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Kenji Kangawa - One of the best experts on this subject based on the ideXlab platform.
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MOLECULAR EVOLUTION OF GPCRS: Ghrelin/Ghrelin receptors
Journal of molecular endocrinology, 2013Co-Authors: Hiroyuki Kaiya, Kenji Kangawa, Mikiya MiyazatoAbstract:After the discovery in 1996 of the GH secretagogue-receptor type-1a (GHS-R1a) as an orphan G-protein coupled receptor, many research groups attempted to identify the endogenous ligand. Finally, Kojima and colleagues successfully isolated the peptide ligand from rat stomach extracts, determined its structure, and named it Ghrelin. The GHS-R1a is now accepted to be the Ghrelin receptor. The existence of the Ghrelin system has been demonstrated in many animal classes through biochemical and molecular biological strategies as well as through genome projects. Our work, focused on identifying the Ghrelin receptor and its ligand Ghrelin in laboratory animals, particularly nonmammalian vertebrates, has provided new insights into the molecular evolution of the Ghrelin receptor. In mammals, it is assumed that the Ghrelin receptor evolution is in line with the plate tectonics theory. In contrast, the evolution of the Ghrelin receptor in nonmammalian vertebrates differs from that of mammals: multiplicity of the Ghrelin receptor isoforms is observed in nonmammalian vertebrates only. This multiplicity is due to genome duplication and polyploidization events that particularly occurred in Teleostei. Furthermore, it is likely that the evolution of the Ghrelin receptor is distinct from that of its ligand, Ghrelin, because only one Ghrelin isoform has been detected in all species examined so far. In this review, we summarize current knowledge related to the molecular evolution of the Ghrelin receptor in mammalian and nonmammalian vertebrates.
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Physiological roles of Ghrelin on obesity
Obesity research & clinical practice, 2013Co-Authors: Takahiro Sato, Kenji Kangawa, Takanori Ida, Yuki Nakamura, Yuki Shiimura, Masayasu KojimaAbstract:Ghrelin is a stomach hormone that acts as an endogenous ligand of orphan G-protein coupled receptor. Ghrelin has various physiological functions, such as the stimulation of growth hormone release and of appetite, and fat accumulation. Ghrelin is the only peripheral hormone to transmit satiety signal. Mature Ghrelin peptide is consisted of 28 amino acid residues, and is unusual among peptide hormones in that Ser3 is n-octanoylated to obtain. Furthermore, this modification is essential for Ghrelin's activity. In order to add this side chain to acyl Ghrelin, it is necessary for the recently discovered enzyme, Ghrelin-O-acyl transferase (GOAT). Therefore, to understand of Ghrelin's functions, it is useful to obtain the knowledge on structures and functions of Ghrelin, Ghrelin receptor and GOAT. Here, we review our current understanding of the structures and functions of Ghrelin, and the relation between obesity and Ghrelin. Finally, we referred to the Ghrelin and related substances as a drug design target for obesity.
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Changes in Subcellular Distribution of n-Octanoyl or n-Decanoyl Ghrelin in Ghrelin-Producing Cells
Frontiers in endocrinology, 2013Co-Authors: Yoshihiro Nishi, Kenji Kangawa, Hiroshi Hosoda, Hiroharu Mifune, Eiichiro Tanaka, Akira Yabuki, Yuji Tajiri, Rumiko Hirata, Masayasu KojimaAbstract:Background: The enzyme Ghrelin O-acyltransferase (GOAT) catalyzes the acylation of Ghrelin. The molecular form of GOAT, together with its reaction in vitro, has been reported previously. However, the sub-cellular processes governing the acylation of Ghrelin remain to be elucidated. Methods: Double immunoelectron microscopy was used to examine changes in the relative proportions of secretory granules containing n-octanoyl Ghrelin (C8-Ghrelin) or n-decanoyl Ghrelin (C10-Ghrelin) in Ghrelin-producing cells of mouse stomachs. The dynamics of C8-type (possessing C8-Ghrelin exclusively), C10-type (possessing C10-Ghrelin only) and mixed-type secretory granules (possessing both C8- and C10-Ghrelin) were investigated after fasting for 48h or after two weeks’ feeding with chow containing glyceryl-tri-octanoate (C8-MCT) or glyceryl-tri-decanoate (C10-MCT). The dynamics of C8- or C10-Ghrelin immunoreactivity (ir-C8- or ir-C10-Ghrelin) within the mixed-type granules were also investigated. Results: Immunoelectron microscopic analysis revealed the co-existence of C8- and C10-Ghrelin within the same secretory granules (mixed-type) in Ghrelin-producing cells. Compared to control mice fed standard chow, the ratio of C10-type secretory granules increased significantly after ingestion of C10-MCT, whereas that of C8-type granules declined significantly under the same treatment. After ingestion of C8-MCT, the proportion of C8-type secretory granules increased significantly. Within the mixed-type granules the ratio of ir-C10-Ghrelin increased significantly and that of ir-C8-Ghrelin decreased significantly upon fasting. Conclusions: These findings confirmed that C10-Ghrelin, another acyl-form of active Ghrelin, is stored within the same secretory granules as C8-Ghrelin, and suggested that the types of medium-chain acyl-molecules surrounding and available to the Ghrelin-GOAT system may affect the physiological processes of Ghrelin acylation.
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Ghrelin prevents the development of experimental diabetic neuropathy in rodents
European Journal of Pharmacology, 2013Co-Authors: Wakaba Tsuchimochi, Itaru Kyoraku, Kazutaka Shiomi, Hideki Yamaguchi, Koji Toshinai, Kenji Kangawa, Masamitsu NakazatoAbstract:Ghrelin is an acylated peptide discovered in gastric extracts as an endogenous ligand for the growth hormone secretagogue (GHS) receptor. This peptide increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. Our study investigated the pharmacological effect of Ghrelin in the prevention of polyneuropathy in streptozotocin-induced diabetes mellitus in C57BL/6N mice, GHS receptor-deficient mice, and growth hormone-deficient rats. Ghrelin or desacyl-Ghrelin was administered daily for four weeks immediately after disease onset. The effects of Ghrelin on food intake, body weight, blood glucose and plasma insulin levels, nerve conduction velocities, temperature sensation, and 8-isoprostaglandin F2α (8-iso-PGF2α) levels were examined. We found that Ghrelin administration did not change food intake, body weight gain, blood glucose levels, or plasma insulin levels in C57BL/6N mice in comparison with mice treated with saline or desacyl-Ghrelin administration. Ghrelin administration, but not desacyl-Ghrelin, prevented motor and sensory polyneuropathy and reduced the plasma concentrations of 8-iso-PGF2α in C57BL/6N mice. Ghrelin also prevented the reduction in nerve conduction velocities in growth hormone-deficient rats, but not in GHS receptor-knockout mice. In conclusion, Ghrelin administration in a rodent model of diabetes prevented polyneuropathy, and this effect was mediated through the GHS receptor and was independent of growth hormone. The protection against the development of experimental diabetic polyneuropathy by Ghrelin could be key in preventing this otherwise intractable disorder.
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Transgenic mice overexpressing Ghrelin or Ghrelin analog.
Methods in enzymology, 2012Co-Authors: Hiroyuki Ariyasu, Kenji Kangawa, Go Yamada, Hiroshi Iwakura, Takashi Akamizu, Kazuwa NakaoAbstract:Abstract To understand the chronic effects of Ghrelin, genetically engineered mouse models would be useful. Early studies, however, suggested that it was challenging to generate Ghrelin gain-of-activity models by standard procedures. Although several groups have been trying to generate transgenic (Tg) mice overexpressing Ghrelin, almost all these animals produced only des-acyl Ghrelin rather than acylated Ghrelin. Therefore, to elucidate the mechanism for the fatty acid modification in Ghrelin, many researchers have been seeking an enzyme that would catalyze the acylation of Ghrelin with an octanoic acid. In 2008, Ghrelin O -acyltransferase (GOAT) was identified at last, and thereafter double-Tg mice overexpressing Ghrelin and GOAT were generated by Kirchner et al. On the other hand, we have succeeded in generating Tg mice overexpressing Trp 3 -Ghrelin, a Ghrelin analog that does not require posttranscriptional modification with GOAT for activity. These Ghrelin gain-of-activity models are useful tools for evaluating the long-term pathophysiological and/or pharmacological effects of Ghrelin or Ghrelin analogs and provide insight into the physiological roles of Ghrelin/GHS-R systems.
Masayasu Kojima - One of the best experts on this subject based on the ideXlab platform.
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Physiological roles of Ghrelin on obesity
Obesity research & clinical practice, 2013Co-Authors: Takahiro Sato, Kenji Kangawa, Takanori Ida, Yuki Nakamura, Yuki Shiimura, Masayasu KojimaAbstract:Ghrelin is a stomach hormone that acts as an endogenous ligand of orphan G-protein coupled receptor. Ghrelin has various physiological functions, such as the stimulation of growth hormone release and of appetite, and fat accumulation. Ghrelin is the only peripheral hormone to transmit satiety signal. Mature Ghrelin peptide is consisted of 28 amino acid residues, and is unusual among peptide hormones in that Ser3 is n-octanoylated to obtain. Furthermore, this modification is essential for Ghrelin's activity. In order to add this side chain to acyl Ghrelin, it is necessary for the recently discovered enzyme, Ghrelin-O-acyl transferase (GOAT). Therefore, to understand of Ghrelin's functions, it is useful to obtain the knowledge on structures and functions of Ghrelin, Ghrelin receptor and GOAT. Here, we review our current understanding of the structures and functions of Ghrelin, and the relation between obesity and Ghrelin. Finally, we referred to the Ghrelin and related substances as a drug design target for obesity.
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Changes in Subcellular Distribution of n-Octanoyl or n-Decanoyl Ghrelin in Ghrelin-Producing Cells
Frontiers in endocrinology, 2013Co-Authors: Yoshihiro Nishi, Kenji Kangawa, Hiroshi Hosoda, Hiroharu Mifune, Eiichiro Tanaka, Akira Yabuki, Yuji Tajiri, Rumiko Hirata, Masayasu KojimaAbstract:Background: The enzyme Ghrelin O-acyltransferase (GOAT) catalyzes the acylation of Ghrelin. The molecular form of GOAT, together with its reaction in vitro, has been reported previously. However, the sub-cellular processes governing the acylation of Ghrelin remain to be elucidated. Methods: Double immunoelectron microscopy was used to examine changes in the relative proportions of secretory granules containing n-octanoyl Ghrelin (C8-Ghrelin) or n-decanoyl Ghrelin (C10-Ghrelin) in Ghrelin-producing cells of mouse stomachs. The dynamics of C8-type (possessing C8-Ghrelin exclusively), C10-type (possessing C10-Ghrelin only) and mixed-type secretory granules (possessing both C8- and C10-Ghrelin) were investigated after fasting for 48h or after two weeks’ feeding with chow containing glyceryl-tri-octanoate (C8-MCT) or glyceryl-tri-decanoate (C10-MCT). The dynamics of C8- or C10-Ghrelin immunoreactivity (ir-C8- or ir-C10-Ghrelin) within the mixed-type granules were also investigated. Results: Immunoelectron microscopic analysis revealed the co-existence of C8- and C10-Ghrelin within the same secretory granules (mixed-type) in Ghrelin-producing cells. Compared to control mice fed standard chow, the ratio of C10-type secretory granules increased significantly after ingestion of C10-MCT, whereas that of C8-type granules declined significantly under the same treatment. After ingestion of C8-MCT, the proportion of C8-type secretory granules increased significantly. Within the mixed-type granules the ratio of ir-C10-Ghrelin increased significantly and that of ir-C8-Ghrelin decreased significantly upon fasting. Conclusions: These findings confirmed that C10-Ghrelin, another acyl-form of active Ghrelin, is stored within the same secretory granules as C8-Ghrelin, and suggested that the types of medium-chain acyl-molecules surrounding and available to the Ghrelin-GOAT system may affect the physiological processes of Ghrelin acylation.
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Structure, regulation and function of Ghrelin.
Journal of biochemistry, 2011Co-Authors: Takahiro Sato, Kenji Kangawa, Yuki Nakamura, Yuki Shiimura, Hideko Ohgusu, Masayasu KojimaAbstract:Ghrelin is a stomach hormone that acts as an endogenous ligand of orphan G-protein-coupled receptor. Ghrelin is a 28-amino acid peptide existing in two major forms: n-octanoyl-modified Ghrelin, which possesses an n-octanoyl modification on serine-3 and des-acyl Ghrelin. Fatty acid modification of Ghrelin is essential for Ghrelin-induced growth hormone release from the pituitary and appetite stimulation. This acyl-modification of Ghrelin is catalysed by Ghrelin-O-acyl transferase recently identified. Despite the number of innovative advancements in this field of research, there are still many aspects of Ghrelin function and biosynthesis process that remain to be clarified. Here, we review the current understanding of the structure, regulation and function of Ghrelin; this review is intended for researchers who will be involved in this field in the future.
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structural divergence of human Ghrelin identification of multiple Ghrelin derived molecules produced by post translational processing
Journal of Biological Chemistry, 2003Co-Authors: Hiroshi Hosoda, Masayasu Kojima, Tsunekazu Mizushima, Shigeomi Shimizu, Kenji KangawaAbstract:Ghrelin, a novel 28-amino acid peptide with an n-octanoyl modification at Ser3, was isolated from rat stomach and found to be an endogenous ligand for the growth-hormone secretagogue receptor (GHS-R). This octanoyl modification is essential for Ghrelin-induced GH release. We report here the purification and identification of human Ghrelin from the stomach, as well as structural analysis of the human Ghrelin gene and quantitation of changes in plasma Ghrelin concentration before and after gastrectomy. Human Ghrelin was purified from the stomach by gel filtration and high performance liquid chromatography, using a Ghrelin-specific radioimmunoassay and an intracellular calcium influx assay on a stable cell line expressing GHS-R to test the fractions. In the course of purification, we isolated human Ghrelin of the expected size, as well as several other Ghrelin-derived molecules. Classified into four groups by the type of acylation observed at Ser3; these peptides were found to be non-acylated, octanoylated (C8:0), decanoylated (C10:0), and possibly decenoylated (C10:1). All peptides found were either 27 or 28 amino acids in length, the former lacking the C-terminal Arg28, and are derived from the same Ghrelin precursor through two alternative pathways. The major active form of human Ghrelin is a 28-amino acid peptide octanoylated at Ser3, as was found for rat Ghrelin. Synthetic octanoylated and decanoylated Ghrelins produce intracellular calcium increases in GHS-R-expressing cells and stimulate GH release in rats to a similar degree. Both Ghrelin and the Ghrelin-derived molecules were found to be present in plasma as well as stomach tissue. Plasma levels of immunoreactive Ghrelin after total gastrectomy in three patients were reduced to approximately half of their pre-gastrectomy values, after which they gradually increased. This suggests that the stomach is the major source of circulating Ghrelin and that other tissues compensate for the loss of Ghrelin production after gastrectomy.
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Plasma Ghrelin and desacyl Ghrelin concentrations in renal failure
Journal of the American Society of Nephrology : JASN, 2002Co-Authors: Akihiro Yoshimoto, Hiroshi Hosoda, Masayasu Kojima, Kazuhiko Takaya, Kiyoshi Mori, Akira Sugawara, Masashi Mukoyama, Kensei Yahata, Takayoshi Suganami, Kenji KangawaAbstract:Ghrelin is a novel hormone that possesses growth hormone (GH)-releasing, cardiovascular, and metabolic activities. Ghrelin is a unique acylated polypeptide, and the naked peptide, desacyl Ghrelin, does not have the activity. This study examines plasma Ghrelin concentrations in 41 patients with mild to severe renal diseases. Two kinds of radioimmunoassays were used: amino-terminal immunoreactivity represents Ghrelin alone (N-IR), and carboxyl-terminal immunoreactivity corresponds to the sum of both Ghrelin and desacyl Ghrelin (C-IR). In all subjects, the plasma N-IR was much smaller than the C-IR, indicating that desacyl Ghrelin predominates over Ghrelin in the circulation. The plasma C-IR, but not N-IR, was significantly correlated with the serum creatinine level and was increased 2.8-fold in patients with end-stage renal disease compared with those in patients with normal renal function. The plasma GH concentration was significantly correlated with the plasma N-IR and the C-IR, as well as with the serum creatinine level. Bilateral nephrectomy in mice caused marked increase in the plasma C-IR without significant changes in the local C-IR and Ghrelin mRNA level in the stomach, which is the main site of Ghrelin production. These findings suggest that circulating Ghrelin concentrations play a role in the regulation of blood GH concentrations and that the kidney is an important site for clearance and/or degradation of desacyl Ghrelin. Furthermore, elevation of blood GH levels in renal failure seems to be caused by a mechanism other than alteration in the circulating Ghrelin concentration.
Akio Inui - One of the best experts on this subject based on the ideXlab platform.
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Regulative Roles of Ghrelin in Ingestive Behavior, Upper Gastrointestinal Motility, and Secretion
Current Nutrition & Food Science, 2012Co-Authors: Hirotaka Ueda, Akihiro Asakawa, Haruka Amitani, Takakazu Yagi, Shouichi Miyawaki, Akio InuiAbstract:Ghrelin was recently identified as the first endogenous ligand for growth hormone secretagogue receptors (previously known as orphan receptors). Two major molecular forms of Ghrelin are found in the stomach and plasma: acyl Ghrelin with O-n-octanoylated serine at position 3 and des-acyl Ghrelin. Interestingly, these distinct molecular forms play contrasting roles in ingestive behavior, upper gastrointestinal motility, and gastric acid secretion. Acyl Ghrelin stimulates food intake both in fed and fasted rodents and induces adiposity, alleviates ingestive behavior, stimulates gastrointestinal motor activity and gastric acid secretion, and accelerates gastric emptying in several species. In contrast, des-acyl Ghrelin has been demonstrated to disrupt gastric motility in rats and delay gastric emptying in mice and rats. Thus, acyl Ghrelin is a potent stimulator of ingestive behavior, gastrointestinal motility, and gastric acid secretion, whereas des-acyl Ghrelin exerts opposing effects on ingestive behavior and gastrointestinal motility but does not affect gastric acid secretion. Ghrelin is expected to be used in various applications such as therapeutic strategies for obesity, anorexia, cachexia, and cardiovascular disease in the clinical setting. In this article, we review the evidence on the roles of acyl Ghrelin and des-acyl Ghrelin in the regulation of ingestive behavior, upper gastrointestinal motility, and gastric acid secretion in mammals; moreover, we mention the effects of Ghrelin on oral functions.
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plasma obestatin concentrations are negatively correlated with body mass index insulin resistance index and plasma leptin concentrations in obesity and anorexia nervosa
Biological Psychiatry, 2008Co-Authors: Toshihiro Nakahara, Daisuke Yasuhara, Takeo Sakoguchi, Mayra Mayumi Kamiji, Nobuhiro Shimada, Toshiro Harada, Akihiro Asakawa, Haruka Amitani, Akio InuiAbstract:Background Obestatin is a recently identified Ghrelin gene product that was reported to inhibit appetite and gastric motility in contrast to Ghrelin. We investigated fasting obestatin and Ghrelin levels in patients with obesity and anorexia nervosa. Methods Fasting plasma obestatin, acyl-Ghrelin, desacyl-Ghrelin, leptin, glucose serum adiponectin, and insulin were measured in 10 obese subjects, 11 restricting-type anorexics, and 11 control subjects. Results Obese group had significantly lower levels of obestatin ( p p r = −.74), glucose ( r = −.56), insulin ( r = −.55), leptin ( r = −.66), and also with the homeostasis model assessment of insulin resistance (HOMA-R) ( r = −.49) and was positively correlated with acyl-Ghrelin ( r = .65) and desacyl-Ghrelin ( r = .60). No correlation was seen between obestatin and adiponectin, but the latter was negatively correlated with both acyl-Ghrelin and desacyl-Ghrelin. Desacyl-Ghrelin to acyl-Ghrelin ratio was significantly different between anorexic and control groups ( p Conclusions Both obestatin and Ghrelin are increased in anorexic and decreased in obesity. We suggest that obestatin is a nutritional marker reflecting body adiposity and insulin resistance.
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The role of Ghrelin and Ghrelin analogues in wasting disease.
Current opinion in clinical nutrition and metabolic care, 2008Co-Authors: Mayra Mayumi Kamiji, Akio InuiAbstract:The purpose of this review is to summarize recent studies that investigated the role of Ghrelin and Ghrelin analogs in wasting conditions. Numerous studies have demonstrated potential beneficial effects exerted by Ghrelin in a number of diseases associated with wasting. Besides Ghrelin's orexigenic effect, anabolic as well as anti-inflammatory activity mediated by Ghrelin have been investigated in wasting conditions such as cancer, diabetes mellitus, malabsorptive diseases, chronic obstructive pulmonary disease, anorexia nervosa, renal failure, liver failure, and chronic heart failure. Encouraging results have been obtained from experimental studies and a few clinical trials using subcutaneous administration of Ghrelin and Ghrelin agonists in cachexia. In-vitro studies have shown Ghrelin and des-acyl Ghrelin biological activities on proliferation of tumor cells and abnormal tissues. The recent studies support the possible positive effects of Ghrelin in therapeutic approaches and adjunct treatment of a number of diseases associated with wasting. Utilization of agonists of the Ghrelin receptor growth hormone secretagogue-1a is a promising approach for clinical use. Randomized and placebo-controlled studies, including large number of patients are further required.
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Stomach regulates energy balance via acylated Ghrelin and desacyl Ghrelin
Gut, 2005Co-Authors: Akihiro Asakawa, Akio Inui, Mineko Fujimiya, Ruka Sakamaki, Naotaka Shinfuku, Y Ueta, Michael M. Meguid, Masato KasugaAbstract:The gastric peptide Ghrelin, an endogenous ligand for growth-hormone secretagogue receptor, has two major molecular forms: acylated Ghrelin and desacyl Ghrelin. Acylated Ghrelin induces a positive energy balance, while desacyl Ghrelin has been reported to be devoid of any endocrine activities. The authors examined the effects of desacyl Ghrelin on energy balance. The authors measured food intake, gastric emptying, c-Fos expression in the hypothalamus, and gene expression of hypothalamic neuropeptides in mice after administration of desacyl Ghrelin. To explore the effects of long term overexpression of desacyl Ghrelin, transgenic mice that overexpressed desacyl Ghrelin were created. Administration of desacyl Ghrelin decreased food intake and gastric emptying rate through an action on the paraventricular nucleus and the arcuate nucleus in the hypothalamus. Gene expression of anorexigenic cocaine and amphetamine regulated transcript and urocortin in the hypothalamus was increased by desacyl Ghrelin. Desacyl Ghrelin overexpressing mice exhibited a decrease in body weight, food intake, and fat pad mass weight accompanied by moderately decreased linear growth. Gastric emptying was also decreased in desacyl Ghrelin overexpressing mice. These findings indicate that in contrast to acylated Ghrelin, desacyl Ghrelin induces a negative energy balance by decreasing food intake and delaying gastric emptying. The effect is mediated via the hypothalamus. Although derived from the same precursor, the inverse effects of these two peptides suggest that the stomach might be involved as an endocrine organ in the regulation of the energy balance.
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stomach regulates energy balance via acylated Ghrelin and desacyl Ghrelin
Gut, 2005Co-Authors: Akihiro Asakawa, Akio Inui, Mineko Fujimiya, Ruka Sakamaki, Naotaka Shinfuku, Y Ueta, Michael M. Meguid, Masato KasugaAbstract:Background/Aims: The gastric peptide Ghrelin, an endogenous ligand for growth-hormone secretagogue receptor, has two major molecular forms: acylated Ghrelin and desacyl Ghrelin. Acylated Ghrelin induces a positive energy balance, while desacyl Ghrelin has been reported to be devoid of any endocrine activities. The authors examined the effects of desacyl Ghrelin on energy balance. Methods: The authors measured food intake, gastric emptying, c-Fos expression in the hypothalamus, and gene expression of hypothalamic neuropeptides in mice after administration of desacyl Ghrelin. To explore the effects of long term overexpression of desacyl Ghrelin, transgenic mice that overexpressed desacyl Ghrelin were created. Results: Administration of desacyl Ghrelin decreased food intake and gastric emptying rate through an action on the paraventricular nucleus and the arcuate nucleus in the hypothalamus. Gene expression of anorexigenic cocaine and amphetamine regulated transcript and urocortin in the hypothalamus was increased by desacyl Ghrelin. Desacyl Ghrelin overexpressing mice exhibited a decrease in body weight, food intake, and fat pad mass weight accompanied by moderately decreased linear growth. Gastric emptying was also decreased in desacyl Ghrelin overexpressing mice. Conclusions: These findings indicate that in contrast to acylated Ghrelin, desacyl Ghrelin induces a negative energy balance by decreasing food intake and delaying gastric emptying. The effect is mediated via the hypothalamus. Although derived from the same precursor, the inverse effects of these two peptides suggest that the stomach might be involved as an endocrine organ in the regulation of the energy balance.
Takafumi Sakai - One of the best experts on this subject based on the ideXlab platform.
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Ghrelin Cells in the Gastrointestinal Tract
International journal of peptides, 2010Co-Authors: Ichiro Sakata, Takafumi SakaiAbstract:Ghrelin is 28-amino-acid peptide that was discovered from the rat and human stomach in 1999. Since the discovery of Ghrelin, various functions of Ghrelin, including growth hormone release, feeding behavior, glucose metabolism, memory, and also antidepressant effects, have been studied. It has also been reported that Ghrelin in the gastrointestinal tract has an important physiological effect on gastric acid secretion and gastrointestinal motility. Ghrelin has a unique structure that is modified by O-acylation with n-octanoic acid at third serine residues, and this modification enzyme has recently been identified and named Ghrelin O-acyl transferase (GOAT). Ghrelin is considered to be a gut-brain peptide and is abundantly produced from endocrine cells in the gastrointestinal mucosa. In the gastrointestinal tract, Ghrelin cells are most abundant in the stomach and are localized in gastric mucosal layers. Ghrelin cells are also widely distributed throughout the gastrointestinal tract. In addition, abundance of Ghrelin cells in the gastric mucosa is evolutionally conserved from mammals to lower vertebrates, indicating that gastric Ghrelin plays important roles for fundamental physiological functions. Ghrelin cells in the gastrointestinal tract are a major source of circulating plasma Ghrelin, and thus understanding the physiology of these cells would reveal the biological significance of Ghrelin.
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Characteristic features of Ghrelin cells in the gastrointestinal tract and the regulation of stomach Ghrelin expression and production.
World journal of gastroenterology, 2008Co-Authors: Zheng Zhao, Takafumi SakaiAbstract:Ghrelin was isolated as an endogenous ligand for the GH secretagogue receptor from the rat stomach. Although physiological effects of Ghrelin have been revealed by numerous studies, the regulation of stomach Ghrelin remains obscure, and the factor that directly regulates Ghrelin expression and production has not been identified. Here, we show some data regarding the characteristic features of Ghrelin cells and the regulation of stomach Ghrelin. In the gastrointestinal tract, Ghrelin cells were identified as opened- and closed-type cells, and it was found that the number of Ghrelin cells decreased from the stomach to the colon. The postnatal change in number of Ghrelin cells in the stomach showed a sexually dimorphic pattern, indicating a role of estrogen in the regulation of stomach Ghrelin. In vitro studies revealed that estrogen stimulated both Ghrelin expression and production and that treatment with formestane, an aromatase (estrogen synthetase) inhibitor, decreased Ghrelin expression level. On the other hand, leptin was found to inhibit both basal and estrogen-stimulated Ghrelin expression. Moreover, both aromatase mRNA-expressing cells and leptin cells were found to be located close to Ghrelin cells in the gastric mucosa. Furthermore, we found an inverse relationship between gastric Ghrelin and leptin levels in a fasting state, and we revealed relative changes in expression of gastric Ghrelin, estrogen and leptin in the postnatal rats. We propose that gastric estrogen and leptin directly regulate stomach Ghrelin and that the balance control through gastric estrogen and leptin contributes to the altered Ghrelin expression level in some physiological states.
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Identification of immunoreactive plasma and stomach Ghrelin, and expression of stomach Ghrelin mRNA in the bullfrog, Rana catesbeiana.
General and comparative endocrinology, 2006Co-Authors: Hiroyuki Kaiya, Kenji Kangawa, Ichiro Sakata, Kazutoshi Yamamoto, Aya Koda, Takafumi Sakai, Sakae KikuyamaAbstract:In this study, we established a radioimmunoassay (RIA) specific for Ghrelin from the bullfrog Rana catesbeiana using a novel antibody raised against the C-terminal amino acid sequence of bullfrog Ghrelin [13-28]. We also examined the distribution of Ghrelin-producing cells in the stomachs of bullfrogs using this antibody and a cRNA probe specific for the bullfrog Ghrelin gene. Ghrelin levels in plasma and stomach extracts were approximately 150 fmol/ml and 83-135 fmol/mg wet tissue, respectively. Reverse-phase high performance liquid chromatographic analysis, combined with bullfrog Ghrelin RIA, revealed that Ghrelin immunoreactivity in the stomach was composed of non-acylated Ghrelin (des-acyl Ghrelin) and several acylated forms of Ghrelin bearing different fatty acid modifications, which could induce increases in intracellular Ca2+ in cells expressing the rat GH secretagogue receptor. In the stomach, the major storage form was acylated Ghrelin. In bullfrog plasma, however, the majority of Ghrelin immunoreactivity was des-acyl Ghrelin and C-terminal fragments of frog Ghrelin. Acylated Ghrelin forms comprised only minor peaks. Ghrelin-immunopositive and Ghrelin mRNA-expressing cells were observed within the mucosal layer of the stomach. Following starvation, significant increases in plasma Ghrelin levels and stomach Ghrelin mRNA levels were observed as early as 10 days after starvation. These results indicate that Ghrelin is present in the stomach and plasma of the bullfrog, which can be detected with our novel antibody. Interestingly, the primary storage form of Ghrelin in the stomach differed from the circulating form dominating in the plasma. Furthermore, increases in Ghrelin levels in plasma and mRNA levels in the stomach after starvation suggest the possible involvement of Ghrelin in energy homeostasis in the bullfrog.
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Postnatal changes in Ghrelin mRNA expression and in Ghrelin-producing cells in the rat stomach
The Journal of endocrinology, 2002Co-Authors: Ichiro Sakata, Kenji Kangawa, Toru Tanaka, Maki Matsubara, Mami Yamazaki, S Tani, Y. Hayashi, Takafumi SakaiAbstract:Ghrelin was recently isolated from the rat stomach as an endogenous ligand for the GH secretagogue receptor. Although it is well known that a large amount of Ghrelin is produced in the gastrointestinal tract, developmental changes in Ghrelin mRNA expression and differentiation of Ghrelin-immunopositive (Ghrelin-ip) and mRNA-expressing (Ghrelin-ex) cells in the stomach have not been elucidated. In this study, we therefore investigated the changes in Ghrelin mRNA expression levels and in the numbers of Ghrelin-ip and -ex cells in the stomachs of 1- to 8-week-old male and female rats by Northern blot analysis, immunohistochemistry and in situ hybridization. Northern blot analysis showed that the level of weak Ghrelin mRNA expression was low in the postnatal period but then increased in a dimorphic pattern, i.e. transient stagnation at 4 weeks in the male rats and at 5 weeks in the female rats. The number of Ghrelin-ip and Ghrelin-ex cells also increased after birth, and more numerous Ghrelin cells were found in female rats than in male rats, and this finding was confirmed by Northern blot analysis. Ghrelin-ip and -ex cells first appeared in the glandular base of the fundic gland and then they were found in the glandular base and the glandular neck at 3 weeks of age, suggesting that the distribution of Ghrelin cells is extended from the glandular base to the glandular neck during the postneonatal development period. This is the first report on detailed changes in postneonatal Ghrelin expression level and in the number of Ghrelin cells in the rat stomach. The sexual dimorphism of Ghrelin expression and Ghrelin cell differentiation suggest that Ghrelin plays an important physiological role in the stomach.
Masato Kasuga - One of the best experts on this subject based on the ideXlab platform.
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Stomach regulates energy balance via acylated Ghrelin and desacyl Ghrelin
Gut, 2005Co-Authors: Akihiro Asakawa, Akio Inui, Mineko Fujimiya, Ruka Sakamaki, Naotaka Shinfuku, Y Ueta, Michael M. Meguid, Masato KasugaAbstract:The gastric peptide Ghrelin, an endogenous ligand for growth-hormone secretagogue receptor, has two major molecular forms: acylated Ghrelin and desacyl Ghrelin. Acylated Ghrelin induces a positive energy balance, while desacyl Ghrelin has been reported to be devoid of any endocrine activities. The authors examined the effects of desacyl Ghrelin on energy balance. The authors measured food intake, gastric emptying, c-Fos expression in the hypothalamus, and gene expression of hypothalamic neuropeptides in mice after administration of desacyl Ghrelin. To explore the effects of long term overexpression of desacyl Ghrelin, transgenic mice that overexpressed desacyl Ghrelin were created. Administration of desacyl Ghrelin decreased food intake and gastric emptying rate through an action on the paraventricular nucleus and the arcuate nucleus in the hypothalamus. Gene expression of anorexigenic cocaine and amphetamine regulated transcript and urocortin in the hypothalamus was increased by desacyl Ghrelin. Desacyl Ghrelin overexpressing mice exhibited a decrease in body weight, food intake, and fat pad mass weight accompanied by moderately decreased linear growth. Gastric emptying was also decreased in desacyl Ghrelin overexpressing mice. These findings indicate that in contrast to acylated Ghrelin, desacyl Ghrelin induces a negative energy balance by decreasing food intake and delaying gastric emptying. The effect is mediated via the hypothalamus. Although derived from the same precursor, the inverse effects of these two peptides suggest that the stomach might be involved as an endocrine organ in the regulation of the energy balance.
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stomach regulates energy balance via acylated Ghrelin and desacyl Ghrelin
Gut, 2005Co-Authors: Akihiro Asakawa, Akio Inui, Mineko Fujimiya, Ruka Sakamaki, Naotaka Shinfuku, Y Ueta, Michael M. Meguid, Masato KasugaAbstract:Background/Aims: The gastric peptide Ghrelin, an endogenous ligand for growth-hormone secretagogue receptor, has two major molecular forms: acylated Ghrelin and desacyl Ghrelin. Acylated Ghrelin induces a positive energy balance, while desacyl Ghrelin has been reported to be devoid of any endocrine activities. The authors examined the effects of desacyl Ghrelin on energy balance. Methods: The authors measured food intake, gastric emptying, c-Fos expression in the hypothalamus, and gene expression of hypothalamic neuropeptides in mice after administration of desacyl Ghrelin. To explore the effects of long term overexpression of desacyl Ghrelin, transgenic mice that overexpressed desacyl Ghrelin were created. Results: Administration of desacyl Ghrelin decreased food intake and gastric emptying rate through an action on the paraventricular nucleus and the arcuate nucleus in the hypothalamus. Gene expression of anorexigenic cocaine and amphetamine regulated transcript and urocortin in the hypothalamus was increased by desacyl Ghrelin. Desacyl Ghrelin overexpressing mice exhibited a decrease in body weight, food intake, and fat pad mass weight accompanied by moderately decreased linear growth. Gastric emptying was also decreased in desacyl Ghrelin overexpressing mice. Conclusions: These findings indicate that in contrast to acylated Ghrelin, desacyl Ghrelin induces a negative energy balance by decreasing food intake and delaying gastric emptying. The effect is mediated via the hypothalamus. Although derived from the same precursor, the inverse effects of these two peptides suggest that the stomach might be involved as an endocrine organ in the regulation of the energy balance.
