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Open AccessArticle

Ghrelin Therapy Decreases Incidents of Intracranial Hemorrhage in Mice after Whole-Body Ionizing Irradiation Combined with Burn Trauma

by Nikolai V. Gorbunov and Juliann G. Kiang

Int. J. Mol. Sci. 2017, 18(8), 1693; https://doi.org/10.3390/ijms18081693 - 3 Aug 2017

Cited by 21 | Viewed by 4324

Abstract

Nuclear industrial accidents and the detonation of nuclear devices cause a variety of damaging factors which, when their impacts are combined, produce complicated injuries challenging for medical treatment. Thus, trauma following acute ionizing irradiation (IR) can deteriorate the IR-induced secondary reactive metabolic and [...] Read more.

Nuclear industrial accidents and the detonation of nuclear devices cause a variety of damaging factors which, when their impacts are combined, produce complicated injuries challenging for medical treatment. Thus, trauma following acute ionizing irradiation (IR) can deteriorate the IR-induced secondary reactive metabolic and inflammatory impacts to dose-limiting tissues, such as bone marrow/lymphatic, gastrointestinal tissues, and vascular endothelial tissues, exacerbating the severity of the primary injury and decreasing survival from the exposure. Previously we first reported that ghrelin therapy effectively improved survival by mitigating leukocytopenia, thrombocytopenia, and bone-marrow injury resulting from radiation combined with burn trauma. This study was aimed at investigating whether radiation combined with burn trauma induced the cerebro-vascular impairment and intracranial hemorrhage that could be reversed by ghrelin therapy. When B6D2F1 female mice were exposed to 9.5 Gy Cobalt-60 γ-radiation followed by 15% total skin surface burn, cerebro-vascular impairment and intracranial hemorrhage as well as platelet depletion were observed. Ghrelin treatment after irradiation combined with burn trauma significantly decreased platelet depletion and brain hemorrhage. The results suggest that ghrelin treatment is an effective therapy for ionizing radiation combined with burn trauma. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Open AccessArticle

Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors

by Fabienne O. Villars, Claudio Pietra, Claudio Giuliano, Thomas A. Lutz and Thomas Riediger

Int. J. Mol. Sci. 2017, 18(5), 986; https://doi.org/10.3390/ijms18050986 - 5 May 2017

Cited by 30 | Viewed by 7294

Abstract

The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing [...] Read more.

The gastrointestinal hormone ghrelin reduces energy expenditure and stimulates food intake. Ghrelin analogs are a possible treatment against cancer anorexia-cachexia syndrome (CACS). This study aimed to investigate whether oral treatment with the non-peptidergic ghrelin receptor agonist HM01 counteracts CACS in colon-26 (C26) tumor-bearing mice. The C26 tumor model is characterized by pronounced body weight (BW) loss and muscle wasting in the absence of severe anorexia. We analyzed the time course of BW loss, body composition, muscle mass, bone mineral density, and the cytokines interleukin-6 (IL-6) and macrophage-inhibitory cytokine-1 (MIC-1). Moreover, we measured the expression of the muscle degradation markers muscle RING-finger-protein-1 (MuRF-1) and muscle atrophy F-box (MAFbx). After tumor inoculation, MIC-1 levels increased earlier than IL-6 and both cytokines were elevated before MuRF-1/MAFbx expression increased. Oral HM01 treatment increased BW, fat mass, and neuronal hypothalamic activity in healthy mice. In tumor-bearing mice, HM01 increased food intake, BW, fat mass, muscle mass, and bone mineral density while it decreased energy expenditure. These effects appeared to be independent of IL-6, MIC-1, MuRF-1 or MAFbx, which were not affected by HM01. Therefore, HM01 counteracts cachectic body weight loss under inflammatory conditions and is a promising compound for the treatment of cancer cachexia in the absence of severe anorexia. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Open AccessArticle

Exploring the Behavioral and Metabolic Phenotype Generated by Re-Introduction of the Ghrelin Receptor in the Ventral Tegmental Area

by Louise J. Skov, Morten Jensen, Søren H. Christiansen, Cecilia Ratner, David P. D. Woldbye and Birgitte Holst

Int. J. Mol. Sci. 2017, 18(5), 914; https://doi.org/10.3390/ijms18050914 - 26 Apr 2017

Cited by 15 | Viewed by 6684

Abstract

Ghrelin receptor (Ghr-R) signaling in neurons of the ventral tegmental area (VTA) can modulate dopaminergic function and the reward-related effects of both palatable foods and drugs of abuse. In this study, we re-introduced the Ghr-R in VTA neurons in Ghr-R knockout mice (Ghr-R [...] Read more.

Ghrelin receptor (Ghr-R) signaling in neurons of the ventral tegmental area (VTA) can modulate dopaminergic function and the reward-related effects of both palatable foods and drugs of abuse. In this study, we re-introduced the Ghr-R in VTA neurons in Ghr-R knockout mice (Ghr-R^VTA mice) to specifically study the importance of the constitutively active Ghr-R for VTA neuronal signaling. Our results showed that re-introduction of the Ghr-R in the VTA had no impact on body weight or food intake under basal conditions. However, during novel environment stress Ghr-R^VTA mice showed increased food intake and energy expenditure compared to Ghr-R knockout mice, demonstrating the significance of Ghr-R signaling in the response to stress. Ghr-R^VTA mice also showed increased cocaine-induced locomotor activity compared to Ghr-R knockout mice, highlighting the importance of ghrelin signaling for the reward-related effects of activation of VTA neurons. Overall, our data suggest that re-introduction of the Ghr-R in the mesolimbic reward system of Ghr-R knockout mice increases the level of activation induced by both cocaine and novelty stress. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Open AccessArticle

Suppression of GHS-R in AgRP Neurons Mitigates Diet-Induced Obesity by Activating Thermogenesis

by Chia-Shan Wu, Odelia Y. N. Bongmba, Jing Yue, Jong Han Lee, Ligen Lin, Kenji Saito, Geetali Pradhan, De-Pei Li, Hui-Lin Pan, Allison Xu, Shaodong Guo, Yong Xu and Yuxiang Sun

Int. J. Mol. Sci. 2017, 18(4), 832; https://doi.org/10.3390/ijms18040832 - 14 Apr 2017

Cited by 43 | Viewed by 10660

Abstract

Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related [...] Read more.

Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (AgRP-Cre;Ghsr^f/f). Our data showed that GHS-R in AgRP neurons is required for ghrelin’s stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Open AccessArticle

Development of Fluorinated Non-Peptidic Ghrelin Receptor Ligands for Potential Use in Molecular Imaging

by Rareş-Petru Moldovan, Sylvia Els-Heindl, Dennis J. Worm, Torsten Kniess, Michael Kluge, Annette G. Beck-Sickinger, Winnie Deuther-Conrad, Ute Krügel and Peter Brust

Int. J. Mol. Sci. 2017, 18(4), 768; https://doi.org/10.3390/ijms18040768 - 5 Apr 2017

Cited by 11 | Viewed by 5296

Abstract

The ghrelin receptor (GhrR) is a widely investigated target in several diseases. However, the current knowledge of its role and distribution in the brain is limited. Recently, the small and non-peptidic compound (S)-6-(4-bromo-2-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one ((S)-9) has [...] Read more.

The ghrelin receptor (GhrR) is a widely investigated target in several diseases. However, the current knowledge of its role and distribution in the brain is limited. Recently, the small and non-peptidic compound (S)-6-(4-bromo-2-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one ((S)-9) has been described as a GhrR ligand with high binding affinity. Here, we describe the synthesis of fluorinated derivatives, the in vitro evaluation of their potency as partial agonists and selectivity at GhrRs, and their physicochemical properties. These results identified compounds (S)-9, (R)-9, and (S)-16 as suitable parent molecules for ¹⁸F-labeled positron emission tomography (PET) radiotracers to enable future investigation of GhrR in the brain. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Open AccessArticle

Caloric Restriction Protects against Lactacystin-Induced Degeneration of Dopamine Neurons Independent of the Ghrelin Receptor

by Jessica Coppens, Eduard Bentea, Jacqueline A. Bayliss, Thomas Demuyser, Laura Walrave, Giulia Albertini, Joeri Van Liefferinge, Lauren Deneyer, Najat Aourz, Ann Van Eeckhaut, Jeanelle Portelli, Zane B. Andrews, Ann Massie, Dimitri De Bundel and Ilse Smolders

Int. J. Mol. Sci. 2017, 18(3), 558; https://doi.org/10.3390/ijms18030558 - 4 Mar 2017

Cited by 6 | Viewed by 5036

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Open AccessArticle

Ghrelin Attenuates Intestinal Barrier Dysfunction Following Intracerebral Hemorrhage in Mice

by Yijun Cheng, Yongxu Wei, Wenlei Yang, Yu Cai, Bin Chen, Guoyuan Yang, Hanbing Shang and Weiguo Zhao

Int. J. Mol. Sci. 2016, 17(12), 2032; https://doi.org/10.3390/ijms17122032 - 6 Dec 2016

Cited by 22 | Viewed by 5638

Abstract

Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier [...] Read more.

Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier dysfunction post-ICH and its possible underlying mechanisms are still unknown. This study was designed to investigate whether ghrelin administration attenuates intestinal barrier dysfunction in experimental ICH using an intrastriatal autologous blood infusion mouse model. Our data showed that treatment with ghrelin markedly attenuated intestinal mucosal injury at both histomorphometric and ultrastructural levels post-ICH. Ghrelin reduced ICH-induced intestinal permeability according to fluorescein isothiocyanate conjugated-dextran (FITC-D) and Evans blue extravasation assays. Concomitantly, the intestinal tight junction-related protein markers, Zonula occludens-1 (ZO-1) and claudin-5 were upregulated by ghrelin post-ICH. Additionally, ghrelin reduced intestinal intercellular adhesion molecule-1 (ICAM-1) expression at the mRNA and protein levels following ICH. Furthermore, ghrelin suppressed the translocation of intestinal endotoxin post-ICH. These changes were accompanied by improved survival rates and an attenuation of body weight loss post-ICH. In conclusion, our results suggest that ghrelin reduced intestinal barrier dysfunction, thereby reducing mortality and weight loss, indicating that ghrelin is a potential therapeutic agent in ICH-induced intestinal barrier dysfunction therapy. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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1409 KiB

Open AccessArticle

Exogenous Ghrelin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats

by Aleksandra Matuszyk, Piotr Ceranowicz, Zygmunt Warzecha, Jakub Cieszkowski, Dagmara Ceranowicz, Krystyna Gałązka, Joanna Bonior, Jolanta Jaworek, Krzysztof Bartuś, Krzysztof Gil, Rafał Olszanecki and Artur Dembiński

Int. J. Mol. Sci. 2016, 17(9), 1455; https://doi.org/10.3390/ijms17091455 - 1 Sep 2016

Cited by 45 | Viewed by 5626

Abstract

Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% [...] Read more.

Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% acetic acid solution led to induction of colitis in all animals. Damage of the colonic wall was accompanied by an increase in mucosal concentration of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well mucosal activity of myeloperoxidase. Moreover, induction of colitis led to a reduction in colonic blood flow and DNA synthesis. Administration of ghrelin after induction of colitis led to faster regeneration of the colonic wall and reduction in colonic levels of IL-1β, TNF-α, and myeloperoxidase. In addition, treatment with ghrelin improved mucosal DNA synthesis and blood flow. Our study disclosed that ghrelin exhibits a strong anti-inflammatory and healing effect in acetic acid-induced colitis. Our current observation in association with previous findings that ghrelin exhibits curative effect in trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis suggest that therapeutic effect of ghrelin in the colon is universal and independent of the primary cause of colitis. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Review

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601 KiB

Open AccessReview

The Role of Ghrelin and Ghrelin Signaling in Aging

by Marie Amitani, Haruka Amitani, Kai-Chun Cheng, Timothy Sean Kairupan, Nanami Sameshima, Ippei Shimoshikiryo, Kimiko Mizuma, Natasya Trivena Rokot, Yasuhito Nerome, Tetsuhiro Owaki, Akihiro Asakawa and Akio Inui

Int. J. Mol. Sci. 2017, 18(7), 1511; https://doi.org/10.3390/ijms18071511 - 12 Jul 2017

Cited by 32 | Viewed by 12320

Abstract

With our aging society, more people hope for a long and healthy life. In recent years, researchers have focused on healthy longevity factors. In particular, calorie restriction delays aging, reduces mortality, and extends life. Ghrelin, which is secreted during fasting, is well known [...] Read more.

With our aging society, more people hope for a long and healthy life. In recent years, researchers have focused on healthy longevity factors. In particular, calorie restriction delays aging, reduces mortality, and extends life. Ghrelin, which is secreted during fasting, is well known as an orexigenic peptide. Because ghrelin is increased by caloric restriction, ghrelin may play an important role in the mechanism of longevity mediated by calorie restriction. In this review, we will discuss the role of orexigenic peptides with a particular focus on ghrelin. We conclude that the ghrelin-growth hormone secretagogue-R signaling pathway may play an important role in the anti-aging mechanism. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Clarifying the Ghrelin System’s Ability to Regulate Feeding Behaviours Despite Enigmatic Spatial Separation of the GHSR and Its Endogenous Ligand

by Alexander Edwards and Alfonso Abizaid

Int. J. Mol. Sci. 2017, 18(4), 859; https://doi.org/10.3390/ijms18040859 - 19 Apr 2017

Cited by 56 | Viewed by 11203

Abstract

Ghrelin is a hormone predominantly produced in and secreted from the stomach. Ghrelin is involved in many physiological processes including feeding, the stress response, and in modulating learning, memory and motivational processes. Ghrelin does this by binding to its receptor, the growth hormone [...] Read more.

Ghrelin is a hormone predominantly produced in and secreted from the stomach. Ghrelin is involved in many physiological processes including feeding, the stress response, and in modulating learning, memory and motivational processes. Ghrelin does this by binding to its receptor, the growth hormone secretagogue receptor (GHSR), a receptor found in relatively high concentrations in hypothalamic and mesolimbic brain regions. While the feeding and metabolic effects of ghrelin can be explained by the effects of this hormone on regions of the brain that have a more permeable blood brain barrier (BBB), ghrelin produced within the periphery demonstrates a limited ability to reach extrahypothalamic regions where GHSRs are expressed. Therefore, one of the most pressing unanswered questions plaguing ghrelin research is how GHSRs, distributed in brain regions protected by the BBB, are activated despite ghrelin’s predominant peripheral production and poor ability to transverse the BBB. This manuscript will describe how peripheral ghrelin activates central GHSRs to encourage feeding, and how central ghrelin synthesis and ghrelin independent activation of GHSRs may also contribute to the modulation of feeding behaviours. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Therapeutic Potential of Targeting the Ghrelin Pathway

by Gustav Colldén, Matthias H. Tschöp and Timo D. Müller

Int. J. Mol. Sci. 2017, 18(4), 798; https://doi.org/10.3390/ijms18040798 - 11 Apr 2017

Cited by 118 | Viewed by 17291

Abstract

Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among [...] Read more.

Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Is Ghrelin Synthesized in the Central Nervous System?

by Agustina Cabral, Eduardo J. López Soto, Jacques Epelbaum and Mario Perelló

Int. J. Mol. Sci. 2017, 18(3), 638; https://doi.org/10.3390/ijms18030638 - 15 Mar 2017

Cited by 88 | Viewed by 6619

Abstract

Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells [...] Read more.

Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Open AccessReview

Neurogenic Effects of Ghrelin on the Hippocampus

by Chanyang Kim, Sehee Kim and Seungjoon Park

Int. J. Mol. Sci. 2017, 18(3), 588; https://doi.org/10.3390/ijms18030588 - 8 Mar 2017

Cited by 35 | Viewed by 5099

Abstract

Mammalian neurogenesis continues throughout adulthood in the subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus in the hippocampus. It is well known that hippocampal neurogenesis is essential in mediating hippocampus-dependent learning and memory. Ghrelin, a peptide [...] Read more.

Mammalian neurogenesis continues throughout adulthood in the subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus in the hippocampus. It is well known that hippocampal neurogenesis is essential in mediating hippocampus-dependent learning and memory. Ghrelin, a peptide hormone mainly synthesized in the stomach, has been shown to play a major role in the regulation of energy metabolism. A plethora of evidence indicates that ghrelin can also exert important effects on neurogenesis in the hippocampus of the adult brain. The aim of this review is to discuss the current role of ghrelin on the in vivo and in vitro regulation of neurogenesis in the adult hippocampus. We will also discuss the possible role of ghrelin in dietary restriction-induced hippocampal neurogenesis and the link between ghrelin-induced hippocampal neurogenesis and cognitive functions. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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Involvement of Astrocytes in Mediating the Central Effects of Ghrelin

by Laura M. Frago and Julie A. Chowen

Int. J. Mol. Sci. 2017, 18(3), 536; https://doi.org/10.3390/ijms18030536 - 2 Mar 2017

Cited by 21 | Viewed by 7035

Abstract

Although astrocytes are the most abundant cells in the mammalian brain, much remains to be learned about their molecular and functional features. Astrocytes express receptors for numerous hormones and metabolic factors, including the appetite-promoting hormone ghrelin. The metabolic effects of ghrelin are largely [...] Read more.

Although astrocytes are the most abundant cells in the mammalian brain, much remains to be learned about their molecular and functional features. Astrocytes express receptors for numerous hormones and metabolic factors, including the appetite-promoting hormone ghrelin. The metabolic effects of ghrelin are largely opposite to those of leptin, as it stimulates food intake and decreases energy expenditure. Ghrelin is also involved in glucose-sensing and glucose homeostasis. The widespread expression of the ghrelin receptor in the central nervous system suggests that this hormone is not only involved in metabolism, but also in other essential functions in the brain. In fact, ghrelin has been shown to promote cell survival and neuroprotection, with some studies exploring the use of ghrelin as a therapeutic agent against metabolic and neurodegenerative diseases. In this review, we highlight the possible role of glial cells as mediators of ghrelin’s actions within the brain. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation

by Ken Howick, Brendan T. Griffin, John F. Cryan and Harriët Schellekens

Int. J. Mol. Sci. 2017, 18(2), 273; https://doi.org/10.3390/ijms18020273 - 27 Jan 2017

Cited by 114 | Viewed by 23097

Abstract

Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition [...] Read more.

Ghrelin is the only known peripherally-derived orexigenic hormone, increasing appetite and subsequent food intake. The ghrelinergic system has therefore received considerable attention as a therapeutic target to reduce appetite in obesity as well as to stimulate food intake in conditions of anorexia, malnutrition and cachexia. As the therapeutic potential of targeting this hormone becomes clearer, it is apparent that its pleiotropic actions span both the central nervous system and peripheral organs. Despite a wealth of research, a therapeutic compound specifically targeting the ghrelin system for appetite modulation remains elusive although some promising effects on metabolic function are emerging. This is due to many factors, ranging from the complexity of the ghrelin receptor (Growth Hormone Secretagogue Receptor, GHSR-1a) internalisation and heterodimerization, to biased ligand interactions and compensatory neuroendocrine outputs. Not least is the ubiquitous expression of the GHSR-1a, which makes it impossible to modulate centrallymediated appetite regulation without encroaching on the various peripheral functions attributable to ghrelin. It is becoming clear that ghrelin’s central signalling is critical for its effects on appetite, body weight regulation and incentive salience of food. Improving the ability of ghrelin ligands to penetrate the blood brain barrier would enhance central delivery to GHSR-1a expressing brain regions, particularly within the mesolimbic reward circuitry. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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The Neurobiological Impact of Ghrelin Suppression after Oesophagectomy

by Conor F. Murphy and Carel W. Le Roux

Int. J. Mol. Sci. 2017, 18(1), 35; https://doi.org/10.3390/ijms18010035 - 26 Dec 2016

Cited by 3 | Viewed by 4368

Abstract

Ghrelin, discovered in 1999, is a 28-amino-acid hormone, best recognized as a stimulator of growth hormone secretion, but with pleiotropic functions in the area of energy homeostasis, such as appetite stimulation and energy expenditure regulation. As the intrinsic ligand of the growth hormone [...] Read more.

Ghrelin, discovered in 1999, is a 28-amino-acid hormone, best recognized as a stimulator of growth hormone secretion, but with pleiotropic functions in the area of energy homeostasis, such as appetite stimulation and energy expenditure regulation. As the intrinsic ligand of the growth hormone secretagogue receptor (GHS-R), ghrelin appears to have a broad array of effects, but its primary role is still an area of debate. Produced mainly from oxyntic glands in the stomach, but with a multitude of extra-metabolic roles, ghrelin is implicated in complex neurobiological processes. Comprehensive studies within the areas of obesity and metabolic surgery have clarified the mechanism of these operations. As a stimulator of growth hormone (GH), and an apparent inducer of positive energy balance, other areas of interest include its impact on carcinogenesis and tumour proliferation and its role in the cancer cachexia syndrome. This has led several authors to study the hormone in the cancer setting. Ghrelin levels are acutely reduced following an oesophagectomy, a primary treatment modality for oesophageal cancer. We sought to investigate the nature of this postoperative ghrelin suppression, and its neurobiological implications. Full article

(This article belongs to the Special Issue Neurobiological Perspectives on Ghrelin)

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