Growth Hormone Secretagogue Research Articles

Ghrelin Represses Thymic Stromal Lymphopoietin Gene Expression through Activation of Glucocorticoid Receptor and Protein Kinase C Delta in Inflamed Skin Keratinocytes.

Ghrelin, a peptide hormone secreted from enteroendocrine cells of the gastrointestinal tract, has anti-inflammatory activity in skin diseases, including dermatitis and psoriasis. However, the molecular mechanism underlying the beneficial effect of ghrelin on skin inflammation is not clear. In this study, we found that ghrelin alleviates atopic dermatitis (AD)-phenotypes through suppression of thymic stromal lymphopoietin (TSLP) gene activation. Knockdown or antagonist treatment of growth hormone secretagogue receptor 1a (GHSR1a), the receptor for ghrelin, suppressed ghrelin-induced alleviation of AD-like phenotypes and suppression of TSLP gene activation. We further found that ghrelin induces activation of the glucocorticoid receptor (GR), leading to the binding of GR with histone deacetylase 3 (HDAC3) and nuclear receptor corepressor (NCoR) NCoR corepressor to negative glucocorticoid response element (nGRE) on the TSLP gene promoter. In addition, ghrelin-induced protein kinase C δ (PKCδ)-mediated phosphorylation of p300 at serine 89 (S89), which decreased the acetylation and DNA binding activity of nuclear factor- κB (NF-κB) p65 to the TSLP gene promoter. Knockdown of PKCδ abolished ghrelin-induced suppression of TSLP gene activation. Our study suggests that ghrelin may help to reduce skin inflammation through GR and PKCδ-p300-NF-κB-mediated suppression of TSLP gene activation.

Energetic demands of lactation produce an increase in the expression of growth hormone secretagogue receptor in the hypothalamus and ventral tegmental area of the rat despite a reduction in circulating ghrelin.

Lactating rats show changes in the secretion of hormones and brain signals that promote hyperphagia and facilitate the production of milk. Little is known, however, about the role of ghrelin in the mechanisms sustaining lactational hyperphagia. Here, we used Wistar female rats that underwent surgery to sever the galactophores to prevent milk delivery (GC rats) and decrease the energetic drain of milk delivery. We compared plasma acyl-ghrelin concentrations and growth hormone secretagogue receptor (GHSR) mRNA expression in different brain regions of GC rats with those of sham operated lactating and nonlactating rats. Additional lactating and nonlactating rats were implanted with cannulae aimed at the lateral ventricles and were used to compare feeding responses to central ghrelin or GHSR antagonist infusions to those of nonlactating rats receiving similar infusions on day 14-16 postpartum (pp). Results show lower plasma acyl-ghrelin concentrations on day 15 pp sham operated lactating rats compared to GC or nonlactating rats. These changes occur in association with increased GHSR mRNA expression in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA) of sham operated lactating rats. Despite lactational hyperphagia, infusions of ghrelin (0.25 or 1μg) resulted in similar increases in food intake in lactating and nonlactating rats. In addition, infusions of the GHSR antagonist JMV3002 (4μg in 1μl of vehicle) produced greater suppression of food intake in lactating rats than in nonlactating rats. These data suggest that, despite lower plasma ghrelin, the energetic drain of lactation increases sensitivity to the orexigenic effects of ghrelin in brain regions important for food intake and energy balance, and these events are associated with lactational hyperphagia.

LEAP2: Next game-changer of pharmacotherapy for overweight and obesity?

The world is seeking effective and safe weight-lowering drugs for centuries. LEAP2, acting on ghrelin and growth hormone secretagogue receptor, according to a study by Hageman et al.1 in this issue of Cell Reports Medicine, found its way toward the next target of pharmacotherapy for obesity and related diseases.

A GH Secretagogue Receptor Agonist (LUM-201) Elicits Greater GH Responses than Standard GH Secretagogues in Subjects of a Pediatric GH Deficiency Trial

Introduction: LUM-201 (ibutamoren, formerly MK-0677) is an orally administered GH secretagogue receptor agonist under development for treatment of pediatric growth hormone deficiency (PGHD). Methods: The GH response to a single dose of LUM-201 and to other GH secretagogues used for diagnosis of PGHD were compared in 68 pediatric subjects participating in a trial for growth hormone deficiency. Results: LUM-201 elicited greater GH responses than observed in GHD diagnostic tests with arginine, glucagon, clonidine, L-dopa, and insulin-induced hypoglycemia [median and interquartile ranges 15.0 ng/mL (3.5, 49) vs. 5.5 ng/mL (1.8, 7.6) (p < 0.0001)]. The difference between responses was greatest in subjects with higher baseline IGF-I concentrations and higher GH responses to standard GH stimuli. Conclusion: LUM-201 elicits greater GH responses than standard stimuli in subjects with higher peak GH in response to conventional testing and is potentially an orally administered treatment alternative to injectable rhGH in a subset of patients with adequate responses to an acute dose of LUM-201.

LEAP2 reduces postprandial glucose excursions and ad libitum food intake in healthy men

SummaryThe gastric hormone ghrelin stimulates food intake and increases plasma glucose through activation of the growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) has been proposed to inhibit actions of ghrelin through inverse effects on GHSR activity. Here, we investigate the effects of exogenous LEAP2 on postprandial glucose metabolism and ad libitum food intake in a randomized, double-blind, placebo-controlled, crossover trial of 20 healthy men. We report that LEAP2 infusion lowers postprandial plasma glucose and growth hormone concentrations and decreases food intake during an ad libitum meal test. In wild-type mice, plasma glucose and food intake are reduced by LEAP2 dosing, but not in GHSR-null mice, pointing to GHSR as a potential mediator of LEAP2’s glucoregulatory and appetite-suppressing effects in mice.

Equine metabolism of the growth hormone secretagogue MK-0677 in vitro and in urine and plasma following oral administration.

Ibutamoren mesylate, or MK-0677, is an orally active, nonpeptide growth hormone secretagogue that has been developed to stimulate excretion of endogenous growth hormone. It has been evaluated for the treatment of a range of clinical conditions but is not available therapeutically. Nonetheless, MK-0677 is widely available to purchase online, sold as 'supplement' products. The mode of action and relative ease of purchase make MK-0677 a potential threat with regard to sports doping. The aim of this study was to investigate the metabolism of MK0677 in the horse following in vitro incubation and oral administration to two Thoroughbred racehorses, in order to identify the most appropriate analytical targets for doping control laboratories. Liquid chromatography high resolution mass spectrometry was used for metabolite identification, and subsequently, liquid chromatography-tandem mass spectrometry was used to generate full metabolite profiles for post-administration urine and plasma samples. Fourteen phase I metabolites were identified in vitro; 13 of these were subsequently detected in urine and nine in plasma collected post-administration, alongside the parent compound in both matrices. In both urine and plasma, the longest duration of detection was observed for an O-dealkylated metabolite of MK-0677, and therefore, this would be the best target for the detection of MK-0677 administration. MK-0677 and the O-dealkylated metabolite were found to be excreted largely unconjugated in urine and plasma.

Ghrelin and Cancer: Examining the Roles of the Ghrelin Axis in Tumor Growth and Progression.

Ghrelin, a hormone produced and secreted from the stomach, is prim arily known as an appetite stimulant. Recently, it has emerged as a potential regulator/biomarker of cancer progression. Inconsistent results on this subject make this body of literature difficult to interpret. Here, we attempt to identify commonalities in the relationships between ghrelin and various cancers, and summarize important considerations for future research. The main players in the ghrelin family axis are unacylated ghrelin (UAG), acylated ghrelin (AG), the enzyme ghrelin O-acyltransferase (GOAT), and the growth hormone secretagogue receptor (GHSR). GOAT is responsible for the acylation of ghrelin, after which ghrelin can bind to the functional ghrelin receptor GHSR-1a to initiate the activation cascade. Splice variants of ghrelin also exist, with the most prominent being In1-ghrelin. In this review, we focus primarily on the potential of In1-ghrelin as a biomarker for cancer progression, the unique characteristics of UAG and AG, the importance of the two known receptor variants GHSR-1a and 1b, as well as the possible mechanisms through which the ghrelin axis acts. Further understanding of the role of the ghrelin axis in tumor cell proliferation could lead to the development of novel therapeutic approaches for various cancers.

The controversial role of the vagus nerve in mediating ghrelin's actions: gut feelings and beyond.

Ghrelin is a stomach-derived peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) and displays a plethora of neuroendocrine, metabolic, autonomic and behavioral actions. It has been proposed that some actions of ghrelin are exerted via the vagus nerve, which provides a bidirectional communication between the central nervous system and peripheral systems. The vagus nerve comprises sensory fibers, which originate from neurons of the nodose and jugular ganglia, and motor fibers, which originate from neurons of the medulla. Many anatomical studies have mapped GHSR expression in vagal sensory or motor neurons. Also, numerous functional studies investigated the role of the vagus nerve mediating specific actions of ghrelin. Here, we critically review the topic and discuss the available evidence supporting, or not, a role for the vagus nerve mediating some specific actions of ghrelin. We conclude that studies using rats have provided the most congruent evidence indicating that the vagus nerve mediates some actions of ghrelin on the digestive and cardiovascular systems, whereas studies in mice resulted in conflicting observations. Even considering exclusively studies performed in rats, the putative role of the vagus nerve in mediating the orexigenic and growth hormone (GH) secretagogue properties of ghrelin remains debated. In humans, studies are still insufficient to draw definitive conclusions regarding the role of the vagus nerve mediating most of the actions of ghrelin. Thus, the extent to which the vagus nerve mediates ghrelin actions, particularly in humans, is still uncertain and likely one of the most intriguing unsolved aspects of the field.

Effect of Bacterial Infection on Ghrelin Receptor Regulation in Periodontal Cells and Tissues.

The effect of bacterial infection on the expression of growth hormone secretagogue receptor (GHS-R) was investigated in periodontal cells and tissues, and the actions of ghrelin were evaluated. GHS-R was assessed in periodontal tissues of rats with and without periodontitis. Human gingival fibroblasts (HGFs) were exposed to Fusobacterium nucleatum in the presence and absence of ghrelin. GHS-R expression was determined by real-time PCR and immunocytochemistry. Furthermore, wound healing, cell viability, proliferation, and migration were evaluated. GHS-R expression was significantly higher at periodontitis sites as compared to healthy sites in rat tissues. F. nucleatum significantly increased the GHS-R expression and protein level in HGFs. Moreover, ghrelin significantly abrogated the stimulatory effects of F. nucleatum on CCL2 and IL-6 expressions in HGFs and did not affect cell viability and proliferation significantly. Ghrelin stimulated while F. nucleatum decreased wound closure, probably due to reduced cell migration. Our results show original evidence that bacterial infection upregulates GHS-R in rat periodontal tissues and HGFs. Moreover, our study shows that ghrelin inhibited the proinflammatory actions of F. nucleatum on HGFs without interfering with cell viability and proliferation, suggesting that ghrelin and its receptor may act as a protective molecule during bacterial infection on periodontal cells.

Growth hormone secretagogue receptor signaling in the supramammillary nucleus targets nitric oxide-producing neurons and controls recognition memory in mice

Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin’s actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within the mouse SuM, but ghrelin also activates SuM cells and intra-SuM ghrelin administration induces feeding in rats. In the current study, we aimed to further characterize ghrelin action in the SuM. We first investigated a mouse model expressing enhanced green fluorescent protein (eGFP) under the promoter of GHSR (GHSR-eGFP mice). We found that the SuM of GHSR-eGFP mice contains a significant amount of eGFP cells, some of which express neuronal nitric oxide synthase. Centrally-, but not systemically-, injected ghrelin reached the SuM, where it induced c-Fos expression. Furthermore, a 5-day 40% calorie restriction protocol, but not a 2-day fast, increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice, whereas c-Fos induction by calorie restriction was not observed in GHSR-deficient mice. Exposure of satiated mice to a binge-like eating protocol also increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice in a GHSR-dependent manner. Finally, intra-SuM-injected ghrelin did not acutely affect food intake, locomotor activity, behavioral arousal or spatial memory but increased recognition memory. Thus, we provide a compelling neuroanatomical characterization of GHSR SuM neurons and its behavioral implications in mice.

Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets.

Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global Ghsr−/− mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr−/− mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr−/− mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr−/− mice, but the ATP/ADP ratio in Ghsr−/− islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in Ghsr−/− islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of Ghsr−/− mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.

Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine

SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein- and β-arrestin (βarr)-dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mitigating side effects. Here, we describe the discovery of a brain-penetrant small molecule, N8279 (NCATS-SM8864), that biases GHSR1a conformations toward Gαq activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR1a-related brain disorders involving the pathological dysregulation of dopamine.

GHS-R1a activity suppresses synaptic function of primary cultured hippocampal neurons

Ghrelin is an orexigenic gastric hormone that promotes feeding behaviors and regulates energy homeostasis in both humans and rodents. Studies have reported intriguing yet conflicting roles that ghrelin and its receptor growth hormone secretagogue receptor 1a (GHS-R1a) play in regulating multiple brain functions, such as learning and memory; however, the underlying mechanism is largely unknown. In this study, we investigated the effect of ghrelin incubation and virus-mediated GHS-R1a overexpression on synaptic functions of primary cultured hippocampal neurons. Our results demonstrated that ghrelin pre-treatment for 24 h, with a concentration of either 4 nM or 200 nM, suppressed the frequency of miniature excitatory postsynaptic currents (mEPSCs), the frequency and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Similarly, GHS-R1a overexpression inhibited both the frequency and the amplitude of mEPSCs, and mIPSCs frequency. Moreover, our in vitro Ca2+-image study with Rhod-3AM reveals that ghrelin pre-treatment for either 3 h or 24 h suppressed glutamate-induced elevation of cytoplasmic [Ca2+]. Our findings thus suggest that GHS-R1a signaling inhibits synaptic function of hippocampal neurons, which may contribute to the blocking effect of ghrelin on memory formation.

"Sibling" battle or harmony: crosstalk between nesfatin-1 and ghrelin.

Ghrelin was first identified as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) in 1999, with the function of stimulating the release of growth hormone (GH), while nesfatin-1 was identified in 2006. Both peptides are secreted by the same kind of endocrine cells, X/A-like cells in the stomach. Compared with ghrelin, nesfatin-1 exerts opposite effects on energy metabolism, glucose metabolism, gastrointestinal functions and regulation of blood pressure, but exerts similar effects on anti-inflammation and neuroprotection. Up to now, nesfatin-1 remains as an orphan ligand because its receptor has not been identified. Several studies have shown the effects of nesfatin-1 are dependent on the receptor of ghrelin. We herein compare the effects of nesfatin-1 and ghrelin in several aspects and explore the possibility of their interactions.

Virus-mediated GHS-R1a expression in the basolateral amygdala blocks extinction of conditioned taste aversion memory in rats

Ghrelin is an orexigenic gastric hormone that promotes feeding behaviors and regulating energy homeostasis in both humans and rodents. Our previous studies have shown that ghrelin, when locally infused into the basolateral amygdala (BLA), blocks both acquisition and extinction of conditioned taste aversion (CTA) memory in rats. In this study, we further investigated the effect of virus-mediated overexpression of ghrelin receptor growth hormone secretagogue receptor 1a (GHS-R1a) in BLA pyramidal neurons on CTA memory processes. We found that upregulation of GHS-R1a expression in BLA pyramidal neurons repressed CTA extinction while it had no effect on CTA acquisition. In addition, we reported that local infusion of the endogenous GHS-R1a antagonist, liver-expressed antimicrobial peptide 2 (LEAP2), in the BLA abolished the inhibitory effect of increased GHS-R1a on CTA memory extinction. Those findings provide new supportive evidence that ghrelin/GHS-R1a signaling in the BLA circuit shapes emotional memory processes.

Blood Acylated Ghrelin Concentrations in Healthy Term Newborns: A Prospective Cohort Study

Objective The effect of ghrelin, a growth hormone (GH) secretagogue on growth of neonates, has been studied in the past, but not fully clarified. We aimed to investigate the relationship between ghrelin and growth parameters at birth and at the age of three months in healthy term infants. Methodology. This was a prospective observational study carried out in a tertiary care hospital. Eighty-four infants born at gestational ages between 37 and 42 weeks and classified as term small for gestational age (SGA) and appropriate for gestational age (AGA) were included in the study. Estimation of acylated ghrelin (AG) concentrations was done in the cord blood at birth and in venous blood at the age of 3 months in all the infants. The correlation between AG concentrations and growth parameters at birth and at 3 months was studied. Results AG concentrations were significantly higher in SGA (236.16 ± 152.4 pg/ml) than AGA neonates (59.45 ± 20.95 pg/ml) at birth. Concentrations were observed to be negatively correlated with birth weight (r = −0.34, p value 0.03), birth length, and head circumference (r = −0.509 and -0.376, respectively) in SGA neonates. However, at 3 months, AG concentrations did not correlate with changes in anthropometric parameters in both the groups. Conclusion Cord acylated ghrelin concentrations are higher in SGA neonates, and the concentrations are inversely proportional to the birth weight. Hence, its role as a surrogate marker for intrauterine nutrition can be suggested. However, its concentrations do not correlate with anthropometric parameters in early postnatal growth, suggesting it may not have a direct role in postnatal growth.

Novel Role of Ghrelin Receptor in Gut Dysbiosis and Experimental Colitis in Aging.

Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout (KO) mice. While young GHS-R KO mice showed marginal changes in Bacteroidetes and Firmicutes, aged GHS-R KO mice exhibited reduced Bacteroidetes and increased Firmicutes, featuring a disease-susceptible microbiome profile. To further study the role of GHS-R in intestinal inflammation in aging, we induced acute colitis in young and aged GHS-R KO mice using dextran sulfate sodium (DSS). The GHS-R KO mice showed more severe disease activity scores, higher proinflammatory cytokine expression, and decreased expression of tight junction markers. These results suggest that GHS-R plays an important role in microbiome homeostasis and gut inflammation during aging; GHS-R suppression exacerbates intestinal inflammation in aging and increases vulnerability to colitis. Collectively, our finding reveals for the first time that GHS-R is an important regulator of intestinal health in aging; targeting GHS-R may present a novel therapeutic strategy for prevention/treatment of aging leaky gut and inflammatory bowel disease.

Could Overt Diabetes Be Triggered by Abuse of Selective Androgen Receptor Modulators and Growth Hormone Secretagogues? A Case Report and Review of the Literature.

Case Studies| July 01 2022 Could Overt Diabetes Be Triggered by Abuse of Selective Androgen Receptor Modulators and Growth Hormone Secretagogues? A Case Report and Review of the Literature Richard Sotorník 0000-0003-0813-3951 ; Richard Sotorník 1Canadian Medical, Prague, Czech Republic2Third Faculty of Medicine, Charles University, Prague, Czech Republic Search for other works by this author on: This Site PubMed Google Scholar Roguel Suissa; Roguel Suissa 1Canadian Medical, Prague, Czech Republic Search for other works by this author on: This Site PubMed Google Scholar Jean-Luc Ardilouze 0000-0001-8160-0320 Jean-Luc Ardilouze 3Division of Endocrinology, University Hospital Center, Sherbrooke, Canada Search for other works by this author on: This Site PubMed Google Scholar Corresponding author: Richard Sotorník, richard.sotornik@lf3.cuni.cz Clin Diabetes 2022;40(3):373–379 https://doi.org/10.2337/cd21-0044 PubMed: 35983415 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation Richard Sotorník, Roguel Suissa, Jean-Luc Ardilouze; Could Overt Diabetes Be Triggered by Abuse of Selective Androgen Receptor Modulators and Growth Hormone Secretagogues? A Case Report and Review of the Literature. Clin Diabetes 1 July 2022; 40 (3): 373–379. https://doi.org/10.2337/cd21-0044 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Diabetes Search Advanced Search In October 2018, a 47-year-old male recreational bodybuilder presented to his general practitioner in Prague, Czech Republic, with polydipsia (daily fluid intake 5–6 L), polyuria, blurred vision, malaise, and weight loss of 10 kg in the past month. He did not complain of any pain or fever and was taking no regular medication except recent (3 months) use of performance-enhancing drugs (PEDs) purchased from a fitness center, including two selective androgen receptor modulators (SARMs)—RAD140 5 mg twice daily and andarine 25 mg twice daily, 5 days per week—as well as the growth hormone (GH) secretagogue (GHS)/ghrelin analog ibutamoren 25 mg daily, 5 days per week. He had no previous use of hormonal supplements. The patient reported no serious disease apart from borreliosis in 2012, seasonal pollinosis, and minor injuries related to physical activities. Three years before this visit, he underwent a routine general check-up. At that time, his weight was... You do not currently have access to this content.

Ghrelin infusion into the basolateral amygdala suppresses CTA memory formation in rats via the PI3K/Akt/mTOR and PLC/PKC signaling pathways.

Ghrelin is a circulating orexigenic hormone that promotes feeding behavior and regulates metabolism in humans and rodents. We previously reported that local infusion of ghrelin into the basolateral amygdala (BLA) blocked memory acquisition for conditioned taste aversion (CTA) by activating growth hormone secretagogue receptor 1a. In this study, we further explored the underlying mechanism and signaling pathways mediating ghrelin modulation of CTA memory in rats. Pharmacological agents targeting distinct signaling pathways were infused into the BLA during conditioning. We showed that preadministration of the PI3K inhibitor LY294002 abolished the repressive effect of ghrelin on CTA memory. Moreover, LY294002 pretreatment prevented ghrelin from inhibiting Arc and zif268 mRNA expression in the BLA triggered by CTA memory retrieval. Preadministration of rapamycin eliminated the repressive effect of ghrelin, while Gsk3 inhibitors failed to mimic ghrelin's effect. In addition, PLC and PKC inhibitors microinfused in the BLA blocked ghrelin's repression of CTA acquisition. These results demonstrate that ghrelin signaling in the BLA shapes CTA memory via the PI3K/Akt/mTOR and PLC/PKC pathways. We conducted in vivo multichannel recordings from mouse BLA neurons and found that microinjection of ghrelin (20 µM) suppressed intrinsic excitability. By means of whole-cell recordings from rat brain slices, we showed that bath application of ghrelin (200 nM) had no effect on basal synaptic transmission or synaptic plasticity of BLA pyramidal neurons. Together, this study reveals the mechanism underlying ghrelin-induced interference with CTA memory acquisition in rats, i.e., suppression of intrinsic excitability of BLA principal neurons via the PI3K/Akt/mTOR and PLC/PKC pathways.

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor.

Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.