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Integrative Physiology of Ghrelin and Synthetic GH Secretagogues

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2019) | Viewed by 58867

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Prof. Dr. Chen Chen

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Endocrinology and Metabolism Group (Chen Lab), School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia
Interests: ion channels; growth hormone; insulin; ghrelin; diabetes; obesity

Special Issue Information

Dear Colleagues,

In parallel with the discovery of hypothalamic growth hormone-releasing hormone (GHRH), a series of synthetic peptides, called GH-releasing peptides (GHRP), were also found to release GH from the pituitary gland. The receptors and signaling systems for GHRH and GHRP are different, but cross-talk with each other to regulate GH secretion. Both GHRH and GHRP receptors have been identified as G-protein coupled receptors (GPCR) in pituitary GH secreting somatotrophs. Ghrelin was discovered in searching for endogenous GHRP or GH secretagogues (GHS) from stomach endocrine cells. The ghrelin receptor or GHS receptor (GHSR) distributes widely in almost all tissues, indicating multiple functions for this hormone. Indeed, in addition to stimulating pituitary GH secretion, ghrelin has been linked to regulating the functions of brain, heart, pancreatic islets, and respiratory and digestive systems. Ghrelin may play a role in the pathophysiologies of obesity, diabetes, heart failure, asthma, and several endocrine-related cancers. This Special Issue would like to bring up the most recent discoveries in ghrelin action on different systems and aims to summarize possible physiological, pathophysiological and therapeutic roles of ghrelin and synthetic GHS. Potential research directions will also be discussed to provide possible leads for future research of ghrelin and its analogues.

Prof. Dr. Chen Chen
Guest Editor

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Keywords

Ghrelin
GHS
GHSR
Eating
Obesity
Diabetes
Secretion
Contraction
Inflammation
Apoptosis

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Related Special Issue

Neurobiological Perspectives on Ghrelin in International Journal of Molecular Sciences (16 articles)

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Research

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12 pages, 1517 KiB

Open AccessArticle

Glucagon-Like Peptide-1 (GLP-1) and 5-Hydroxytryptamine 2c (5-HT_2c) Receptor Agonists in the Ventral Tegmental Area (VTA) Inhibit Ghrelin-Stimulated Appetitive Reward

by Erin Howell, Hannah M. Baumgartner, Lia J. Zallar, Joaquín A. Selva, Liv Engel and Paul J. Currie

Int. J. Mol. Sci. 2019, 20(4), 889; https://doi.org/10.3390/ijms20040889 - 19 Feb 2019

Cited by 22 | Viewed by 5843

Abstract

Current literature indicates that the orexigenic peptide ghrelin increases appetitive motivation via signaling in the mesolimbic reward system. Another gastric peptide, glucagon-like peptide-1 (GLP-1), and the neurotransmitter 5-hydroxytryptamine (5-HT), are both known to suppress operant responding for food by acting on key mesolimbic nuclei, including the ventral tegmental area (VTA). In order to investigate the interaction effects of ghrelin, GLP-1, and 5-HT within the VTA, we measured operant responding for sucrose pellets after the administration of ghrelin, the GLP-1 receptor agonist exendin-4 (Ex-4), and the 5-HT_2c receptor agonist Ro60-0175 in male Sprague-Dawley rats. Following training on a progressive ratio 3 (PR3) schedule, animals were first injected with ghrelin into the VTA at doses of 3 to 300 pmol. In subsequent testing, separate rats were administered intraperitoneal (IP) Ex-4 (0.1–1.0 µg/kg) or VTA Ex-4 (0.01–0.1 µg) paired with 300 pmol ghrelin. In a final group of rats, the 5-HT_2c agonist Ro60-0175 was injected IP (0.25–1.0 mg/kg) or into the VTA (1.5–3.0 µg), and under both conditions paired with 300 pmol ghrelin delivered into the VTA. Our results indicated that ghrelin administration increased operant responding for food reward and that this effect was attenuated by IP and VTA Ex-4 pretreatment as well as pre-administration of IP or VTA Ro60-0175. These data provide compelling evidence that mesolimbic GLP-1 and serotonergic circuitry interact with the ghrelinergic system to suppress ghrelin’s effects on the mediation of food reinforcement. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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13 pages, 4225 KiB

Open AccessArticle

Ghrelin Restores the Disruption of the Circadian Clock in Steatotic Liver

by Qin Wang, Yue Yin and Weizhen Zhang

Int. J. Mol. Sci. 2018, 19(10), 3134; https://doi.org/10.3390/ijms19103134 - 12 Oct 2018

Cited by 29 | Viewed by 4797

Abstract

Obese mice demonstrate disruption of the circadian clock and feeding cycle. Circulating ghrelin, a hormone secreted mainly by gastric X/Alike cells, is significantly reduced in obese humans and animals. Here, we examined whether ghrelin improves the disruption of the circadian rhythm in steatotic hepatocytes and liver. The effects of ghrelin on hepatic circadian clock genes were studied in steatotic hepatocytes and liver of mice fed a high-fat diet (HFD) for 12 weeks. The circadian clock of cultured hepatocytes was synchronized by treatment with 100 nM dexamethasone for 1 h. Ghrelin was administrated to the cultured hepatocytes (10⁻⁸ M) or to mice at a dose of 11 nmol/kg/d for two weeks via a subcutaneous minipump. The mRNA and protein levels of core clock genes were analyzed. Steatosis significantly blunted the circadian pattern of clock genes such as Bmal1, Clock, and Per in cultured hepatocytes and liver. Treatment with ghrelin markedly restored the daily rhythm of the clock genes, with a robust oscillation between peak and trough in cultured hepatocytes isolated from obese mice. It also increased the abundance and expression amplitude of clock genes in steatotic liver, causing the peak of Clock to shift to the dark period and the peak of Per2 to shift to the light period compared with the control groups. Deletion of GHSR1a further deteriorated the derangement of clock gene patterns in obese mice. Ghrelin significantly increased the oscillations of mTOR/S6 signaling. We demonstrate that ghrelin restored the derangement of the circadian rhythm in steatotic liver via mTOR signaling. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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11 pages, 1531 KiB

Open AccessArticle

Enhanced Pulsatile Growth Hormone Secretion and Altered Metabolic Hormones by in Vivo Hexarelin Treatment in Streptozotocin-Induced Diabetic Rats

by Xinli Zhang, Jin-Kui Yang and Chen Chen

Int. J. Mol. Sci. 2018, 19(10), 3067; https://doi.org/10.3390/ijms19103067 - 8 Oct 2018

Cited by 4 | Viewed by 4708

Abstract

Significant growth hormone (GH) reductions have been reported in diabetic animal models with disturbed metabolic balance coinciding with GH deficiency. Therefore, enhanced GH secretion may have beneficial effects in controlling diabetes. Thus, we aim to investigate the effect of hexarelin, a synthetic GH secretagogue (GHS), on GH secretion in streptozotocin (STZ, 65 mg/kg)-induced diabetic rats. Daily hexarelin (100 μg/kg) treatment was performed for two weeks in four-week-long STZ-diabetic and vehicle control rats. Pulsatile GH secretion in STZ-rats was significantly reduced in total, pulsatile, basal, and mass of GH secretion per burst. In addition, impaired GH secretion was followed by an increase in fasting-level free fatty acids (FFAs) and a decrease in insulin-like growth factor 1 (IGF-1) compared to control rats. After hexarelin treatment, pulsatile GH secretion in STZ-rats was significantly increased in total, pulsatile, and basal, but not in the mass GH secretion per burst, compared to STZ-rats without hexarelin treatment. However, there was no significant elevation in GH secretion in the hexarelin-treated control group. In addition, hexarelin-treated STZ-rats showed a significant decrease in fasting level FFAs, whereas suppression of fasting level for IGF-1 was maintained. These results suggest that STZ-induced diabetic rats have impaired pulsatile GH secretion, causing increased FFAs and decreased IGF-1 levels in circulation. Hexarelin injections for two weeks is able to normalize impaired pulsatile GH secretion with normal fasting levels of FFAs, but fails to recover IGF-1 levels. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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16 pages, 2483 KiB

Open AccessArticle

aP2-Cre Mediated Ablation of GHS-R Attenuates Adiposity and Improves Insulin Sensitivity during Aging

by Ligen Lin, Jong Han Lee, Ruitao Wang, Ru Wang, David Sheikh‐Hamad, Qun S. Zang and Yuxiang Sun

Int. J. Mol. Sci. 2018, 19(10), 3002; https://doi.org/10.3390/ijms19103002 - 1 Oct 2018

Cited by 11 | Viewed by 4446

Abstract

Ghrelin via its receptor, the growth hormone secretagogue receptor (GHS-R), increases food intake and adiposity. The tissue-specific functions of GHS-R in peripheral tissues are mostly unknown. We previously reported that while GHS-R expression is very low in white and brown fat of young mice, expression increases during aging. To investigate whether GHS-R has cell-autonomous effects in adipose tissues, we generated aP2-Cre-mediated GHS-R knockdown mice (aP2-Cre/Ghsr^f/f). We studied young (5–6 months) and old (15–17 months) aP2-Cre/Ghsr^f/f mice and their age-matched controls. Interestingly, young aP2-Cre/Ghsr^f/f mice had normal body weight but reduced fat; old mice showed pronounced reductions of both body weight and body fat. Calorimetry analysis revealed that aP2-Cre/Ghsr^f/f mice had normal food intake and locomotor activity at both young and old age; but intriguingly, while energy expenditure was normal at young age, it was significantly increased at old age. Both young and old aP2-Cre/Ghsr^f/f mice exhibited improved insulin sensitivity and glucose tolerance. Importantly, old aP2-Cre/Ghsr^f/f mice maintained higher core body temperature at 4 °C, and showed higher expression of the thermogenic uncoupling protein 1 (UCP1) gene. The ex vivo studies further demonstrated that GHS-R deficient white adipocytes from old mice exhibit increased glucose uptake and lipolysis, promoting lipid mobilization. Despite the fact that the in vivo phenotypes of aP2-Cre/Ghsr^f/f mice may not be exclusively determined by GHS-R knockdown in adipose tissues, our data support that GHS-R has cell-autonomous effects in adipocytes. The anabolic effect of GHS-R in adipocytes is more pronounced in aging, which likely contributes to age-associated obesity and insulin resistance. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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22 pages, 2770 KiB

Open AccessArticle

Ghrelin Receptor Antagonism of Methamphetamine-Induced Conditioned Place Preference and Intravenous Self-Administration in Rats

by Tereza Havlickova, Chrysostomos Charalambous, Marek Lapka, Nina Puskina, Pavel Jerabek and Magdalena Sustkova-Fiserova

Int. J. Mol. Sci. 2018, 19(10), 2925; https://doi.org/10.3390/ijms19102925 - 26 Sep 2018

Cited by 22 | Viewed by 4087

Abstract

Methamphetamine abuse imposes a significant burden on individuals and society worldwide, and an effective therapy of methamphetamine addiction would provide distinguished social benefits. Ghrelin significantly participates in reinforcing neurobiological mechanisms of stimulants, including amphetamines; thus, ghrelin antagonism is proposed as a promising addiction treatment. The aim of our study was to elucidate whether the pretreatment with growth hormone secretagogue receptor (GHS-R1A) antagonist, substance JMV2959, could reduce the methamphetamine intravenous self-administration (IVSA) and the tendency to relapse, and whether JMV2959 could reduce or prevent methamphetamine-induced conditioned place preference (CPP) in rats. Following an adequate maintenance period, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 180 min sessions of methamphetamine IVSA under a fixed ratio FR1, which significantly reduced the number of active lever-pressings, the number of infusions, and the amount of the consumed methamphetamine dose. Pretreatment with JMV2959 also reduced or prevented relapse-like behavior tested in rats on the 12th day of the abstinence period. Pretreatment with JMV2959 significantly reduced the expression of methamphetamine-induced CPP. Simultaneous administration of JMV2959 with methamphetamine during the conditioning period significantly reduced the methamphetamine-CPP. Our results encourage further research of the ghrelin antagonism as a potential new pharmacological tool for methamphetamine addiction treatment. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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14 pages, 4402 KiB

Open AccessArticle

Ghrelin Stimulates Endothelial Cells Angiogenesis through Extracellular Regulated Protein Kinases (ERK) Signaling Pathway

by Jun Wang, Lin He, Bahetiyaer Huwatibieke, Lingchao Liu, He Lan, Jing Zhao, Yin Li and Weizhen Zhang

Int. J. Mol. Sci. 2018, 19(9), 2530; https://doi.org/10.3390/ijms19092530 - 26 Aug 2018

Cited by 12 | Viewed by 3869

Abstract

Adipose tissue is hyper-vascularized. Vessels in adipose tissue not only supply nutrients and oxygen to nourish adipocytes, but also provide cytokines that regulate mass and function of adipose tissue. Understanding the fundamental mechanisms how vessels modulate adipocyte functions would provide new therapeutic options for treatment of metabolic disease and obesity. In recent years, researches about ghrelin are focused on glucose and lipid metabolism, but its effect on vascular function remains uncharacterized. In the present study, ghrelin receptor gene deletion mice (Ghsr^−/− mice) were used to study ghrelin-regulated vascular metabolism in white adipose tissue. Ghsr^−/− mice demonstrated lower food intake, lower body weight, and resistance to high-fat diet-induced obesity. The number of vessels in white adipose tissue was decreased in Ghsr^−/− mice when compared with wild type mice fed with high-fat diet. To further define ghrelin effects in vitro, we used endothelial progenitor cells from wild type and Ghsr^−/− mice as well as human umbilical vein endothelial cells in our experiments. We found that ghrelin stimulated endothelial cells angiogenesis and migration through the MEK-ERK signaling pathway. [d-Lys3]-GHRP-6 and PD98059 could reverse the effects of ghrelin on endothelial cells. Our study indicates that ghrelin activates its receptor on endothelial cells to promote angiogenesis and migration via a mechanism involving the extracellular regulated protein kinases (ERK) signaling pathway. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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17 pages, 5671 KiB

Open AccessArticle

Treatment with Obestatin—A Ghrelin Gene-Encoded Peptide—Reduces the Severity of Experimental Colitis Evoked by Trinitrobenzene Sulfonic Acid

by Katarzyna Konarska, Jakub Cieszkowski, Zygmunt Warzecha, Piotr Ceranowicz, Anna Chmura, Beata Kuśnierz-Cabala, Krystyna Gałązka, Paweł Kowalczyk, Andrzej Miskiewicz, Thomas Jan Konturek, Michał Pędziwiatr and Artur Dembiński

Int. J. Mol. Sci. 2018, 19(6), 1643; https://doi.org/10.3390/ijms19061643 - 1 Jun 2018

Cited by 28 | Viewed by 4576

Abstract

Obestatin is a 23-amino acid peptide derived from proghrelin, a common prohormone for ghrelin and obestatin. Previous studies showed that obestatin exhibited some protective and therapeutic effects in the gut. The aim of our presented study was to examine the effect of treatment with obestatin on trinitrobenzene sulfonic acid (TNBS)-induced colitis. In rats anesthetized with ketamine, colitis was induced through intrarectal administration of 25 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Obestatin was administered intraperitoneally at doses of 4, 8, or 16 nmol/kg, twice per day for four consecutive days. The first dose of obestatin was given one day before the induction of colitis, and the last one was given two days after administration of TNBS. Fourteen days after the induction of colitis, rats were anesthetized again with ketamine, and the severity of colitis was determined. The administration of obestatin had no effect on the parameters tested in rats without the induction of colitis. In rats with colitis, administration of obestatin at doses of 8 or 16 nmol/kg reduced the area of colonic damage, and improved mucosal blood flow in the colon. These effects were accompanied by a reduction in the colitis-evoked increase in the level of blood leukocytes, and mucosal concentration of pro-inflammatory interleukin-1β. Moreover, obestatin administered at doses of 8 or 16 nmol/kg reduced histological signs of colonic damage. The administration of obestatin at a dose of 4 nmol/kg failed to significantly affect the parameters tested. Overall, treatment with obestatin reduced the severity of TNBS-induced colitis in rats. This effect was associated with an improvement in mucosal blood flow in the colon, and a decrease in local and systemic inflammatory processes. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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15 pages, 2014 KiB

Open AccessArticle

Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia

by Cristina Torres-Fuentes, Elena Pastor-Cavada, Rafael Cano, Dalia Kandil, Rachel Shanahan, Rocio Juan, Hamdy Shaban, Gerard P. McGlacken and Harriët Schellekens

Int. J. Mol. Sci. 2018, 19(6), 1605; https://doi.org/10.3390/ijms19061605 - 30 May 2018

Cited by 10 | Viewed by 7383

Abstract

Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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Review

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16 pages, 998 KiB

Open AccessReview

Efficacy of Anamorelin, a Novel Non-Peptide Ghrelin Analogue, in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) and Cachexia—Review and Expert Opinion

by David C. Currow, Matthew Maddocks, David Cella and Maurizio Muscaritoli

Int. J. Mol. Sci. 2018, 19(11), 3471; https://doi.org/10.3390/ijms19113471 - 5 Nov 2018

Cited by 23 | Viewed by 6811

Abstract

Cancer cachexia is a multilayered syndrome consisting of the interaction between tumor cells and the host, at times modulated by the pharmacologic treatments used for tumor control. Key cellular and soluble mediators, activated because of this interaction, induce metabolic and nutritional alterations. This results in mass and functional changes systemically, and can lead to increased morbidity and reduced length and quality of life. For most solid malignancies, a cure remains an unrealistic goal, and targeting the key mediators is ineffective because of their heterogeneity/redundancy. The most beneficial approach is to target underlying systemic mechanisms, an approach where the novel non-peptide ghrelin analogue anamorelin has the advantage of stimulating appetite and possibly food intake, as well as promoting anabolism and significant muscle mass gain. In the ROMANA studies, compared with placebo, anamorelin significantly increased lean body mass in non-small cell lung cancer (NSCLC) patients. Body composition analysis suggested that anamorelin is an active anabolic agent in patients with NSCLC, without the side effects of other anabolic drugs. Anamorelin also induced a significant and meaningful improvement of anorexia/cachexia symptoms. The ROMANA trials have provided unprecedented knowledge, highlighting the therapeutic effects of anamorelin as an initial, but significant, step toward directly managing cancer cachexia. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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16 pages, 1984 KiB

Open AccessReview

The Role of Ghrelin in Anorexia Nervosa

by Martha A. Schalla and Andreas Stengel

Int. J. Mol. Sci. 2018, 19(7), 2117; https://doi.org/10.3390/ijms19072117 - 20 Jul 2018

Cited by 55 | Viewed by 11395

Abstract

Ghrelin, a 28-amino acid peptide hormone expressed in X/A-like endocrine cells of the stomach, is the only known peripherally produced and centrally acting peptide that stimulates food intake and therefore attracted a lot of attention with one major focus on the treatment of conditions where an increased energy intake or body weight gain is desired. Anorexia nervosa is an eating disorder characterized by a pronounced reduction of body weight, a disturbed body image and hormonal alterations. Ghrelin signaling has been thoroughly investigated under conditions of anorexia nervosa. The present review will highlight these alterations of ghrelin in anorexia and discuss possible treatment strategies targeting ghrelin signaling. Lastly, gaps in knowledge will be mentioned to foster future research. Full article

(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)

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