion blunted the early insulin response to dinner (p<0.03) but enhanced the second-phase insulin response to dinner and breakfast (p<0.05). CONCLUSIONS The continuous exposure to AG in humans enhances somatotroph secretion but also worsens glucose metabolism, although it inhibits lipolysis. These findings in normal young volunteers are consistent with data from studies in animals and suggest that acylated ghrelin is likely to play a negative role in glucose metabolism.
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Affiliation(s)
- F Broglio
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy
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Hagiwara S, Iwasaka H, Shingu C, Noguchi T. Comparison of effects of total enteral versus total parenteral nutrition on ischemia/reperfusion-induced heart injury in rats. Eur Surg Res 2008; 40:361-7. [PMID: 18319602 DOI: 10.1159/000119414] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2007] [Accepted: 12/03/2007] [Indexed: 11/19/2022]
Abstract
BACKGROUND The long-term effect of nutrition on cardiac function remains to be elucidated. One possible link is the newly discovered gastric hormone ghrelin, which has been reported to be cardioprotective. AIM The present study examined whether total enteral nutrition (TEN) and total parenteral nutrition (TPN) differ in their modulation of ghrelin production and their effects on cardiac function after ischemia/reperfusion injury. METHODS Rats received isocaloric parenteral or enteral nutrition through implanted vascular catheters or gastrostomy tubes. TEN was administered in a conventional (TEN-C) or immunonutrition (TEN-I) form. After 7 days, serum ghrelin levels were determined by enzyme-linked immunosorbent assays and myocardial function was assessed using the Langendorff isolated heart technique. RESULTS TEN-I animals had significantly higher plasma ghrelin levels than the other groups. After ischemia/reperfusion injury, left ventricular developed pressure decreased in animals receiving TPN when compared to animals receiving TEN-I. Animals receiving TPN also had significant reductions in their maximal rates of increase and decrease in left ventricular pressure when compared to animals receiving TEN-I (unpaired t test, p < 0.05). CONCLUSION TEN-I increases serum levels of ghrelin, which protects cardiac function after ischemic/reperfusion injury. Because TEN-I more effectively protects cardiac function, we recommend it for long-term nutritional support.
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Affiliation(s)
- S Hagiwara
- Anesthesiology, Department of Brain and Nerve Science, Oita University Faculty of Medicine, Oita, Japan.
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Rodríguez-Pacheco F, Luque RM, Tena-Sempere M, Malagón MM, Castaño JP. Ghrelin induces growth hormone secretion via a nitric oxide/cGMP signalling pathway. J Neuroendocrinol 2008; 20:406-12. [PMID: 18208548 DOI: 10.1111/j.1365-2826.2008.01645.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The presence of ghrelin and its receptor, growth hormone (GH) secretagogue receptor, in the hypothalamus and pituitary, and its ability to stimulate GH release in vivo and in vitro, strongly support a significant role for this peptide in the control of somatotroph function. We previously demonstrated that ghrelin elicits GH secretion directly in somatotrophs by activating two major signalling cascades, which involve inositol phosphate and cAMP. In as much as nitric oxide (NO) and its mediator cGMP have been recently shown to contribute substantially to the response of somatotrophs to key regulatory hormones, including GH-releasing hormone, somatostatin and leptin, we investigated the possible role of this signalling pathway in ghrelin-induced GH release in vitro. Accordingly, cultures of pituitary cells from prepuberal female pigs were challenged with ghrelin (10(-8) m, 30 min) in the absence or presence of activators or blockers of key steps of the NO synthase (NOS)/NO/guanylate cyclase (GC)/cGMP route and GH secretion was measured. Two distinct activators of the NO route, S-nitroso-N-acetylpenicillamine (SNAP) (5 x 10(-4) m) and L-arginine methyl ester hydrochloride (L-AME) (10(-3) m), comparably stimulated GH secretion when applied alone. The presence of L-AME enhanced ghrelin-stimulated GH secretion, whereas SNAP did not alter its effect. Conversely, two different NOS/NO pathway inhibitors, N(w)-nitro-L-arginine methyl ester hydrochloride (10(-5) m) or haemoglobin (20 microg/ml), similarly blocked ghrelin-induced (but not basal) GH release, thus indicating that NO contributes critically to ghrelin action in somatotrophs. Moreover, incubation with a permeable cGMP analogue, 8-Br-cGMP (10(-8) m) stimulated GH secretion, but did not modify the stimulatory action of ghrelin, suggesting that cGMP could mediate the action of NO. Indeed, inhibition of GC by 10 microm LY-53,583 did not alter basal GH secretion but abolished the GH-releasing action of ghrelin. Taken together, our results provide novel evidence indicating that ghrelin requires activation of the NOS/NO route, and its subsequent GC/cGMP signal transduction pathway, as necessary steps to induce GH secretion from somatotrophs.
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Affiliation(s)
- F Rodríguez-Pacheco
- Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain
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Wang S, Zhang J, Zhao A, Hipkens S, Magnuson MA, Gu G. Loss of Myt1 function partially compromises endocrine islet cell differentiation and pancreatic physiological function in the mouse. Mech Dev 2007; 124:898-910. [PMID: 17928203 PMCID: PMC2141686 DOI: 10.1016/j.mod.2007.08.004] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2007] [Revised: 08/22/2007] [Accepted: 08/25/2007] [Indexed: 10/22/2022]
Abstract
Myelin transcription factor 1 (Myt1) is one of the three vertebrate C2HC-type zinc finger transcription factors that include Myt1 (Nzf1), Myt1L (Png1), and Myt3 (Nzf3, St18). All three paralogs are widely expressed in developing neuronal cells. Yet their function for mammalian development has not been investigated directly. Here we report that only Myt1 is expressed in the embryonic pancreas, in both endocrine progenitors and differentiated islet cells. Myt1(-/-) animals die postnatally, likely due to confounding effects in multiple tissues. The endocrine tissues in the embryonic Myt1(-/-) pancreas contained abnormal islet cells that expressed multiple hormones; although hormone levels were normal. We also created pancreas-specific Myt1 knockout mice. These mutant animals had no obvious physical defects from their wild-type littermates. Male mutant animals had reduced glucose-clearing abilities and abnormal multi-hormone-expressing cells present in their endocrine islets. In addition, they also had reduced Glut2 expression, and attenuated glucose-induced insulin secretion in the adult islets. Surprisingly, the expression of the Myt1 paralogs, Myt1l and Myt3, was induced in the embryonic Myt1(-/-) pancreas. The consequences of Myt1 inactivation in the developing pancreas could be masked by activation of its paralogs, Myt1l and Myt3. These findings suggest Myt1 is involved in proper endocrine differentiation and function.
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Affiliation(s)
- Sui Wang
- Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University Medical Center, 465 21st Avenue South, Room 4128, Nashville, TN 37232, USA
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Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, Bullock W, Daly M, Decarr L, Li Y, Milardo L, Molstad D, Zhu J, Gardell SJ, Livingston JN, Sweet LJ. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology 2007; 148:5175-85. [PMID: 17656463 DOI: 10.1210/en.2007-0239] [Citation(s) in RCA: 174] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss.
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Affiliation(s)
- William P Esler
- Bayer Research Center, Bayer Healthcare, West Haven, CT 06516, USA.
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Riedl M, Maier C, Handisurya A, Luger A, Kautzky-Willer A. Insulin resistance has no impact on ghrelin suppression in pregnancy. J Intern Med 2007; 262:458-65. [PMID: 17875182 DOI: 10.1111/j.1365-2796.2007.01832.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Ghrelin is reduced in various states of insulin resistance. The aim of this study was to examine the relationship between ghrelin and glucose metabolism during pregnancy - a natural insulin-resistant state - in women with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or gestational diabetes mellitus (GDM) and potential changes 3 months after delivery. A total of 54 women, 37 pregnant and with various degrees of insulin resistance and 24 postpartum (PP, seven of them also studied during pregnancy) were studied. Ghrelin plasma concentrations at fasting and 60' following glucose loading (75 g-2 h-oral glucose tolerance test), area under the curve of plasma glucose (G-AUC(OGTT)) and insulin sensitivity [homeostatic model assessment (HOMA) and oral glucose sensitivity index (OGIS) indices, respectively] were determined. Both baseline and 60' ghrelin concentrations were to a comparable degree ( approximately by 65%) suppressed in NGT, IGT and GDM as compared to the PP group (the latter being indistinguishable from NGT regarding glucose tolerance and insulin sensitivity). In all women studied both during and after pregnancy, ghrelin levels rose from pregnancy to PP (mean increase 313.8%; P < 0.03). There was no correlation between baseline ghrelin and insulin sensitivity as estimated from both baseline (HOMA) and dynamic (OGTT:OGIS) glucose and insulin data. Ghrelin is substantially decreased during pregnancy, but glucose-induced ghrelin suppression is preserved at a lower level. There is apparently no relation to the degree of insulin resistance.
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Affiliation(s)
- M Riedl
- Department of Medicine III, Clinical Division of Endocrinology & Metabolism, Medical University of Vienna, Vienna, Austria
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Qader SS, Håkanson R, Rehfeld JF, Lundquist I, Salehi A. Proghrelin-derived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas. ACTA ACUST UNITED AC 2007; 146:230-7. [PMID: 17942170 DOI: 10.1016/j.regpep.2007.09.017] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2007] [Revised: 08/14/2007] [Accepted: 09/11/2007] [Indexed: 12/25/2022]
Abstract
Proghrelin, the precursor of the orexigenic and adipogenic peptide hormone ghrelin, is synthetized in endocrine (A-like) cells in the gastric mucosa. During its cellular processing, proghrelin gives rise to the 28-amino acid peptide desacyl ghrelin, which after octanoylation becomes active acyl ghrelin, and to the 23-amino acid peptide obestatin, claimed to be a physiological opponent of acyl ghrelin. This study examines the effects of the proghrelin products, alone and in combinations, on the secretion of insulin, glucagon, pancreatic polypeptide (PP) and somatostatin from isolated islets of mice and rats. Surprisingly, acyl ghrelin and obestatin had almost identical effects in that they stimulated the secretion of glucagon and inhibited that of PP and somatostatin from both mouse and rat islets. Obestatin inhibited insulin secretion more effectively than acyl ghrelin. In mouse islets, acyl ghrelin inhibited insulin secretion at low doses and stimulated at high. In rat islets, acyl ghrelin inhibited insulin secretion in a dose-dependent manner but the IC(50) for the acyl ghrelin-induced inhibition of insulin release was 7.5 x 10(-8) M, while the EC(50) and IC(50) values, with respect to stimulation of glucagon release and to inhibition of PP and somatostatin release, were in the 3 x 10(-12)-15 x 10(-12) M range. The corresponding EC(50) and IC(50) values for obestatin ranged from 5 x 10(-12) to 20 x 10(-12) M. Desacyl ghrelin per se did not affect islet hormone secretion. However, at a ten times higher concentration than acyl ghrelin (corresponding to the ratio of the two peptides in circulation), desacyl ghrelin abolished the effects of acyl ghrelin but not those of obestatin. Acyl ghrelin and obestatin affected the secretion of glucagon, PP and somatostatin at physiologically relevant concentrations; with obestatin this was the case also for insulin secretion. The combination of obestatin, acyl ghrelin and desacyl ghrelin in concentrations and proportions similar to those found in plasma resulted in effects that were indistinguishable from those induced by obestatin alone. From the data it seems that the effects of endogenous, circulating acyl ghrelin may be overshadowed by obestatin or blunted by desacyl ghrelin.
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Affiliation(s)
- Saleem S Qader
- Department of Clinical Science, Malmö University Hospital, UMAS, S-20502 Malmö, Sweden
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Qader SS, Jimenez-Feltström J, Ekelund M, Lundquist I, Salehi A. Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27. Am J Physiol Endocrinol Metab 2007; 292:E1447-55. [PMID: 17264229 DOI: 10.1152/ajpendo.00172.2006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Chronic exposure of pancreatic islets to elevated plasma lipids (lipotoxicity) can lead to beta-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase (iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to beta-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive (nc)NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP- and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in beta-cells.
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Iantorno M, Chen H, Kim JA, Tesauro M, Lauro D, Cardillo C, Quon MJ. Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. Am J Physiol Endocrinol Metab 2007; 292:E756-64. [PMID: 17106060 DOI: 10.1152/ajpendo.00570.2006] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Ghrelin is an orexigenic peptide hormone secreted by the stomach. In patients with metabolic syndrome and low ghrelin levels, intra-arterial ghrelin administration acutely improves their endothelial dysfunction. Therefore, we hypothesized that ghrelin activates endothelial nitric oxide synthase (eNOS) in vascular endothelium, resulting in increased production of nitric oxide (NO) using signaling pathways shared in common with the insulin receptor. Similar to insulin, ghrelin acutely stimulated increased production of NO in bovine aortic endothelial cells (BAEC) in primary culture (assessed using NO-specific fluorescent dye 4,5-diaminofluorescein) in a time- and dose-dependent manner. Production of NO in response to ghrelin (100 nM, 10 min) in human aortic endothelial cells was blocked by pretreatment of cells with NG-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor], or (D-Lys3)-GHRP-6 (selective antagonist of ghrelin receptor GHSR-1a), as well as by knockdown of GHSR-1a using small-interfering (si) RNA (but not by mitogen/extracellular signal-regulated kinase inhibitor PD-98059). Moreover, ghrelin stimulated increased phosphorylation of Akt (Ser473) and eNOS (Akt phosphorylation site Ser1179) that was inhibitable by knockdown of GHSR-1a using siRNA or by pretreatment of cells with wortmannin but not with PD-98059. Ghrelin also stimulated phosphorylation of mitogen-activated protein (MAP) kinase in BAEC. However, unlike insulin, ghrelin did not stimulate MAP kinase-dependent secretion of the vasoconstrictor endothelin-1 from BAEC. We conclude that ghrelin has novel vascular actions to acutely stimulate production of NO in endothelium using a signaling pathway that involves GHSR-1a, PI 3-kinase, Akt, and eNOS. Our findings may be relevant to developing novel therapeutic strategies to treat diabetes and related diseases characterized by reciprocal relationships between endothelial dysfunction and insulin resistance.
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Affiliation(s)
- Micaela Iantorno
- Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, 10 Center Dr., Bldg. 10, Rm. 6C-205, Bethesda, MD 20892-1632, USA
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Secretory and electrophysiological characteristics of insulin cells from gastrectomized mice: evidence for the existence of insulinotropic agents in the stomach. ACTA ACUST UNITED AC 2006; 139:31-8. [PMID: 17109976 DOI: 10.1016/j.regpep.2006.10.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2006] [Revised: 09/14/2006] [Accepted: 10/03/2006] [Indexed: 02/08/2023]
Abstract
Mice were subjected to gastrectomy (GX) or sham operation (controls). Four to six weeks later the pancreatic islets were isolated and analysed for cAMP or alternatively incubated in a Krebs-Ringer based medium in an effort to study insulin secretion and cAMP accumulation in response to glucose or the adenylate cyclase activator forskolin. Freshly isolated islets from GX mice had higher cAMP content than islets from control mice, a difference that persisted after incubation for 1 h at a glucose concentration of 4 mmol/l. Addition of forskolin to this medium induced much greater cAMP and insulin responses in islets from GX mice than in islets from control mice. In contrast, the insulin response to high glucose (16.7 mmol/l) was much weaker in GX islets than in control islets. Glucose-induced insulin release was associated with a 2-fold rise in the cAMP content in control islets. Surprisingly no rise in cAMP was noted in GX islets incubated at high glucose. Capacitance measurements conducted on isolated insulin cells from GX mice revealed a much lower exocytotic response to a single 500 ms depolarisation (from -70 mV to zero) than in control insulin cells. Addition of cAMP to the cytosol enhanced the exocytotic response in insulin cells from control mice but not from GX mice. The depolarisation-triggered inward Ca(2+) current in insulin cells from GX mice did not differ from that in control mice, and hence the reduced exocytotic response following GX cannot be ascribed to a decreased Ca(2+) influx. Experiments involving a train of ten 500 ms depolarisations revealed that the exocytotic response was prominent in control insulin cells but modest in GX insulin cells. It seems that cAMP is capable of eliciting insulin release from insulin cells of GX mice only when cAMP is generated in a specific microdomain conceivably through the intervention of membrane-associated adenylate cyclases that can be activated by forskolin. The GX-evoked impairment of depolarisation-induced exocytosis and glucose-stimulated insulin release may reflect the lack of a gastric agent that serves to maintain an appropriate insulin response to glucose and an appropriate exocytotic response to depolarisation by raising cAMP in a special glucose-sensitive compartment possibly regulated by a soluble adenylate cyclase.
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N/A, 李 琳. N/A. Shijie Huaren Xiaohua Zazhi 2006; 14:1445-1447. [DOI: 10.11569/wcjd.v14.i15.1445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Yabuki A, Taharaguchi S, Ichii O, Kojima M, Nishi Y, Mifune H, Kamimura R, Matsumoto M, Suzuki S. Immunohistochemical localization of ghrelin in rodent kidneys. Histochem Cell Biol 2006; 126:231-8. [PMID: 16514547 DOI: 10.1007/s00418-006-0165-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2006] [Indexed: 12/27/2022]
Abstract
Ghrelin is a novel peptide hormone, originally identified in the rat and human stomach that plays various important roles. In the present study, we report the intra-renal localization of ghrelin in laboratory rodents. Kidneys from 3 month-old mice, rats and hamsters of both sexes were analyzed by immunohistochemistry. Positive signals were clearly observed in the epithelium of the distal tubules, whereas other segments of the nephron or interstitial cells, including juxtaglomerular cells, showed negative reactions. Pre-embedding immunoelectron microscopy revealed positive signals exclusively on the basolateral membrane in the distal tubular cells and in the collecting ducts. In addition, prepro-ghrelin gene expression was assessed by RT-PCR, and the expected 329-bp prepro-ghrelin mRNA was clearly detected in the kidney. On Western blot analysis, although a specific band for ghrelin (3 kDa) was not detected in the kidney, the expected band for prepro-ghrelin (13 kDa) was clearly detected in both the stomach and the kidney. This paper clarified the intra-renal localization of ghrelin.
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Affiliation(s)
- Akira Yabuki
- Laboratory of Veterinary Anatomy, Department of Veterinary Medicine, Faculty of Agriculture, Kagoshima University, 1-21-24 Korimoto, 890-0065 Kagoshima, Japan.
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Abstract
Ghrelin, a gastric peptide involved in growth hormone release and energy homeostasis, is the endogenous ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), a G-protein coupled receptor mainly expressed in the pituitary and hypothalamus. This receptor mediates the main ghrelin-stimulated endocrine actions and some of the nonendocrine actions. However, a number of nonendocrine actions associated with ghrelin appear to be mediated by various GHS-R1a-related receptor subtypes, which are widely distributed in the central and peripheral tissues. This review summarises data concerning the localisation, regulation and function of GHS-R1a, as well as related receptors.
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Affiliation(s)
- J P Camiña
- Laboratory of Molecular Endocrinology, Research Area, Complexo Hospitalario Universitario de Santiago (CHUS), PO Box 563, E-15780 Santiago de Compostela, Spain.
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