Ghrelin stimulates gastric emptying and hunger in normal-weight humans

CONTEXT: Ghrelin is produced primarily by enteroendocrine cells in the gastric mucosa and increases gastric emptying in patients with gastroparesis. MAIN OBJECTIVE: The objective of the study was to evaluate the effect of ghrelin on gastric emptying, appetite, and postprandial hormone secretion in normal volunteers. DESIGN: This was a randomized, double-blind, crossover study. SUBJECTS: Subjects included normal human volunteers and patients with GH deficiency. INTERVENTION: Intervention included saline or ghrelin (10 pmol/kg.min) infusion for 180 min after intake of a radioactively labeled omelette (310 kcal) or GH substitution in GH-deficient patients. MAIN OUTCOME MEASURES: Measures consisted of gastric empty-ing parameters and postprandial plasma levels of ghrelin, cholecystokinin, glucagon-like peptide-1, peptide YY, and motilin. RESULTS: The emptying rate was significantly faster for ghrelin (1.26 +/- 0.1% per minute), compared with saline (0.83% per minute) (P < 0.001). The lag phase (16.2 +/- 2.2 and 26.5 +/- 3.8 min) and half-emptying time (49.4 +/- 3.9 and 75.6 +/- 4.9 min) of solid gastric emptying were shorter during ghrelin infusion, compared with infusion of saline (P < 0.001). The postprandial peak in plasma concentration for cholecystokinin and glucagon-like peptide-1 occurred earlier and was higher during ghrelin infusion. There was no significant effect of ghrelin on plasma motilin or peptide YY. There was no difference in gastric emptying before and after GH substitution. CONCLUSION: Our results demonstrate that ghrelin increases the gastric emptying rate in normal humans. The effect does not seem to be mediated via GH or motilin but may be mediated by the vagal nerve or directly on ghrelin receptors in the stomach. Ghrelin receptor agonists may have a role as prokinetic agents.     

Influence of ghrelin on interdigestive gastrointestinal motility in humans

BACKGROUND: Recent studies in animals have shown that ghrelin stimulates upper gastrointestinal motility through the vagus and enteric nervous system. The aim of the present study therefore was to simultaneously investigate the effect of administration of ghrelin on upper gastrointestinal motility and to elucidate its mode of action by measuring plasma levels of gastrointestinal hormones in humans. MATERIALS AND METHODS: Nine healthy volunteers (four males; aged 22-35 years) underwent combined antroduodenal manometry and proximal stomach barostat study on two separate occasions at least one week apart. Twenty minutes after the occurrence of phase III of the migrating motor complex (MMC), saline or ghrelin 40 mug was administered intravenously over 30 minutes in a double blind, randomised, crossover fashion. Ghrelin, motilin, pancreatic polypeptide, glucagon, and somatostatin were measured by radioimmunoassay in blood samples obtained at 15-30 minute intervals. The influence of ghrelin or saline on MMC phases, hormone levels, and intraballoon volume was compared using paired t test, ANOVA, and chi(2) testing. RESULTS: Spontaneous phase III occurred in all subjects, with a gastric origin in four. Administration of ghrelin induced a premature phase III (12 (3) minutes, p<0.001; gastric origin in nine, p<0.05), compared with saline (95 (13) minutes, gastric origin in two). Intraballoon volumes before infusion were similar (135 (13) v 119 (13) ml; NS) but ghrelin induced a longlasting decrease in intraballoon volume (184 (31) v 126 (21) ml in the first 60 minutes; p<0.05). Administration of ghrelin increased plasma levels of pancreatic polypeptide and ghrelin but motilin, somatostatin, and glucagon levels were not altered. CONCLUSIONS: In humans, administration of ghrelin induces a premature gastric phase III of the MMC, which is not mediated through release of motilin. This is accompanied by prolonged increased tone of the proximal stomach.     

Effects of ghrelin on interdigestive contractions of the rat gastrointestinal tract

Ghrelin causes interdigestive contractions of the stom- ach in rats. However, it remains unknown whether ghrelin causes interdigestive contractions in the small intestine. Four strain gauge transducers were implanted on the antrum, duodenum, proximal and distal jejunum. After an overnight fast, gastrointestinal （GI） contrac- tions were recorded in freely moving conscious rats. Spontaneous phase m-like contractions were observed at every 13-16 min in rat GI tract. The fasted motor patterns were replaced by the fed motor pattern imme- diately after food intake. Two minutes after finishing the spontaneous phase Ill-like contractions in the antrum, acyl ghrelin （0.8, 2.4 and 8.0 μg/kg per min） was con- tinuously infused for 30 min. Three-five minutes after the starting ghrelin infusion, augmented phase Ⅲ-like contractions were observed at the antrum, duodenum, and jejunum. Ghrelin infusion （0.8, 2.4 and 8.0μg/kg per min） significantly increased motility index of phase Ⅲ-like contractions at the antrum and jejunum in a dose dependent manner, compared to that of saline in- jection. Thus, it is likely that exogenously administered ghrelin causes phase Ⅲ-like contraction at the antrum, which migrates to the duodenum and jejunum. The possible role of 5-HT, in addition to ghrelin, in mediating intestinal migrating motor complex （MMC）, is discussed.     

Ghrelin - a novel appetite-stimulating hormone which also affects gastrointestinal functions]

Ghrelin, a novel gastrointestinal peptide with 28 amino acids, is secreted from the A-like cells of the gastric fundus. This peptide hormone does not only promote the release of growth hormone, but also stimulates food intake, gastric motility and cardiac output. Increased plasma ghrelin level has been reported in patients with upper gastrointestinal (GI) disease or in their disease animal model, suggesting its important role in the pathogenesis of upper GI disease.     

Identification of genes for the ghrelin and motilin receptors and a novel related gene in fish, and stimulation of intestinal motility in zebrafish (Danio rerio) by ghrelin and motilin

In mammals ghrelin has a diverse range of effects including stimulation of gut motility but although present in teleost fish its effects on motility have not been investigated. The present study used bioinformatics to search for fish paralogues of the ghrelin receptor and the closely related motilin receptor, and investigated the effects of ghrelin and motilin on gut motility in zebrafish, Danio rerio. Fish paralogues of the human ghrelin and motilin receptor genes were identified, including those from the zebrafish. In addition, a third gene was identified in three species of pufferfish (the only fish genome completely sequenced), which is distinct from the ghrelin and motilin receptors but more closely aligned to these receptors relative to other G-protein coupled receptors. Immunohistochemistry demonstrated strong ghrelin receptor-like reactivity in the muscle of the zebrafish intestine. In isolated intestinal bulb and mid/distal intestine preparations, ghrelin, motilin, and the motilin receptor agonist erythromycin all evoked contraction; these responses ranged between 9% and 51% of the contractions evoked by carbachol (10(-6) M). There were some variations in the concentrations found to be active in the different tissues, e.g., whereas motilin and rat ghrelin caused contraction of the intestinal bulb circular muscle at concentrations as low as 10(-8) M, human ghrelin (10(-8) to 10(-6) M) was without activity. Neither ghrelin (10(-7) M) nor erythromycin (10(-5) M) affected the contractions evoked by electrical field stimulation. The results suggest that both ghrelin and motilin can regulate intestinal motility in zebrafish and most likely other teleosts, and are discussed in relation to the evolution of these regulatory peptides.     

Role of Ghrelin in the Pathophysiology of Gastrointestinal Disease

Ghrelin is a 28-amino-acid peptide that plays multiple roles in humans and other mammals. The functions of ghrelin include food intake regulation, gastrointestinal (GI) motility, and acid secretion by the GI tract. Many GI disorders involving infection, inflammation, and malignancy are also correlated with altered ghrelin production and secretion. Although suppressed ghrelin responses have already been observed in various GI disorders, such as chronic gastritis, Helicobacter pylori infection, irritable bowel syndrome, functional dyspepsia, and cachexia, elevated ghrelin responses have also been reported in celiac disease and inflammatory bowel disease. Moreover, we recently reported that decreased fasting and postprandial ghrelin levels were observed in female patients with functional dyspepsia compared with healthy subjects. These alterations of ghrelin responses were significantly correlated with meal-related symptoms (bloating and early satiation) in female functional dyspepsia patients. We therefore support the notion that abnormal ghrelin responses may play important roles in various GI disorders. Furthermore, human clinical trials and animal studies involving the administration of ghrelin or its receptor agonists have shown promising improvements in gastroparesis, anorexia, and cancer. This review summarizes the impact of ghrelin, its family of peptides, and its receptors on GI diseases and proposes ghrelin modulation as a potential therapy.     

胃促生长素与消化道运动

胃促生长素(ghrelin)是新发现的内源性多肽,有促生长激素分泌和调节食欲、调节能量代谢的作用,它主要由胃底X/A样细胞分泌,广泛分布于胃和肠道组织,且与胃动素在结构上有高度相同性,故其与消化道运动的关系近来备受关注,现综合有关文献,对ghrelin与消化道运动的关系作一综述.     

Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract

Background Motilin and ghrelin have been recognized as important endogenous regulators of gastrointestinal motor function in mammals, mediated respectively by the motilin receptor and by the closely related ghrelin receptor. The aims of this study were to explore the distribution of motilin and ghrelin receptors along the human gastrointestinal tract and to establish the molecular nature of the human motilin receptor. Methods Post mortem and surgical human tissue specimens with no hemorrhage, necrosis, or tumor were obtained from various parts of the gastrointestinal tract. We analyzed levels of expression of mRNA for motilin and ghrelin receptors and examined their molecular identities. Portions of some specimens were also studied by immunohistochemistry for expression of the motilin and ghrelin receptor. Results The long form of the motilin receptor, but not the short form, was expressed in all parts of the gastrointestinal tract, and expressed at higher levels in muscle than in mucosa. Motilin receptor immunoreactivity was present in muscle cells and the myenteric plexus, but not in mucosal or submucosal cells. In contrast, ghrelin receptor mRNA was expressed equally in all parts of the gastrointestinal tract, with similar levels of expression in mucosal and muscle layers. Conclusions Both the motilin and ghrelin receptors are expressed along the human gastrointestinal tract, but they have clearly distinct distributions in regard to both level and layer. The diffuse muscle expression of the motilin receptor, at both the levels of the gene and the protein product, along the entire gastrointestinal tract makes it a useful potential target for motilide drugs for dysmotility.     

Ontogeny and tissue-specific regulation of ghrelin mRNA expression suggest that ghrelin is primarily involved in the control of extraendocrine functions in the rat

Ghrelin is a 28-amino-acid gastric peptide that potently stimulates growth hormone (GH) secretion in vivo and in vitro. Ghrelin-expressing cells have been found in the oxyntic region of the stomach and in the arcuate nucleus of the hypothalamus. The aim of this work was to investigate the regional distribution and developmental changes in ghrelin mRNA levels in the pituitary, hypothalamus and gastrointestinal (GI) tract of the rat using a semiquantitative RT-PCR assay. We also describe the effects of ghrelin immunoneutralization in late gestation and those resulting from induction of an isolated GH deficiency in adult rats. Ghrelin mRNA was already expressed in the fetus by embryonic day 12 (E12), by E17 most of ghrelin mRNA was in the trunk. At E17, in situ hybridization did not reveal a clear expression of ghrelin mRNA in fetal stomach but showed high ghrelin mRNA levels in the placenta. In the pituitary gland, levels of ghrelin mRNA were high after birth but declined significantly with puberty, whereas in the hypothalamus they were barely detectable at birth and remained very low at all subsequent time points tested. In the GI tract, ghrelin mRNA levels were high from birth to 270 days of life. Immunoneutralization of ghrelin at E16 had no effect on survival or development. Rats showed normal somatotropic function, ghrelin expression and onset of puberty. In young adult rats, passive immunization against GHRH did not affect ghrelin mRNA levels in the pituitary, hypothalamus and stomach. Only a 72-hour fasting period induced a significant increase in ghrelin mRNA levels in the stomach, but not in the pituitary and hypothalamus. These results strongly indicate that ghrelin is an important GI hormone expressed early in life and primarily sensitive to nutritional status.     

Ghrelin in small intestine, its contribution to regulation of food intake and body weight in cross-intestinal parabiotic rats

Ghrelin has been shown to be associated with feeding behavior in humans and rodents. It has been suggested that ghrelin may play a role behind the effect of bariatric surgery. Inbred rats were made into parabiotic pairs so that they shared a single abdominal cavity. A further operation is performed later in which the small intestines are transected and re-connected so that one rat continually lost nutrition to its partner. Changes in food intake and body weight were recorded. Seven weeks later, content of ghrelin in the plasma, stomach and upper intestines were measured in the paired rats. Rats which lost nutrients to its counterpart (Loss rats) ingested significantly more food than sham control rats (p<0.001). Rats which gained nutrient (Gain rats) ingested less than controls (p<0.001). There was no significant difference in body weight, blood glucose, insulin, free fatty acids and triglycerides between the paired rats. There was significantly higher levels of ghrelin in the plasma (p<0.008) and the intestine of the Loss rats (p<0.02). There were no difference in ghrelin in the stomach between parabiotic rats and sham operated controls. The ghrelin content of the plasma and intestines were significantly higher in the Loss rats, which ate more, and normal in the Gain rats, which ate less than controls. Because no remarkable changes in the ghrelin content were observed in the stomach, difference in the quality of the chime may affect the local synthesis and release of ghrelin.     

Ghrelin suppresses secretion of luteinizing hormone in humans

CONTEXT: Ghrelin affects the hypothalamic-pituitary-gonadal axis in various nonhuman mammalians, predominantly by suppressing secretion of LH. However, for humans, no such evidence exists. OBJECTIVE: Our objective was to study the effect of ghrelin on secretion of LH and testosterone in humans. DESIGN, PARTICIPANTS, AND INTERVENTION: Nocturnal (2000-0700 h) secretion profiles of LH and testosterone were determined in 10 healthy males (25.7 +/- 3.0 yr) twice, receiving 50 microg ghrelin or placebo at 2200, 2300, 2400, and 0100 h, in this single-blind, randomized, cross-over study. RESULTS: Ghrelin was associated with significantly (P < 0.05) lower mean plasma levels of both LH (2340-0200 h) and testosterone (0040-0300 h) than placebo. LH peak levels of the pulse after first administration of ghrelin/placebo were significantly (P = 0.014) smaller in the ghrelin (2.98 +/- 1.34 mIU/ml) than in the placebo condition (4.37 +/- 1.09 mIU/ml). In addition, the interval between this and the preceding peak was significantly (P = 0.010) longer in the ghrelin (255.8 +/- 79.1 min) than in the placebo condition (190.8 +/- 51.0 min). Significantly (P = 0.005) more LH pulses occurred with placebo (3.2 +/- 0.75) than ghrelin (2.6 +/- 0.7) subsequent to ghrelin/placebo administration. CONCLUSIONS: Ghrelin caused both a delay and suppression of the amplitude of LH pulses. These findings are in accordance with those in nonhuman mammalians.     

Ghrelin secretion in humans is sexually dimorphic,suppressed by somatostatin,and not affected by the ambient growth hormone levels

We studied plasma ghrelin and GH concentrations over a 24-h period in young healthy men and women and in patients with acromegaly. Healthy subjects were restudied after administration of GH-lowering agents, octreotide or GHRH antagonist. Ghrelin concentrations in women studied during the late follicular stage of the cycle were about 3-fold higher than in men. Suppression of GH secretion by GHRH antagonist did not alter ghrelin concentration profiles. In the presence of high GH levels (acromegaly), ghrelin levels were similar to those found in healthy men. Administration of somatostatin analog octreotide suppressed both GH and ghrelin concentration profiles. We conclude that: 1) ghrelin secretion is sexually dimorphic in humans, with women in the late follicular stage having higher levels than men; 2) ghrelin secretion is suppressed by somatostatin; and 3) GH has no influence over ghrelin secretion.     

Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans

Ghrelin, a novel GH-releasing acylated peptide, was recently isolated from rat stomach. It stimulated the release of GH from the anterior pituitary through the GH secretagogue receptor (GHS-R). Ghrelin messenger RNA and the peptide are present in rat stomach, but its cellular source has yet to be determined. Using two different antibodies against the N- and C-terminal regions of rat ghrelin, we identified ghrelin-producing cells in the gastrointestinal tracts of rats and humans by light and electron microscopic immunohistochemistry and in situ hybridization combined with immunohistochemistry. Ghrelin-immunoreactive cells, which are not enterochromaffin-like cells, D cells, or enterochromaffin cells, accounted for about 20% of the endocrine cell population in rat and human oxyntic glands. Rat ghrelin was present in round, compact, electron-dense granules compatible with those of X/A-like cells whose hormonal product and physiological functions have not previously been clarified. The localization, population, and ultrastructural features of ghrelin-producing cells (Gr cells) indicate that they are X/A-like cells. Ghrelin also was found in enteric endocrine cells of rats and humans. Using two RIAs for the N- and C-terminal regions of ghrelin, we determined its content in the rat gastrointestinal tract. Rat ghrelin was present from the stomach to the colon, with the highest content being in the gastric fundus. Messenger RNAs of ghrelin and GHS-R also were found in these organs. Ghrelin probably functions not only in the control of GH secretion, but also in the regulation of diverse processes of the digestive system. Our findings provide clues to additional, as yet undefined, physiological functions of this novel gastrointestinal hormone.     

Circulating Ghrelin Levels in Patients with Various Upper Gastrointestinal Diseases

The stomach is the main source of circulating ghrelin. Plasma concentrations of this hormone in patients with various upper gastrointestinal diseases remain undetermined. Thus we measured plasma ghrelin levels by radioimmunoassay in 225 subjects, including 134 Helicobacter pylori-infected and 91 uninfected subjects. They included 67 patients with chronic gastritis (CG), 26 with benign gastric polyp (BGP), 24 with gastric ulcer (GU), 24 with reflux esophagitis (RE), 18 with duodenal ulcer (DU), 28 with acute gastritis (AG), 23 with gastric cancer (GC), and 39 who had normal mucosa on upper endoscopy (N). Plasma pepsinogen I and II levels were also measured. The extent of gastritis was assessed endoscopically. Ghrelin levels differed significantly among the different disease groups. Plasma ghrelin concentrations were lowest in the CG group, followed by the GU group, and highest in the AG patients. There was a significant difference in the levels between differentiated and undifferentiated GC. Ghrelin concentrations in BGP, RE, and DU patients were comparable to those in the N group. Ghrelin circulating levels were lower in H. pylori-positive than –negative individuals, but the significant differences among disease groups were still observed in H. pylori-infected and uninfected populations. Ghrelin concentrations correlated positively with plasma pepsinogen I levels and I/II ratios and inversely with the extent of H. pylori-related gastritis. Plasma ghrelin levels varied widely in diverse conditions of the upper digestive tract, reflecting the inflammatory and atrophic events of the background gastric mucosa. Further investigation is warranted to unravel the mechanisms of the high circulating ghrelin levels in certain upper gastrointestinal diseases.     

Ghrelin与消化系统的关系研究进展

Ghrelin是新近发现的一种脑肠肽,1999年由日本科学家Kojima从大鼠胃中分离出来,是生长激素促分泌素受体(GHSR)的天然配体,故又称生长素。Ghrelin可调节生长激素(GH)和其他激素的释放,调节能量代谢,抑制肿瘤细胞增殖,影响心血管功能。近来研究发现,Ghrelin与胃动素(motilin)及消化系统关系密切,此文就这方面的研究进展作一综述。     

Ghrelin suppresses secretion of FSH in males

Background  Ghrelin decreases the secretion of LH probably by suppressing the release of hypothalamic GnRH. So far however, there is no evidence that ghrelin affects also the secretion of FSH in humans, the other gonadotrophin regulated by GnRH.
Objective  Our objective was to study the effect of ghrelin on secretion of FSH in humans.
Design/study subjects  Nocturnal (20:00–07:00 h) secretion profiles of FSH were measured in 10 healthy males (25·3 ± 3·2 years) twice, receiving 50 µg ghrelin or placebo at 22:00, 23:00, 24:00, and 01:00 h, in this single-blind, randomized, cross-over study.
Results  Mean FSH plasma levels were significantly ( P <  0·05) lower with ghrelin than placebo between 01:00 and 02:20. Consistently, a significant decrease from baseline was only observed in the ghrelin but not in the placebo condition.
Conclusion  This study provides first evidence that ghrelin suppresses the secretion of FSH in humans.     

Effects of small intestinal and gastric glucose administration on the suppression of plasma ghrelin concentrations in healthy older men and women

OBJECTIVE: Ghrelin is a peptide hormone secreted primarily from the gastric mucosa. It plays a role in energy balance by stimulating appetite, thereby increasing food intake and enhancing weight gain and fat mass deposition. Plasma ghrelin concentrations increase with fasting and are suppressed by nutrient intake. The aim of this study was to examine in humans the relative contributions of small intestinal and gastric nutrient exposure to postprandial suppression of ghrelin, to determine whether gastric exposure is necessary for ghrelin suppression. PATIENTS: Twelve healthy older (age range 65-85 years) men (n = 7) and women (n = 5) were studied. DESIGN: On three separate days, equivolaemic (315 ml) intragastric (IG) and intraduodenal (ID) carbohydrate solutions (both 300 kcal) or intragastric water (control) were infused over 150 min. MEASUREMENTS: Food intake was quantified at a buffet meal offered immediately following each 150-min infusion. Blood ghrelin, cholecystokinin and glucose concentrations were measured. RESULTS: There was a 25% suppression of mean plasma ghrelin concentrations following ID glucose (ID 2016 vs. control 2686 ng/l, P < 0.0001) and a 19% suppression following IG glucose (IG 2181 vs. control 2686 ng/l, P < 0.0001), with ghrelin concentrations slightly (7.6%) and nonsignificantly lower after ID than after IG glucose infusions (P = 0.2). There was no difference between the treatments for the amount of food consumed at the buffet meal (P = 0.88). CONCLUSIONS: Although the primary source of ghrelin is the gastric mucosa, these results suggest that small intestinal nutrient exposure is sufficient for food-induced plasma ghrelin suppression in humans, and that gastric nutrient exposure is not necessary for suppression.     

Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations.

Ghrelin, an endogenous ligand for the GH secretagogue receptor was characterized recently from extracts of rat stomach. We describe the enteric distribution of ghrelin, ontogeny of stomach ghrelin gene expression, effects of dietary and endocrine manipulations, and vagotomy on stomach ghrelin mRNA and peptide levels and secretion in the rat. Ghrelin expression was examined by Northern blotting. Tissue and plasma ghrelin levels were measured by RIA. A gradient of ghrelin production occurs in the rat gastrointestinal tract with the highest ghrelin expression and peptide levels in the mucosal layer of the stomach-fundus and the lowest levels in the colon. Ghrelin was not detectable in the fetal stomach and increased progressively after birth especially during the second and third postnatal weeks. Plasma ghrelin levels also increased in parallel with stomach ghrelin levels postnatally. Exogenous GH treatment decreased stomach ghrelin expression significantly. A high-fat diet decreased plasma ghrelin levels, whereas a low-protein diet increased plasma ghrelin levels significantly. Intravenous administration of ghrelin stimulates gastrin and insulin secretion. Our findings indicate that ghrelin is an important stomach hormone sensitive to nutritional intake; ghrelin may link enteric nutrition with secretion of GH, insulin, and gastrin.     

Intravenous administration of ghrelin stimulates growth hormone secretion in vagotomized patients as well as normal subjects

OBJECTIVE: Ghrelin is a potent peptide stimulating GH secretion. Besides its direct action on the pituitary, ghrelin has been reported to stimulate GH release via the vagal afferent nerve in rats. To examine the involvement of vagal nerve in ghrelin-induced GH secretion in humans, GH responses to ghrelin were compared between vagotomized patients with gastrectomy and normal subjects. METHODS: Ghrelin (0.2 microg/kg) or GHRH (1 microg/kg) was administered intravenously in vagotomized patients and normal subjects on separate days, and plasma GH responses to the stimuli were examined. RESULTS: Ghrelin caused a significant plasma GH rise in both vagotomized patients and normal subjects. Peak GH levels in vagotomized patients (37.5+/-16.9 ng/ml) were not different from those in normal subjects (29.9+/-23.1 ng/ml). The areas under the curve of GH response to ghrelin did not differ between the two groups. GHRH also increased GH levels, and peak GH levels and areas under the curve after GHRH stimulation were also comparable between vagotomized patients and normal subjects. CONCLUSIONS: In the present study, the involvement of the afferent vagal nerve in ghrelin-induced GH secretion was not confirmed in humans.