Plasma Acylated Ghrelin Levels Research Articles

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

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.

Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling

Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training. Here, we explored this hypothesis by implementing food deprivation (FD) stress in mice to determine its effects on fear extinction and LTD induction at T-LA synapses. We found that FD increased plasma acylated ghrelin levels and enhanced fear extinction and its retention. Augmentation of fear extinction by FD was blocked by pretreatment with growth hormone secretagogue receptor type-1a antagonist D-Lys3-GHRP-6, suggesting an involvement of ghrelin signaling. Confirming previous findings, two distinct forms of LTD coexist at thalamic inputs to LA pyramidal neurons that can be induced by low-frequency stimulation (LFS) or paired-pulse LFS (PP-LFS) paired with postsynaptic depolarization, respectively. Unexpectedly, we found that FD impaired the induction of PP-LFS- and group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, but not LFS-induced LTD. Ghrelin mimicked the effects of FD to impair the induction of PP-LFS- and DHPG-induced LTD at T-LA synapses, which were blocked by co-application of D-Lys3-GHRP-6. The sensitivity of synaptic transmission to 1-naphthyl acetyl spermine was not altered by either FD or ghrelin treatment. These results highlight distinct features of fear extinction and LTD at T-LA synapses.

Fetuin-A and Ghrelin Levels in Children with End Stage Renal Disease and the Effect of a Single Hemodialysis Session on Them.

BACKGROUND:Fetuin-A and ghrelin have been implicated in cardiovascular diseases and mortality among end stage renal disease patients. The exact mechanisms have not been fully elucidated. There is robust data supporting an association between ghrelin and various cardiovascular conditions, and some common processes such as inflammation, oxidative stress, and endoplasmic reticulum stress have been implicated.AIM:This study was conducted to assay serum fetuin-A and ghrelin in chronic renal failure pediatric patients and to study changes in their level that may occur after a single hemodialysis.MATERIAL AND METHODS:Forty nine pediatric patients suffering from ESRD on maintenance hemodialysis (HD), 20 patients with chronic renal failure (CRF) not on dialysis and 35 healthy subjects as control group were included. The mean age of the study population was 10.58 ± 3.94, 10.62 ± 3.24 and 10.61 ± 3.97 years respectively. Serum fetuin-A and plasma acyl ghrelin levels were measured by using ELISA method.RESULTS:The present study revealed that predialysis serum fetuin-A level was significantly increased in pediatric HD patients compared with the normal population, while ghrelin levels were significantly reduced. Furthermore, serum levels of fetuin-A decreased significantly after a single HD session.CONCLUSION:Our study concluded that fetuin-A and acyl ghrelin may play a role in inflammatory process among HD pediatric patients which may account for cardiovascular insults and mortality but their use as biochemical markers among ESRD pediatric patients have limitations due to wide fluctuations.

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model.

BackgroundFunctional dyspepsia (FD) is one of the most common disorders of gastrointestinal (GI) diseases. However, no curable treatment is available for FD because the detailed mechanism of GI dysfunction in stressed conditions remains unclear. We aimed to clarify the association between endogenous acylated ghrelin signaling and gastric motor dysfunction and explore the possibility of a drug with ghrelin signal‐enhancing action for FD treatment.MethodsSolid gastric emptying (GE) and plasma acylated ghrelin levels were evaluated in an urocortin1 (UCN1) ‐induced stress model. To clarify the role of acylated ghrelin on GI dysfunction in the model, exogenous acylated ghrelin, an endogenous ghrelin enhancer, rikkunshito, or an α 2‐adrenergic receptor (AR) antagonist was administered. Postprandial motor function was investigated using a strain gauge force transducer in a free‐moving condition.Key ResultsExogenous acylated ghrelin supplementation restored UCN1‐induced delayed GE. Alpha2‐AR antagonist and rikkunshito inhibited the reduction in plasma acylated ghrelin and GE in the stress model. The action of rikkunshito on delayed GE was blocked by co‐administration of the ghrelin receptor antagonist. UCN1 decreased the amplitude of contraction in the antrum while increasing it in the duodenum. The motility index of the antrum but not the duodenum was significantly reduced by UCN1 treatment, which was improved by acylated ghrelin or rikkunshito.Conclusions & InferencesThe UCN1‐induced gastric motility dysfunction was mediated by abnormal acylated ghrelin dynamics. Supplementation of exogenous acylated ghrelin or enhancement of endogenous acylated ghrelin secretion by rikkunshito may be effective in treating functional GI disorders.

Plasma Levels of Acylated Ghrelin in Children with Pulmonary Hypertension Associated with Congenital Heart Disease.

This study aims to estimate plasma levels of acylated ghrelin in children with pulmonary hypertension (PH) associated with congenital heart disease (CHD) and to correlate the levels of acylated ghrelin with endothelin-1 (ET-1), nitric oxide (NO), and clinical hemodynamic parameters. We investigated the plasma concentration of acylated ghrelin, ET-1, NO, and the hemodynamic parameters in 20 children with CHD, 20 children with PH-CHD, and 20 normal children. Plasma-acylated ghrelin and NO levels were significantly higher in CHD group than in control subjects (P < 0.001). Moreover, plasma-acylated ghrelin, ET-1, and NO levels were significantly elevated in PH-CHD group compared with the CHD group (P < 0.05). In PH-CHD children, plasma-acylated ghrelin levels correlated positively with pulmonary artery systolic pressure (PASP; r = 0.740, P < 0.001), pulmonary artery diastolic pressure (PADP; r = 0.613, P = 0.004), right ventricular systolic pressure (RVSP; r = 0.642, P = 0.002), mean pulmonary arterial hypertension (mPAP; r = 0.685, P = 0.001), right ventricle diameter (RVD; r = 0.473, P = 0.035), pulmonary artery trunk diameter (PAD; r = 0.613, P = 0.004), NO (r = 0.463, P = 0.04), and ET-1 (r = 0.524, P = 0.018). Plasma-acylated ghrelin levels were elevated both in CHD and in PH-CHD. Increased acylated ghrelin levels correlated positively with ET-1, NO, PASP, PADP, RVSP, mPAP, RVD, and PAD. Acylated ghrelin may be a new biomarker of PH-CHD.

Maximum Tolerated Volume and Plasma Acylated Ghrelin Levels after Drink Tests in Patients with Functional Dyspepsia

Background: Impaired gastric accommodation and visceral hypersensitivity are major pathophysiological mechanism in functional dyspepsia (FD). Ghrelin, as gut hormone, may play a pathophysiological role in functional dyspepsia. Nutrient drink test was developed to assess impaired gastric accommodation in FD patients. The aims of this study are to compare maximum tolerated volume, postprandial symptoms and acylated ghrelin levels between dyspepsia functional patients and healthy subjects as controls.Method: A cross sectional study was conducted from July 2014 to November 2014, at Sardjito General Hospital, Yogyakarta. Twenties functional dyspepsia patients and 20 healthy subjects ingested nutrient drink tests (Ultra Milk contain 0.6 kcal/mL). The maximum tolerated volume was recorded. After ingested maximal tolerated volume, nausea, bloating and pain were rated using visual analogue scales (VAS) with 100 mm lines. The levels of acylated ghrelin was recorded before and 30 minutes after maximal drinking.Results: The demographic characteristics (age, sex, and body mass index) between dyspepsia patients and healthy subjects were compared. Patients with functional dyspepsia ingested 600 (350–1000) mL and healthy subjects ingested 1375 (1000–1900) mL (p 0.001). The total symptom scores were higher in dyspepsia patients compared healthy subjects; 215 (110–350) vs. 75 (50–120) (p 0,001). The fasting plasma levels of acylated ghrelin (20.65 : 2 – 31.37 pg/mL) in FD patients were significantly lower than healthy subjects (30.61 : 2 – 251.19 pg/mL) ( p = 0.012). Conclusion: Patients with functional dyspepsia ingested significantly lower volume and significantly have higher score symptoms than healthy subjects. The fasting plasma levels of acylated ghrelin in functional dyspepsia patients were significantly lower than healthy subjects.

Ghrelin Level in Syndrome Dyspepsia

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Serotonin 2C receptor contributes to gender differences in stress-induced hypophagia in aged mice

The combination of depression and anorexia may influence morbidity and progressive physical disability in the elderly. Gender differences exist in hypothalamic-pituitary-adrenal axis activation following stress exposure. The objective of this study was to investigate gender differences in feeding behavior under novelty stress in aged mice. Food intake measurement, immunohistochemical assessment, and mRNA expression analysis were conducted to investigate the role of serotonin 2C receptor (5-HT(2C)R) and its relationship with ghrelin in stress-induced suppression of feeding behavior in aged mice. After exposure to novelty stress, a 21-fold increase in plasma corticosterone and remarkable suppression of food intake were observed in aged male mice. Furthermore, a 5-HT(2C)R agonist suppressed food intake in aged male mice. Novelty stress induced a 7-fold increase in 5-HT(2C)R and c-Fos co-expressing cells in the paraventricular nucleus of the hypothalamus in aged male mice but caused no change in aged female mice. Plasma acylated ghrelin levels decreased in stressed aged male mice and administration of the 5-HT(2C)R antagonist inhibited this decrease. The 5-HT(2C)R antagonist also reversed the suppression of food intake in estrogen receptor α agonist-treated aged male mice. Therefore, conspicuously suppressed feeding behavior in novelty stress-exposed aged male mice may be mediated by 5-HT(2C)R hypersensitivity, leading to hypoghrelinemia. The hypersensitivity may partly be due to estrogen receptor activation in aged male mice.

Effect of moderate- and high-intensity acute exercise on appetite in obese individuals.

The effect of acute exercise, and exercise intensity, on appetite control in obese individuals requires further study. The aim of this study was to compare the effects of acute isocaloric bouts (250 kcal) of high-intensity intermittent cycling (HIIC) and moderate-intensity continuous cycling (MICC) or short-duration HIIC (S-HIIC) (125 kcal) and a resting control condition on the appetite hormone responses, subjective feelings of appetite, energy intake (EI), and food reward in overweight/obese individuals. This study is a randomized crossover study on 12 overweight/obese volunteers. Participants were assigned to the control, MICC, HIIC, and S-HIIC conditions, 1 wk apart, in a counterbalanced order. Exercise was performed 1 h after a standard breakfast. An ad libitum test lunch was served 3 h after breakfast. Fasting/postprandial plasma samples of insulin, acylated ghrelin, polypeptide YY3-36, and glucagon-like peptide 1 and subjective feelings of appetite were measured every 30 min for 3 h. Nutrient and taste preferences were measured at the beginning and end of each condition using the Leeds Food Preference Questionnaire. Insulin levels were significantly reduced, and glucagon-like peptide 1 levels significantly increased during all exercise bouts compared with those during rest. Acylated ghrelin plasma levels were lower in the MICC and HIIC, but not in S-HIIC, compared with those in control. There were no significant differences for polypeptide YY3-36 plasma levels, hunger or fullness ratings, EI, or food reward. Our findings suggest that, in overweight/obese individuals, isocaloric bouts of moderate- or high-intensity exercise lead to a similar appetite response. This strengthens previous findings in normal-weight individuals that acute exercise, even at high intensity, does not induce any known physiological adaptation that would lead to increased EI.

Peripheral α2-β1 adrenergic interactions mediate the ghrelin response to brain urocortin 1 in rats.

SummaryThe autonomic nervous system (ANS) conveys neuronal input from the brain to the stomach. We investigated mechanisms through which urocortin 1 (UCN1) injected intracerebroventricularly (ICV, 300 pmol/rat) inhibits circulating ghrelin in rats. This was achieved by assessing (1) the induction of c-fos gene expression as a marker of neuronal activation in specific hypothalamic and caudal brainstem regulating ANS; (2) the influence of vagotomy and pharmacological blockade of central and peripheral α- and β-adrenergic receptor (AR) on ICV UCN1 -induced reduction of plasma ghrelin levels (determined by ELISA); and (3) the relevance of this pathway in the feeding response to a fast in rats. UCN1 increased c-fos mRNA expression in key brain sites influencing sympathetic activity namely the hypothalamic paraventricular and ventromedial nuclei, locus coeruleus, nucleus of the solitary tract, and rostral ventrolateral medulla, by 16-, 29-, 6-, 37-, and 13-fold, respectively. In contrast, the dorsal motor nucleus of the vagus had little c-fos mRNA expression and ICV UCN1 induced a similar reduction in acylated ghrelin in the sham-operated (31%) and vagotomized (41%) rats. An intraperitoneal (IP) injection of either a non-selective α- or selective α2-AR antagonist reduced, while a selective α2-AR agonist enhanced ICV UCN1-induced suppression of plasma acylated ghrelin levels. In addition, IP injection of a non-selective β- or selective β1-AR agonist blocked, and selective β1-AR antagonist augmented, the ghrelin response to ICV UCN1. The IP injections of a selective α1- or non-selective β or β2-AR antagonists, or any of the pretreatments given ICV had no effect. ICV UCN1 reduced the 2-h food intake in response to a fast by 80%, and this effect was partially prevented by a selective α2-AR antagonist. These data suggest that ICV UCN1 reduces plasma ghrelin mainly through the brain sympathetic component of the ANS and peripheral AR specifically α2-AR activation and inactivation of β1-AR. The α2-AR pathway contributes to the associated reduction in food intake.

L-cysteine suppresses ghrelin and reduces appetite in rodents and humans.

Background:High-protein diets promote weight loss and subsequent weight maintenance, but are difficult to adhere to. The mechanisms by which protein exerts these effects remain unclear. However, the amino acids produced by protein digestion may have a role in driving protein-induced satiety.Methods:We tested the effects of a range of amino acids on food intake in rodents and identified l-cysteine as the most anorexigenic. Using rodents we further studied the effect of l-cysteine on food intake, behaviour and energy expenditure. We proceeded to investigate its effect on neuronal activation in the hypothalamus and brainstem before investigating its effect on gastric emptying and gut hormone release. The effect of l-cysteine on appetite scores and gut hormone release was then investigated in humans.Results:l-Cysteine dose-dependently decreased food intake in both rats and mice following oral gavage and intraperitoneal administration. This effect did not appear to be secondary to behavioural or aversive side effects. l-Cysteine increased neuronal activation in the area postrema and delayed gastric emptying. It suppressed plasma acyl ghrelin levels and did not reduce food intake in transgenic ghrelin-overexpressing mice. Repeated l-cysteine administration decreased food intake in rats and obese mice. l-Cysteine reduced hunger and plasma acyl ghrelin levels in humans.Conclusions:Further work is required to determine the chronic effect of l-cysteine in rodents and humans on appetite and body weight, and whether l-cysteine contributes towards protein-induced satiety.

Increased acyl ghrelin but decreased total ghrelin and unacyl ghrelin in Chinese Han people with impaired fasting glucose combined with impaired glucose tolerance

We assessed the plasma acyl ghrelin (AG), unacyl ghrelin (UAG), and total ghrelin (TGhr) levels in Chinese adults with pre-diabetes and newly diagnosed diabetes mellitus (NDDM) after an oral glucose tolerance test (OGTT), and abdominal subcutaneous fat area and visceral fat area (VFA) were measured. Fasting AG level was increased in the impaired fasting glucose (IFG) combined with impaired glucose tolerance (IFG+IGT) and NDDM groups. AG, UAG, and TGhr levels were significantly decreased post-OGTT, and the decrements of 30-min AG, UAG, and TGhr post-OGTT were not significantly different among groups. UAG and TGhr levels did not differ significantly among the normal glucose tolerance (NGT), IFG and NDDM groups, but they decreased obviously in the IFG+IGT and impaired glucose tolerance (IGT) groups. The NDDM group had larger VFA than the NGT, IGT, and IFG+IGT groups, even after adjustment for height, it was still larger than the NGT group. The factors such as dyslipidemia and obesity which are prone to develop insulin resistance (IR) and decrease insulin sensitivity (IS) were negatively correlated with UAG and TGhr, positively with AG/UAG, while no correlations with AG. In terms of evaluating IS and IR, AG/UAG ratio may be superior in AG concentration. Our findings suggest that relative sufficiency of AG, the deficiency of TGhr and UAG are already present in IFG+IGT patients. We speculate that there is UAG resistance in severe hyperglycemia (diabetic state), which could produce elevated TGhr and UAG compared to IFG+IGT group. In the development of T2D, increase of VFA could be the initiating factor, leading elevated AG, reduced UAG, IR, decreased IS, and finally hyperglycemia.

Administration of exogenous acylated ghrelin or rikkunshito, an endogenous ghrelin enhancer, improves the decrease in postprandial gastric motility in an acute restraint stress mouse model

BackgroundPhysical or psychological stress causes functional disorders in the upper gastrointestinal tract. This study aims to elucidate the ameliorating effect of exogenous acylated ghrelin or rikkunshito, a Kampo medicine which acts as a ghrelin enhancer, on gastric dysfunction during acute restraint stress in mice.MethodsFasted and postprandial motor function of the gastric antrum was wirelessly measured using a strain gauge force transducer and solid gastric emptying was detected in mice exposed to restraint stress. Plasma corticosterone and ghrelin levels were also measured. To clarify the role of ghrelin on gastrointestinal dysfunction in mice exposed to stress, exogenous acylated ghrelin or rikkunshito was administered, then the mice were subjected to restraint stress.Key ResultsMice exposed to restraint stress for 60 min exhibited delayed gastric emptying and increased plasma corticosterone levels. Gastric motility was decreased in mice exposed to restraint stress in both fasting and postprandial states. Restraint stress did not cause any change in plasma acylated ghrelin levels, but it significantly increased the plasma des-acyl ghrelin levels. Administration of acylated ghrelin or rikkunshito improved the restraint stress-induced delayed gastric emptying and decreased antral motility. Ameliorating effects of rikkunshito on stress-induced gastric dysfunction were abolished by simultaneous administration of a ghrelin receptor antagonist.Conclusions & InferencesPlasma acylated/des-acyl ghrelin imbalance was observed in acute restraint stress. Supplementation of exogenous acylated ghrelin or enhancement of endogenous ghrelin signaling may be useful in the treatment of decreased gastric function caused by stress.

Gastric Bypass Surgery May Improve Beta Cell Apoptosis with Ghrelin Overexpression in Patients with BMI ≥ 32.5 kg/m2

Roux-en-Y gastric bypass (RYGB) surgery can lead to long-term remission of type 2 diabetes mellitus, depending on changes in weight and circulating levels of gut hormones. The general objectives of this study were to evaluate changes in plasma levels of the ghrelin gene products following RYGB surgery and to determine the role of ghrelin in inhibiting apoptosis of INS-1 cells induced by hyperglycemia. Sixteen obese Chinese patients with type 2 diabetes mellitus who underwent gastric bypass surgery were assessed in this investigation. Blood plasma levels of acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (OB) were measured both before and 12months after RYGB surgery. To determine the effect of ghrelin on inhibition of apoptosis, INS-1 cells were cultured in a high glucose concentration and treated with AG, UAG, or OB. Cell viability was assessed using the MTT assay, and apoptosis was evaluated by flow cytometry with Annexin-V FITC/PI double staining and transmission electron microscopy. Intracellular calcium trafficking was assessed using flow cytometry and confocal microscopy. All the data was processed using the SPSS statistical package and expressed as means ± SD, with p < 0.05 considered statistically significant. Fasting and postprandial plasma levels of AG, UAG, and OB were significantly elevated 1year after RYGB surgery. Mean fasting plasma AG, UAG, and OB increased from preoperative levels of 37.0, 462, and 69.4pg/mL, respectively, to 61.4, 804, and 112pg/mL (with p < 0.05) 1year after surgery. Mean 120-min postprandial plasma AG, UAG, and OB increased from preoperative levels of 23.8, 287, and 53.8pg/mL, respectively, to 39.7, 516, and 69.0pg/mL (with p < 0.05) postoperatively. After a 1-week culture of INS-1 beta cell in high glucose, peptide treatment showed increased cell survival by 69% (AG), 60% (UAG), and 73% (OB) and decreased apoptosis by 49% (AG), 37% (UAG), and 38% (OB) compared to cells cultured in high glucose without peptides, respectively (with p < 0.05). Treatment with AG, UAG, and OB inhibited intracellular calcium mobilization and intramitochondrial calcium accumulation in INS-1 cells to protect the cells from hyperglycemia-induced apoptosis. The remission of diabetes following RYGB surgery seems to be associated with increased plasma levels of AG, UAG, and OB. Moreover, the ghrelin gene products probably protect β cells by maintaining calcium homeostasis. Additional mechanisms, currently unclear, are likely to be involved as well.

Tu2101 Gastric Myenteric Plexus Changes and Autonomic Dysfunction in Patients With Chronic Migraine and Gastroparesis

groups according to Rome III classification; postprandial distress syndrome (PDS, n = 67) and epigastric pain syndrome (EPS, n = 36). Since irritable bowel syndrome (IBS) tends to overlap with FD, the patients with IBS symptoms were not excluded. Questionnaire including FD, GERD and IBS symptoms was used. Fasting blood sample for acylated ghrelin, leptin and serotoin levels by ELISA method and two body specimens for evaluating the relative amount of mRNA expression of ghrelin and leptin were compared. Results: Compared to the control (14.4%), the FD group (28.4%) had more patients with IBS symptom (P = 0.016). Plasma acylated ghrelin level of FD was significantly lower than that of control (P = 0.036), while there was no significant difference in leptin and serotonin levels between control and FD (P = 0.123 and P = 0.442, respectively). In addition, when we subclassified FD to PDS and EPS, plasma acylated ghrelin level of PDS was significantly lower than EPS and control (P = 0.013, P = 0.003). On the other hand, plasma leptin in EPS was higher than that of control (P = 0.038). However, no significant difference was shown in quantity of mRNA expression of ghrelin and leptin (P = 0.538 and P = 0.796, respectively). Conclusion: Our results suggest that acylated ghrelin might play an important role in development of PDS and leptin may be related with the pathophysiology of EPS via posttranslational modification.

Changes in Plasma Ghrelin and Serum Leptin Levels after Cisplatin-Based Transcatheter Arterial Infusion Chemotherapy for Hepatocellular Carcinoma

Background and Objective. Cisplatin-based chemotherapy is widely recognized to cause severe gastrointestinal disorders like nausea, vomiting, and appetite loss. The aim of this study was to assess whether cisplatin-based transcatheter arterial infusion (TAI) chemotherapy reduces plasma ghrelin levels and food intake in hepatocellular carcinoma (HCC) patients. Methods. Seventeen patients with HCC who underwent cisplatin-based TAI chemotherapy (80–100 mg/body) were enrolled in this study. Changes in peptide hormones, including ghrelin and leptin, as well as cytokines, were measured before and after chemotherapy. Appetite was evaluated by visual analog scale (VAS) and food intake was scored by eleven stages (0–10). Results. Appetite and food intake were significantly decreased after chemotherapy (P < 0.05). Plasma acylated ghrelin levels before therapy and at day 1, day 7, and day 14 after chemotherapy were 10.4 ± 7.2, 4.7 ± 4.7, 11.7 ± 8.9, and 9.3 ± 6.6 fmol/mL, respectively. The level on day 1 was decreased significantly (P < 0.05). In contrast, the levels of leptin, granulocyte colony-stimulating factor (G-CSF), and monocyte chemotactic protein-1 (MCP-1) on day 1 were increased significantly (P < 0.05). Conclusions. TAI for HCC reduced plasma acylated ghrelin levels, appetite, and food intake significantly. In addition, it increased serum leptin levels.

Changes in Ghrelin-Related Factors in Gastroesophageal Reflux Disease in Rats

To examine gastrointestinal hormone profiles and functional changes in gastroesophageal reflux disease (GERD), blood levels of the orexigenic hormone ghrelin were measured in rats with experimentally induced GERD. During the experiment, plasma acyl ghrelin levels in GERD rats were higher than those in sham-operated rats, although food intake was reduced in GERD rats. Although plasma levels of the appetite-suppressing hormone leptin were significantly decreased in GERD rats, no changes were observed in cholecystokinin levels. Repeated administration of rat ghrelin to GERD rats had no effect on the reduction in body weight or food intake. Therefore, these results suggest that aberrantly increased secretion of peripheral ghrelin and decreased ghrelin responsiveness may occur in GERD rats. Neuropeptide Y and agouti-related peptide mRNA expression in the hypothalamus of GERD rats was significantly increased, whereas proopiomelanocortin mRNA expression was significantly decreased compared to that in sham-operated rats. However, melanin-concentrating hormone (MCH) and prepro-orexin mRNA expression in the hypothalamus of GERD rats was similar to that in sham-operated rats. These results suggest that although GERD rats have higher plasma ghrelin levels, ghrelin signaling in GERD rats may be suppressed due to reduced MCH and/or orexin synthesis in the hypothalamus.

The Preproghrelin 3056 TT Genotype is Associated with the Feeling of Hunger and Low Acylated Ghrelin Levels in Japanese Patients with &lt;i&gt;Helicobacter pylori&lt;/i&gt;-negative Functional Dyspepsia

An impairment of gastric motility is strongly associated with the pathophysiology of functional dyspepsia (FD). Plasma ghrelin is one of the key molecules linked to gastric motility. Therefore, this study aimed to evaluate whether ghrelin (GHRL) gene polymorphisms are associated with clinical symptoms, the plasma ghrelin levels and gastric emptying in patients with FD as defined by the Rome III classification. We enrolled 74 Helicobacter pylori-negative patients presenting with typical symptoms of FD (epigastric pain syndrome (EPS), n=23; postprandial distress syndrome (PDS), n=51) and 102 healthy volunteers. Gastric motility was evaluated according to the Tmax value and T1/2 using the (13)C-acetate breath test. We used the Rome III criteria to evaluate upper abdominal symptoms and SRQ-D scores to determine the depression status. The Arg51Gln(346G->A), preproghrelin3056T->C, Leu72Met(408C->A) and Gln90Leu(3412T->A) polymorphisms were analyzed in DNA in blood samples obtained from the enrolled subjects. Genotyping was performed using polymerase chain reaction. There was a significant relationship (p=0.048) between the preproghrelin 3056TT genotype and the serum levels of acylated ghrelin in the H. pylori-negative FD patients. The preproghrelin 3056TT genotype was significantly (p=0.047) associated with the feeling of hunger in the H. pylori-negative FD patients. The preproghrelin 3056TT genotype is significantly associated with the acylated ghrelin levels and the feeling of hunger in H. pylori-negative FD patients. Further studies are needed to clarify the association between the preproghrelin 3056TT genotype and lower plasma acylated ghrelin levels and the impact of this relationship on the feeling of hunger in H. pylori-negative FD patients.

Rikkunshito, a Japanese Kampo Medicine, Ameliorates Decreased Feeding Behavior via Ghrelin and Serotonin 2B Receptor Signaling in a Novelty Stress Murine Model

We investigated the effects of rikkunshito (RKT), a ghrelin signal enhancer, on the decrease in food intake after exposure to novelty stress in mice. RKT administration (500 mg/kg, per os) improved the decrease in 6 h cumulative food intake. In control mice, the plasma acylated ghrelin levels significantly increased by 24 h fasting. In contrast, the acylated ghrelin levels did not increase by fasting in mice exposed to the novelty stress. RKT administration to the novelty stress mice showed a significant increase in the acylated ghrelin levels compared with that in the distilled-water-treated control mice. Food intake after administering serotonin 2B (5-HT2B) receptor antagonists was evaluated to clarify the role of 5-HT2B receptor activation in the decrease in feeding behavior after novelty stress. SB215505 and SB204741, 5-HT2B receptor antagonists, significantly improved the decrease in food intake after exposure to novelty stress. A component of RKT, isoliquiritigenin, prevented the decrease in 6 h cumulative food intake. Isoliquiritigenin showed 5-HT2B receptor antagonistic activity in vitro. In conclusion, the results suggested that RKT improves the decrease in food intake after novelty stress probably via 5-HT2B receptor antagonism of isoliquiritigenin contained in RKT.

Intragastric administration of rikkunshito stimulates upper gastrointestinal motility and gastric emptying in conscious dogs

Traditional Japanese medicine, known as Kampo medicine, consists of mixtures of several medicinal herbs widely used to treat upper gastrointestinal disorders in Japan. Rikkunshito, one of these medicines, has not been evaluated with respect to its influence on gastrointestinal motor activity. We investigated the effect of rikkunshito on upper gastrointestinal motility and plasma ghrelin concentrations in conscious dogs. Contractile response to intragastric administration of rikkunshito was studied via surgically implanted force transducers. A powdered extract of rikkunshito (1.3, 2.7, and 4.0 g) dissolved in water was administered into the stomachs of normal and vagotomized dogs before feeding and gastric emptying was evaluated. Several inhibitors of gastrointestinal motility (atropine, hexamethonium, and ondansetron) were injected intravenously before intragastric administration of rikkunshito. Plasma acylated ghrelin levels after intragastric administration of rikkunshito were measured. In a fasting state, intragastric administration of rikkunshito induced phasic contractions in the duodenum and jejunum in normal dogs. Rikkunshito-induced contractions were inhibited by atropine, hexamethonium and ondansetron. In vagotomized dogs, rikkunshito induced phasic contractions, similar to normal dogs. Gastric emptying was accelerated by intragastric administration of rikkunshito in a dose-dependent manner. The plasma acylated ghrelin level 150 min after intragastric administration of 4.0 g of rikkunshito was significantly higher than the control value. Intragastric administration of rikkunshito stimulates gastrointestinal contractions in the interdigestive state through cholinergic neurons and 5-HT type 3 receptors. Moreover, rikkunshito increases plasma acylated ghrelin levels. Rikkunshito may alleviate gastrointestinal disorders through its prokinetic effects.