Showing papers on "Growth hormone secretagogue published in 2015"

Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin.

Abstract: Objective Excess nutrient supply and rapid weight gain during early life are risk factors for the development of obesity during adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Ghrelin is a metabolic hormone secreted from the stomach that acts centrally to promote feeding behavior by binding to growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. Here, we examined whether neonatal overnutrition causes changes in the ghrelin system.

Ghrelin Attenuates Liver Fibrosis through Regulation of TGF-β1 Expression and Autophagy.

Abstract: Ghrelin is a stomach-derived growth hormone secretagogue that promotes various physiological effects, including energy metabolism and amelioration of inflammation. The purpose of this study was to investigate the protective mechanism of ghrelin against liver fibrosis. Liver fibrosis was induced in C57BL/6 mice by intraperitoneal injection of CCl₄ (2.0 mL/kg of 10% CCl₄ v/v solution in peanut oil) two times per week for eight weeks. Ghrelin (10 μg/kg) was intraperitoneally injected two times per week for eight weeks. A second murine liver fibrosis model was induced by bile duct ligation (BDL) and concurrent ghrelin administration for four weeks. Hematoxylin eosin (H&E), and Masson's trichrome were used to detect pathological changes to liver tissue. Western blotting was used to detect protein levels of transforming growth factor (TGF)-β1, phosphorylated Smad3 (p-Smad3), I-collage, α-smooth muscle actin (α-SMA), matrix metalloproteinases (MMPs) 2, tissue inhibitor of matrix metalloproteinases (TIMPs) 1, phosphorylated NF-κB (p-NF-κB), and microtubule-associated protein light chain 3 (LC3). In addition, qRT-PCR was used to detect mRNA levels of TGF-β1, I-collage, α-SMA, MMP2, TIMP1 and LC3, while levels of TGF-β1, p-Smad3, I-collage, α-SMA, and LC3 were detected immunohistochemically. Levels of aspartate aminotransferase and alanine aminotransferase were significantly decreased by ghrelin treatment. Ghrelin administration also significantly reduced the extent of pathological changes in both murine liver fibrosis models. Expression levels of I-collage and α-SMA in both models were clearly reduced by ghrelin administration. Furthermore, ghrelin treatment decreased protein expression of TGF-β1 and p-Smad3. The protein levels of NF-κB and LC3 were increased in the CCl₄- and BDL-treatment groups but were significantly reduced following ghrelin treatment. In addition, ghrelin inhibited extracellular matrix formation by decreasing NF-κB expression and maintaining the balance between MMP2 and TIMP1. Our results demonstrated that ghrelin attenuates liver fibrosis via inhibition of the TGF-β1/Smad3 and NF-κB signaling pathways, as well as autophagy suppression.

Emerging treatments in Neurogastroenterology: relamorelin: a novel gastrocolokinetic synthetic ghrelin agonist.

Abstract: Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately 6-fold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a pre-specified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders.

Ghrelin reduces liver impairment in a model of concanavalin A-induced acute hepatitis in mice.

Abstract: Background and aims Ghrelin is a 28-amino-acid gut hormone that was first discovered as a potent growth hormone secretagogue. Recently, it has been shown to exert a strong anti-inflammatory effect. The purpose of the study reported here was to explore the effect and mechanism of ghrelin on concanavalin (Con) A-induced acute hepatitis.

Ghrelin Receptor Ligands Reaching Clinical Trials: From Peptides to Peptidomimetics; from Agonists to Antagonists.

Abstract: In the recent decades, great progress has been made in the development of ghrelin receptor ligands. The discovery of the first in vitro only active peptide growth hormone secretagogue derived from Met-enkephalin was the foundation for later discoveries of the receptor and the endogenous ligand ghrelin. Since then, the scope of peptides, peptidomimetics, and small-molecules targeting the ghrelin receptor, GHS-R1a, has expanded dramatically. Numerous agonists have been tested in animals and several in humans, and a handful have progressed to clinical trials for indications such as growth hormone release, gastric emptying, and cachexia. However, with the exception of the approval of GHRP-2 for diagnostic purposes in Japan, none of the candidates have been successfully introduced into the market. More recently, the attention of researchers has been concentrated on developing antagonists and inverse agonists for pharmacological treatment of the ever-expanding obese and overweight population. In this review, we describe the development of GHS-R1a targeting agonists, antagonists, and inverse agonists. We focus on current and completed clinical trials and the therapeutic potential of currently available ligands.

Site and mechanism of the colokinetic action of the ghrelin receptor agonist, HM01

Abstract: Background It has been recently demonstrated that the ghrelin receptor agonist, HM01, caused defecation in rats that were treated to provide a model for the constipation of Parkinson's disease. HM01 significantly increased fecal output and increased Fos activity in neurons of the hypothalamus and hindbrain, but not in the spinal defecation center. Other ghrelin agonists act on the defecation center. Methods Receptor pharmacology was examined in ghrelin receptor (GHSR1a) transfected cells. Anesthetized rats were used to investigate sites and mechanisms of action. Key Results HM01 activated rat GHSR1a at nanomolar concentrations and was antagonized by the GHSR1a antagonist, YIL781. HM01, intravenous, was potent to activate propulsive colorectal contractions. This was prevented by pelvic nerve section and by intravenous YIL781, but not by spinal cord section rostral to the defecation centers. Direct intrathecal application of HM01 to the defecation center at spinal level L6-S1 initiated propulsive contractions of the colorectum. Conclusions & Inferences HM01 stimulates GHSR1a receptors on neurons in the lumbosacral defecation centers to cause propulsive contractions and emptying of the colorectum. It has greater potency when given systemically, compared with other GHSR1a agonists.

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

Abstract: Ghrelin and its synthetic analog hexarelin are specific ligands of growth hormone secretagogue (GHS) receptor. GHS have strong growth hormone-releasing effect and other neuroendocrine activities such as stimulatory effects on prolactin and adrenocorticotropic hormone secretion. Recently, several studies have reported other beneficial functions of GHS that are independent of GH. Ghrelin and hexarelin, for examples, have been shown to exert GH-independent cardiovascular activity. Hexarelin has been reported to regulate peroxisome proliferator-activated receptor gamma (PPAR-γ) in macrophages and adipocytes. PPAR-γ is an important regulator of adipogenesis, lipid metabolism, and insulin sensitization. Ghrelin also shows protective effects on beta cells against lipotoxicity through activation of phosphatidylinositol-3 kinase/protein kinase B, c-Jun N-terminal kinase (JNK) inhibition, and nuclear exclusion of forkhead box protein O1. Acylated ghrelin (AG) and unacylated ghrelin (UAG) administration reduces glucose levels and increases insulin-producing beta cell number, and insulin secretion in pancreatectomized rats and in newborn rats treated with streptozotocin, suggesting a possible role of GHS in pancreatic regeneration. Therefore, the discovery of GHS has opened many new perspectives in endocrine, metabolic, and cardiovascular research areas, suggesting the possible therapeutic application in diabetes and diabetic complications especially diabetic cardiomyopathy. Here, we review the physiological roles of ghrelin and hexarelin in the protection and regeneration of beta cells and their roles in the regulation of insulin release, glucose, and fat metabolism and present their potential therapeutic effects in the treatment of diabetes and diabetic-associated heart diseases.

Novel Regulator of Acylated Ghrelin, CF801, Reduces Weight Gain, Rebound Feeding after a Fast, and Adiposity in Mice

Abstract: Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades, ultimately resulting in an increase in food intake and adiposity. Because ghrelin has been linked to overeating and the development of obesity, a number of pharmacological interventions have been generated in order to interfere with either the activation of ghrelin or interrupting ghrelin signaling as a means to reducing appetite and decrease weight gain. Here, we present a novel peptide, CF801, capable of reducing circulating acylated ghrelin levels and subsequent body weight gain and adiposity. To this end, we show that IP administration of CF801 is sufficient to reduce circulating plasma acylated ghrelin levels. Acutely, intraperitoneal injections of CF801 resulted in decreased rebound feeding after an overnight fast. When delivered chronically, they decreased weight gain and adiposity without affecting caloric intake. CF801, however, did cause a change in diet preference, decreasing preference for a high-fat diet and increasing preference for regular chow diet. Given the complexity of ghrelin receptor function, we propose that CF801, along with other compounds that regulate ghrelin secretion, may prove to be a beneficial tool in the study of the ghrelin system, and potential targets for ghrelin-based obesity treatments without altering the function of ghrelin receptors.

Ghrelin, food intake, and botanical extracts: A Review

Abstract: A kind of growth hormone secretagogue (GHS), ghrelin, was first isolated from the rat stomach and plays a major role in the activation of the growth hormone secretagogue receptor 1a (GHS-R1a) resulting the release of growth hormone (GH). The preproghrelin gene is placed on chromosome 3, at locus 3p25 -2 in humans and constitutes five exons and three introns. Ghrelin is most plentifully expressed in particular cells in the oxyntic glands of the gastric epithelium, initially named X/A-like cells. Almost 60-70% of circulating ghrelin is secreted by the stomach. Plasma ghrelin concentration alters throughout the day. Ghrelin has been suggested to act as a meal initiator because of its appetite-stimulating influences in free feeding rats in short period. In addition to ghrelin's function as a meal motivator, it seems to contribute in long-term energy balance and nutritional status. In addition, many studies have been carried out in order to investigate the effects of natural and medicinal plants and botanical extracts on appetite, food intake, energy hemostasis, and the level of related hormones including ghrelin. Due to the importance of ghrelin in nutritional and medical sciences, this review was performed to understand new aspects of this hormone's function.

Evaluation and Diagnostic Potential of Serum Ghrelin in Feline Hypersomatotropism and Diabetes Mellitus

Abstract: Background Ghrelin is a growth hormone secretagogue. It is a potent regulator of energy homeostasis. Ghrelin concentration is down-regulated in humans with hypersomatotropism (HS) and increases after successful treatment. Additionally, ghrelin secretion seems impaired in human diabetes mellitus (DM). Hypothesis Serum ghrelin concentration is down-regulated in cats with HS-induced DM (HSDM) compared to healthy control cats or cats with DM unrelated to HS and increases after radiotherapy. Animals Cats with DM (n = 20) and with HSDM (n = 32), 13 of which underwent radiotherapy (RT-group); age-matched controls (n = 20). Methods Retrospective cross-sectional study. Analytical performance of a serum total ghrelin ELISA was assessed and validated for use in cats. Differences in serum ghrelin, fructosamine, IGF-1 and insulin were evaluated. Results Ghrelin was significantly higher (P < .001) in control cats (mean ± SD: 12.9 ± 6.8 ng/mL) compared to HSDM- (7.9 ± 3.3 ng/mL) and DM-cats (6.7 ± 2.3 ng/mL), although not different between the HSDM- and DM-cats. After RT ghrelin increased significantly (P = .003) in HSDM-cats undergoing RT (from 6.6 ± 1.9 ng/mL to 9.0 ± 2.2 ng/mL) and the after RT ghrelin concentrations of HSDM cats were no longer significantly different from the serum ghrelin concentration of control cats. Serum IGF-1 did not significantly change in HSDM-cats after RT, despite significant decreases in fructosamine and insulin dose. Conclusion and Clinical Importance Ghrelin appears suppressed in cats with DM and HSDM, although increases after RT in HSDM, suggesting possible presence of a direct or indirect negative feedback system between growth hormone and ghrelin. Serum ghrelin might therefore represent a marker of treatment effect.

Distribution of ghrelin in pancreatic islet cells of normal and diabetic rats and its effect on diabetes mellitus

Abstract: Ghrelin, a 28-amino acid peptide, is identified as the endogenous ligand of the orphan growth hormone secretagogue-receptor type 1a. Ghrelin presents a unique modification at Ser3 position essential for its activity. It was first discovered in the stomach of rat in 1999. Aside from ghrelin’s role as a potent growth hormone secretagogue and food intake modulator, ghrelin is thought to play a role in insulin and glucagon secretion and in glucose homeostasis. A lot of contradictory data have been reported in the literature regarding ghrelins co-localization with other hormones in the islets of Langerhans, its role in insulin secretion and attenuation of type 2 diabetes mellitus. In this study, we investigated the effect of chronic ghrelin treatment on glucose, body weight and insulin level in normal, STZ-induced diabetic and ghrelin-treated male Wistar rats. We also examined the distribution pattern and co-localization of ghrelin in the pancreatic islet of Langerhans with both pancreatic hormones; insulin and glucagon. In addition, we examined how ghrelin treatment influences liver function in normal and STZ-diabetic Wistar rats. Control groups received intraperitoneal injection of normal saline while treated groups received intraperitoneal injections of 5μg/kg ghrelin on daily basis for duration of four weeks. Our results show that administration of ghrelin increases the serum insulin level in both normal and diabetic rats. We also demonstrated that ghrelin co-localizes with insulin as well as glucagon in the pancreatic islet cells and that the pattern of ghrelin distribution is shown to alter after the onset of diabetes. Moreover, ghrelin treatment increased insulin secretion as a result of increasing insulin-secreting β cells. In conclusion ghrelin co-localizes with both insulin and glucagon in pancreatic islet cells and plays a regulatory role in insulin secretion.

The ghrelin system

Abstract: Ghrelin is now a well known hormone that has actions both in the hypothalamo-pituitary system as well as the gut, and also has a regulatory role in metabolism. Current evidence suggests that ghrelin has a plethora of actions on several systems that have been well outlined and discussed in this book. There are 16 chapters in the book written by experts principally devoted to decipher the action of ghrelin in their respective areas of research. Starting from the discovery of ghrelin and its actions on the G-coupled receptors, various authors have outlined the role of ghrelin in the functions of the gut; its neuroendocrine actions; possible actions on the cardiovascular system including its ability to lower peripheral resistance, cardioprotective actions; and in the release of insulin. Its regulatory role in glucose metabolism and thus its involvement in the pathobiology of obesity and type 2 diabetes mellitus has also been discussed. All the chapters are well written outlining not only the authors’ own work but also current advances in the respective areas of work done by others. The only criticism about this book is the lack of any reference to the role of ghrelin in sepsis and a detailed discussion about its anti-inflammatory action. There is a brief mention about the anti-inflammatory role/action of ghrelin and a passing mention about its usefulness in ischaemia/reperfusion injury. The cytoprotective actions of ghrelin especially against ischaemic injury imply that it may play a role in cardiovascular diseases especially in myocardial infarction. The anti-inflammatory action of ghrelin is particularly relevant to its suggested role in the management of sepsis/septic shock. Thus, ghrelin is not only a growth hormone secretagogue produced by the gut, but it may also have an important role in some inflammatory conditions. Ghrelin not only plays an important role in the regulation of appetite, energy balance and glucose homeostasis, but also shows antibacterial activity, suppresses pro-inflammatory cytokine production and restores gut-barrier function. In experimental animals, ghrelin showed significant beneficial actions in preventing mortality from sepsis. In the critically ill, corticosteroid insufficiency as a result of dysfunction of the hypothalamic-pituitary-adrenal axis is known to occur. It is, therefore, possible that both gut and hypothalamus play an important role in the pathogenesis of sepsis by virtue of their ability to produce ghrelin, which, in turn, could be a protective phenomenon to suppress inflammation. However, it remains to be seen whether ghrelin and its analogues are of benefit in treating patients with sepsis and other inflammatory conditions. Despite some limitations, this book is a comprehensive guide for those who wish to update themselves about ghrelin. This book is especially useful to those who are new entrants in this area. Reading this book will not only give a comprehensive knowledge of ghrelin but also provides what is not known about it. The references provided are also comprehensive and useful.

Pressure Overload, Sympathetic Drive, and Inflammation: Is Ghrelin the Link?

Abstract: See related article, pp 1238–1244 Multicellular organisms regulate the activity of their individual cells and organs in a coordinated way. As a potential mechanism, they use either the nervous system, allowing the exchange of information in a rapid way, or hormones, controlling activity status over a longer time period. Furthermore, there is need for coordinated defense mechanisms against bacteria and virus, mediated by the immune system. These 3 levels of communication, nervous system, hormonal system, and immune system, have many interactions. These interactions are rather complex, and we learn more about the individual players from day to day. This is important as deregulation in any of these pathways significantly contributes to disease conditions, including systemic hypertension and the subsequent end-organ damages. Ghrelin is a 28-aa peptide released into the circulation mainly, but not exclusively, by cells in the stomach. It circulates in a highly active acylated form, although large amounts of nonacylated ghrelin are found. The latter does not bind to classical ghrelin receptors, called growth hormone secretagogue receptors, and may have nonclassical functions. However, active ghrelin binds to these receptors, which have a widespread distribution in the cardiovascular system.1 Ghrelin is a good example of a peptide …