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Alvarez-Crespo M, Gil-Lozano M, Diz-Chaves Y, González-Matias LC, Mallo F. Elevation of ghrelin by B-adrenergic activation is independent of glucose variations and feeding regimen in the rat. Endocrine 2025; 88:434-445. [PMID: 40169505 PMCID: PMC12069131 DOI: 10.1007/s12020-024-04156-w] [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: 10/15/2024] [Accepted: 12/28/2024] [Indexed: 04/03/2025]
Abstract
Ghrelin is a signal involved in the initiation of meals in rodents and humans. Circulating ghrelin levels are elevated before mealwes and reduced after food intake. Several factors have been identified as effective modulators of ghrelin levels. Vagal activation reduced ghrelin in rats, as well as oral carbohydrate and lipid administration in rats and humans. Some hormones, such as incretins, also reduce ghrelin: GLP-1 reduced ghrelin in humans, and Ex4, a GLP-1 receptor agonist, potently inhibited ghrelin in rodents. On the other hand, fasting promotes increases in ghrelin that anticipate the start of meals. We report that beta-adrenergic activation with isoproterenol promotes large acute elevations of circulating ghrelin levels, both in anesthetized and conscious freely-moving rats, either on "ad libitum" feeding or on a fasting regimen.These effects are dose-dependent, caused by intravenous, intraperitoneal, and oral administration, and independent of variations in glucose levels. Pharmacological modulation of β1 and β2 adrenergic receptors with specific agonists and antagonists showed that ghrelin increases are stimulated by β1-adrenergic activation, but also partially by β2-adrenergic activation, suggesting that activation of both is necessary to elicit complete ghrelin elevations. Meanwhile, glucose increases dependent on adrenergic activation appear to be mediated only by β2-adrenergic receptors. In addition, the effects of isoproterenol on increasing ghrelin levels are potent enough to overcome the marked inhibition exerted by exendin-4 that we have previously demonstrated. We also found that administration of isoproterenol in drinking water increases basal ghrelin levels and simultaneous food intake in animals eating ad libitum. Beta-adrenergic activation promotes increases in ghrelin levels in vivo prior to food intake, both in rats eating ad libitum and in fasting rats that already have elevated ghrelin levels, in a time- and dose-dependent manner. In addition, the effects of isoproterenol on increasing ghrelin levels are potent enough to overcome the marked inhibition exerted by exendin-4 that we have previously demonstrated. We also found that administration of isoproterenol in drinking water increases basal ghrelin levels and simultaneous food intake in animals eating ad libitum. Beta-adrenergic activation promotes increases in ghrelin levels in vivo prior to food intake, both in eating ad libitum and in fasting rats that already have elevated ghrelin levels, in a time- and dose-dependent manner.
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Affiliation(s)
- Mayte Alvarez-Crespo
- LabEndoTeam - Laboratory of Endocrinology - Department of Functional Biology and Health Sciences - University of Vigo - Campus as Lagoas - Marcosende, Vigo, Spain
| | - Manuel Gil-Lozano
- LabEndoTeam - Laboratory of Endocrinology - Department of Functional Biology and Health Sciences - University of Vigo - Campus as Lagoas - Marcosende, Vigo, Spain
| | - Yolanda Diz-Chaves
- LabEndoTeam - Laboratory of Endocrinology - Department of Functional Biology and Health Sciences - University of Vigo - Campus as Lagoas - Marcosende, Vigo, Spain
| | - Lucas Carmelo González-Matias
- LabEndoTeam - Laboratory of Endocrinology - Department of Functional Biology and Health Sciences - University of Vigo - Campus as Lagoas - Marcosende, Vigo, Spain
- Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO, Vigo, Spain
| | - Federico Mallo
- LabEndoTeam - Laboratory of Endocrinology - Department of Functional Biology and Health Sciences - University of Vigo - Campus as Lagoas - Marcosende, Vigo, Spain.
- Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO, Vigo, Spain.
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2
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Craig CF, Finkelstein DI, McQuade RM, Diwakarla S. Understanding the potential causes of gastrointestinal dysfunctions in multiple system atrophy. Neurobiol Dis 2023; 187:106296. [PMID: 37714308 DOI: 10.1016/j.nbd.2023.106296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/12/2023] [Accepted: 09/13/2023] [Indexed: 09/17/2023] Open
Abstract
Multiple system atrophy (MSA) is a rare, progressive neurodegenerative disorder characterised by autonomic, pyramidal, parkinsonian and/or cerebellar dysfunction. Autonomic symptoms of MSA include deficits associated with the gastrointestinal (GI) system, such as difficulty swallowing, abdominal pain and bloating, nausea, delayed gastric emptying, and constipation. To date, studies assessing GI dysfunctions in MSA have primarily focused on alterations of the gut microbiome, however growing evidence indicates other structural components of the GI tract, such as the enteric nervous system, the intestinal barrier, GI hormones, and the GI-driven immune response may contribute to MSA-related GI symptoms. Here, we provide an in-depth exploration of the physiological, structural, and immunological changes theorised to underpin GI dysfunction in MSA patients and highlight areas for future research in order to identify more suitable pharmaceutical treatments for GI symptoms in patients with MSA.
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Affiliation(s)
- Colin F Craig
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia
| | - David I Finkelstein
- Parkinson's Disease Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
| | - Rachel M McQuade
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC 3021, Australia
| | - Shanti Diwakarla
- Gut Barrier and Disease Laboratory, Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Australian Institute for Musculoskeletal Science (AIMSS), Western Centre for Health Research and Education (WCHRE), Sunshine Hospital, St Albans, VIC 3021, Australia.
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3
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Azimzadeh M, Beheshti S. Down regulation of the hippocampal ghrelin receptor type-1a during electrical kindling-induced epileptogenesis. Epilepsy Res 2023; 189:107064. [PMID: 36516566 DOI: 10.1016/j.eplepsyres.2022.107064] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/17/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022]
Abstract
Numerous studies have shown that the ghrelin hormone is involved in epileptic conditions. However, the profile of ghrelin or its functional receptor mRNAs in seizure-susceptible brain areas was not assessed during epileptogenesis. Here, we measured the expression levels of the hippocampal ghrelin or its receptor mRNAs during electrical kindling-induced epileptogenesis. The study was conducted on twenty adult male Wistar rats. One tri-polar and two uni-polar electrodes were stereotaxically implanted in the baso-lateral amygdala or skull surface, respectively. Animals were divided into four groups, consisting of two sham groups (sham1 and sham2), and two other groups, which were partially or fully kindled. After the establishment of partial or full kindling, the hippocampi of the animals and that of the corresponding sham groups were removed. A quantitative real-time PCR technique was used to measure the expression levels of ghrelin or its functional receptor mRNAs. The results indicated that the expression levels of ghrelin did not alter in either of the partially or fully kindled rats compared to the corresponding sham groups. Ghrelin receptor (ghrelinR) down regulated, significantly in the fully-kindled rats, compared to sham2 group. Meanwhile, the mRNA expression levels of ghrelinR did not change in partially-kindled rats compared to sham1 group. The outcomes of the current study highlight the crucial, unknown impact of the hippocampal ghrelinR through the development of electrical kindling epileptogenesis, and points out the importance of ghrelinR as a goal to adjust epileptogenic progression.
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Affiliation(s)
- Mansour Azimzadeh
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Siamak Beheshti
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
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4
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Hypoglycemia and Dysautonomia After Bariatric Surgery: a Systematic Review and Perspective. Obes Surg 2022; 32:1681-1688. [PMID: 35133603 DOI: 10.1007/s11695-022-05960-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/24/2022] [Accepted: 02/02/2022] [Indexed: 12/27/2022]
Abstract
INTRODUCTION With the increasing performance of bariatric surgery, rare complications are becoming prevalent. We review the diagnosis and treatment of dysautonomia after bariatric surgery and the limited treatment options available. We summarize the suggested mechanisms and explain why a complete understanding of the etiology has yet to be determined. METHODS In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review was performed. RESULTS Of 448 studies identified in the literature search, 4 studies were reviewed, describing 87 patients diagnosed with dysautonomia. We present a patient who developed severe dysautonomia following conversion of sleeve gastrectomy to gastric bypass. CONCLUSION Treatment needs to focus on optimizing nutrition, avoiding hypoglycemia, and optimizing volume status.
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Nunez‐Salces M, Li H, Feinle‐Bisset C, Young RL, Page AJ. The regulation of gastric ghrelin secretion. Acta Physiol (Oxf) 2021; 231:e13588. [PMID: 33249751 DOI: 10.1111/apha.13588] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022]
Abstract
Ghrelin is a gastric hormone with multiple physiological functions, including the stimulation of food intake and adiposity. It is well established that circulating ghrelin levels are closely associated with feeding patterns, rising strongly before a meal and lowering upon food intake. However, the mechanisms underlying the modulation of ghrelin secretion are not fully understood. The purpose of this review is to discuss current knowledge on the circadian oscillation of circulating ghrelin levels, the neural mechanisms stimulating fasting ghrelin levels and peripheral mechanisms modulating postprandial ghrelin levels. Furthermore, the therapeutic potential of targeting the ghrelin pathway is discussed in the context of the treatment of various metabolic disorders, including obesity, type 2 diabetes, diabetic gastroparesis and Prader-Willi syndrome. Moreover, eating disorders including anorexia nervosa, bulimia nervosa and binge-eating disorder are also discussed.
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Affiliation(s)
- Maria Nunez‐Salces
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
| | - Hui Li
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
| | - Christine Feinle‐Bisset
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
| | - Richard L. Young
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
- Intestinal Nutrient Sensing Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
| | - Amanda J. Page
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
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6
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Tuero C, Valenti V, Rotellar F, Landecho MF, Cienfuegos JA, Frühbeck G. Revisiting the Ghrelin Changes Following Bariatric and Metabolic Surgery. Obes Surg 2020; 30:2763-2780. [PMID: 32323063 DOI: 10.1007/s11695-020-04601-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Since the description of ghrelin in 1999, several studies have dug into the effects of this hormone and its relationship with bariatric surgery. While some aspects are still unresolved, a clear connection between ghrelin and the changes after metabolic surgery have been established. Besides weight loss, a significant amelioration in obesity-related comorbidities following surgery has also been reported. These changes in patients occur in the early postoperative period, before the weight loss appears, so that amelioration may be mainly due to hormonal changes. The purpose of this review is to go through the current body of knowledge of ghrelin's physiology, as well as to update and clarify the changes that take place in ghrelin concentrations following bariatric/metabolic surgery together with their potential consolidation to outcomes.
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Affiliation(s)
- Carlota Tuero
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain.
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain.
| | - Victor Valenti
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
- CIBEROBN, Instituto de Salud Carlos III, Pamplona, Navarra, Spain
- Obesity and Adipobiology Group, IdiSNA, Pamplona, Spain
| | - Fernando Rotellar
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
- CIBEROBN, Instituto de Salud Carlos III, Pamplona, Navarra, Spain
- Obesity and Adipobiology Group, IdiSNA, Pamplona, Spain
| | - Manuel F Landecho
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain
- Department of Internal Medicine, General Health Check-up unit, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier A Cienfuegos
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
- CIBEROBN, Instituto de Salud Carlos III, Pamplona, Navarra, Spain
- Obesity and Adipobiology Group, IdiSNA, Pamplona, Spain
| | - Gema Frühbeck
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain.
- CIBEROBN, Instituto de Salud Carlos III, Pamplona, Navarra, Spain.
- Obesity and Adipobiology Group, IdiSNA, Pamplona, Spain.
- Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
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7
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Nili-Ahmadabadi A, Akbari Z, Ahmadimoghaddam D, Larki-Harchegani A. The role of ghrelin and tumor necrosis factor alpha in diazinon-induced dyslipidemia: insights into energy balance regulation. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2019; 157:138-142. [PMID: 31153461 DOI: 10.1016/j.pestbp.2019.03.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 03/12/2019] [Accepted: 03/17/2019] [Indexed: 06/09/2023]
Abstract
The evidence shows that organophosphate compounds (OPCs), as toxic agents that stimulate the cholinergic system, can increase the incidence of metabolic disorders such as dyslipidemia. In the present study, we focused on the role of tumor necrosis factor alpha (TNF-α) and serum leptin and ghrelin in Diazinon (DZN)-induced dyslipidemia. The rats were randomly divided into five groups comprising eight animals, and all were treated via oral gavage for 28 consecutive days as follows: group one received only corn oil daily, while groups two through five received different doses of DZN dissolved in corn oil equal to 1/40, 1/20, 1/10 and 1/5 of the LD50 daily, respectively. The alteration of the serum lipid profile, such as triglycerides, high-density lipoprotein (HDL) and very-low-density lipoprotein (VLDL), was confirmed the occurrence of dyslipidemia in the range of doses 1/20-1/5 LD50 of DZN. Although no changes were found in the serum leptin levels, a significant increase was observed in the size of adipocytes, as well as in the TNF-α and ghrelin serum levels, and in the accumulation of epididymal fat, especially at a dose of 1/5 LD50 of DZN. It seems that interactions among the inflammatory reaction, cholinergic pathways and ghrelin secretion may be effective causes of DZN-induced dyslipidemia.
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Affiliation(s)
- Amir Nili-Ahmadabadi
- Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Zahra Akbari
- Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Davoud Ahmadimoghaddam
- Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Amir Larki-Harchegani
- Medicinal Plants and Natural Products Research Center, Hamadan University of Medical Sciences, Hamadan, Iran; Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
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Veedfald S, Wu T, Bound M, Grivell J, Hartmann B, Rehfeld JF, Deacon CF, Horowitz M, Holst JJ, Rayner CK. Hyperosmolar Duodenal Saline Infusion Lowers Circulating Ghrelin and Stimulates Intestinal Hormone Release in Young Men. J Clin Endocrinol Metab 2018; 103:4409-4418. [PMID: 30053031 DOI: 10.1210/jc.2018-00699] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023]
Abstract
CONTEXT The mechanisms regulating the postprandial suppression of ghrelin secretion remain unclear, but recent observations in rats indicate that an increase in duodenal osmolarity is associated with a reduction in ghrelin levels. Several hormones have been implicated in the regulation of ghrelin. OBJECTIVE We hypothesized that intraduodenal infusion of a hyperosmolar solution would lower plasma ghrelin concentrations. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS Eighteen healthy young men were studied after an overnight fast on two occasions in a randomized double-blinded fashion. A nasoduodenal catheter was positioned and isoosmolar (300 mOsm/L) or hyperosmolar (1500 mOsm/L) saline was infused intraduodenally (4 mL/min, t = 0 to 45 minutes). Venous blood was sampled at t = -45, -30, -15, 0, 15, 30, 45, 60, 75, 90, 120, and 180 minutes. MAIN OUTCOME MEASURES Plasma concentrations of ghrelin, glucagonlike peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glucagon, pancreatic polypeptide (PP), neurotensin (NT), peptide YY (PYY), motilin, and glucose. RESULTS Ghrelin concentrations were suppressed with hyperosmolar when compared with isoosmolar saline, and remained lower until t = 180 minutes. CCK, NT, GLP-1, PYY, and glucagon all increased during hyperosmolar, but not isoosmolar, saline infusion (P < 0.01 for all), whereas GIP, PP, and motilin levels were not affected by either infusion. CONCLUSIONS Plasma ghrelin concentrations are lowered, whereas CCK, GLP-1, PYY, NT, and glucagon concentrations are augmented, by hyperosmolar duodenal content in healthy individuals. These observations have implications for the evaluation of studies comparing the effects of different types and loads of nutrients and chemicals on gut hormone secretion.
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Affiliation(s)
- Simon Veedfald
- Discipline of Medicine and National Health and Medical Research Council Centre of Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide, South Australia, Australia
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tongzhi Wu
- Discipline of Medicine and National Health and Medical Research Council Centre of Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide, South Australia, Australia
| | - Michelle Bound
- Discipline of Medicine and National Health and Medical Research Council Centre of Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide, South Australia, Australia
| | - Jacqueline Grivell
- Discipline of Medicine and National Health and Medical Research Council Centre of Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide, South Australia, Australia
| | - Bolette Hartmann
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Michael Horowitz
- Discipline of Medicine and National Health and Medical Research Council Centre of Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide, South Australia, Australia
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Christopher K Rayner
- Discipline of Medicine and National Health and Medical Research Council Centre of Research Excellence in Nutritional Physiology, Interventions and Outcomes, University of Adelaide, Adelaide, South Australia, Australia
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9
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Veedfald S, Plamboeck A, Hartmann B, Vilsbøll T, Knop FK, Deacon CF, Svendsen LB, Holst JJ. Ghrelin secretion in humans - a role for the vagus nerve? Neurogastroenterol Motil 2018; 30:e13295. [PMID: 29392854 DOI: 10.1111/nmo.13295] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/25/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Ghrelin, an orexigenic peptide, is secreted from endocrine cells in the gastric mucosa. Circulating levels rise in the preprandial phase, suggesting an anticipatory or cephalic phase of release, and decline in the postprandial phase, suggesting either the loss of a stimulatory factor or inhibition by factors released when nutrients enter the intestine. We hypothesized that vagal signals are not required for the (i) preprandial increase or (ii) postprandial suppression of ghrelin levels. Further, we wanted to investigate the hypothesis that (iii) glucagon-like peptide-1 might be implicated in the postprandial decline in ghrelin levels. METHODS We measured ghrelin levels in plasma from sham-feeding and meal studies carried out in vagotomized individuals and controls, and from a GLP-1 infusion study carried out in fasting healthy young individuals. KEY RESULTS We find that (i) ghrelin secretion is unchanged during indirect vagal stimulation as elicited by modified sham-feeding in vagotomized individuals and matched controls, (ii) ghrelin secretion is similarly suppressed after meal ingestion in vagotomized individuals and controls, and (iii) infusion of GLP-1 does not lower ghrelin levels. CONCLUSIONS & INFERENCES We conclude that for postprandial suppression of circulating ghrelin levels, a circulating factor (but not GLP-1) or short (duodeno-gastric) reflexes seem to be implicated.
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Affiliation(s)
- S Veedfald
- Endocrinology Research Section, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - A Plamboeck
- Endocrinology Research Section, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - B Hartmann
- Endocrinology Research Section, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - T Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - F K Knop
- Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - C F Deacon
- Endocrinology Research Section, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - L B Svendsen
- Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - J J Holst
- Endocrinology Research Section, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Section for Translational Metabolic Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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10
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Lecomte MJ, Bertolus C, Ramanantsoa N, Saurini F, Callebert J, Sénamaud-Beaufort C, Ringot M, Bourgeois T, Matrot B, Collet C, Nardelli J, Mallet J, Vodjdani G, Gallego J, Launay JM, Berrard S. Acetylcholine Modulates the Hormones of the Growth Hormone/Insulinlike Growth Factor-1 Axis During Development in Mice. Endocrinology 2018; 159:1844-1859. [PMID: 29509880 DOI: 10.1210/en.2017-03175] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Accepted: 02/23/2018] [Indexed: 12/28/2022]
Abstract
Pituitary growth hormone (GH) and insulinlike growth factor (IGF)-1 are anabolic hormones whose physiological roles are particularly important during development. The activity of the GH/IGF-1 axis is controlled by complex neuroendocrine systems including two hypothalamic neuropeptides, GH-releasing hormone (GHRH) and somatostatin (SRIF), and a gastrointestinal hormone, ghrelin. The neurotransmitter acetylcholine (ACh) is involved in tuning GH secretion, and its GH-stimulatory action has mainly been shown in adults but is not clearly documented during development. ACh, together with these hormones and their receptors, is expressed before birth, and somatotroph cells are already responsive to GHRH, SRIF, and ghrelin. We thus hypothesized that ACh could contribute to the modulation of the main components of the somatotropic axis during development. In this study, we generated a choline acetyltransferase knockout mouse line and showed that heterozygous mice display a transient deficit in ACh from embryonic day 18.5 to postnatal day 10, and they recover normal ACh levels from the second postnatal week. This developmental ACh deficiency had no major impact on weight gain and cardiorespiratory status of newborn mice. Using this mouse model, we found that endogenous ACh levels determined the concentrations of circulating GH and IGF-1 at embryonic and postnatal stages. In particular, serum GH level was correlated with brain ACh content. ACh also modulated the levels of GHRH and SRIF in the hypothalamus and ghrelin in the stomach, and it affected the levels of these hormones in the circulation. This study identifies ACh as a potential regulator of the somatotropic axis during the developmental period.
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Affiliation(s)
- Marie-José Lecomte
- Univercell-Biosolutions, Centre de Recherche des Cordeliers, Paris, France
| | - Chloé Bertolus
- Département de Chirurgie Maxillo-Faciale, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France
| | - Nélina Ramanantsoa
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
| | - Françoise Saurini
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
| | - Jacques Callebert
- U942-Inserm, Université Paris-Descartes, Sorbonne Paris Cité, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | | | - Maud Ringot
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
| | - Thomas Bourgeois
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
| | - Boris Matrot
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
| | - Corinne Collet
- U1132-Inserm, Université Paris-Descartes, Sorbonne Paris Cité, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Jeannette Nardelli
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
| | - Jacques Mallet
- UMRS1127-CNRS, Inserm, Université Pierre et Marie Curie, Sorbonne Universités, Hôpital Pitié-Salpêtrière, Paris, France
| | - Guilan Vodjdani
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
- CNRS, Paris, France
| | - Jorge Gallego
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
| | - Jean-Marie Launay
- U942-Inserm, Université Paris-Descartes, Sorbonne Paris Cité, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Sylvie Berrard
- PROTECT UMR1141-Inserm, Université Paris-Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France
- CNRS, Paris, France
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Foradori CD, Whitlock BK, Daniel JA, Zimmerman AD, Jones MA, Read CC, Steele BP, Smith JT, Clarke IJ, Elsasser TH, Keisler DH, Sartin JL. Kisspeptin Stimulates Growth Hormone Release by Utilizing Neuropeptide Y Pathways and Is Dependent on the Presence of Ghrelin in the Ewe. Endocrinology 2017; 158:3526-3539. [PMID: 28977590 DOI: 10.1210/en.2017-00303] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 07/13/2017] [Indexed: 12/31/2022]
Abstract
Although kisspeptin is the primary stimulator of gonadotropin-releasing hormone secretion and therefore the hypothalamic-pituitary-gonadal axis, recent findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Here we show that central delivery of kisspeptin causes a robust rise in plasma GH in fasted but not fed sheep. Kisspeptin-induced GH secretion was similar in animals fasted for 24 hours and those fasted for 72 hours, suggesting that the factors involved in kisspeptin-induced GH secretion are responsive to loss of food availability and not the result of severe negative energy balance. Pretreatment with the neuropeptide Y (NPY) Y1 receptor antagonist, BIBO 3304, blocked the effects of kisspeptin-induced GH release, implicating NPY as an intermediary. Kisspeptin treatment induced c-Fos in NPY and GH-releasing hormone (GHRH) cells of the arcuate nucleus. The same kisspeptin treatment resulted in a reduction in c-Fos in somatostatin (SS) cells in the periventricular nucleus. Finally, blockade of systemic ghrelin release or antagonism of the ghrelin receptor eliminated or reduced the ability of kisspeptin to induce GH release, suggesting the presence of ghrelin is required for kisspeptin-induced GH release in fasted animals. Our findings support the hypothesis that during short-term fasting, systemic ghrelin concentrations and NPY expression in the arcuate nucleus rise. This permits kisspeptin activation of NPY cells. In turn, NPY stimulates GHRH cells and inhibits SS cells, resulting in GH release. We propose a mechanism by which kisspeptin conveys reproductive and hormone status onto the somatotropic axis, resulting in alterations in GH release.
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Affiliation(s)
- Chad D Foradori
- Department of Anatomy, Physiology & Pharmacology, Auburn University, Auburn, Alabama 36849
| | - Brian K Whitlock
- Department of Large Animal Clinical Sciences, University of Tennessee, Knoxville, Tennessee 37996
| | - Jay A Daniel
- Department of Animal Science, Berry College, Mt. Berry, Georgia 30149
| | - Arthur D Zimmerman
- Department of Anatomy, Physiology & Pharmacology, Auburn University, Auburn, Alabama 36849
| | - Melaney A Jones
- Department of Anatomy, Physiology & Pharmacology, Auburn University, Auburn, Alabama 36849
| | - Casey C Read
- Department of Anatomy, Physiology & Pharmacology, Auburn University, Auburn, Alabama 36849
| | - Barbara P Steele
- Department of Anatomy, Physiology & Pharmacology, Auburn University, Auburn, Alabama 36849
| | - Jeremy T Smith
- School of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Crawley, Washington 6009, Australia
| | - Iain J Clarke
- Neuroscience Program, Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Victoria 3800, Australia
| | - Theodore H Elsasser
- Animal Genomics and Improvement Laboratory, US Department of Agriculture, Agricultural Research Service, Beltsville, Maryland 20705
| | - Duane H Keisler
- Division of Animal Sciences, University of Missouri, Columbia, Missouri 65211
| | - James L Sartin
- Department of Anatomy, Physiology & Pharmacology, Auburn University, Auburn, Alabama 36849
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12
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Sfera A, Osorio C, Inderias LA, Parker V, Price AI, Cummings M. The Obesity-Impulsivity Axis: Potential Metabolic Interventions in Chronic Psychiatric Patients. Front Psychiatry 2017; 8:20. [PMID: 28243210 PMCID: PMC5303716 DOI: 10.3389/fpsyt.2017.00020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2016] [Accepted: 01/25/2017] [Indexed: 12/20/2022] Open
Abstract
Pathological impulsivity is encountered in a broad range of psychiatric conditions and is thought to be a risk factor for aggression directed against oneself or others. Recently, a strong association was found between impulsivity and obesity which may explain the high prevalence of metabolic disorders in individuals with mental illness even in the absence of exposure to psychotropic drugs. As the overlapping neurobiology of impulsivity and obesity is being unraveled, the question asked louder and louder is whether they should be treated concomitantly. The treatment of obesity and metabolic dysregulations in chronic psychiatric patients is currently underutilized and often initiated late, making correction more difficult to achieve. Addressing obesity and metabolic dysfunction in a preventive manner may not only lower morbidity and mortality but also the excessive impulsivity, decreasing the risk for aggression. In this review, we take a look beyond psychopharmacological interventions and discuss dietary and physical therapy approaches.
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Affiliation(s)
- Adonis Sfera
- Patton State Hospital, Psychiatry, Patton, CA, USA
| | | | | | | | - Amy I. Price
- Oxford University, Evidence Based Medicine, Oxford, UK
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13
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Ghrelin Actions on Somatotropic and Gonadotropic Function in Humans. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 138:3-25. [PMID: 26940384 DOI: 10.1016/bs.pmbts.2015.11.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ghrelin, a 28 amino-acid octanoylated peptide predominantly produced by the stomach, was discovered to be the natural ligand of the type 1a GH secretagogue receptor (GHS-R1a). It was thus considered as a natural GHS additional to GHRH, although later on ghrelin has mostly been considered a major orexigenic factor. The GH-releasing action of ghrelin takes place both directly on pituitary cells and through modulation of GHRH from the hypothalamus; some functional antisomatostatin action has also been shown. However, ghrelin is much more than a natural GH secretagogue. In fact, it also modulates lactotroph and corticotroph secretion in humans as well as in animals and plays a relevant role in the modulation of the hypothalamic-pituitary-gonadal function. Several studies have indicated that ghrelin plays an inhibitory effect on gonadotropin pulsatility, is involved in the regulation of puberty onset in animals, and may regulate spermatogenesis, follicular development and ovarian cell functions in humans. In this chapter ghrelin actions on the GH/IGF-I and the gonadal axes will be revised. The potential therapeutic role of ghrelin as a treatment of catabolic conditions will also be discussed.
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Veedfald S, Plamboeck A, Deacon CF, Hartmann B, Knop FK, Vilsbøll T, Holst JJ. Cephalic phase secretion of insulin and other enteropancreatic hormones in humans. Am J Physiol Gastrointest Liver Physiol 2016; 310:G43-51. [PMID: 26492921 DOI: 10.1152/ajpgi.00222.2015] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/17/2015] [Indexed: 01/31/2023]
Abstract
Enteropancreatic hormone secretion is thought to include a cephalic phase, but the evidence in humans is ambiguous. We studied vagally induced gut hormone responses with and without muscarinic blockade in 10 glucose-clamped healthy men (age: 24.5 ± 0.6 yr, means ± SE; body mass index: 24.0 ± 0.5 kg/m(2); HbA1c: 5.1 ± 0.1%/31.4 ± 0.5 mmol/mol). Cephalic activation was elicited by modified sham feeding (MSF, aka "chew and spit") with or without atropine (1 mg bolus 45 min before MSF + 80 ng·kg(-1)·min(-1) for 2 h). To mimic incipient prandial glucose excursions, glucose levels were clamped at 6 mmol/l on all days. The meal stimulus for the MSF consisted of an appetizing breakfast. Participants (9/10) also had a 6 mmol/l glucose clamp without MSF. Pancreatic polypeptide (PP) levels rose from 6.3 ± 1.1 to 19.9 ± 6.8 pmol/l (means ± SE) in response to MSF and atropine lowered basal PP levels and abolished the MSF response. Neither insulin, C-peptide, glucose-dependent insulinotropic polypeptide (GIP), nor glucagon-like peptide-1 (GLP-1) levels changed in response to MSF or atropine. Glucagon and ghrelin levels were markedly attenuated by atropine prior to and during the clamp: at t = 105 min on the atropine (ATR) + clamp (CLA) + MSF compared with the saline (SAL) + CLA and SAL + CLA + MSF days; baseline-subtracted glucagon levels were -10.7 ± 1.1 vs. -4.0 ± 1.1 and -4.7 ± 1.9 pmol/l (means ± SE), P < 0.0001, respectively; corresponding baseline-subtracted ghrelin levels were 303 ± 36 vs. 39 ± 38 and 3.7 ± 21 pg/ml (means ± SE), P < 0.0001. Glucagon and ghrelin levels were unaffected by MSF. Despite adequate PP responses, a cephalic phase response was absent for insulin, glucagon, GLP-1, GIP, and ghrelin.
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Affiliation(s)
- Simon Veedfald
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; and Department of Surgical Gastroenterology, Rigshospitalet, University of Copenhagen, Denmark
| | - Astrid Plamboeck
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; and
| | - Carolyn F Deacon
- Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; and
| | - Bolette Hartmann
- Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; and
| | - Filip K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; and
| | - Tina Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; NNF Center for Basic Metabolic Research, The Panum Institute, University of Copenhagen, Copenhagen, Denmark; and
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Kiyici S, Basaran NF, Cavun S, Savci V. Central injection of CDP-choline suppresses serum ghrelin levels while increasing serum leptin levels in rats. Eur J Pharmacol 2015; 764:264-270. [PMID: 26162700 DOI: 10.1016/j.ejphar.2015.07.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 07/03/2015] [Accepted: 07/06/2015] [Indexed: 12/17/2022]
Abstract
In this study we aimed to test central administration of CDP-choline on serum ghrelin, leptin, glucose and corticosterone levels in rats. Intracerebroventricular (i.c.v.) 0.5, 1.0 and 2.0 µmol CDP-choline and saline were administered to male Wistar-Albino rats. For the measurement of serum leptin and ghrelin levels, blood samples were obtained baseline and at 5, 15, 30, 60 and 120 min following i.c.v. CDP-choline injection. Equimolar doses of i.c.v. choline (1.0 µmol) and cytidine (1.0 µmol) were administered and measurements were repeated throughout the second round of the experiment. Atropine (10 µg) and mecamylamine (50 µg) were injected intracerebroventricularly prior to CDP-choline and measurements repeated in the third round of the experiment. After 1 µmol CDP-choline injection, serum ghrelin levels were suppressed significantly at 60 min (P=0.025), whereas serum leptin levels were increased at 60 and 120 min (P=0.012 and P=0.017 respectively). CDP-choline injections also induced a dose- and time-dependent increase in serum glucose and corticosterone levels. The effect of choline on serum leptin and ghrelin levels was similar with CDP-choline while no effect was seen with cytidine. Suppression of serum ghrelin levels was eliminated through mecamylamine pretreatment while a rise in leptin was prevented by both atropine and mecamylamine pretreatments. In conclusion; centrally injected CDP-choline suppressed serum ghrelin levels while increasing serum leptin levels. The observed effects following receptor antagonist treatment suggest that nicotinic receptors play a role in suppression of serum ghrelin levels,whereas nicotinic and muscarinic receptors both play a part in the increase of serum leptin levels.
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Affiliation(s)
- Sinem Kiyici
- Uludag University Medical Faculty, Department of Pharmacology, Bursa, Turkey.
| | | | - Sinan Cavun
- Uludag University Medical Faculty, Department of Pharmacology, Bursa, Turkey.
| | - Vahide Savci
- Uludag University Medical Faculty, Department of Pharmacology, Bursa, Turkey.
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16
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Iwakura H, Kangawa K, Nakao K. The regulation of circulating ghrelin - with recent updates from cell-based assays. Endocr J 2015; 62:107-22. [PMID: 25273611 DOI: 10.1507/endocrj.ej14-0419] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Ghrelin is a stomach-derived orexigenic hormone with a wide range of physiological functions. Elucidation of the regulation of the circulating ghrelin level would lead to a better understanding of appetite control in body energy homeostasis. Earlier studies revealed that circulating ghrelin levels are under the control of both acute and chronic energy status: at the acute scale, ghrelin levels are increased by fasting and decreased by feeding, whereas at the chronic scale, they are high in obese subjects and low in lean subjects. Subsequent studies revealed that nutrients, hormones, or neural activities can influence circulating ghrelin levels in vivo. Recently developed in vitro assay systems for ghrelin secretion can assess whether and how individual factors affect ghrelin secretion from cells. In this review, on the basis of numerous human, animal, and cell-based studies, we summarize current knowledge on the regulation of circulating ghrelin levels and enumerate the factors that influence ghrelin levels.
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Affiliation(s)
- Hiroshi Iwakura
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
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17
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Rashti F, Gupta E, Ebrahimi S, Shope TR, Koch TR, Gostout CJ. Development of minimally invasive techniques for management of medically-complicated obesity. World J Gastroenterol 2014; 20:13424-13445. [PMID: 25309074 PMCID: PMC4188895 DOI: 10.3748/wjg.v20.i37.13424] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 06/15/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
The field of bariatric surgery has been rapidly growing and evolving over the past several decades. During the period that obesity has become a worldwide epidemic, new interventions have been developed to combat this complex disorder. The development of new laparoscopic and minimally invasive treatments for medically-complicated obesity has made it essential that gastrointestinal physicians obtain a thorough understanding of past developments and possible future directions in bariatrics. New laparoscopic advancements provide patients and practitioners with a variety of options that have an improved safety profile and better efficacy without open, invasive surgery. The mechanisms of weight loss after bariatric surgery are complex and may in part be related to altered release of regulatory peptide hormones from the gut. Endoscopic techniques designed to mimic the effects of bariatric surgery and endolumenal interventions performed entirely through the gastrointestinal tract offer potential advantages. Several of these new techniques have demonstrated promising, preliminary results. We outline herein historical and current trends in the development of bariatric surgery and its transition to safer and more minimally invasive procedures designed to induce weight loss.
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18
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Hayakawa M, Ono Y, Wada T, Yanagida Y, Sawamura A, Takeda H, Gando S. Effects of Rikkunshito (traditional Japanese medicine) on enteral feeding and the plasma ghrelin level in critically ill patients: a pilot study. J Intensive Care 2014; 2:53. [PMID: 25705411 PMCID: PMC4336131 DOI: 10.1186/s40560-014-0053-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Accepted: 08/25/2014] [Indexed: 12/24/2022] Open
Abstract
Background Rikkunshito is a traditional Japanese medicine that has been widely prescribed for patients with various gastrointestinal symptoms. Recently, the prokinetic effects of Rikkunshito in patients with a variety of diseases have attracted attention in Japan. The prokinetic effects of Rikkunshito are believed to result from an increase of active ghrelin, which is most abundant in the stomach and which has a gastrokinetic function. The aim of the present pilot study was to investigate the effects of Rikkunshito on intragastric enteral feeding and plasma ghrelin levels in critically ill patients. Methods The study population consisted of critically ill patients who were projected to require intragastric tube feeding for more than 7 days. The patients were prospectively assigned to one of two treatment groups and were randomized to receive either Rikkunshito (2.5 g) or metoclopramide (10 mg) every 8 h. All patients received standard enteral nutrition. Patients in both groups were begun on intragastric tube feeding according to our institution’s feeding protocol. Results All patients were undergoing mechanical ventilation at the time of enrollment. The portions of enteral nutrition provided to the target amount and the quantity of gastric discharge were not statistically significantly different between the two groups. The Rikkunshito group reached 50% of the target amount of enteral feeding significantly earlier than the metoclopramide group, although the proportion of patients in whom enteral feeding was successful did not differ significantly between the two groups. Patients in the Rikkunshito group showed significantly higher plasma levels of active ghrelin compared to those in the metoclopramide group. Conclusions The administration of Rikkunshito increased the plasma level of active ghrelin, and induced prokinetic effects that were greater than those observed following treatment with metoclopramide in critically ill patients. Trial registration UMIN00000356
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Affiliation(s)
- Mineji Hayakawa
- Emergency and Critical Care Center, Hokkaido University Hospital, N14W5 Kita-ku, Sapporo, 060-8648 Japan
| | - Yuichi Ono
- Emergency and Critical Care Center, Hokkaido University Hospital, N14W5 Kita-ku, Sapporo, 060-8648 Japan
| | - Takeshi Wada
- Emergency and Critical Care Center, Hokkaido University Hospital, N14W5 Kita-ku, Sapporo, 060-8648 Japan
| | - Yuichiro Yanagida
- Emergency and Critical Care Center, Hokkaido University Hospital, N14W5 Kita-ku, Sapporo, 060-8648 Japan
| | - Atsushi Sawamura
- Emergency and Critical Care Center, Hokkaido University Hospital, N14W5 Kita-ku, Sapporo, 060-8648 Japan
| | - Hiroshi Takeda
- Gastroenterology and Hematology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638 Japan
| | - Satoshi Gando
- Emergency and Critical Care Center, Hokkaido University Hospital, N14W5 Kita-ku, Sapporo, 060-8648 Japan
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19
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Huda MSB, Mani H, Durham BH, Dovey TM, Halford JCG, Aditya BS, Pinkney JH, Wilding JP, Hart IK. Plasma obestatin and autonomic function are altered in orexin-deficient narcolepsy, but ghrelin is unchanged. Endocrine 2013. [PMID: 23179778 DOI: 10.1007/s12020-012-9838-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Narcolepsy-cataplexy is characterised by orexin deficiency, sleep disturbance, obesity and dysautonomia. Ghrelin and obestatin affect both energy intake and sleep. Our aim was to investigate ghrelin, obestatin and metabolic/autonomic function in narcolepsy-cataplexy. Eight narcolepsy-cataplexy patients (seven CSF orexin-deficient) and eight matched controls were studied. The subjects had a fixed energy meal with serial blood samples and measurement of heart rate variability (HRV). Fasting plasma obestatin was more than threefold higher in narcolepsy subjects (narcolepsy 89.6 ± 16 pg/ml vs. control 24.9 ± 3 pg/ml, p < 0.001). There was no change in HRV total power, but post-prandial low-frequency (LF) power and high-frequency (HF) power were lower in the narcolepsy group [area under the curve (AUC): HF power narcolepsy 1.4 × 10(5) ± 0.2 × 10(5) vs. control 3.3 × 10(5) ± 0.6 × 10(5 )ms(2)/h, p < 0.001]. On multiple regression analyses, the only significant predictor of plasma obestatin was HF power, which was inversely correlated with obestatin (β = -0.65 R (2) = 38 %, p = 0.009). Fasting and post-prandial plasma ghrelin were similar in both groups (narcolepsy 589.5 ± 88 pg/ml vs. control 686.9 ± 81 pg/ml, p = 0.5; post-prandial AUC-narcolepsy 161.3 ± 22 ng/ml/min vs. control 188.6 ± 62 ng/ml/min, p = 0.4). Only the narcolepsy group had significant suppression of plasma ghrelin after the meal (ANOVA, p = 0.004). In orexin-deficient narcolepsy, fasting plasma ghrelin is unaltered, and post-prandial suppression is preserved. Fasting plasma obestatin is increased and correlates with autonomic dysfunction. As obestatin affects NREM sleep, we suggest that increased plasma levels contribute to the disrupted sleep-state control in narcolepsy.
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Affiliation(s)
- M S B Huda
- University of Liverpool Diabetes and Endocrinology Research Group, Clinical Sciences Centre, University Hospital Aintree, Liverpool, L9 7AL, UK.
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Ozawa T, Tokunaga J, Arakawa M, Ishikawa A, Takeuchi R, Mezaki N, Miura T, Sakai N, Hokari M, Takeshima A, Utsumi K, Kondo T, Yokoseki A, Nishizawa M. Abnormal ghrelin secretion contributes to gastrointestinal symptoms in multiple system atrophy patients. J Neurol 2013; 260:2073-7. [PMID: 23652420 PMCID: PMC3734593 DOI: 10.1007/s00415-013-6944-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Revised: 04/26/2013] [Accepted: 04/27/2013] [Indexed: 12/24/2022]
Abstract
Patients with multiple system atrophy (MSA) often have evidence of compromised gastrointestinal motility. Ghrelin is a gut hormone that influences gastrointestinal motility in humans. The aim of this study was to determine whether ghrelin secretion is affected in MSA patients, and to investigate the relation between ghrelin secretion and gastrointestinal symptoms. Plasma levels of active ghrelin and unacylated ghrelin were measured in patients with MSA (n = 30), other atypical parkinsonian disorders including progressive supranuclear palsy-Richardson syndrome and corticobasal syndrome (n = 24), and control subjects (n = 24) using enzyme-linked immunosorbent assays. Gastrointestinal symptoms were quantified in all subjects using a self-report questionnaire. The ratio of active ghrelin to total ghrelin in the plasma (active ghrelin ratio) was lower in patients with MSA (mean: 8.0 %) than in patients with other atypical parkinsonian disorders (mean: 13.7 %, P = 0.001) and control subjects (mean: 13.9 %, P = 0.001). The active ghrelin ratio was correlated with the severity of gastrointestinal symptoms in MSA (r = −0.5, P = 0.004). Our observations indicate that ghrelin secretion is affected in patients with MSA. The low active ghrelin ratio may contribute to gastrointestinal symptoms in MSA.
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Affiliation(s)
- Tetsutaro Ozawa
- Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi-dori Chuoku, Niigata 951-8585, Japan.
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Garin MC, Burns CM, Kaul S, Cappola AR. Clinical review: The human experience with ghrelin administration. J Clin Endocrinol Metab 2013; 98:1826-37. [PMID: 23533240 PMCID: PMC3644599 DOI: 10.1210/jc.2012-4247] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
CONTEXT Ghrelin is an endogenous stimulator of GH and is implicated in a number of physiological processes. Clinical trials have been performed in a variety of patient populations, but there is no comprehensive review of the beneficial and adverse consequences of ghrelin administration to humans. EVIDENCE ACQUISITION PubMed was utilized, and the reference list of each article was screened. We included 121 published articles in which ghrelin was administered to humans. EVIDENCE SYNTHESIS Ghrelin has been administered as an infusion or a bolus in a variety of doses to 1850 study participants, including healthy participants and patients with obesity, prior gastrectomy, cancer, pituitary disease, diabetes mellitus, eating disorders, and other conditions. There is strong evidence that ghrelin stimulates appetite and increases circulating GH, ACTH, cortisol, prolactin, and glucose across varied patient populations. There is a paucity of evidence regarding the effects of ghrelin on LH, FSH, TSH, insulin, lipolysis, body composition, cardiac function, pulmonary function, the vasculature, and sleep. Adverse effects occurred in 20% of participants, with a predominance of flushing and gastric rumbles and a mild degree of severity. The few serious adverse events occurred in patients with advanced illness and were not clearly attributable to ghrelin. Route of administration may affect the pattern of adverse effects. CONCLUSIONS Existing literature supports the short-term safety of ghrelin administration and its efficacy as an appetite stimulant in diverse patient populations. There is some evidence to suggest that ghrelin has wider ranging therapeutic effects, although these areas require further investigation.
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Affiliation(s)
- Margaret C Garin
- Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-5160, USA
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Ghrelin inhibits insulin release by regulating the expression of inwardly rectifying potassium channel 6.2 in islets. Am J Med Sci 2012; 343:215-9. [PMID: 22270395 DOI: 10.1097/maj.0b013e31824390b9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION The objective is to investigate the influence of ghrelin administration on both the insulin secretion and the expression of ATP-sensitive K(+) channels in islet. METHODS Ghrelin and [D-Lys] growth hormone releasing peptide-6 were administered via intraperitoneal injection in Wistar rats at the doses 10 and 10 μmol/kg/d for 2 weeks, respectively. Then glucose tolerance tests were performed and plasma insulin concentrations were measured. Islets were isolated for insulin release experiments. Single β cells were isolated for electrophysiological experiments. Determination of the Kir6.2 and SUR1 mRNA and protein expression levels in islets was performed by polymerase chain reaction and western blotting. RESULTS Intraperitoneal administration of exogenous ghrelin significantly (P < 0.05) increased blood glucose concentrations, attenuated insulin responses during glucose tolerance tests, reduced insulin release from the isolated islets induced by 11.1 and 16.7 mmol/L glucose, hyperpolarized the resting membrane potential and increased the Kir6.2 mRNA and protein expression levels. In contrast, counteraction of ghrelin by intraperitoneal injection of [D-Lys(3)] growth hormone releasing peptide-6 significantly (P < 0.05) attenuated the aforementioned changes. SUR1 expression levels were not altered in this study. CONCLUSIONS Ghrelin via pancreatic growth hormone secretagogue receptor up-regulates the Kir6.2 expression in islet by hyperpolarizing the resting membrane potential which results in the inhibition of insulin release.
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Abstract
The migrating motor complex (MMC) is a cyclic, recurring motility pattern that occurs in the stomach and small bowel during fasting; it is interrupted by feeding. The MMC is present in the gastrointestinal tract of many species, including humans. The complex can be subdivided into four phases, of which phase III is the most active, with a burst of contractions originating from the antrum or duodenum and migrating distally. Control of the MMC is complex. Phase III of the MMC with an antral origin can be induced in humans through intravenous administration of motilin, erythromycin or ghrelin, whereas administration of serotonin or somatostatin induces phase III activity with duodenal origin. The role of the vagus nerve in control of the MMC seems to be restricted to the stomach, as vagotomy abolishes the motor activity in the stomach, but leaves the periodic activity in the small bowel intact. The physiological role of the MMC is incompletely understood, but its absence has been associated with gastroparesis, intestinal pseudo-obstruction and small intestinal bacterial overgrowth. Measuring the motility of the gastrointestinal tract can be important for the diagnosis of gastrointestinal disorders. In this Review we summarize current knowledge of the MMC, especially its role in health and disease.
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Kirsz K, Zieba DA. Ghrelin-mediated appetite regulation in the central nervous system. Peptides 2011; 32:2256-64. [PMID: 21524673 DOI: 10.1016/j.peptides.2011.04.010] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Revised: 04/07/2011] [Accepted: 04/08/2011] [Indexed: 11/28/2022]
Abstract
The gut hormone and neuropeptide ghrelin was initially identified in the periphery as a compound released in the bloodstream in response to a negative energetic status. In the central nervous system (CNS), ghrelin mainly acts on the hypothalamus and the limbic system, with its best-known biological role being the regulation of appetitive functions. Recent research has shown that ghrelin is not an indispensable factor in the regulation of food intake. However, it plays a key role in the metabolic changes of lipids, mainly those involving hypothalamic NOS, AMPK, CaMKK2, CPT1 and UCP2 proteins. Ghrelin participates in the regulation of memory processes and the feeling of pleasure resulting from eating, both of which are metabolism-dependent and may be essential for the successful achievement of adaptive appetitive behavior. Ghrelin exerts its biological effect through a complicated network of neuroendocrine links, including the melanocortin and endocannabinoid systems. The activity of ghrelin is connected with circadian and annual fluctuations, which depend on seasons and food availability.
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Affiliation(s)
- Katarzyna Kirsz
- Department of Swine and Small Ruminant Breeding, Laboratory of Genomics and Biotechnology, University of Agriculture, Krakow 30-059, Poland
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Stengel A, Wang L, Taché Y. Stress-related alterations of acyl and desacyl ghrelin circulating levels: mechanisms and functional implications. Peptides 2011; 32:2208-17. [PMID: 21782868 PMCID: PMC3220774 DOI: 10.1016/j.peptides.2011.07.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2011] [Revised: 07/04/2011] [Accepted: 07/05/2011] [Indexed: 12/11/2022]
Abstract
Ghrelin is the only known peripherally produced and centrally acting peptide hormone that stimulates food intake and digestive functions. Ghrelin circulates as acylated and desacylated forms and recently the acylating enzyme, ghrelin-O-acyltransferase (GOAT) and the de-acylating enzyme, thioesterase 1/lysophospholipase 1 have been identified adding new layers of complexity to the regulation of ghrelin. Stress is known to alter gastrointestinal motility and food intake and was recently shown to modify circulating ghrelin and GOAT levels with differential responses related to the type of stressors including a reduction induced by physical stressors (abdominal surgery and immunological/endotoxin injection, exercise) and elevation by metabolic (cold exposure, acute fasting and caloric restriction) and psychological stressors. However, the pathways underlying the alterations of ghrelin under these various stress conditions are still largely to be defined and may relate to stress-associated autonomic changes. There is evidence that alterations of circulating ghrelin may contribute to the neuroendocrine and behavioral responses along with sustaining the energetic requirement needed upon repeated exposure to stressors. A better understanding of these mechanisms will allow targeting components of ghrelin signaling that may improve food intake and gastric motility alterations induced by stress.
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Affiliation(s)
- Andreas Stengel
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine, University of California Los Angeles and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States.
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Scott WR, Batterham RL. Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: understanding weight loss and improvements in type 2 diabetes after bariatric surgery. Am J Physiol Regul Integr Comp Physiol 2011; 301:R15-27. [PMID: 21474429 DOI: 10.1152/ajpregu.00038.2011] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obesity increases the likelihood of diseases like type 2 diabetes (T2D), heart disease, and cancer, and is one of the most serious public health problems of this century. In contrast to ineffectual prevention strategies, lifestyle modifications, and pharmacological therapies, bariatric surgery is a very effective treatment for morbid obesity and also markedly improves associated comorbidities like T2D. However, weight loss and resolution of T2D after bariatric surgery is heterogeneous and specific to type of bariatric procedure performed. Conventional mechanisms like intestinal malabsorption and gastric restriction do not fully explain this, and potent changes in appetite and the enteroinsular axis, as a result of anatomical reorganization and altered hormonal, neuronal, and nutrient signaling, are the portended cause. Uniquely these signaling changes appear to override vigorous homeostatic defenses of stable body weight and compelling self-gratifying motivations to eat and to reverse defects in beta-cell function and insulin sensitivity. Here we review mechanisms of weight loss and T2D resolution after Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy bariatric surgery, two markedly different procedures with robust clinical outcomes.
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Affiliation(s)
- William R Scott
- Centre for Obesity Research, Dept. of Medicine, Rayne Institute, University College London, WC1E 6JJ, UK
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Shiiya T, Ueno H, Toshinai K, Kawagoe T, Naito S, Tobina T, Nishida Y, Shindo M, Kangawa K, Tanaka H, Nakazato M. Significant lowering of plasma ghrelin but not des-acyl ghrelin in response to acute exercise in men. Endocr J 2011; 58:335-42. [PMID: 21436599 DOI: 10.1507/endocrj.k11e-021] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and growth hormone (GH) secretion via interaction with the GH secretagogue receptor. Ghrelin molecules are present in two major endogenous forms, an acylated form (ghrelin) and a des-acylated form (des-acyl ghrelin). Recent studies indicated that aerobic exercise did not change plasma total ghrelin levels, however, dynamics of circulating ghrelin and des-acyl ghrelin during aerobic exercise remains unclear. The purpose of this study is to examine the effects of moderate intensity exercise on plasma ghrelin and des-acyl ghrelin concentrations, and to investigate the relationship between ghrelin molecules and other hormonal and metabolic parameters during exercise. Nine healthy males (25.2 ± 0.5 years) exercised for 60 min at 50% of their maximal oxygen consumptions. We measured the plasma concentrations of ghrelin, des-acyl ghrelin, GH, norepinephrine (NE), epinephrine (E), dopamine (DA), insulin, and glucose. Plasma ghrelin level significantly decreased during exercise, whereas plasma des-acyl ghrelin and total ghrelin levels did not change. Plasma NE, E, DA and GH levels were significantly increased during exercise. Plasma insulin level significantly decreased during exercise, and plasma glucose levels remained steady during exercise. NE, E, DA, and GH were correlated negatively with plasma ghrelin levels. These findings suggest that acute moderate exercise may suppress ghrelin release from the stomach, decrease ghrelin O-acyltransferase activity, and/or activate ghrelin utilization in peripheral tissues and that exercise-induced ghrelin suppression may be mediated by activated adrenergic system.
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Affiliation(s)
- Tomomi Shiiya
- Faculty of Medicine, Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, Miyazaki, Japan
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Zietlow A, Nakajima H, Taniguchi H, Ludwig K, Takahashi T. Association between plasma ghrelin and motilin levels during MMC cycle in conscious dogs. ACTA ACUST UNITED AC 2010; 164:78-82. [PMID: 20609429 DOI: 10.1016/j.regpep.2010.05.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2009] [Revised: 05/10/2010] [Accepted: 05/25/2010] [Indexed: 11/16/2022]
Abstract
BACKGROUND Migrating motor complex (MMC) is well characterized by the appearance of gastrointestinal contractions in the interdigestive state. Gastric phase III contractions of MMC are regulated by motilin, but not ghrelin, in dogs. Ghrelin regulates feeding activity in dogs and rodents. It remains unclear how motilin and ghrelin interact during the MMC cycle in dogs. METHODS Four strain gauge transducers were implanted on stomach and intestine in 6 female dogs. To investigate the correlation between ghrelin and motilin, plasma motilin and acyl ghrelin (active type) levels were measured by radioimmunoassay (RIA) during MMC cycle. RESULTS The peak of plasma motilin levels was always observed at the period of gastric phase III contractions. The peak of ghrelin levels were followed 20-25 min after the peak of plasma motilin levels in 13 cases of 18 observations (72.2%). These were frequently observed at the early stage of gastric phase I contractions. In 3 of 16 observations (18.8%), the ghrelin peak was not associated with the motilin peaks. Immediately after the feeding, the interdigestive GI motor pattern was changed to the postprandial pattern. No significant increases of the plasma motilin levels and ghrelin levels were observed after the feeding. CONCLUSION This is the first demonstration showing the correlation between ghrelin and motilin levels during gastric MMC cycle in conscious dogs. As it is rather difficult to evaluate the hunger score in dogs, it remains unclear whether increased ghrelin levels after finishing gastric phase III contractions may mediate hunger sensation in dogs.
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Affiliation(s)
- Aaron Zietlow
- Department of Surgery, Medical College of Wisconsin and Zablocki VA Medical Center, Milwaukee, WI, USA
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Ghrelin attenuates acute pancreatitis-induced lung injury and inhibits substance P expression. Am J Med Sci 2010; 339:49-54. [PMID: 19926967 DOI: 10.1097/maj.0b013e3181b9c3d3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To investigate the effect of ghrelin administration on the severity of acute lung injury and on the production of proinflammatory cytokines and Substance P (SP) in rats with acute pancreatitis (AP). METHODS AP was induced in rats by sodium taurocholate injection through pancreaticobiliary duct. Ghrelin 20 nmol/kg was given before and after the treatment. Tumor necrosis factor-alpha, interleukin-1beta, and -6 levels in the serum were measured using the radioimmunoassay method. Morphological signs of lung injury, pulmonary water content, microvascular permeability, and myeloperoxidase activity were measured. Meanwhile, the determination of pulmonary SP mRNA level and its expression were performed by reverse transcriptase polymerase chain reaction and immunohistochemistry. RESULTS The serum proinflammatory cytokines, pulmonary water content, microvascular permeability, and myeloperoxidase activity were increased, and morphological damages were observed in the lung of AP rats. SP mRNA level and its expression were significantly higher in sham-operated rats (P < 0.05). Morphological damages were attenuated and serum cytokines and pulmonary parameters were reduced by pre- and posttreatment with ghrelin. Pulmonary SP expression was also significantly down-regulated by ghrelin (P < 0.05). CONCLUSIONS Ghrelin attenuates the severity of acute lung injury induced by AP. The reduction of neutrophil sequestration, limitation of proinflammatory cytokines release, and inhibition of pulmonary SP expression may be the mechanisms involved in the therapeutic effect of ghrelin.
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Ghrelin inhibits the development of acute pancreatitis and nuclear factor kappaB activation in pancreas and liver. Pancreas 2009; 38:752-7. [PMID: 19506532 DOI: 10.1097/mpa.0b013e3181a86b74] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVES To investigate the influence of ghrelin on the development of severe acute pancreatitis (SAP) and the expression of nuclear factor kappaB (NF-kappaB) p65 in the pancreas and liver. METHODS Severe acute pancreatitis was induced in rat by sodium taurocholate injection in the pancreaticobiliary duct. Ghrelin was administrated twice at the dose 10 or 20 nmol/kg per injection, respectively. Then, serum amylase activity; serum tumor necrosis factor alpha, interleukin 1beta, and interleukin 6 concentrations; and morphological signs of pancreatitis and hepatic damage were measured. Meanwhile, determination of pancreatic and hepatic NF-kappaB p65 expression was performed by Western blotting and immunohistochemistry. RESULTS The serumal parameters increased, and morphological damages were observed in the pancreas and liver in SAP rats. Nuclear factor kappaB p65 expression was significantly higher in the pancreas and liver than sham-operated rats (P < 0.05). Treatment with ghrelin attenuated the morphological damages, and reduced the serumal parameters. Nuclear factor kappaB p65 expression was also significantly reduced by ghrelin (P < 0.05), both in the pancreas and liver. CONCLUSIONS Ghrelin inhibits the development of acute pancreatitis induced by sodium taurocholate. It exerts the therapeutic effects through inhibiting NF-kappaB expression, thereby blocks the inflammatory signal transduction pathway and reduces the release of inflammatory media and cytokines.
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Hattori N. Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system. Growth Horm IGF Res 2009; 19:187-197. [PMID: 19144554 DOI: 10.1016/j.ghir.2008.12.001] [Citation(s) in RCA: 138] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2008] [Revised: 11/05/2008] [Accepted: 12/08/2008] [Indexed: 12/20/2022]
Abstract
Immune and neuroendocrine systems have bidirectional communications. Growth hormone (GH) and an orexigenic hormone ghrelin are expressed in various immune cells such as T lymphocytes, B lymphocytes, monocytes and neutrophils. These immune cells also bear receptors for hormones: growth hormone receptor (GHR) for GH and growth hormone secretagogue receptor (GHS-R) for ghrelin. The expression of GH in immune cells is stimulated by ghrelin as in anterior pituitary cells, whereas the regulation of GH secretion in the immune system by other peptides seems to be different from that in the anterior pituitary gland. Cytokines and mitogens enhance GH secretion from immune cells. GH has several biological actions in the immune system: enhancing thymopoiesis and T cell development, modulating cytokine production, enhancing B cell development and antibody production, priming neutrophils and monocytes for superoxide anion secretion, enhancing neutrophil adhesion and monocyte migration and anti-apoptotic action. Biological actions of ghrelin include attenuation of septic shock and anti-inflammatory actions, modulating phagocytosis, and enhancing thymopoiesis. The effect of ghrelin may be direct or through GH production, and that of GH may be direct or through insulin like growth factor-I (IGF-I) production. Elucidation of the roles of GH and ghrelin in the immune system may shed light on the treatment and prevention of immunological disorders such as AIDS and organ damages due to obesity/ageing-related chronic inflammation.
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Affiliation(s)
- Naoki Hattori
- Department of Pharmacology, Kansai Medical University, Moriguchi-city, Osaka, Japan.
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32
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Shrestha YB, Wickwire K, Giraudo SQ. Direct effects of nutrients, acetylcholine, CCK, and insulin on ghrelin release from the isolated stomachs of rats. Peptides 2009; 30:1187-91. [PMID: 19463754 PMCID: PMC2687321 DOI: 10.1016/j.peptides.2009.02.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2009] [Revised: 02/04/2009] [Accepted: 02/05/2009] [Indexed: 11/29/2022]
Abstract
Ghrelin is a powerful orexigenic peptide predominantly secreted by the stomach. Blood concentration of ghrelin increases before meals and fall postprandial. Its regulation appears to be influenced by the type of macronutrient ingested, the vagus nerve stimulation and by other post-meal stimulated hormonal factors. However, the direct role of nutrients (amino acids or lipids), neuronal (vagal neurotransmitter acetylcholine) and satiety-inducing factor such as CCK are not known. To study this we applied amino acids, lipids, acetylcholine and CCK via vascular perfusion to the isolated stomachs and found that amino acids significantly reduced ghrelin release from the isolated stomach by approximately approximately 30% vs. the control while lipids (10% intralipid) had no affect. Acetylcholine (1 microM) increased ghrelin release from the stomach by approximately 37% whereas insulin (10nM) decreased it by approximately 30% vs. the control. Interestingly, CCK (100 nM) potently increased ghrelin release by approximately 200% vs. the control. Therefore it appears that ghrelin secretion from the stomach is under direct influence of amino acids, neurotransmitter acetylcholine and hormones such as insulin and CCK.
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Affiliation(s)
| | | | - Silvia Q. Giraudo
- Corresponding Author and Address: Dr. Silvia Giraudo, Department of Foods and Nutrition, 280 Dawson Hall, University of Georgia, Athens, Georgia 30602, U.S.A, , Phone: 706-542-6977, Fax: 706-542-5059
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Motivala SJ, Tomiyama AJ, Ziegler M, Khandrika S, Irwin MR. Nocturnal levels of ghrelin and leptin and sleep in chronic insomnia. Psychoneuroendocrinology 2009; 34:540-5. [PMID: 19059729 PMCID: PMC2725023 DOI: 10.1016/j.psyneuen.2008.10.016] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2008] [Revised: 10/13/2008] [Accepted: 10/21/2008] [Indexed: 02/05/2023]
Abstract
Experimental sleep deprivation in healthy humans affects levels of ghrelin and leptin, two primary hormones involved in energy balance that regulate appetite and body weight. No study to date has examined levels of these hormones in patients with chronic insomnia. In this study, men diagnosed with primary insomnia using DSM-IV criteria (n=14) and age and body weight comparable healthy control men (n=24) underwent polysomnography. Circulating levels of ghrelin and leptin were measured at 2300h, 0200h and 0600h. As compared to controls, insomnia patients showed less total sleep time, stage 2 and REM sleep and decreased sleep efficiency and more stage 1 sleep than controls (p's<.05). Ghrelin levels across the night were significantly lower in insomnia patients (p<.0001). Leptin was not significantly different between the groups. In conclusion, decreased nocturnal ghrelin in insomnia is consistent with findings for nighttime levels in sleep deprivation studies in healthy sleepers. These findings suggest that insomnia patients have a dysregulation in energy balance that may play a role in explaining prospective weight gain in this population.
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Affiliation(s)
- Sarosh J Motivala
- University of California, Los Angeles - Cousins Center for Psychoneuroimmunology, Los Angeles, CA 90095-7076, United States.
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Maier C, Riedl M, Vila G, Nowotny P, Wolzt M, Clodi M, Ludvik B, Luger A. Cholinergic regulation of ghrelin and peptide YY release may be impaired in obesity. Diabetes 2008; 57:2332-40. [PMID: 18567824 PMCID: PMC2518484 DOI: 10.2337/db07-0758] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2007] [Accepted: 06/17/2008] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Ghrelin and peptide YY (PYY) are both hormones derived from the gastrointestinal tract involved in appetite regulation. The cholinergic part of the vagal nerve is involved in the regulation of glucose and insulin. The aim of this study was to examine the effects of the cholinergic antagonist atropine on ghrelin, PYY, glucose, and insulin under basal conditions and after meal ingestion in lean and obese subjects. RESEARCH DESIGN AND METHODS Eight lean and eight obese subjects were included in a randomized, double-blind, placebo-controlled crossover study with 4 study days in randomized order (atropine/placebo +/- breakfast). Plasma ghrelin, PYY, insulin, and glucose were measured. Hunger and satiety feelings were rated on a 10-cm visual analog scale. RESULTS In lean individuals, atropine led to a decrease in ghrelin concentrations comparable and nonadditive with breakfast ingestion and a significant decrease in both basal and meal-induced PYY concentrations. In obese subjects, atropine did not significantly change ghrelin or PYY concentrations, whereas it induced a comparable increase in heart rate and meal-induced glucose concentrations in the two study groups. Only lean, not obese, subjects experienced sustained feelings of satiety after breakfast. CONCLUSIONS The impaired cholinergic regulation of the postprandial drop in ghrelin concentrations and rise in PYY concentrations might be part of the deregulated food intake in obese subjects.
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Affiliation(s)
- Christina Maier
- Clinical Division of Endocrinology and Metabolism, Department ofMedicine III, Medical University of Vienna, Vienna, Austria.
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Perathoner A, Weiss H, Santner W, Brandacher G, Laimer E, Höller E, Aigner F, Klaus A. Vagal nerve dissection during pouch formation in laparoscopic Roux-Y-gastric bypass for technical simplification: does it matter? Obes Surg 2008; 19:412-7. [PMID: 18704604 DOI: 10.1007/s11695-008-9657-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2008] [Accepted: 06/27/2008] [Indexed: 01/11/2023]
Abstract
BACKGROUND In Roux-Y gastric bypass surgery pouch formation is the most demanding part of the operation. The vagal nerve is usually tempted to be preserved although results reporting beneficial effects are lacking. Dividing the perigastric tissue including the anterior vagal trunk may technically alleviate gastric pouch formation. We evaluated the clinical outcome in patients with and without vagal nerve dissection in patients after Roux-Y gastric bypass (RY-BP). METHODS In this study 40 morbidly obese patients undergoing RY-BP have been included. Patients were divided into two groups according to vagal nerve preservation (Group 1, n = 25) or vagal nerve dissection (Group 2, n = 22). Clinical parameters (weight loss, complications, gastrointestinal symptoms), esophageal endoscopy, and motility data (manometry, pH-metry) and a satiety score were assessed. Serum values of ghrelin and gastrin were measured. RESULTS All procedures were performed by laparoscopy with a 0% mortality rate. One patient of each groups necessitated redo-laparoscopy (bleeding and a lost drainage). All patients significantly reduced body weight (p < 0.01 compared to preoperative) during a median follow-up of 36.1 months. Two patients of Group 2 showed acid reflux demonstrated by pathologic postoperative DeMeester scores. Esophageal body peristalsis and barium swallows did not reveal statistically significant differences between the two groups. Parameters of satiety assessment did not differ between the two groups as did serum values of gastrin and ghrelin. CONCLUSION Pouch formation during RY-BP may be alleviated by simply dissecting the perigastric fatty tissue. In this way the anterior vagal trunk is dissected, however, no influence on clinical, functional and laboratory results occur.
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Affiliation(s)
- A Perathoner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
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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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Vila G, Maier C, Riedl M, Nowotny P, Ludvik B, Luger A, Clodi M. Bacterial endotoxin induces biphasic changes in plasma ghrelin in healthy humans. J Clin Endocrinol Metab 2007; 92:3930-4. [PMID: 17666475 DOI: 10.1210/jc.2007-1194] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
CONTEXT Ghrelin is a gut hormone with a highly preserved biological activity, which seems not to be restricted to the regulation of food intake, body composition, and growth. Continuous research is unraveling new properties of ghrelin, among others cardiovascular and antiinflammatory activities. Ghrelin is recently implicated in the host response to bacterial endotoxin in rodents and suggested as a possible therapeutic tool in sepsis. OBJECTIVE This study aimed to investigate plasma ghrelin levels during human bacterial endotoxemia. DESIGN AND SETTING We conducted a randomized, placebocontrolled, crossover clinical trial at a university medical center. STUDY PARTICIPANTS Participants included 10 healthy men. INTERVENTION After an overnight fast, study subjects were randomized to 2 ng/kg Escherichia coli endotoxin [lipopolysaccharide (LPS)] or placebo and monitored for 6 h. MAIN OUTCOME MEASURES We measured ghrelin, GH, ACTH, cortisol, glucose, free fatty acids, TNF-alpha, IL-6, and IL-1 receptor antagonist. RESULTS LPS administration induced a rapid ghrelin surge at 120 min (Delta ghrelin 100.2 +/- 30.3 vs. 7.2 +/- 26.4 pg/ml on the placebo day, P = 0.042). This ghrelin peak occurred 30 min after the TNF-alpha peak and corresponded with IL-6, GH, and ACTH peaks. Starting from 120 min and thereafter, ghrelin continuously decreased, reaching a nadir at 5 h after LPS administration (Delta ghrelin, -43.8 +/- 28.4 compared with 70.3 +/- 38.2 pg/ml on the control days, P = 0.038). CONCLUSIONS Ghrelin is one of the first hormones rapidly increasing in the human physiological response to bacterial endotoxic shock. Plasma ghrelin might be part of the complex immuno-neuroendocrine mechanisms activated by systemic infection and inflammation in humans.
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Affiliation(s)
- Greisa Vila
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, A-1090, Vienna, Austria
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Sundbom M, Holdstock C, Engström BE, Karlsson FA. Early changes in ghrelin following Roux-en-Y gastric bypass: influence of vagal nerve functionality? Obes Surg 2007; 17:304-10. [PMID: 17546836 DOI: 10.1007/s11695-007-9056-8] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Roux-en-Y gastric bypass (RYGBP) effectively produces massive weight reduction, improving health in morbidly obese patients. The mechanisms for the weight loss, and the fate of the excluded gastric mucosa, are not fully clarified. To what extent the appetite-stimulating gastric peptide ghrelin is affected remains controversial. METHODS Circulating concentrations of ghrelin, pancreatic polypeptide (PP), pepsinogen I (PGI) and gastrin were examined in 15 morbidly obese patients (median BMI 45 kg/m2) preoperatively, and on days 1, 2, 4, 6 and at months 1, 6 and 12 after RYGBP. RESULTS Ghrelin levels fell on postoperative day 1 and increased after 1 month to preoperative levels, and rose further at 6 and 12 months. PP concentrations decreased on day 1 and subsequently returned to preoperative levels. PGI levels peaked transiently the first days after surgery and subsequently declined to lower than preoperative levels. Gastrin levels were gradually reduced postoperatively. CONCLUSION Ghrelin and PP fall transiently after surgery, possibly due to vagal dysfunction, and ultimately, as weight loss ensues, ghrelin secretion increases to higher than preoperative levels. The RYBGP procedure affects the gastric mucosa, as reflected by a transient increase in circulating PGI, and subsequently, the mucosa in the excluded stomach is at rest, as shown by low levels of PGI and gastrin.
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Affiliation(s)
- Magnus Sundbom
- Department of Surgery, University Hospital, S-751 85 Uppsala, Sweden.
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de la Cour CD, Norlén P, Håkanson R. Secretion of ghrelin from rat stomach ghrelin cells in response to local microinfusion of candidate messenger compounds: a microdialysis study. ACTA ACUST UNITED AC 2007; 143:118-26. [PMID: 17573135 DOI: 10.1016/j.regpep.2007.05.001] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2006] [Revised: 04/25/2007] [Accepted: 05/01/2007] [Indexed: 12/12/2022]
Abstract
Ghrelin is produced by A-like cells (ghrelin cells) in the mucosa of the acid-producing part of the stomach. The mobilization of ghrelin is stimulated by nutritional deficiency and suppressed by nutritional abundance. In an attempt to identify neurotransmitters and regulatory peptides that may contribute to the physiological, nutrient-related regulation of ghrelin secretion, we challenged the ghrelin cells in situ with a wide variety of candidate messengers, including known neurotransmitters (e.g. acetylcholine, catecholamines), candidate neurotransmitters (e.g. neuropeptides), local tissue hormones (e.g. serotonin, histamine, bradykinin, endothelin), circulating gut hormones (e.g. gastrin, CCK, GIP, neurotensin, PYY, secretin) and other circulating hormones/regulatory peptides (e.g. calcitonin, glucagon, insulin, PTH). Microdialysis probes were placed in the submucosa of the acid-producing part of the rat stomach. Three days later, the putative messenger compounds were administered via the microdialysis probe (reverse microdialysis) at a screening dose of 0.1 mmol l(-1) for regulatory peptides and 0.1 and 1 mmol l(-1) for amines and amino acids. The rats were awake during the experiments. The resulting microdialysate ghrelin concentration was monitored continuously for 3 h (radioimmunoassay), thereby revealing stimulators or inhibitors of ghrelin secretion. Dose-response curves were constructed for each candidate messenger that significantly (p<0.05) affected ghrelin mobilization at the screening dose. Peptides that showed a (non-significant) tendency to affect ghrelin release at the screening dose were also given at a dose of 0.3 or 1 mmol l(-1). Adrenaline, noradrenaline, endothelin and secretin stimulated ghrelin release, while somatostatin and GRP inhibited. Whether these agents act directly or indirectly on the ghrelin cells remains to be investigated. All other candidate messengers were without measurable effects, including acetylcholine, serotonin, histamine, GABA, aspartic acid, glutamic acid, glycine, VIP, PACAP, CGRP, substance P, NPY, PYY, PP, gastrin, CCK, GIP, insulin, glucagon, GLP and glucose.
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Abstract
In the current review we summarize the available data concerning the gastric hormone ghrelin and its receptor. Ghrelin stimulates short-term food intake and long-term body weight regulation via its adipogenic and diabetogenic effects. Ghrelin stimulates gastric emptying, and these effects could be explored from a therapeutic point of view. Ghrelin levels change profoundly in anorexia, in states of insulin resistance, in obesity, and after bariatric surgery, suggesting that this is an important hormone in body weight regulation.
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Affiliation(s)
- Susie C Higgins
- Department of Endocrinology, Barts and the London Medical School, London, UK
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Dimaraki EV, Jaffe CA. Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism. Rev Endocr Metab Disord 2006; 7:237-49. [PMID: 17195943 DOI: 10.1007/s11154-006-9022-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Ghrelin, a 28-amino acid hormone that is acylated post-translation, is the endogenous ligand for the growth hormone (GH) secretagogue (GHS) receptor (GHS-R). The highest concentrations of ghrelin are found in the stomach; however ghrelin peptide is also present in hypothalamic nuclei known to be important in the control of GH and feeding behavior. Exogenous ghrelin potently stimulates pituitary GH release through a mechanism that is dependent, in part, on endogenous GH-releasing hormone. Whether endogenous ghrelin plays a role in the control of GH secretion and growth is not clear and ghrelin deficient animals appear to grow normally. In contrast, experimental animal and clinical data suggest that abnormalities in GHS-R signaling could impact growth. Ghrelin or other GHS are clinically useful for GH-testing and limited data suggest that they might be useful in the treatment of some patients with GH deficiency. Substantial data have implicated ghrelin as an important regulator of feeding behavior and energy equilibrium. Ghrelin has a potent orexigenic effect in both animals and humans and this effect is mediated through hypothalamic neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Appetite simulation coupled with other metabolic effects promotes weight gain during chronic treatment with ghrelin. These metabolic effects are in part mediated through an increase in respiratory quotient (VQ). Presence of ghrelin appears to be necessary for the development of obesity in some animal models. Whether abnormalities in ghrelin signaling are involved in human obesity is not yet known.
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Affiliation(s)
- Eleni V Dimaraki
- Department of Medicine, Division of Endocrinology and Metabolic Diseases, Evanston Northwestern Healthcare and Northwestern University Feinberg School of Medicine, Evanston, IL 60201, USA
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Engström BE, Ohrvall M, Sundbom M, Lind L, Karlsson FA. Meal suppression of circulating ghrelin is normalized in obese individuals following gastric bypass surgery. Int J Obes (Lond) 2006; 31:476-80. [PMID: 16924271 DOI: 10.1038/sj.ijo.0803440] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE It has been proposed that the success of maintained weight loss in morbidly obese subjects following Roux-en-Y gastric bypass (RYGBP) surgery depends on inappropriately low circulating concentrations of the appetite-stimulating peptide ghrelin, being unresponsive to food intake. In this study, this hypothesis was examined. DESIGN Cross-sectional study with repeated blood samples in 40 subjects after 14 h of prolonged overnight fasting followed by a standardized mixed meal (770 kcal). SUBJECTS Twenty men and 20 women were included: 10 middle-aged morbidly obese (body mass index (BMI) 43.9+/-3.3 kg/m(2)), 10 middle-aged subjects who had undergone RYGBP at the Uppsala University Hospital (BMI 34.7+/-5.8 kg/m(2)), 10 middle-aged non-obese (BMI 23.5+/-2.2 kg/m(2)) and 10 young non-obese (BMI 22.7+/-1.8 kg/m(2)). MEASUREMENTS Ghrelin, glucose and insulin levels were analysed pre- and postprandially. RESULTS In the morbidly obese, ghrelin concentrations were lower in the morning than in the RYGBP group and did not change following the meal. In the RYGBP group, fasting ghrelin levels fell after meal intake and showed similar suppression as both age-matched and young non-obese controls. The RYGBP surgery resulted in an increased meal-induced insulin secretion, which was related to the degree of postprandial ghrelin suppression. CONCLUSION The present study demonstrates low circulating concentrations of ghrelin and blunted responses to fast and feeding in morbidly obese subjects. Marked weight reduction after RYGBP at our hospital is followed by a normalization of ghrelin secretion, illustrated by increased fasting levels compared to the preoperative obese state and regain of meal-induced ghrelin suppression.
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Affiliation(s)
- B E Engström
- Department of Medical Sciences, Internal Medicine, University Hospital, Uppsala, Sweden.
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Lengyel AMJ. Novel mechanisms of growth hormone regulation: growth hormone-releasing peptides and ghrelin. Braz J Med Biol Res 2006; 39:1003-11. [PMID: 16906274 DOI: 10.1590/s0100-879x2006000800002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2005] [Accepted: 05/29/2006] [Indexed: 01/08/2023] Open
Abstract
Growth hormone secretion is classically modulated by two hypothalamic hormones, growth hormone-releasing hormone and somatostatin. A third pathway was proposed in the last decade, which involves the growth hormone secretagogues. Ghrelin is a novel acylated peptide which is produced mainly by the stomach. It is also synthesized in the hypothalamus and is present in several other tissues. This endogenous growth hormone secretagogue was discovered by reverse pharmacology when a group of synthetic growth hormone-releasing compounds was initially produced, leading to the isolation of an orphan receptor and, finally, to its endogenous ligand. Ghrelin binds to an active receptor to increase growth hormone release and food intake. It is still not known how hypothalamic and circulating ghrelin is involved in the control of growth hormone release. Endogenous ghrelin might act to amplify the basic pattern of growth hormone secretion, optimizing somatotroph responsiveness to growth hormone-releasing hormone. It may activate multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, since ghrelin has a greater ability to release growth hormone in vivo, its main site of action is the hypothalamus. In the current review we summarize the available data on the: a) discovery of this peptide, b) mechanisms of action of growth hormone secretagogues and ghrelin and possible physiological role on growth hormone modulation, and c) regulation of growth hormone release in man after intravenous administration of these peptides.
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Affiliation(s)
- A-M J Lengyel
- Divisão de Endocrinologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.
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Lengyel AMJ. From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion. ACTA ACUST UNITED AC 2006; 50:17-24. [PMID: 16628271 DOI: 10.1590/s0004-27302006000100004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Growth hormone (GH)-releasing hormone and somatostatin modulate GH secretion. A third mechanism has been discovered in the last decade, involving the action of GH secretagogues. Ghrelin is a new acylated peptide produced mainly by the stomach, but also synthesized in the hypothalamus. This compound increases both GH release and food intake. The relative roles of hypothalamic and circulating ghrelin on GH secretion are still unknown. Endogenous ghrelin might amplify the basic pattern of GH secretion, optimizing somatotroph responsiveness to GH-releasing hormone. This peptide activates multiple interdependent intracellular pathways at the somatotroph, involving protein kinase C, protein kinase A and extracellular calcium systems. However, as ghrelin induces a greater release of GH in vivo, its main site of action is the hypothalamus. In this paper we review the available data on the discovery of ghrelin, the mechanisms of action and possible physiological roles of GH secretagogues and ghrelin on GH secretion, and, finally, the regulation of GH release in man after intravenous administration of these peptides.
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Affiliation(s)
- Ana Maria J Lengyel
- Division of Endocrinology, Federal University of São Paulo (UNIFESP/EPM), São Paulo, Brazil.
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Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 2006; 494:528-48. [PMID: 16320257 PMCID: PMC4524499 DOI: 10.1002/cne.20823] [Citation(s) in RCA: 806] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Ghrelin is a hormone that stimulates growth hormone secretion and signals energy insufficiency via interaction with its receptor, the growth hormone secretagogue receptor (GHSR). The GHSR is located in both the central nervous system and the periphery. Its distribution in the CNS, as assessed by in situ hybridization histochemistry (ISHH), has been described previously in a few mammalian species, although these studies were limited by either the detail provided or the extent of the regions examined. In the present study, we systematically examined the distribution of GHSR mRNA in the adult rat and mouse brains and cervical spinal cords by using ISHH with novel cRNA probes specific for the mRNA encoding functional GHSR (the type 1a variant). We confirmed GHSR mRNA expression in several hypothalamic nuclei, many of which have long been recognized as playing roles in body weight and food intake. GHSR also was found in several other regions previously unknown to express GHSR mRNA, including many parasympathetic preganglionic neurons. Additionally, we found GHSR mRNA within all three components of the dorsal vagal complex, including the area postrema, the nucleus of the solitary tract, and the dorsal motor nucleus of the vagus. Finally, we examined the coexpression of GHSR with tyrosine hydroxylase and cholecystokinin and demonstrate a high degree of GHSR mRNA expression within dopaminergic, cholecystokinin-containing neurons of the substantia nigra and ventral tegmental area.
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Affiliation(s)
- Jeffrey M Zigman
- Department of Medicine and Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
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