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From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion
Lengyel, Ana Maria J.;
Arquivos Brasileiros de Endocrinologia & Metabologia , 2006, DOI: 10.1590/S0004-27302006000100004
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.
From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion
Lengyel Ana Maria J.
Arquivos Brasileiros de Endocrinologia & Metabologia , 2006,
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.
Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus  [PDF]
Guillaume Osterstock,Pauline Escobar,Violeta Mitutsova,Laurie-Anne Gouty-Colomer,Pierre Fontanaud,Fran?ois Molino,Jean-Alain Fehrentz,Danielle Carmignac,Jean Martinez,Nathalie C. Guerineau,Iain C. A. F. Robinson,Patrice Mollard,Pierre-Fran?ois Méry
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009159
Abstract: Ghrelin targets the arcuate nucleus, from where growth hormone releasing hormone (GHRH) neurones trigger GH secretion. This hypothalamic nucleus also contains neuropeptide Y (NPY) neurons which play a master role in the effect of ghrelin on feeding. Interestingly, connections between NPY and GHRH neurons have been reported, leading to the hypothesis that the GH axis and the feeding circuits might be co-regulated by ghrelin.
Gastric motor effects of ghrelin and growth hormone releasing peptide 6 in diabetic mice with gastroparesis  [cached]
Wen-Cai Qiu, Zhi-Gang Wang, Wei-Gang Wang, Jun Yan and Qi Zheng
World Journal of Gastroenterology , 2008,
Abstract: AIM: To investigate the potential therapeutic significance of ghrelin and growth hormone releasing peptide 6 (GHRP-6) in diabetic mice with gastric motility disorders.METHODS: A diabetic mouse model was established by intraperitoneal (ip) injection of alloxan. Diabetic mice were injected ip with ghrelin or GHRP-6 (20-200 μg/kg), and the effects on gastric emptying were measured after intragastric application of phenol red. The effect of atropine, NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) or D-Lys3-GHRP-6 (a growth hormone secretagogue receptor (GHS-R) antagonist) on the gastroprokinetic effect of ghrelin or GHRP-6 (100 μg/kg) was also investigated. The effects of ghrelin or GHRP-6 (0.01-10 μmol/L) on spontaneous or carbachol-induced contractile amplitude were also investigated in vitro, in gastric fundic circular strips taken from diabetic mice. The presence of growth hormone secretagogue receptor 1a transcripts in the fundic strips of diabetic mice was detected by reverse transcriptase polymerase chain reaction (RT-PCR).RESULTS: We established a diabetic mouse model with delayed gastric emptying. Ghrelin and GHRP-6 accelerated gastric emptying in diabetic mice with gastroparesis. In the presence of atropine or L-NAME, which delayed gastric emptying, ghrelin and GHRP-6 (100 μg/kg) failed to accelerate gastric emptying. D-Lys3-GHRP-6 also delayed gastric emptying induced by the GHS-R agonist. Ghrelin and GHRP-6 increased the carbachol-induced contractile amplitude in gastric fundic strips taken from diabetic mice. RT-PCR confirmed the presence of GHS-R mRNA in the strip preparations.CONCLUSION: Ghrelin and GHRP-6 increase gastric emptying in diabetic mice with gastroparesis, perhaps by activating peripheral cholinergic pathways in the enteric nervous system.
Effect of Ghrelin on Glucose-Insulin Homeostasis: Therapeutic Implications  [PDF]
Susana Sangiao-Alvarellos,Fernando Cordido
International Journal of Peptides , 2010, DOI: 10.1155/2010/234709
Abstract: Ghrelin is a 28-amino-acid peptide that displays a strong growth hormone- (GH-) releasing activity through the activation of the growth hormone secretagogue receptor (GHSR). The first studies about role of ghrelin were focused on its orexigenic ability, but despite indisputable pharmacological data, the evidence for a physiological role for ghrelin in the control of appetite is much less clear. Mice with targeted deletion of either ghrelin or the GHSR exhibit an essentially normal metabolic phenotype when fed a regular chow diet, suggesting that ghrelin may have a redundant role in the regulation of food intake. RNAs for ghrelin as well as GHSR are expressed in the pancreas of rats and humans and several studies propose that ghrelin could have an important function in glucose homeostasis and insulin release, independent of GH secretion. Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance, suggesting both physiological and pathophysiological roles for ghrelin. For this reason, at least theoretically, ghrelin and/or its signalling manipulation could be useful for the treatment or prevention of diseases of glucose homeostasis such as type 2 diabetes. 1. Introduction GH is released from the pituitary gland in a pulsatile manner and it is mainly regulated by episodic changes in two hypothalamic hormones, growth hormone-releasing hormone (GHRH) and somatostatin. GHRH stimulates GH secretion whereas that somatostatin inhibits it [1]. In 1976, it was revealed that modified opioid peptides had low GH secretory activity [2]. Since then, many efforts have been made to develop and improve potential applications of these GH secretagogues (GHSs) [3–7]. GHSs act on the pituitary and hypothalamus to release GH, not through the growth hormone releasing hormone receptor (GHRHR) but through an orphan receptor, the GHSR [8]. These facts indicated that an unknown endogenous ligand for GHSR should exist. In 1999, ghrelin was identified as the endogenous ligand for the GHSR. It is a 28-amino-acid peptide predominantly produced by the stomach that functions as a somatotrophic and orexigenic signal from the stomach [9, 10]. Ghrelin is most abundantly expressed in specialized cells in the oxyntic glands of the gastric epithelium, originally termed X/A-like cells [11]. Approximately 60%–70% of circulating ghrelin is secreted by the stomach, and most of the remainder originates in the small intestine [11]. Nevertheless low-level ghrelin expression also occurs in several tissues outside the gut, including hypothalamus (arcuate
Growth hormone response to growth hormone-releasing peptide-2 in growth hormone-deficient Little mice
Peroni, Cibele N.;Hayashida, Cesar Y.;Nascimento, Nancy;Longuini, Viviane C.;Toledo, Rodrigo A.;Bartolini, Paolo;Bowers, Cyril Y.;Toledo, Sergio P.A.;
Clinics , 2012, DOI: 10.6061/clinics/2012(03)11
Abstract: objective: to investigate a possible direct, growth hormone-releasing, hormone-independent action of a growth hormone secretagogue, ghrp-2, in pituitary somatotroph cells in the presence of inactive growth hormonereleasing hormone receptors. materials and methods: the responses of serum growth hormone to acutely injected growth hormone-releasing p-2 in lit/litmice, which represent a model of gh deficiency arising frommutated growth hormone-releasing hormonereceptors, were compared to those observed in the heterozygous (lit/+) littermates and wild-type (+/+) c57bl/6j mice. results: after the administration of 10 mcg of growth hormone-releasing p-2 to lit/lit mice, a growth hormone release of 9.3±1.5 ng/ml was observed compared with 1.04±1.15 ng/ml in controls (p<0.001). in comparison, an intermediate growth hormone release of 34.5±9.7 ng/ml and a higher growth hormone release of 163±46 ng/ml were induced in the lit/+ mice and wild-type mice, respectively. thus, ghrp-2 stimulated growth hormone in the lit/lit mice, and the release of growth hormone in vivo may be only partially dependent on growth hormone-releasing hormone. additionally, the plasma leptin and ghrelin levels were evaluated in the lit/lit mice under basal and stimulated conditions. conclusions: here, we have demonstrated that lit/lit mice, which harbor a germline mutation in the growth hormone-releasing hormone gene, maintain a limited but statistically significant growth hormone elevation after exogenous stimulation with ghrp-2. the present data probably reflect a direct, growth hormone-independent effect on growth hormone s (ghrelin) stimulation in the remaining pituitary somatotrophs of little mice that is mediated by growth hormone s-r 1a.
A Natural Variant of Obestatin, Q90L, Inhibits Ghrelin's Action on Food Intake and GH Secretion and Targets NPY and GHRH Neurons in Mice  [PDF]
Rim Hassouna, Philippe Zizzari, Odile Viltart, Seung-Kwon Yang, Robert Gardette, Catherine Videau, Emilio Badoer, Jacques Epelbaum, Virginie Tolle
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051135
Abstract: Background Ghrelin and obestatin are two gut-derived peptides originating from the same ghrelin/obestatin prepropeptide gene (GHRL). While ghrelin stimulates growth hormone (GH) secretion and food intake and inhibits γ-aminobutyric-acid synaptic transmission onto GHRH (Growth Hormone Releasing Hormone) neurons, obestatin blocks these effects. In Humans, GHRL gene polymorphisms have been associated with pathologies linked to an unbalanced energy homeostasis. We hypothesized that one polymorphism located in the obestatin sequence (Q to L substitution in position 90 of the ghrelin/obestatin prepropeptide, rs4684677) may impact on the function of obestatin. In the present study, we tested the activity of native and Q90L obestatin to modulate ghrelin-induced food intake, GH secretion, cFos activity in GHRH and Neuropeptide Y (NPY) neurons and γ-aminobutyric-acid activity onto GHRH neurons. Methodology/Principal findings Food intake, GH secretion and electrophysiological recordings were assessed in C57BL/6 mice. cFos activity was measured in NPY-Renilla-GFP and GHRH-eGFP mice. Mice received saline, ghrelin or ghrelin combined to native or Q90L obestatin (30 nmol each) in the early light phase. Ghrelin stimulation of food intake and GH secretion varied considerably among individual mice with 59–77% eliciting a robust response. In these high-responders, ghrelin-induced food intake and GH secretion were reduced equally by native and Q90L obestatin. In contrast to in vivo observations, Q90L was slightly more efficient than native obestatin in inhibiting ghrelin-induced cFos activation within the hypothalamic arcuate nucleus and the nucleus tractus solitarius of the brainstem. After ghrelin injection, 26% of NPY neurons in the arcuate nucleus expressed cFos protein and this number was significantly reduced by co-administration of Q90L obestatin. Q90L was also more potent that native obestatin in reducing ghrelin-induced inhibition of γ-aminobutyric-acid synaptic transmission onto GHRH neurons. Conclusions/Significance These data support the hypothesis that Q90L obestatin partially blocks ghrelin-induced food intake and GH secretion by acting through NPY and GHRH neurons.
Integrating GHS into the Ghrelin System  [PDF]
Johannes D. Veldhuis,Cyril Y. Bowers
International Journal of Peptides , 2010, DOI: 10.1155/2010/879503
Abstract: Oligopeptide derivatives of metenkephalin were found to stimulate growth-hormone (GH) release directly by pituitary somatotrope cells in vitro in 1977. Members of this class of peptides and nonpeptidyl mimetics are referred to as GH secretagogues (GHSs). A specific guanosine triphosphatate-binding protein-associated heptahelical transmembrane receptor for GHS was cloned in 1996. An endogenous ligand for the GHS receptor, acylghrelin, was identified in 1999. Expression of ghrelin and homonymous receptor occurs in the brain, pituitary gland, stomach, endothelium/vascular smooth muscle, pancreas, placenta, intestine, heart, bone, and other tissues. Principal actions of this peptidergic system include stimulation of GH release via combined hypothalamopituitary mechanisms, orexigenesis (appetitive enhancement), insulinostasis (inhibition of insulin secretion), cardiovascular effects (decreased mean arterial pressure and vasodilation), stimulation of gastric motility and acid secretion, adipogenesis with repression of fat oxidation, and antiapoptosis (antagonism of endothelial, neuronal, and cardiomyocyte death). The array of known and proposed interactions of ghrelin with key metabolic signals makes ghrelin and its receptor prime targets for drug development. 1. Overview Fundamental questions in peptide biology are the extent to which any given peptide operates in isolation versus interdependently, locally or systemically, and via a single pleiotropic or multiple distinct receptors. Identification of the ghrelin/GHS family initially disclosed GH-releasing properties [1]. Investigations subsequently unveiled multiorgan expression [2–4], multivariate actions [5], and complex modulation of and by collateral effectors [1, 4]: Table 1. The burgeoning repertoire of ghrelin actions mimics that of inhibin and activin [6, 7], which were originally isolated as regulators of follicle-stimulating hormone secretion, and thereafter recognized for hematopoietic and oncologic activity. Analogously, prominent clinical applications of ghrelin/GHS may involve not only GH-stimulating effects but also appetitive, metabolic, cardiovascular, locomotive, and gastrointestinal signaling: Figure 1. Recent development of transgenic mice expressing ghrelin-eGFP (enhanced green fluorescent protein) should permit more detailed mapping of ghrelin-expressing neurons in hypothalamic arcuate and ventromedial nuclei [8–10] and ghrelin-expressing cells in gastric oxyntic glands, pancreatic islets (epsilon cells), the anterior pituitary gland, bone marrow, and other less well-studied sites [4,
Neuroactive Peptides as Putative Mediators of Antiepileptic Ketogenic Diets  [PDF]
Maddalena Marchiò,Giuseppe Biagini
Frontiers in Neurology , 2014, DOI: 10.3389/fneur.2014.00063
Abstract: Various ketogenic diet (KD) therapies, including classic KD, medium chain triglyceride administration, low glycemic index treatment, and a modified Atkins diet, have been suggested as useful in patients affected by pharmacoresistant epilepsy. A common goal of these approaches is to achieve an adequate decrease in the plasma glucose level combined with ketogenesis, in order to mimic the metabolic state of fasting. Although several metabolic hypotheses have been advanced to explain the anticonvulsant effect of KDs, including changes in the plasma levels of ketone bodies, polyunsaturated fatty acids, and brain pH, direct modulation of neurotransmitter release, especially purinergic (i.e., adenosine) and γ-aminobutyric acidergic neurotransmission, was also postulated. Neuropeptides and peptide hormones are potent modulators of synaptic activity, and their levels are regulated by metabolic states. This is the case for neuroactive peptides such as neuropeptide Y, galanin, cholecystokinin and peptide hormones such as leptin, adiponectin, and growth hormone-releasing peptides (GHRPs). In particular, the GHRP ghrelin and its related peptide des-acyl ghrelin are well-known controllers of energy homeostasis, food intake, and lipid metabolism. Notably, ghrelin has also been shown to regulate the neuronal excitability and epileptic activation of neuronal networks. Several lines of evidence suggest that GHRPs are upregulated in response to starvation and, particularly, in patients affected by anorexia and cachexia, all conditions in which also ketone bodies are upregulated. Moreover, starvation and anorexia nervosa are accompanied by changes in other peptide hormones such as adiponectin, which has received less attention. Adipocytokines such as adiponectin have also been involved in modulating epileptic activity. Thus, neuroactive peptides whose plasma levels and activity change in the presence of ketogenesis might be potential candidates for elucidating the neurohormonal mechani
Neuroprotective Actions of Ghrelin and Growth Hormone Secretagogues  [PDF]
Laura M. Frago,Jesús Argente,Julie A. Chowen
Frontiers in Molecular Neuroscience , 2011, DOI: 10.3389/fnmol.2011.00023
Abstract: The brain incorporates and coordinates information based on the hormonal environment, receiving information from peripheral tissues through the circulation. Although it was initially thought that hormones only acted on the hypothalamus to perform endocrine functions, it is now known that they in fact exert diverse actions on many different brain regions including the hypothalamus. Ghrelin is a gastric hormone that stimulates growth hormone secretion and food intake to regulate energy homeostasis and body weight by binding to its receptor, growth hormone secretagogues–GH secretagogue-receptor, which is most highly expressed in the pituitary and hypothalamus. In addition, ghrelin has effects on learning and memory, reward and motivation, anxiety, and depression, and could be a potential therapeutic agent in neurodegenerative disorders where excitotoxic neuronal cell death and inflammatory processes are involved.
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