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Ghrelin Receptors (ghrelin + receptor)
Terms modified by Ghrelin Receptors Selected AbstractsPRECLINICAL STUDY: FULL ARTICLE: Ghrelin increases intake of rewarding food in rodentsADDICTION BIOLOGY, Issue 3 2010Emil Egecioglu ABSTRACT We investigated whether ghrelin action at the level of the ventral tegmental area (VTA), a key node in the mesolimbic reward system, is important for the rewarding and motivational aspects of the consumption of rewarding/palatable food. Mice with a disrupted gene encoding the ghrelin receptor (GHS-R1A) and rats treated peripherally with a GHS-R1A antagonist both show suppressed intake of rewarding food in a free choice (chow/rewarding food) paradigm. Moreover, accumbal dopamine release induced by rewarding food was absent in GHS-R1A knockout mice. Acute bilateral intra-VTA administration of ghrelin increased 1-hour consumption of rewarding food but not standard chow. In comparison with sham rats, VTA-lesioned rats had normal intracerebroventricular ghrelin-induced chow intake, although both intake of and time spent exploring rewarding food was decreased. Finally, the ability of rewarding food to condition a place preference was suppressed by the GHS-R1A antagonist in rats. Our data support the hypothesis that central ghrelin signaling at the level of the VTA is important for the incentive value of rewarding food. [source] Growth hormone-releasing peptide 6 protection of hypothalamic neurons from glutamate excitotoxicity is caspase independent and not mediated by insulin-like growth factor IEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2009A. Delgado-Rubín Abstract Treatment of the fetal hypothalamic neuronal cell line RCA-6 with growth hormone-releasing peptide 6, an agonist of the ghrelin receptor, or insulin-like growth factor I activates intracellular signalling cascades associated with anti-apoptotic actions. Abnormally high concentrations of glutamate provoke over-excitation of neurons leading to cell damage and apoptosis. Thus, the aim of this study was to investigate whether the administration of growth hormone-releasing peptide 6 and insulin-like growth factor I attenuates monosodium glutamate-induced apoptosis in RCA-6 neurons and the mechanisms involved. Two different mechanisms are involved in glutamate-induced cell death, one by means of caspase activation and the second through activation of a caspase-independent pathway of apoptosis mediated by the translocation of apoptosis-inducing factor. Growth hormone-releasing peptide 6 partially reversed glutamate-induced cell death but not the activation of caspases, suggesting blockage of the caspase-independent cell death pathway, which included interference with the translocation of apoptosis-inducing factor to the nucleus associated with the induction of Bcl-2. In contrast, the addition of insulin-like growth factor I to RCA-6 neurons abolished glutamate-induced caspase activation and cell death. These data demonstrate for the first time a neuroprotective role for growth hormone secretagogues in the caspase-independent cell death pathway and indicate that these peptides have neuroprotective effects independent of its induction of insulin-like growth factor I. [source] Growth Hormone-Releasing Peptide-6 Increases Insulin-Like Growth Factor-I mRNA Levels and Activates Akt in RCA-6 Cells as a Model of Neuropeptide Y NeuronesJOURNAL OF NEUROENDOCRINOLOGY, Issue 11 2005L. M. Frago Abstract Chronic systemic administration of growth hormone (GH)-releasing peptide-6 (GHRP-6), an agonist for the ghrelin receptor, to normal adult rats increases insulin-like growth factor (IGF)-I mRNA and phosphorylated Akt (pAkt) levels in various brain regions, including the hypothalamus. Because neuropeptide Y (NPY) neurones of the arcuate nucleus express receptors for ghrelin, we investigated whether these neurones increase their IGF-I and p-Akt levels in response to this agonist. In control rats, immunoreactive pAkt was practically undetectable; however, GHRP-6 increased p-Akt immunoreactivity in the arcuate nucleus, with a subset of neurones also being immunoreactive for NPY. Immunoreactivity for IGF-I was detected in NPY neurones in both experimental groups. To determine if activation of this intracellular pathway is involved in modulation of NPY synthesis RCA-6 cells, an embryonic rat hypothalamic neuronal cell line that expresses NPY was used. We found that GHRP-6 stimulates NPY and IGF-I mRNA synthesis and activates Akt in this cell line. Furthermore, inhibition of Akt activation by LY294002 treatment did not inhibit GHRP-6 induction of NPY or IGF-I synthesis. These results suggest that some of the effects of GHRP-6 may involve stimulation of local IGF-I production and Akt activation in NPY neurones in the arcuate nucleus. However, GHRP-6 stimulation of NPY production does not involve this second messenger pathway. [source] Oral administration of a centrally acting ghrelin receptor agonist to conscious rats triggers defecationNEUROGASTROENTEROLOGY & MOTILITY, Issue 1 2009A. D. Shafton Abstract, Agonists of ghrelin receptors that cross the blood,brain barrier, but not ghrelin itself, administered peripherally (intravenous or subcutaneous), cause defecation by acting on centres in the lumbo-sacral spinal cord. It is not established whether orally administered ghrelin receptor agonists can have this action. We tested GSK894281 for its effectiveness at the ghrelin receptor and its ability to cross the blood,brain barrier. GSK894281 was effective at the human and rat ghrelin receptors at 1,10 nmol L,1, but was >1000-fold less potent at the motilin receptor. It achieved a similar blood concentration by oral or intravenous administration. Oral bioavailability was 74% and brain : blood ratio at steady state was 0.7 : 1. GSK894281 administered orally (1,100 mg kg,1) caused a prompt, dose-related production of faecal pellets; at 10 mg kg,1 faecal output was four times greater than after carrier. The output was the greatest in the first half hour and subsided over the next 90 min. At an oral dose of 10 mg kg,1, the compound was effective on eight successive days. Faecal output was, on average, increased threefold over control in the 2 h after administration on each of the 8 days. This dose also significantly increased food consumption. Rats showed no adverse behavioural effects to the drug on a single application, but at the end of a week of administration they avoided the gavaging pipette. Oral administration of ghrelin receptor agonists that enter the central nervous system could possibly be used to relieve acute cases of constipation or to clear the bowel for colonoscopy. [source] A Genetic Study of the Ghrelin and Growth Hormone Secretagogue Receptor (GHSR) Genes and StatureANNALS OF HUMAN GENETICS, Issue 1 2009M. Gueorguiev Summary Growth and nutrition are interrelated and influenced by multiple genetic and environmental factors. We studied whether common variants in ghrelin and ghrelin receptor (GHSR) genes could play a role in stature variation in the general population and in families ascertained for obesity. Selected tagging SNPs in the ghrelin and GHSR genes were genotyped in 263 Caucasian families recruited for childhood obesity (1,275 subjects), and in 287 families from a general population (1,072 subjects). We performed familial testing for associations in the entire population and in a sub-set of the samples selected for a case-control study. In the case-control study for height (cases were selected from the obese cohort with mean ZH = 3.17 ± 0.15 confidence interval (CI) versus controls with mean ZH 0.14 ± 0.09), we found an association with a 2 base-pair intronic deletion in the GHSR gene (rs10618418) (p = 0.006, odds ratio (OR) 1.86, 95% CI [1.26;2.74] under additive model), although when adjusting for BMI, the association disappeared (p = 0.06). Individuals carrying no deletion or who were heterozygous were significantly more frequent among the tall obese population (52% vs. 36% in controls, p = 0.007, OR 1.97, 95%CI [1.22;3.18]). However, the association was not maintained after correcting for multiple testing. Familial association testing of the ghrelin and GHSR genes and their interaction testing failed to show that any combination of SNPs had any significant effect. Thus, our results suggest that common variants of the ghrelin and GHSR genes are not major contributors to height variation in a French population. [source] Ghrelin: a new peptide regulating the neurohormonal system, energy homeostasis and glucose metabolismDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2008Peter Pusztai Abstract Identification of ghrelin started with the discovery of growth hormone secretagogues, continued with the description of ghrelin receptors and ended with the elucidation of the chemical structure of ghrelin. However, several issues concerning the role of ghrelin in physiological and pathophysiological processes are still under investigation. Most of the ghrelin produced in the body is secreted in the stomach, but it is also expressed in the hypothalamus, pituitary, pancreas, intestine, kidney, heart and gonads. Ghrelin stimulates growth hormone secretion via growth hormone secretagogue receptors. Ghrelin secretion in the stomach depends on both acute and chronic changes in nutritional status and energy balance. Current data support the hypothesis that the stomach, in addition to its important role in digestion, not only influences pituitary hormone secretion but, via ghrelin production, it also sends orexigenic (appetite increasing) signals to hypothalamic nuclei involved in the regulation of energy homeostasis. In addition to these main effects, ghrelin influences insulin secretion and glucose metabolism and it may exert potentially important effects on cardiovascular and gastrointestinal functions. Because of its effects on a large number of physiological functions, ghrelin may be involved in the pathomechanism of several human disorders, including disturbances of appetite, energy homeostasis and glucose metabolism. Further research might lead to a better understanding of the pathophysiology of ghrelin and might provide more effective therapy for the above disorders. Copyright © 2008 John Wiley & Sons, Ltd. [source] The Ghrelin/Obestatin Balance in the Physiological and Pathological Control of Growth Hormone Secretion, Body Composition and Food IntakeJOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2010R. Hassouna Ghrelin and obestatin are two gastrointestinal peptides obtained by post-translational processing of a common precursor, preproghrelin. Ghrelin is an orexigenic and adipogenic peptide and a potent growth hormone secretagogue (GHS) modified by the enzyme ghrelin- O -acyl-transferase to bind and activate its receptor, the GHS-R. The ghrelin/GHS-R pathway is complex and the effects of ghrelin on GH secretion, adiposity and food intake appear to be relayed by distinct mechanisms involving different transduction signals and constitutive activity for the GH-R, different cofactors as modulators of endogenous ghrelin signalling and/or alternative ghrelin receptors. The discovery of obestatin in 2005 brought an additional level of complexity to this fascinating system. Obestatin was initially identified as an anorexigenic peptide and as the cognate ligand for GPR39, but its effect on food intake and its ability to activate GPR39 are still controversial. Although several teams failed to reproduce the anorexigenic actions of obestatin, this peptide has been shown to antagonise GH secretion and food intake induced by ghrelin and could be an interesting pharmacological tool to counteract the actions of ghrelin. Ghrelin and obestatin immunoreactivities are recovered in the blood with an ultradian pulsatility and their concentrations in plasma vary with the nutritional status of the body. It is still a matter of debate whether both hormones are regulated by independent mechanisms and whether obestatin is a physiologically relevant peptide. Nevertheless, a significant number of studies show that the ghrelin/obestatin ratio is modified in anorexia nervosa and obesity. This suggests that the ghrelin/obestatin balance could be essential to adapt the body's response to nutritional challenges. Although measuring ghrelin and obestatin in plasma is challenging because many forms of the peptides circulate, more sensitive and selective assays to detect the different preproghrelin-derived peptides are being developed and may be the key to obtaining a better understanding of their roles in different physiological and pathological conditions. [source] Ghrelin Receptor Antagonism Decreases Alcohol Consumption and Activation of Perioculomotor Urocortin-Containing NeuronsALCOHOLISM, Issue 9 2010Simranjit Kaur Background:, The current therapies for alcohol abuse disorders are not effective in all patients, and continued development of pharmacotherapies is needed. One approach that has generated recent interest is the antagonism of ghrelin receptors. Ghrelin is a gut-derived peptide important in energy homeostasis and regulation of hunger. Recent studies have implicated ghrelin in alcoholism, showing altered plasma ghrelin levels in alcoholic patients as well as reduced intakes of alcohol in ghrelin receptor knockout mice and in mice treated with ghrelin receptor antagonists. The aim of this study was to determine the neuroanatomical locus/loci of the effect of ghrelin receptor antagonism on alcohol consumption using the ghrelin receptor antagonist, D-Lys3-GHRP-6. Methods:, In Experiment 1, male C57BL/6J mice were injected with saline 3 hours into the dark cycle and allowed access to 15% (v/v) ethanol or water for 2 hours in a 2-bottle choice experiment. On test day, the mice were injected with either saline or 400 nmol of the ghrelin receptor antagonist, D-Lys3-GHRP-6, and allowed to drink 15% ethanol or water for 4 hours. The preference for alcohol and alcohol intake were determined. In Experiment 2, the same procedure was followed as in Experiment 1 but mice were only allowed access to a single bottle of 20% ethanol (v/v), and alcohol intake was determined. Blood ethanol levels were analyzed, and immunohistochemistry for c-Fos was carried out to investigate changes in neural activity. To further elucidate the mechanism by which D-Lys3-GHRP-6 affects alcohol intake, in Experiment 3, the effect of D-Lys3-GHRP-6 on the neural activation induced by intraperitoneal ethanol was investigated. For the c-Fos studies, brain regions containing ghrelin receptors were analyzed, i.e. the perioculomotor urocortin population of neurons (pIIIu), the ventral tegmental area (VTA), and the arcuate nucleus (Arc). In Experiment 4, to test if blood ethanol concentrations were affected by D-Lys3-GHRP-6, blood samples were taken at 2 time-points after D-Lys3-GHRP-6 pretreatment and systemic ethanol administration. Results:, In Experiment 1, D-Lys3-GHRP-6 reduced preference to alcohol and in a follow-up experiment (Experiment 2) also dramatically reduced alcohol intake when compared to saline-treated mice. The resulting blood ethanol concentrations were lower in mice treated with the ghrelin receptor antagonist. Immunohistochemistry for c-Fos showed fewer immunopositive cells in the pIIIu of the antagonist-treated mice but no difference was seen in the VTA or Arc. In Experiment 3, D-Lys3-GHRP-6 reduced the induction of c-Fos by intraperitoneal ethanol in the pIIIu but had no effect in the VTA. In the Arc, there was a significant increase in the number of c-Fos immunopositive cells after D-Lys3-GHRP-6 administration, but the antagonist had no effect on ethanol-induced expression of c-Fos. D-Lys3-GHRP-6-pretreatment also did not affect the blood ethanol concentrations observed after a systemic injection of ethanol when compared to saline-pretreated mice (Experiment 4). Conclusions:, These findings indicate that the action of ghrelin on the regulation of alcohol consumption may occur via the pIIIu. [source] Oral administration of a centrally acting ghrelin receptor agonist to conscious rats triggers defecationNEUROGASTROENTEROLOGY & MOTILITY, Issue 1 2009A. D. Shafton Abstract, Agonists of ghrelin receptors that cross the blood,brain barrier, but not ghrelin itself, administered peripherally (intravenous or subcutaneous), cause defecation by acting on centres in the lumbo-sacral spinal cord. It is not established whether orally administered ghrelin receptor agonists can have this action. We tested GSK894281 for its effectiveness at the ghrelin receptor and its ability to cross the blood,brain barrier. GSK894281 was effective at the human and rat ghrelin receptors at 1,10 nmol L,1, but was >1000-fold less potent at the motilin receptor. It achieved a similar blood concentration by oral or intravenous administration. Oral bioavailability was 74% and brain : blood ratio at steady state was 0.7 : 1. GSK894281 administered orally (1,100 mg kg,1) caused a prompt, dose-related production of faecal pellets; at 10 mg kg,1 faecal output was four times greater than after carrier. The output was the greatest in the first half hour and subsided over the next 90 min. At an oral dose of 10 mg kg,1, the compound was effective on eight successive days. Faecal output was, on average, increased threefold over control in the 2 h after administration on each of the 8 days. This dose also significantly increased food consumption. Rats showed no adverse behavioural effects to the drug on a single application, but at the end of a week of administration they avoided the gavaging pipette. Oral administration of ghrelin receptor agonists that enter the central nervous system could possibly be used to relieve acute cases of constipation or to clear the bowel for colonoscopy. [source] | |||||||||||||