scholarly journals Ghrelin and Growth Hormone Secretagogue Receptor Expression in Mice during Aging

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1323-1329 ◽  
Author(s):  
Yuxiang Sun ◽  
Jose Manuel Garcia ◽  
Roy G. Smith
Keyword(s):  
Pituitary Gland ◽  
Receptor Expression ◽  
Elderly Subjects ◽  
Mrna Levels ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Igf I ◽  
The Impact ◽  
The Brain

In well-nourished humans, GH and IGF-I decline during aging, and the responsiveness of the GH axis to exogenous ghrelin is attenuated with age. Intriguingly, the GH/IGF-I axis is rejuvenated by chronic treatment with the ghrelin mimetic MK-0677, resulting in improvements in body composition, suggesting that frail elderly subjects might benefit from treatment with ghrelin and ghrelin mimetics. Mouse models are widely used to study the effects of ghrelin, but the impact of age on the ghrelin pathway is unclear. In this study, total and active ghrelin peptides were measured in plasma, and ghrelin mRNA was quantitated in brain tissue from different aged C57BL/6J mice. Surprisingly, plasma levels of ghrelin peptide slightly increased with age; ghrelin mRNA levels were similar in brains from mice aged 2, 6, 12, and 28 months but higher in mice aged 18 and 24 months. The tissue distribution of Ghsr1a mRNA (ghrelin receptor) was also characterized, and pituitary and brain exhibited the highest levels of expression. In the pituitary gland, the highest concentration of Ghsr1a mRNA was observed at age 1–2 months, it was lower at 6 months, and remained unchanged for up to 30 months of age. This result is consistent with the finding that GH release in response to exogenous ghrelin was not significantly different in mice aged 7–30 months. In the brain, Ghsr1a mRNA levels remained stable during aging. Hence, in C57BL/6J male mice, aging is not associated with changes in circulating ghrelin levels or changes in ghrelin receptor expression in the pituitary gland and brain.

scholarly journals Ghrelin receptors in rat and human nodose ganglia: putative role in regulating CB-1 and MCH receptor abundance

2006 ◽  
Vol 290 (6) ◽  
pp. G1289-G1297 ◽  
Author(s):  
Galina Burdyga ◽  
Andrea Varro ◽  
Rod Dimaline ◽  
David G. Thompson ◽  
Graham J. Dockray
Keyword(s):  
Receptor Expression ◽  
Afferent Neurons ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Nodose Ganglia ◽  
Melanin Concentrating Hormone ◽  
Ghrelin Receptors ◽  
Vagal Afferent ◽  
Immunohistochemical Studies

Intact vagal afferent neurons are required for the satiety effects of the intestinal hormone cholecystokinin (CCK) and the orexigenic effects of the gastric regulatory peptide ghrelin. In this study, we examined the localization of ghrelin receptors in nodose ganglia and their function in regulating the expression of other orexigenic receptors, notably cannabinoid (CB)-1 and melanin-concentrating hormone (MCH)-1 receptors. With the use of RT-PCR, transcripts corresponding to both functional [growth hormone secretagogue receptor (GHS-R)1a] and truncated forms (GHS-R1b) of the ghrelin receptor were detected in rat nodose ganglia. There was no difference in expression between rats fed ad libitum or fasted for up to 48 h. Immunohistochemical studies using antibodies directed at GHS-R1a revealed expression in over 75% of neurons also expressing CCK-1 receptors in the mid- and caudal regions of the ganglion. There was also expression in human nodose ganglia. In fasted rats in which CB-1 and MCH-1 receptor expression was increased, administration of ghrelin prevented the downregulation by refeeding. We conclude that the actions of CCK and ghrelin are mediated by a common population of vagal afferent neurons. Ghrelin may act to limit the action of CCK in depressing expression of CB-1 and MCH-1 receptors and other receptors.

scholarly journals Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes

2006 ◽  
Vol 188 (2) ◽  
pp. 263-270 ◽  
Author(s):  
E Kim ◽  
S Sohn ◽  
M Lee ◽  
J Jung ◽  
R D Kineman ◽  
...  
Keyword(s):  
Receptor Expression ◽  
High Dose ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Β Cells ◽  
Igf I ◽  
Chemical Destruction ◽  
Catabolic State ◽  
Rats And Mice ◽  
The Impact

The impact of streptozotocin (STZ)-induced, insulinopenic diabetes on the GH axis of rats and mice differs from study to study, where this variation may be related to the induction scheme, severity of the diabetes and/or the genetic background of the animal model used. In order to begin differentiate between these possibilities, we compared the effects of two different STZ induction schemes on the GH axis of male Sprague–Dawley rats: (1) a single high-dose injection of STZ (HI STZ, 80 mg/kg, i.p.), which results in rapid chemical destruction of the pancreatic β-cells, and (2) multiple low-dose injections of STZ (LO STZ, 20 mg/kg for 5 consecutive days, i.p.), which results in a gradual, autoimmune destruction of β-cells. STZ-treated animals were killed after 3 weeks of hyperglycemia (>400 mg/dl), and in both paradigms circulating insulin levels were reduced to <40% of vehicle-treated controls. HI STZ-treated rats lost weight, while body weights of LO STZ-treated animals gradually increased over time, similar to vehicle-treated controls. As previously reported, HI STZ resulted in a decrease in circulating GH and IGF-I levels which was associated with a rise in hypothalamic neuropeptide Y (NPY) mRNA (355% of vehicle-treated controls) and a fall in GH-releasing hormone (GHRH) mRNA (45% of vehicle-treated controls) levels. Changes in hypothalamic neuropeptide expression were reflected by an increase in immunoreactive NPY within the arcuate and paraventricular nuclei and a decrease in GHRH immunoreactivity in the arcuate nucleus, as assessed by immunohistochemistry. Consistent with the decline in circulating GH and hypothalamic GHRH, pituitary GH mRNA levels of HI STZ-treated rats were 58% of controls. However, pituitary receptor mRNA levels for GHRH and ghrelin increased and those for somatostatin (sst2, sst3 and sst5) decreased following HI STZ treatment. The impact of LO STZ treatment on the GH axis differed from that observed following HI STZ treatment, despite comparable changes in circulating glucose and insulin. Specifically, LO STZ treatment did suppress circulating IGF-I levels to the same extent as HI STZ treatment; however, the impact on hypothalamic NPY mRNA levels was less dramatic (158% of vehicle-treated controls) where NPY immunoreactivity was increased only within the paraventricular nucleus. Also, there were no changes in circulating GH, hypothalamic GHRH or pituitary receptor expression following LO STZ treatment, with the exception that pituitary sst3 mRNA levels were suppressed compared with vehicle-treated controls. Taken together these results clearly demonstrate that insulinopenia, hyperglycemia and reduced circulating IGF-I levels are not the primary mediators of hypothalamic and pituitary changes in the GH axis of rats following HI STZ treatment. Changes in the GH axis of HI STZ-treated rats were accompanied by weight loss, and these changes are strikingly similar to those observed in the fasted rat, which suggests that factors associated with the catabolic state are critical in modifying the GH axis following STZ-induced diabetes.

scholarly journals Gastrointestinal stromal tumors express the orexigen ghrelin

2006 ◽  
Vol 13 (3) ◽  
pp. 963-970 ◽  
Author(s):  
Sara Ekeblad ◽  
Bengt Nilsson ◽  
Margareta Halin Lejonklou ◽  
Térèse Johansson ◽  
Peter Stålberg ◽  
...  
Keyword(s):  
Gastrointestinal Stromal Tumors ◽  
Mrna Levels ◽  
Growth Hormone Secretagogue Receptor ◽  
Hormone Production ◽  
Growth Hormone Secretagogue ◽  
Neuroendocrine Marker ◽  
Ghrelin Receptor ◽  
Stromal Tumors ◽  
Real Time Quantitative Pcr ◽  
Disease Stages

Expression of the neuroendocrine marker synaptic vesicle protein 2 (SV2) has been reported in a few cases of gastrointestinal stromal tumors (GISTs). The goal of the present study was to assess the relevance of this finding and identify a possible hormone production in these tumors. We chose to study the orexigen ghrelin and its receptor, since these patients are seldom cachexic, even in advanced disease stages. We investigated ghrelin expression by means of immunohistochemistry on frozen or paraffin-embedded sections from 22 GISTs from a well-characterized patient material. Expression of the growth hormone secretagogue receptor, the ghrelin receptor, was investigated in a subset of lesions. In six tumors, mRNA levels of ghrelin, the ghrelin receptor, and SV2 were analyzed by real-time quantitative PCR. Totally 17 out of 22 tumors showed immunoreactivity for ghrelin. Five out of ten tumors were immunoreactive for the ghrelin receptor, and all of these co-expressed ghrelin. All tumors expressed ghrelin, ghrelin receptor, and SV2 mRNA. GISTs frequently express SV2, ghrelin, and its receptor, indicating the presence of autocrine/paracrine loops.

scholarly journals Cannabinoid-Induced Conditioned Place Preference, Intravenous Self-Administration, and Behavioral Stimulation Influenced by Ghrelin Receptor Antagonism in Rats

2021 ◽  
Vol 22 (5) ◽  
pp. 2397
Author(s):  
Chrysostomos Charalambous ◽  
Tereza Havlickova ◽  
Marek Lapka ◽  
Nina Puskina ◽  
Romana Šlamberová ◽  
...  
Keyword(s):  
Conditioned Place Preference ◽  
Fixed Ratio ◽  
Place Preference ◽  
Self Administration ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Addiction Therapy ◽  
Significant Efficacy ◽  
Lever Pressing

Cannabis/cannabinoids are widely used for recreational and therapy purposes, but their risks are largely disregarded. However, cannabinoid-associated use disorders and dependence are alarmingly increasing and an effective treatment is lacking. Recently, the growth hormone secretagogue receptor (GHSR1A) antagonism was proposed as a promising mechanism for drug addiction therapy. However, the role of GHS-R1A and its endogenous ligand ghrelin in cannabinoid abuse remains unclear. Therefore, the aim of our study was to investigate whether the GHS-R1A antagonist JMV2959 could reduce the tetrahydrocannabinol (THC)-induced conditioned place preference (CPP) and behavioral stimulation, the WIN55,212-2 intravenous self-administration (IVSA), and the tendency to relapse. Following an ongoing WIN55,212-2 self-administration, JMV2959 3 mg/kg was administered intraperitoneally 20 min before three consequent daily 120-min IVSA sessions under a fixed ratio FR1, which significantly reduced the number of the active lever-pressing, the number of infusions, and the cannabinoid intake. Pretreatment with JMV2959 suggested reduction of the WIN55,212-2-seeking/relapse-like behavior tested in rats on the twelfth day of the forced abstinence period. On the contrary, pretreatment with ghrelin significantly increased the cannabinoid IVSA as well as enhanced the relapse-like behavior. Co-administration of ghrelin with JMV2959 abolished/reduced the significant efficacy of the GHS-R1A antagonist in the cannabinoid IVSA. Pretreatment with JMV2959 significantly and dose-dependently reduced the manifestation of THC-induced CPP. The THC-CPP development was reduced after the simultaneous administration of JMV2959 with THC during conditioning. JMV2959 also significantly reduced the THC-induced behavioral stimulation in the LABORAS cage. Our findings suggest that GHS-R1A importantly participates in the rewarding/reinforcing effects of cannabinoids.

scholarly journals Cortistatin Is Not a Somatostatin Analogue but Stimulates Prolactin Release and Inhibits GH and ACTH in a Gender-Dependent Fashion: Potential Role of Ghrelin

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4800-4812 ◽  
Author(s):  
José Córdoba-Chacón ◽  
Manuel D. Gahete ◽  
Ana I. Pozo-Salas ◽  
Antonio J. Martínez-Fuentes ◽  
Luis de Lecea ◽  
...  
Keyword(s):  
Metabolic Phenotype ◽  
Somatostatin Analogue ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ancestral Gene ◽  
Ghrelin Receptor ◽  
Physiological Relevance

Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Although CST has been considered as a natural SST-analogue acting through their shared receptors (SST receptors 1–5), emerging evidence indicates that these peptides might in fact exert unique roles via selective receptors [e.g. CST, not SST, binds ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a)]. To determine whether the role of endogenous CST is different from SST, we characterized the endocrine-metabolic phenotype of male/female CST null mice (cort−/−) at hypothalamic-pituitary-systemic (pancreas-stomach-adrenal-liver) levels. Also, CST effects on hormone expression/secretion were evaluated in primary pituitary cell cultures from male/female mice and female primates (baboons). Specifically, CST exerted an unexpected stimulatory role on prolactin (PRL) secretion, because both male/female cort−/− mice had reduced PRL levels, and CST treatment (in vivo and in vitro) increased PRL secretion, which could be blocked by a GHS-R1a antagonist in vitro and likely relates to the decreased success of female cort−/− in first-litter pup care at weaning. In contrast, CST inhibited GH and adrenocorticotropin-hormone axes in a gender-dependent fashion. In addition, a rise in acylated ghrelin levels was observed in female cort−/− mice, which were associated with an increase in stomach ghrelin/ghrelin O-acyl transferase expression. Finally, CST deficit uncovered a gender-dependent role of this peptide in the regulation of glucose-insulin homeostasis, because male, but not female, cort−/− mice developed insulin resistance. The fact that these actions are not mimicked by SST and are strongly gender dependent offers new grounds to investigate the hitherto underestimated physiological relevance of CST in the regulation of physiological/metabolic processes.

scholarly journals IGF-I regulates pro-opiomelanocortin and GH gene expression in the mouse pituitary gland

2003 ◽  
Vol 178 (1) ◽  
pp. 71-82 ◽  
Author(s):  
J Honda ◽  
Y Manabe ◽  
R Matsumura ◽  
S Takeuchi ◽  
S Takahashi
Keyword(s):  
Pituitary Gland ◽  
Anterior Pituitary ◽  
Northern Blotting ◽  
Pituitary Cells ◽  
Mrna Levels ◽  
Gh Treatment ◽  
Gh Receptor ◽  
Pomc Mrna ◽  
Igf I ◽  
Mouse Pituitary

IGF-I is expressed in somatotrophs, and IGF-I receptors are expressed in most somatotrophs and some corticotrophs in the mouse pituitary gland. Our recent study demonstrated that IGF-I stimulates the proliferation of corticotrophs in the mouse pituitary. These results suggested that somatotrophs regulate corticotrophic functions as well as somatotrophic functions by the mediation of IGF-I molecules. The present study aimed to clarify factors regulating pituitary IGF-I expression and also the roles exerted by IGF-I within the mouse anterior pituitary gland. Mouse anterior pituitary cells were isolated and cultured under serum-free conditions. GH (0.5 or 1 microg/ml), ACTH (10(-8) or 10(-7) M), GH-releasing hormone (GHRH; 10(-8) or 10(-7) M), dexamethasone (DEX; 10(-8) or 10(-7) M) and estradiol-17beta (e2; 10(-11) or 10(-9) M) were given for 24 h. IGF-I mRNA levels were measured using competitive RT-PCR, and GH and pro-opiomelanocortin (POMC) mRNA levels were measured using Northern blotting analysis. GH treatment significantly increased IGF-I mRNA levels (1.5- or 2.1-fold). ACTH treatment did not alter GH and IGF-I mRNA levels. IGF-I treatment decreased GH mRNA levels (0.7- or 0.5-fold), but increased POMC mRNA levels (1.8-fold). GH treatment (4 or 8 microg/ml) for 4 days increased POMC mRNA levels. GHRH treatment increased GH mRNA levels (1.3-fold), but not IGF-I mRNA levels. DEX treatment significantly decreased IGF-I mRNA levels (0.8-fold). e2 treatment did not affect IGF-I mRNA levels. GH receptor mRNA, probably with GH-binding protein mRNA, was detected in somatotrophs, and some mammotrophs and gonadotrophs by in situ hybridization using GH receptor cDNA as a probe. These results suggested that IGF-I expression in somatotrophs is regulated by pituitary GH, and that IGF-I suppresses GH expression and stimulates POMC expression at the transcription level. Pituitary IGF-I produced in somatotrophs is probably involved in the regulation of somatotroph and corticotroph functions.

scholarly journals Ghrelin Amplifies Dopamine Signaling by Cross Talk Involving Formation of Growth Hormone Secretagogue Receptor/Dopamine Receptor Subtype 1 Heterodimers

2006 ◽  
Vol 20 (8) ◽  
pp. 1772-1785 ◽  
Author(s):  
Hong Jiang ◽  
Lorena Betancourt ◽  
Roy G. Smith
Keyword(s):  
Dopamine Receptor ◽  
Fluorescent Protein ◽  
Green Fluorescent Protein Fluorescence ◽  
Receptor Subtype ◽  
Protein Fluorescence ◽  
Growth Hormone Secretagogue Receptor ◽  
Growth Hormone Secretagogue ◽  
Ghrelin Receptor ◽  
Dopamine Signaling

Abstract Our objective is to determine the neuromodulatory role of ghrelin in the brain. To identify neurons that express the ghrelin receptor [GH secretagogue receptor (GHS-R)], we generated GHS-R-IRES-tauGFP mice by gene targeting. Neurons expressing the GHS-R exhibit green fluorescence and are clearly evident in the hypothalamus, hippocampus, cortex, and midbrain. Using immunohistochemistry in combination with green fluorescent protein fluorescence, we identified neurons that coexpress the dopamine receptor subtype 1 (D1R) and GHS-R. The potential physiological relevance of coexpression of these two receptors and the direct effect of ghrelin on dopamine signaling was investigated in vitro. Activation of GHS-R by ghrelin amplifies dopamine/D1R-induced cAMP accumulation. Intriguingly, amplification involves a switch in G protein coupling of the GHS-R from Gα11/q to Gαi/o by a mechanism consistent with agonist-dependent formation of GHS-R/D1R heterodimers. Most importantly, these results indicate that ghrelin has the potential to amplify dopamine signaling selectively in neurons that coexpress D1R and GHS-R.

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