Acylated Ghrelin Levels Research Articles

Traditional Japanese herbal medicine rikkunshito increases food intake and plasma acylated ghrelin levels in patients with esophageal cancer treated by cisplatin-based chemotherapy

Cisplatin (CDDP) is an important chemotherapeutic drug for treating esophageal cancer that often induces nausea and vomiting. Rikkunshito (RKT), a traditional Japanese herbal medicine, can increase levels of plasma ghrelin, which is an orexigenic gut hormone that can alleviate chemotherapy-induced nausea and vomiting (CINV) and anorexia. This prospective randomized crossover study included 20 patients with esophageal cancer who were administered with CDDP-based chemotherapy. Ten of them were assigned to group A [1st course: with RKT 7.5 g/day on days 1-14; 2nd course: without RKT (control)] and 10 were assigned to group B [1st course: without RKT (control); 2nd course: with RKT 7.5 g/day on days 22-35]. Food intake and levels of plasma acylated ghrelin (AG) were compared between the control and RKT courses. Data from 18 patients were included in this analysis, as chemotherapy was immediately stopped due to deteriorating renal function in one patient and intracerebral bleeding in another. The median rate at which food intake decreased between days 4 and 6 was considerably lower in the course with, than without RKT (2% vs. 30%; P=0.02). Median levels of AG significantly increased from days 3 to 8 in patients in both courses with and without RKT (9.6 to 15.7 fmol/mL, P<0.0001; control, 10.2 to 17.8, P=0.0002). The rate at which median plasma AG levels increased from days 3 to 8 tend to be higher in the RKT, than in the control course (68% vs. 48%, P=0.08). RKT can improve CDDP-induced, delayed-onset anorexia and increase plasma AG levels among patients with esophageal cancer who undergo highly emetogenic chemotherapy (HEC).

Chronic predator stress in female mice reduces primordial follicle numbers: implications for the role of ghrelin.

Chronic stress is a known suppressor of female reproductive function. However, attempts to isolate single causal links between stress and reproductive dysfunction have not yet been successful due to their multi-faceted aetiologies. The gut-derived hormone ghrelin regulates stress and reproductive function and may therefore be pivotal in the neuroendocrine integration of the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes. Here, we hypothesised that chronic stress disrupts ovarian follicle maturation and that this effect is mediated by a stress-induced increase in acyl ghrelin and activation of the growth hormone secretatogue receptor (GHSR). We gave C57BL/6J female mice 30 min daily chronic predator stress for 4 weeks, or no stress, and gave them daily GHSR antagonist (d-Lys3-GHRP-6) or saline. Exposure to chronic predator stress reduced circulating corticosterone, elevated acyl ghrelin levels and led to significantly depleted primordial follicle numbers. GHSR antagonism stress-dependently altered the expression of genes regulating ovarian responsiveness to gonadotropins and was able to attenuate the stress-induced depletion of primordial follicles. These findings suggest that chronic stress-induced elevations of acyl ghrelin may be detrimental for ovarian follicle maturation.

Effects of Motilin Receptor Agonists and Ghrelin in Human motilin receptor Transgenic Mice.

Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human motilin receptor transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a μ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.

Postoperative decrease in plasma acyl ghrelin levels after pediatric living donor liver transplantation in association with hepatic damage due to ischemia and reperfusion injury.

Ghrelin was recently reported to promote recovery from hepatic injury. We hypothesized that it could also be associated with clinical recovery of the transplanted liver from ischemia and reperfusion injury. Our aims were to investigate perioperative ghrelin changes following pediatric living donor liver transplantation (LDLT) and to analyze the association of these changes with postoperative hepatic function. We measured plasma acyl ghrelin (AG) concentrations before surgery, at the end of surgery and on postoperative days (PODs) 1, 3 and 7 in 12 children who underwent LDLTs, and, as controls, pre- and post-operatively and on POD1 in 7 children who underwent benign abdominal mass resection. The correlations between the participants' ghrelin profiles and hepatic function-related data were evaluated. AG levels significantly declined to 15.6% of preoperative levels after LDLT and almost returned to baseline on POD3. Post-operative AG levels were significantly reduced to a greater extent following LDLT than benign abdominal mass resection. AG levels on POD1 inversely correlated with aspartate aminotransferase levels and cold/total ischemia time (P < 0.05). These results suggest that reduced AG levels on POD1 may reflect the degree of damage to the transplanted liver due to ischemia and reperfusion injury.

ETV5 regulates GOAT/ghrelin system in an mTORC1-dependent manner

Ghrelin, a 28 amino acid peptide hormone, regulates multiple important metabolic functions. Its acylation by ghrelin-O-acyl-transferase enzyme (GOAT) is required for binding to and activating its receptor, the growth hormone secretagogue receptor 1a. Mechanism underlying the regulation of GOAT and acyl ghrelin remains unclear. The present study demonstrated that ETV5 could transactivate GOAT promoter region and increase its expression, leading to subsequent increase in the production of acyl ghrelin. mTORC1 modulated ETV5 expression levels, likely via altering its protein stability, in the murine hypothalamic CLU122 cells and in mice. Moreover, ETV5 mediated the effects of mTORC1 signaling on the expression level of acyl ghrelin. Our study suggests a novel mTORC1-ETV5-GOAT/ghrelin axis in the regulation of ghrelin system. ETV5 may be a key regulator of mTORC1-GOAT/ghrelin axis in ghrelin producing cells and a potential therapeutic target for organism energy imbalance.

Acylated Ghrelin Supports the Ovarian Transcriptome and Follicles in the Mouse: Implications for Fertility.

Ghrelin, an orexigenic gut-derived peptide, is gaining increasing attention due to its multifaceted role in a number of physiological functions, including reproduction. Ghrelin exists in circulation primarily as des-acylated and acylated ghrelin. Des-acyl ghrelin, until recently considered to be an inactive form of ghrelin, is now known to have independent physiological functionality. However, the relative contribution of acyl and des-acyl ghrelin to reproductive development and function is currently unknown. Here we used ghrelin-O-acyltransferase (GOAT) knockout (KO) mice that have no measurable levels of endogenous acyl ghrelin and chronically high levels of des-acyl ghrelin, to characterize how the developmental and life-long absence of acyl ghrelin affects ovarian development and reproductive capacity. We combined the assessment of markers of reproductive maturity and the capacity to breed with measures of ovarian morphometry, as well as with ovarian RNA sequencing analysis. Our data show that while GOAT KO mice retain the capacity to breed in young adulthood, there is a diminished number of ovarian follicles (per mm3) in the juvenile and adult ovaries, due to a significant reduction in the number of small follicles, particularly the primordial follicles. We also show pronounced specific changes in the ovarian transcriptome in the juvenile GOAT KO ovary, indicative of a potential for premature ovarian development. Collectively, these findings indicate that an absence of acyl ghrelin does not prevent reproductive success but that appropriate levels of acyl and des-acyl ghrelin may be necessary for optimal ovarian maturation.

Two weeks of exercise training intensity on appetite regulation in obese adults with prediabetes.

No short-term exercise data exist testing whether training intensity modifies hormonal and perceived appetite in obese adults with prediabetes. Therefore, we compared the effects of short-term moderate-continuous (CONT) vs. high-intensity interval (INT) training on appetite regulation. Twenty-eight obese adults [age: 61.3 ± 1.5 yr; body mass index (BMI): 33.2 ± 1.1 kg/m2] with prediabetes were randomized to work-matched CONT ( n = 14) or INT ( n = 14) training for 2 wk. Plasma acylated ghrelin (AG), des-acylated ghrelin (dAG), active glucagon-like peptide-1 (GLP-1), and insulin were measured at 0, 30, and 60 min of a 75-g oral glucose tolerance test (OGTT) before and after training. Visual analog scales were administered at 0 and 120 min during the OGTT to examine perceived appetite. Three-day food logs were collected before and after testing to assess ad libitum diet. CONT and INT increased peak oxygen consumption ( P < 0.01) and decreased BMI ( P < 0.01). Although neither intervention altered fasting levels of AG ( P = 0.94), dAG ( P = 0.36), or insulin ( P = 0.67), CONT raised GLP-1 compared with INT ( P = 0.05). Exercise training did not affect postprandial suppression of AG ( P = 0.81) and dAG ( P = 0.67) or stimulation of GLP-1 ( P = 0.67) and insulin ( P = 0.32). Both interventions tended to decrease total energy and protein intake ( P = 0.09 and P = 0.05, respectively), despite no change in fasting hunger ( P = 0.88) and reduced perceived fullness at 120 min during the OGTT ( P = 0.05). We conclude that 2 wk of exercise training intensity does not modulate appetite-regulatory hormones in obese adults with prediabetes. Although perceived fullness to the OGTT was reduced after exercise, CONT and INT decreased energy intake, suggesting that exercise does not elicit compensatory appetite behavior to gain weight. NEW & NOTEWORTHY Adults with prediabetes are at risk for appetite dysregulation. Although exercise promotes weight management, it is unclear whether moderate-continuous or high-intensity interval training is more beneficial for appetite regulation. We show that 2 wk of exercise, independent of intensity, does not alter postprandial appetite hormones or hunger, despite slight reductions in food intake and weight. These data support exercise as an effective method to induce negative energy balance without compensatory weight gain.

Acylated ghrelin levels were associated with depressive status, physical quality of life, endoscopic findings based on Kyoto classification in Japan.

Background and Aims: To determine whether serum acylated ghrelin levels were associated with anxiety, clinical symptoms, depressive status, quality of life, gastric motility and endoscopic findings based on Kyoto classification in functional dyspepsia (FD) patients. Methods: We enrolled three groups, FD patients (n = 15) with high levels of acylated ghrelin, FD patients (n = 33) with normal levels of acylated ghrelin and FD patients (n = 35) with low levels of acylated ghrelin. There was no significant differences in the positivity of Helicobacter pylori infection among the three groups. Clinical symptoms were evaluated by Gastrointestinal Symptom Rating Scale (GSRS) and FD symptoms based on Rome III classification. Acylated ghrelin levels were measured by ELISA methods. Depressive status, anxiety, sleep disturbance were respectively asscessed by Self-rating questionnaire for depression (SRQ-D) score, STAI-state/-trait, Pittsburgh sleep quality index (PSQI) scores. Endoscopic findings were evaluated based on Kyoto classification. Results: Body Mass Index (BMI) in FD patients with low levels of acylated ghrelin was significantly higher (p<0.001 and p = 0.008, respectively) compared to those in FD patients with high and normal levels of acylated ghrelin. SRQ-D scores in FD patients with low levels of acylated ghrelin was significantly lower (p = 0.008 and p<0.001, respectively) compared to those in FD patients with high and normal levels of acylated ghrelin. Scoring of gastric atrophy, intestinal metaplasia, xanthoma and mucus based on Kyoto classification in FD patients with low levels of acylated ghrelin were significantly higher (p<0.001, p = 0.0077, p = 0.036 and p = 0.0063, respectively) compared to those in FD patients with more than low levels of acylated ghrelin. Conclusion: Acylated ghrelin levels were associated with BMI, depressive status, and endoscopic findings based on Kyoto classification in FD patients.

Ghrelin acylation by ghrelin- O-acyltransferase can occur in healthy part of oncological liver in humans.

Activation of ghrelin is controlled by the enzyme ghrelin- O-acyl transferase (GOAT). In humans, localization of this acylation is poorly understood. The aim of this study is to explore GOAT localization and activation in the human liver by evaluating both bioactive and non-bioactive ghrelin in the bloodstream entering and leaving the liver and to simultaneously evaluate GOAT mRNA expression in the liver. A healthy part of oncologic hepatic tissue collected from nine patients undergoing hepatectomy was used to evaluate GOAT mRNA expression by quantitative real-time polymerase chain reaction (RT-qPCR). Simultaneously, blood from the portal vein, the suprahepatic vein, the subclavicular vein, and the radial artery was also sampled to assay total and acylated ghrelin. Acylated ghrelin level was significantly increased in the suprahepatic vein compared with the portal vein level (385 ± 42 ng/ml vs. 268 ± 24 ng/ml, P = 0.04). Suprahepatic-to-portal vein ratio for acylated ghrelin (acylation ratio) is 1.4 ± 0.1. Mean expression of GOAT mRNA in the liver, expressed as 2-∆Ct·µg total RNA-1·1 µl of liver tissue-1 was at 0.042 ± 0.021 arbitrary units. GOAT mRNA expression in the liver was correlated with acylated-to-total ghrelin ratio in the suprahepatic vein ( P = 0.016, R = 0.75) and with the acylation liver ratio ( P = 0.05, R = 0.61). Blood concentration of acylated ghrelin was found significantly increased after its passage through the liver, suggesting that acylation can occur in the liver. RT-qPCR data confirmed the presence of GOAT in the liver, with a positive correlation between GOAT expression and acylated ghrelin liver ratio. This study strongly suggests that the liver is a site of ghrelin acylation in humans. NEW & NOTEWORTHY Although the activation of ghrelin by the enzyme ghrelin- O-acyl transferase (GOAT) is yet well demonstrated, its localization, especially in humans, remains poorly understood. We explored GOAT localization and activation in the human liver by simultaneously evaluating both bioactive and non-bioactive ghrelin in the bloodstream entering and leaving the liver and also GOAT mRNA expression in the liver. We therefore showed for the first time, to our knowledge, that GOAT localized in the liver is active and takes part in ghrelin activation.

Acyl-ghrelin mediated lipid retention and inflammation in obesity-related Type 2 diabetes

Acyl-ghrelin has various peripheral effects including the potential role in mediating cellular lipid removal and macrophage polarization. Previous reports are contradictory as to how glycaemia and acyl-ghrelin mediates lipid retention and inflammation within individuals with Type 2 diabetes (T2D). Our aim was to explore acyl-ghrelin levels and ghrelin expression in relation to lipid and inflammatory markers within an ex vivo human model, biopsied visceral adipose tissue.Results indicated that acyl-ghrelin was associated with a decline in key lipid homeostasis genes ABCG1 and LXRβ expression. Within T2D there was also a down regulation of these genes which was independent of acyl-ghrelin levels. Circulatory pro-inflammatory markers (IL-6 and TNFα) had no association with ghrelin expression nor circulating acyl-ghrelin levels. Anti-inflammatory marker (IL-10) and total antioxidant status (TAOS%) were positively associated with ghrelin expression across samples from all groups combined (total sample cohort) and specifically within the obesity sample cohorts.Data supported the hypothesis that hyperglycaemia and acyl-ghrelin have a regulatory role in lipid retention. Furthermore, that both acyl- and desacyl-ghrelin is responsible for a protective inflammatory response; however this response is diminished in T2D.

Gender Differences in Plasma Ghrelin Levels in Hemodialysis Patients.

Ghrelin is an orexigenic hormone mainly secreted by the stomach, and it decreases according to the severity of gastric atrophy. Ghrelin has multiple favorable functions, including protein anabolism enhancement, anti-inflammatory activity, and cardiovascular protection, and is associated with survival in hemodialysis (HD) patients. Although the plasma level and role of ghrelin may be different depending on gender, they have not been completely assessed in HD patients. We enrolled 80 (male/female: 51/29) maintenance HD patients. An upper gastrointestinal endoscopic examination was performed for all patients to determine the severity of gastric mucosal atrophy and Helicobacter pylori infection. We measured plasma acyl and desacyl ghrelin levels and assessed the association between ghrelin levels and relevant clinical parameters, including nutrition, inflammation, atherosclerosis, and bone metabolism, by gender. Both acyl and desacyl ghrelin levels in female HD patients were significantly higher than those in male HD patients. When stratified by gastric mucosal atrophy, these gender differences were observed only in patients without gastric atrophy. In female patients, acyl ghrelin level was negatively correlated with age. In male patients, both acyl and desacyl ghrelin levels were positively correlated with bone mineral density. Multiple regression analysis showed significant positive correlations between both ghrelin levels and female gender after adjusting for confounding factors. Plasma ghrelin levels were higher in female HD patients than in male HD patients. The gender difference was more evident in patients without gastric atrophy.

Eradication Therapy for Helicobacter pylori Improves Nutrition Status Depended on Severity of Gastric Mucosal Atrophy and Plasma Ghrelin Level in Japanese Hemodialysis Patients

Introduction: The state of metabolic and nutritional derangement, called protein—energy wasting (PEW), has a major impact on mortality in hemodialysis (HD) patients. Ghrelin has multiple favorable functions and associates with the pathogenesis of PEW in HD patients. Plasma and gastric ghrelin levels are affected in H pylori status. Here, we investigated relationships among nutrition status, ghrelin level, H. pylori and severity of atrophy in HD patients and investigated the efficacy of H. pylori eradication therapy for improvement of nutrition status related with ghrelin in H. pylori—positive HD patients. Methods: H. pylori&#x2014;IgG and pepsinogen levels of 500 HD patients at 8 dialysis centers were measured. We classified H. pylori infectionstatus into three groups: present infection, past infection and non—infection. Plasma ghrelin levels were measured and we investigated above relationship among three groups. H. pylori—positives underwent endoscopy for evaluation of the severity of atrophy, and eradicated by PPI, amoxocollin and clarithromycin for 7days. We evaluated nutrition markers and ghrelin levels before and 1 year after eradication. Results: Acyl— and desacyl—ghrelin levels were 29.7±21.3 fmol/mland 279.2±168.5 fmol/ml, respectively. Acyl—ghrelin in the non—infection group was significantly higher than in the present and past infection groups. Acyl—ghrelin level was positively correlated with serum PG I level and PG I/II ratio and was significantly lower in patients with severe atrophy than in those with no atrophy (20.9±14.6and 40.4±21.9, p<0.001). Cholinesterase level was significantly increased after eradication compared with before eradication (303.2±76.0 vs. 287.3±68.1, p=0.029). In particular, cholesterol(before, 196.6±23.2; after, 206.1±25.9, p=0.042) and cholinesterase levels(before, 296.9±70.8; after, 316.4±73.8, p=0.049) increased more strongly in patients with mild-moderate atrophy than those with severe atrophy. Conclusion: Plasma ghrelin level was associated with endoscopic and serological severity of atrophy related with H. pylori infection in HD patients. Eradication improved nutrition status by increasing serum cholinesterase and cholesterol levels, especially those with mild and moderate gastric mucosal atrophy. In HD patients, eradication therapy may contribute to an improvement in prognosis associated with PEW.

One Year of Yoga Training Alters Ghrelin Axis in Centrally Obese Adults With Metabolic Syndrome.

Introduction: Metabolic syndrome (MetS) is a multiplex cardiometabolic manifestation associated with type 2 diabetes mellitus and cardiovascular diseases. Yoga training has been shown to alleviate MetS. Recently, circulatory ghrelin profile was demonstrated to be associated with MetS. This study examined the effects of 1 year of yoga training on β-cell function and insulin resistance, and the involvement of metabolic peptides, including unacylated ghrelin (UnAG), acylated ghrelin (AG), obestatin, growth hormone (GH), and insulin, in the beneficial effects of yoga training in centrally obese adults with MetS.Methods: This was a follow up study, in which data of risk factors of MetS, physical performance tests [resting heart rate (HR), chair stand test (CS), chair sit and reach test (CSR), back scratch test (BS), and single leg stand tests (SLS)] and serum samples of 79 centrally obese MetS subjects aged 58 ± 8 years (39 subjects received 1-year yoga training and 40 subjects received no training) were retrieved for analyses. β-cell function and insulin resistance were examined by Homeostasis Model Assessment (HOMA). Circulating levels of UnAG, AG, obestatin, GH, and insulin were determined by enzyme-linked immunosorbent assay using fasting serum samples. Generalized estimating equation analysis and Mann–Whitney U-test were used to detect statistically significant differences between groups.Results: Waist circumference (WC) was significantly decreased after yoga intervention (control: +2%; yoga: -4%). Significant improvements in HR (control: +2%; yoga: -5%), CS (control: -1%; yoga: +24%), CSR left (control: worsen by 0.90 cm; yoga: improved by 4.21 cm), CSR right (control: worsen by 0.75 cm; yoga: improved by 4.28 cm), right side of BS (control: improved by 0.19 cm; yoga: improved by 4.31 cm), SLS left (control: -10%; yoga: +86%), and SLS right (control: -6%; yoga: +47%) were observed after 1-year yoga training. No significant difference was found between the two groups in insulin, HOMA indices, and disposition index. Yoga training significantly increased circulating GH (control: -3%; yoga: +22%), total circulating ghrelin (control: -26%; yoga: +13%), and UnAG (control: -27%; yoga: +14%), whereas decreased AG (control: -7%; yoga: -33%) and obestatin (control: +24%; yoga: -29%).Conclusion: One-year of yoga training modulated total ghrelin, UnAG, AG, obestatin, and GH while exerting beneficial effects on physical functions and central obesity in adults with MetS. The beneficial effects of yoga may be associated with the alteration of ghrelin gene product and GH.

Ghrelin Axis Reveals the Interacting Influence of Central Obesity and Hypertension.

Objective: This study aimed to investigate how central obesity and hypertension modulate unacylated ghrelin (UnAG), acylated ghrelin (AG), obestatin, growth hormone (GH), and the ratios of UnAG/obestatin, AG/obestatin, and total ghrelin/obestatin.Methods: Circulatory abundances of UnAG, AG, obestatin and GH were determined in 387 Hong Kong Chinese female adults with age between 24 to 86 years based on a 2 × 2 factorial design of hypertension (blood pressure ≥140/90 mmHg) and central obesity (waist circumference or WC ≥80 cm). Participants were categorized as neither hypertensive nor centrally obese (NHNO; n = 105), hypertensive but not centrally obese (HNO; n = 102), centrally obese but not hypertensive (NHO; n = 74) and hypertensive and centrally obese (NO; n = 106). Pearson's correlation analyses were performed to detect the association between the peptides examined with WC and blood pressure. The main and interaction effects of hypertension and central obesity were examined by generalized estimating equations analyses.Results: Correlation analyses revealed that systolic blood pressure was negatively correlated with AG/obestatin, UnAG/obestatin and total ghrelin/obestatin ratios, AG, total ghrelin, and GH, while diastolic blood pressure was negatively correlated with UnAG/obestatin, total ghrelin/obestatin ratios, and GH. WC was negatively correlated with AG/obestatin, UnAG/obestatin, and total ghrelin/obestatin ratios, UnAG, AG, total ghrelin, GH, and obestatin. Interaction effects of hypertension and central obesity were observed on UnAG/obestatin, AG/obestatin and total ghrelin/obestatin ratios, and obestatin. Obestatin in NHO group was significantly higher compared to NHNO and HO groups. UnAG/obestatin, AG/obestatin, and total ghrelin/obestatin ratios were higher in NHNO group compared to HNO and HO groups. Main effects of central obesity and hypertension were observed in UnAG, total ghrelin and GH. The HO group manifested the lowest level of UnAG, total ghrelin and GH among all the groups studied. Main effect of hypertension was observed on AG, suggesting that hypertensive individuals exhibited lower levels of AG regardless of central obesity.Conclusion: Circulatory ghrelin gene products and GH exhibit different modes of modulation in response to the co-manifestation of multiple cardiovascular risk factors compared with a single risk factor alone.

Divergent associations between ghrelin and neural responsivity to palatable food in hyperphagic and hypophagic depression

BackgroundThe neurobiological mechanisms involved in divergent appetitive phenotypes in major depressive disorder (MDD) are not well understood, although recent data suggest disruption in mesolimbic reward circuitry. Ghrelin, an orexigenic hormone, has been shown to modulate the reward circuitry. We aimed to investigate the relationship between acylated ghrelin levels and the neural response to food stimuli in individuals with hyperphagic and hypophagic MDD in remission. MethodsWomen with hyperphagic MDD (n = 10), hypophagic MDD (n = 18), and healthy controls (HC; n = 18) underwent fMRI scanning during which they viewed images of food. The fMRI session was followed by a standardized meal, appetite ratings, and serial blood draws. ResultsIn individuals with hyperphagic MDD, greater change in acylated ghrelin in response to a meal was associated with increased BOLD response to high-calorie food in the bilateral ventral tegmental area and left hypothalamus. In contrast, negative associations were observed between acylated ghrelin AUC and BOLD activity in the right hypothalamus in the hypophagic MDD group. LimitationsUnbalanced group sizes with a relatively small sample in the hyperphagic MDD group. ConclusionsIn the absence of differences in absolute ghrelin levels between the hyperphagic MDD and HC groups, results in hyperphagic MDD might suggest a ghrelinergic signaling mechanism for increased appetite during an MDD episode in this group. Our findings shed light on interactions between appetite hormones and mesolimbic circuitry which could contribute to development of therapeutic targets for opposing appetite phenotypes in depression.

Ghrelin and acyl ghrelin levels are associated with inflammatory and nutritional markers and with cardiac and vascular dysfunction parameters in hemodialysis patients

Exogenous ghrelin is associated with cardiovascular protection in experimental and human studies. Nevertheless ESRD patients have increased ghrelin levels and severe cardiovascular comorbidities. This study aims to elucidate the metabolic factors influencing endogenous ghrelin/acyl ghrelin levels and to analyze the relation between endogenous ghrelin/acyl ghrelin levels and cardiac and vascular function markers in hemodialysis patients. The cross-sectional study was conducted in hemodialysis patients (n = 88); 50 of them were men, mean age 61.1 ± 13.5years, 17% had diabetes. We assessed nutritional and inflammatory status and analyzed the determinants of ghrelin/acyl ghrelin and their relation with cardiac and vascular function. Ghrelin is correlated with IL-1β (r = 0.88, p < 0.0001), triglycerides, total cholesterol (TC), and Kt/V. IL-1β is the strongest predictor of ghrelin levels (p < 0.0001). Acyl ghrelin is correlated with TC (r = 0.36, p = 0.001), LDL-cholesterol, serum bicarbonate, body mass index. TC is the strongest predictor for acyl ghrelin levels (p = 0.038). Patients with high ghrelin levels had significantly decreased nitroglycerin-mediated dilation (p = 0.05) and higher IL-1β levels (p < 0.001); increased NT-proBNP is associated with lower levels of acyl ghrelin (r = - 0.33, p = 0.02) in male patients. The inflammatory marker IL-1β is in our study the strongest predictor of ghrelin levels while the nutritional marker-total cholesterol is the strongest predictor for acyl ghrelin levels in HD patients. High endogenous ghrelin level is associated with high IL-1β and with vascular smooth muscle cell dysfunction. Low acyl ghrelin level is associated with high NT-proBNP (a cardiac dysfunction marker) in male HD patients. There is a direct correlation between endogenous ghrelin level and inflammatory markers, which is not related with cardiovascular protection.

The effect of ghrelin O-acyltransferase inhibitor on gastric H+–K+-ATPase activity and GOAT/ghrelin system in gastric mucosal cells in vitro

Ghrelin is implicated in the regulation of gastric functional development. The octanoylation of ghrelin is critical for its physiological functions which dependent upon ghrelin O-acyltransferase (GOAT) catalyzation. To investigate the effect of GOAT on gastric acid secretion and expression of ghrelin in vitro. Primary cultures of gastric mucosal cells were challenged with 1.5 × 10−5, 1.5 × 10−4 and 1.5 × 10−3 mol/mL GO-CoA-Tat (The GOAT inhibitor), respectively, for 24 h in order to further clarify the effect of GOAT on H+–K+-ATPase activity. In vitro, GO-CoA-Tat significantly increased ghrelin and GOAT mRNA expression at 1.5 × 10−5, 1.5 × 10−4 and 1.5 × 10−3 mol/mL, and augmented cell total ghrelin secretion at 1.5 × 10−3 mol/mL. But cell acylated ghrelin secretion was reduced at 1.5 × 10−3 mol/mL GO-CoA-Tat (P < 0.05). And cell acylated ghrelin synthesis was reduced at 1.5 × 10−4 and 1.5 × 10−3 mol/mL GO-CoA-Tat (P < 0.05). In accordance with acylated ghrelin level, H+–K+-ATPase activity were decreased with 1.5 × 10−4 and 1.5 × 10−3 mol/mL GO-CoA-Tat (P < 0.05). These results indicated that GOAT inhibitor decreases the acylated ghrelin level and H+–K+-ATPase activity in vitro.

\u03b2-Oxidation in ghrelin-producing cells is important for ghrelin acyl-modification

Ghrelin is a unique fatty acid-modified peptide hormone produced in the stomach and has important roles in energy homeostasis and gastrointestinal motility. However, the medium-chain fatty acid source for ghrelin acyl-modification is not known. We found that a fat-free diet and the removal of intestinal microbiota did not decrease acyl-ghrelin production in the stomach or plasma acyl-ghrelin levels in mice. RT-PCR analysis showed that genes involving fatty acid synthesis, metabolism, and transport were expressed in pancreas-derived ghrelinoma (PG-1) cells. Treatment with an irreversible inhibitor of carnitine palmitoyltransferase-1 (CPT-1) strongly decreased acylated ghrelin levels but did not affect ghrelin or ghrelin o-acyl transferase (GOAT) mRNA levels in PG-1 cells. Our results suggest that the medium-chain fatty acid used for the acyl-modification of ghrelin is produced in ghrelin-producing cells themselves by β-oxidation of long-chain fatty acids provided from the circulation.

Comparison of total/active ghrelin levels in primary open angle glaucoma, pseudoexfoliation glaucoma and pseudoexfoliation syndrome.

To investigate the levels of ghrelin (Gh), acylated ghrelin (AGh) and AGh/Gh ratio in the humor aqueous (HA) of cases with pseudoexfoliation syndrome (PXS), pseudoexfoliation glaucoma (PXG), primary open angle glaucoma (POAG) and to compare these with control subjects. A prospective examination was made of the total Gh, and AGh levels in HA of 67 patients undergoing cataract surgery. Patients were divided into 4 groups. HA samples were aspirated at the beginning of the surgery, stored at -70°C. Gh and AGh quantification was performed with ELISA kits and the AGh/total-Gh ratios were calculated. ANOVA, Kruskal-Wallis, Chi-square and post-hoc tests were used for statistical analysis. Total Gh levels in HA were 189.2±45.6 pg/mL in the control group, 199.2±32.9 pg/mL in PXS, 180.6±20.9 pg/mL in PXG and 176.8±21.4 pg/mL in POAG groups (P>0.05). AGh levels in HA were 23.09±5.01 pg/mL in the control group, 24.13±5.22 pg/mL in PXS, 22.29±1.55 pg/mL in PXG and 19.69±2.93 pg/mL in POAG groups (P>0.05). The ratio of AGh/Gh was 10.3%±2.34% in the control group, 13.03%±2.58% in PXS, 12.3%±1.54% in PXG and 11.79%±1.41% in POAG groups (P=0.044). The difference between the PXS and control groups was significant (P=0.03). In spite of statistically insignificant results, the HA total Gh levels were lower than those of the control subjects but not parallel with the AGh levels in glaucoma patients. The relative increase in the AGh/Gh ratio in glaucoma cases supports the view that proportional increases of AGh might play a role in the pathogenesis of glaucoma.

Ghrelin is a persistent biomarker for chronic stress exposure in adolescent rats and humans

Prolonged stressor exposure in adolescence enhances the risk of developing stress-sensitive mental illnesses, including posttraumatic stress disorder (PTSD), for many years following exposure cessation, but the biological underpinnings of this long-term vulnerability are unknown. We show that severe stressor exposure increased circulating levels of the hormone acyl-ghrelin in adolescent rats for at least 130 days and in adolescent humans for at least 4.5 years. Using a rodent model of longitudinal PTSD vulnerability in which rodents with a history of stressor exposure during adolescence display enhanced fear in response to fear conditioning administered weeks after stressor exposure ends, we show that systemic delivery of a ghrelin receptor antagonist for 4 weeks surrounding stressor exposure (2 weeks during and 2 weeks following) prevented stress-enhanced fear memory. These data suggest that protracted exposure to elevated acyl-ghrelin levels mediates a persistent vulnerability to stress-enhanced fear after stressor exposure ends.