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Ghrelin is an appetite hormone-containing 28-amino acid and has 4 different forms in the body. Ghrelin forms have different physiological functions in the body. This study aims to analyze the effect of acyl and desacyl ghrelin hormone on hepatic steatosis and biochemical findings in 36 male Wistar rats. Rats were split into 6 equal groups, consisting of control, acyl ghrelin, desacyl ghrelin, acyl/desacyl 3:1, acyl/desacyl 1:1, and acyl/desacyl 1:3 groups, and administered placebo or 200 ng/kg hormone subcutaneous twice a day for 14 days. Oral Glucose Tolerance Test (OGTT) was performed on Day 15, Insulin Tolerance Test (ITT) on Day 16, and scarification procedure on Day 17. Certain biochemical data and liver diacylglycerol (DAG), glycogen, protein kinase C and PPAR-γ levels were detected in the blood. Histological analyses were also conducted on the liver tissues. The highest plasma total cholesterol and VLDL-K levels were found in the acyl/desacyl 1:3 group, and lower insulin, and HOMA-IR levels were found in groups where acyl and desacyl were administered together (p < 0.05). PPAR-γ gene expression level increased in acyl ghrelin and acyl/desacyl 1:3 groups compared to the control group. Protein kinase C gene expression was highest in the acyl/desacyl 1:3 group. The most severe degenerative findings compliant with steatosis in the liver were observed in the acyl ghrelin group (p < 0.05). It was determined that administering rats acyl alone and acyl/desacyl by 1:3 caused the highest PPAR-γ gene expression, serum total cholesterol, HDL-K, and VLDL-K levels in the body. Besides, it is shown that desacyl ghrelin effectively regulates the blood glucose level when administered alone. [ABSTRACT FROM AUTHOR]

Abstract Aim Acyl ghrelin increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). This could impair the right ventricular‐pulmonary arterial coupling (RVPAC), both through an increased venous return and right ventricular afterload. We aim to investigate if acyl ghrelin increases CO with or without worsening the right‐sided haemodynamics in HFrEF assessed by RVPAC. Methods and results The Karolinska Acyl ghrelin Trial was a randomized double‐blind placebo‐controlled trial of acyl ghrelin versus placebo (120‐min intravenous infusion) in HFrEF. RVPAC was assessed echocardiographically at baseline and 120 min. ANOVA was used for difference in change between acyl ghrelin versus placebo, adjusted for baseline values. Of the 30 randomized patients, 22 had available RVPAC (acyl ghrelin n = 12, placebo n = 10). Despite a 15% increase in CO in the acyl ghrelin group (from 4.0 (3.5–4.6) to 4.6 (3.9–6.1) L/min, P = 0.003), RVPAC remained unchanged; 5.9 (5.3–7.6) to 6.3 (4.8–7.5) mm·(m/s)−1, P = 0.372, while RVPAC was reduced in the placebo group, 5.2 (4.3–6.4) to 4.8 (4.2–5.8) mm·(m/s)−1, P = 0.035. Comparing change between groups, CO increased in the acyl ghrelin group versus placebo (P = 0.036) while RVPAC and the right ventricular pressure gradient remained unchanged. Conclusion Treatment with acyl ghrelin increases CO while preserving or even improving RVPAC in HFrEF, possibly due to increased contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF with right ventricular failure.

Aim: Acyl ghrelin increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). This could impair the right ventricular‐pulmonary arterial coupling (RVPAC), both through an increased venous return and right ventricular afterload. We aim to investigate if acyl ghrelin increases CO with or without worsening the right‐sided haemodynamics in HFrEF assessed by RVPAC. Methods and results: The Karolinska Acyl ghrelin Trial was a randomized double‐blind placebo‐controlled trial of acyl ghrelin versus placebo (120‐min intravenous infusion) in HFrEF. RVPAC was assessed echocardiographically at baseline and 120 min. ANOVA was used for difference in change between acyl ghrelin versus placebo, adjusted for baseline values. Of the 30 randomized patients, 22 had available RVPAC (acyl ghrelin n = 12, placebo n = 10). Despite a 15% increase in CO in the acyl ghrelin group (from 4.0 (3.5–4.6) to 4.6 (3.9–6.1) L/min, P = 0.003), RVPAC remained unchanged; 5.9 (5.3–7.6) to 6.3 (4.8–7.5) mm·(m/s)−1, P = 0.372, while RVPAC was reduced in the placebo group, 5.2 (4.3–6.4) to 4.8 (4.2–5.8) mm·(m/s)−1, P = 0.035. Comparing change between groups, CO increased in the acyl ghrelin group versus placebo (P = 0.036) while RVPAC and the right ventricular pressure gradient remained unchanged. Conclusion: Treatment with acyl ghrelin increases CO while preserving or even improving RVPAC in HFrEF, possibly due to increased contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF with right ventricular failure. [ABSTRACT FROM AUTHOR]

Background and Aims Ghrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes. Methods and results In a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11 b.p.m.; placebo 69 ± 8 to 68 ± 10 b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3. Conclusion In patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT05277415 [ABSTRACT FROM AUTHOR]

Introduction: Peripheral neuropathy is one of the most common complications in chronic kidney disease (CKD). The neuroprotective role of ghrelin is being explored recently. Here we aim to determine the burden of neuropathy in nondiabetic CKD and to find the association of peripheral nerve function with plasma ghrelin levels in these patients. Methods: This was a cross-sectional study conducted in nondiabetic CKD patients on conservative management to determine the magnitude of neuropathy. The association of ghrelin isoforms with nerve functions was assessed between three groups, namely CKD with neuropathy, CKD without neuropathy, and healthy volunteers, with 20 participants in each group. Results: The proportion of neuropathy in nondiabetic CKD was 78% (n = 78), of which 51% (n = 40) were asymptomatic. Des acyl ghrelin (DAG) and total ghrelin (TG) levels were 1545.5 ± 487.4 and 1567.4 ± 485.3 pg/mL, respectively, in CKD patients with neuropathy and were found to be elevated compared to those without neuropathy, who had 1000.4 ± 264.2 and 1019.7 ± 264.3 pg/mL of DAG and TG, respectively (P < 0.001). Assessment of correlation between nerve conduction parameters and DAG levels showed positive correlation between DAG levels and common peroneal latency (r = 0.69; P < 0.01), median sensory latency (r = 0.45; P < 0.05), and sural latency (r = 0.51; P < 0.05). We found negative correlation between median velocity (r =-0.56; P < 0.05), common peroneal velocity (r = -0.64; P < 0.01), median sensory velocity (r =-0.49; P < 0.05), and sural velocity (r = -0.54; P < 0.05). There was no statistically significant difference in acyl ghrelin levels among the groups. Conclusion: The prevalence of peripheral neuropathy in CKD is significantly higher with almost half of them being asymptomatic. Impaired renal clearance in CKD leads to the accumulation of DAG, which subsequently inhibits the neuroprotective functions of AG leading to neuropathy in CKD. [ABSTRACT FROM AUTHOR]

Background: Craving plays an important role in maintenance of alcohol dependence. Earlier studies have analyzed the role of ghrelin in craving and their results have been heterogenous. Acyl ghrelin is its more active form as it crosses the blood brain barrier. Hence we aimed to examine the relationship between plasma acyl ghrelin and craving in Indian patients having alcohol dependence syndrome. Methods: The present study was a hospital-based prospective study. A total of 60 drug-naive patients of alcohol dependence and 30 healthy controls were included. After taking informed consent fasting blood samples were collected from them on day 1 and tested for plasma acyl ghrelin level. Fasting blood samples were repeated in all cases on day 14. During this time, we also assessed the patients' cravings by obsessive compulsive drinking scale, and alcohol craving questionnaire; and withdrawal by clinical institute withdrawal assessment for alcohol scale. These scales were repeated on day 14. Data analysis was done by SPSS version 25.0. Results: Plasma concentrations of acyl ghrelin increased significantly during early abstinence in patients from day 1 to day 14 (P < 0.0001). Pearson correlation test revealed a trend of positive correlation between plasma concentration of acyl ghrelin on day 14 and severity of craving on day 1. Conclusion: Our results suggest the plasma concentration of acyl ghrelin may be a predictor of severity of alcohol craving during early abstinence. Anti-craving drugs acting on acyl ghrelin level in brain may open an innovative avenue for optimum treatment of alcohol dependence. [ABSTRACT FROM AUTHOR]

Context: Acylated ghrelin increases growth hormone (GH) and adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary gland. Additionally, it increases free fatty acid levels independently of GH and ACTH, but the impact of ghrelin on fatty acid turnover has not been determined. This study was designed to test whether acylated ghrelin directly increases the turnover rate of fatty acids. Design: Eight hypopituitary patients on stable replacement with GH and hydrocortisone were included in a randomized, double‐blinded, placebo‐controlled crossover study including two study days: (a) infusion of acylated ghrelin and (b) infusion of saline. The study day comprised a basal period (t = 0‐120 minutes) and a hyperinsulinaemic‐euglycemic clamp period (t = 120‐300 minutes). Whole‐body lipolysis was estimated at t = 90‐120 and t = 270‐300 minutes with a palmitate isotope dilution technique. Results: Infusion of acylated ghrelin resulted in 10 times increased total ghrelin area under the curve (AUC) levels in the basal period and 15 times increased AUC levels in the clamp period compared with saline infusion (P <.001). GHAUC levels were largely unaffected by ghrelin compared to saline infusion during both the basal and clamp period, but cortisolAUC levels increased by 15% after ghrelin compared to saline infusion in the basal period (P =.03). Palmitate turnover was increased by 43% in the basal period (difference: 77 (20) µmol/min, P =.01) and unchanged in the clamp period (difference 0.9 (17) µmol/min, P = 1.0) after ghrelin compared to saline infusion. Conclusions: Our results support the hypothesis that pharmacological levels of acylated ghrelin directly activate lipolysis at the whole‐body level. [ABSTRACT FROM AUTHOR]

Background: The effects of dietary macronutrients on orexigenic and anorexigenic hormones in children are poorly understood. Objective: To explore effects of varying dietary macronutrients on appetite‐regulating hormones [acyl ghrelin (AG) and desacyl ghrelin (DAG), glucagon‐like peptide 1 (GLP‐1), peptide tyrosine tyrosine (PYY) and insulin] in children with PWS and healthy children (HC). Design: Randomized, cross‐over experiments compared two test diets [high protein‐low carbohydrate (HP‐LC) and high protein‐low fat (HP‐LF)] to a STANDARD meal (55% carbohydrate, 30% fat, 15% protein). Experiment 1 included ten children with PWS (median age 6.63 years; BMI z 1.05); experiment 2 had seven HC (median age 12.54 years; BMI z 0.95). Blood samples were collected at baseline and at 60‐minute intervals for 4 hours. Independent linear mixed models were adjusted for age, sex and BMI z‐score. Results: Fasting and post‐prandial AG and DAG concentrations are elevated in PWS children; the ratio of AG/DAG is normal. Food consumption reduced AG and DAG concentrations in both PWS and HC. GLP‐1 levels were higher in PWS after the HP‐LC and HP‐LF meals than the STANDARD meal (P =.02‐0.04). The fasting proinsulin to insulin ratio (0.08 vs 0.05) was higher in children with PWS (P =.05) than in HC. Average appetite scores in HC declined after all three meals (P =.02) but were lower after the HP‐LC and HP‐LF meals than the STANDARD meal. Conclusion: Altered processing of proinsulin and increased GLP‐1 secretion in children with PWS after a high protein meal intake might enhance satiety and reduce energy intake. [ABSTRACT FROM AUTHOR]

Hsien-Hao Huang,1,2 Liang-Yu Chen,3,4 Ming-Luen Doong,5 Shi-Chuan Chang,6,7 Chih-Yen Chen8–10 1Institute of Clinical Medicine, National Yang-Ming University of Medicine, 2Department of Emergency Medicine, Taipei Veterans General Hospital, 3Aging and Health Research Center, National Yang-Ming University, 4Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, 5Institute of Physiology, National Yang-Ming University School of Medicine, 6Institute of Emergency and Critical Medicine, National Yang-Ming University School of Medicine, 7Department of Chest Medicine, Taipei Veterans General Hospital, 8Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 9Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, 10Taiwan Association for the Study of Small Intestinal Diseases, Guishan, Taiwan Background: Acyl ghrelin-induced intake depends on hypothalamic neuropeptide Y and agouti-related protein (AgRP) neurotransmitters. Intracerebroventricular (ICV) injection of AgRP increases feeding through competitive antagonism at melanocortin receptors. ICV administration of α-melanocyte stimulating hormone (α-MSH), a natural antagonist of AgRP, may modulate the acyl ghrelin-induced orexigenic effect.Objective: This study aimed to investigate the modulating effect of α-MSH on the central acyl ghrelin-induced food intake, gastrointestinal motility, and colonic secretion in rats.Methods and procedures: We examined the effects of α-MSH and acyl ghrelin on food intake, gastric emptying, small intestinal transit, colonic motility, and secretion in conscious rats with a chronic implant of ICV catheters.Results: ICV injection of O-n-octanoylated ghrelin (0.1 nmol/rat) significantly increased the cumulative food intake up to 8 h (P

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.

The current study aimed to clarify the significance of the preoperative desacyl ghrelin (DG)-to-acyl ghrelin (AG) ratio in patients undergoing pancreaticoduodenectomy (PD). Ghrelin, a peptide hormone mainly produced in the stomach, possesses unique functions. Recently, studies have determined the involvement of plasma gherlin in certain postoperative outcomes, particularly in surgical resections of the stomach. Although PD involves gastric resection, few reports have determined the involvement of ghrelin following PD. From April 2003 to December 2011, 195 patients underwent PD for tumors of the pancreatic head, bile duct and ampulla of Vater at the Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, University of Miyazaki Faculty of Medicine (Miyazaki, Japan). Of these, 83 patients were enrolled into the present study as their plasma gherlin levels were measured. AG, DG, total ghrelin (TG) and the DG-to-AG ratio (D/A) were subsequently assessed. Furthermore, the prognostic nutritional index (PNI) and high-sensitivity modified Glasgow Prognostic Score (HS-mGPS) were determined. Morbidity was examined in all 83 patients, but mortality was only determined in 69 individuals after 14 patients were excluded due to the presence of benign disease. The results revealed that the TG of patients undergoing standard PD (SPD) was significantly lower than that of patients undergoing pylorus-preserving PD or subtotal stomach-preserving PD. It was also determined that TG levels declined significantly in SPD patients at 2 weeks after surgery. Negative associations were identified between plasma ghrelin levels and PNI, and between serum albumin and HS-mGPS. Patient morbidity was determined to be 31.3% and the severe complications exhibited by patients included pancreatic fistula (14.5%), intra-abdominal abscess (15.7%), intra-abdominal bleeding (6.0%) and liver abscess (1.2%). Multivariate analysis revealed that disease location and low D/A were independent risk factors for severe complications. The 5-year overall survival (OS) rate was 41.5%. Multivariate analysis also demonstrated that diabetes mellitus, long postoperative hospital stay and low D/A were independent risk factors for OS. The present study revealed the D/A may serve as a useful predictive factor for postoperative complications and prognosis after PD. [ABSTRACT FROM AUTHOR]

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 primordia l follicles. These findings suggest that chronic stress-induced elevations of acyl ghrelin may be detrimental for ovarian follicle maturation. [ABSTRACT FROM AUTHOR]

Acyl ghrelin, a novel brain-gut peptide, is an endogenous ligand for the growth hormone secretagogue receptor. Accumulated research data have shown that acyl ghrelin exercises a significant neuroprotective effect against cerebral ischemia/reperfusion (I/R) injury in animal models and in cultured neurons during the acute phase, usually, 1 day after cerebral ischemia. The chronic effects of acyl ghrelin 1 week after brain ischemia remain largely unknown. In this study, we explored the effects of acyl ghrelin on cultured organotypic brain slices and cortical neurons which were injured by oxygen–glucose deprivation/reperfusion(OGD/R) for 7 days. The underlying molecular mechanisms were deciphered based on label-free proteomic analysis. Acyl ghrelin treatment promoted neurite (axons and dendrites) growth and alleviated the neuronal damage in both cultured brain slices and neurons. Proteomic analysis showed that cell division control protein 42 (Cdc42) mediates the effects of acyl ghrelin on neurite growth. Acyl ghrelin stimulated the expression of Cdc42 and neurite growth in cultured neurons comparing with OGD/R group. Inhibition of Cdc42 attenuated the effects of acyl ghrelin. These results suggest that acyl ghrelin promotes neurite growth during the later stage after OGD/R injury via Cdc42. Our study suggests that acyl ghrelin may be promising to restore the neuronal structure in the late phase after stroke. [ABSTRACT FROM AUTHOR]

This review evaluates published studies regarding alpha-melanocyte stimulating hormone (α-MSH) in ghrelin-elicited feeding and gut motility. We have sought to integrate all available evidences to provide a complete review on the properties of melanocortin receptors (MCR) and the potential clinical treatment of α-MSH after ghrelin-elicited feeding and gut motility. The available studies were grouped into four categories: food intake, gastric emptying, small intestinal transit, and colonic transit. As we describe, the literature provides evidence of the ability of ghrelin to increase food intake, gastric emptying, small intestinal transit, and colonic transit. α-MSH, which displays high affinity for the MC3 and MC4 receptors, can competitively activate MCRs with agouti-related protein stimulated by ghrelin, and partly attenuates the effect of acyl ghrelin on food intake. Central ghrelin-induced acceleration of gastric emptying is not mediated by MCRs, but the acceleration of the small intestinal transit is at least partly mediated via MCRs in the brain. Similar to fecal pellets and total fecal weight, distal colonic motility and secretion are partly mediated by MCRs in the brain. The interplay between acyl ghrelin and MCRs may provide a new therapeutic avenue to ameliorate anorexia and constipation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract In the current study we investigated the interaction of hypothalamic paraventricular nucleus (PVN) glucagon-like peptide-1 (GLP-1) and ghrelin signaling in the control of metabolic function. We first demonstrated that acylated ghrelin injected directly into the PVN reliably altered the respiratory exchange ratio (RER) of adult male Sprague Dawley rats. All testing was carried out during the initial 2 h of the nocturnal cycle using an indirect open circuit calorimeter. Results indicated that acylated ghrelin induced a robust increase in RER representing a shift toward enhanced carbohydrate oxidation and reduced lipid utilization. In contrast, treatment with comparable dosing of des-acyl ghrelin failed to significantly impact metabolic activity. In separate groups of rats we subsequently investigated the ability of exendin-4 (Ex-4), a GLP-1 analogue, to alter acylated ghrelin's metabolic effects. Rodents were treated with either systemic or direct PVN Ex-4 followed by acyl ghrelin microinjection. While our results showed that both systemic and PVN administration of Ex-4 significantly reduced RER, importantly, Ex-4 pretreatment itself reliably inhibited the impact of ghrelin on RER. Overall, these findings provide increasingly compelling evidence that GLP-1 and ghrelin signaling interact in the neural control of metabolic function within the PVN. [ABSTRACT FROM AUTHOR]

Abstract The neuroprotective effect of ghrelin has recently been reported in Alzheimer's disease (AD). Ghrelin is converted from des-acyl ghrelin to the activated form, acyl ghrelin, by membrane bound o-acyltransferase 4 (MBOAT4), and then binds to growth hormone secretagogue receptor (GHS-R). We examined the levels of plasma acyl/des-acyl ghrelin in 75 AD subjects and age- and sex-matched controls, as well as the DNA methylation and mRNA expression of MBOAT4 and GHS-R in peripheral leukocytes. The acyl ghrelin concentration was significantly higher in AD subjects than in controls (2.18 ± 1.25 vs. 1.49 ± 2.3, p = 0.001). The methylation rate of MBOAT4 CpG 2 was significantly lower in AD subjects than in controls (4.0 ± 0.9 vs. 4.7 ± 1.2, p < 0.001). The mRNA expression levels of MBOAT4 and GHS-R1b were significantly higher in AD subjects than in controls (MBOAT4 : 1.10 ± 0.48 vs. 1.0 ± 0.55, p = 0.049; GHS-R1b : 1.76 ± 3.18 vs. 1.0 ± 1.56, p = 0.030). These changes in the ghrelin cascade in peripheral blood may reflect those in the brain, and may be a neuroprotective biomarker in AD. [ABSTRACT FROM AUTHOR]

Highlights • Des-acylated ghrelin does not influence the cytokine or HPA axis response to LPS. • Acylated ghrelin suppresses the pro- and anti-inflammatory cytokine response to LPS in vivo. • Acylated ghrelin stimulates neuronal activation in the PVN but does not affect the HPA axis responses to LPS. • Acyl ghrelin's anti-inflammatory effects are independent of its actions on the HPA axis. Abstract Ghrelin, one of the major metabolic hormones involved in controlling energy balance, has recently been shown to have other properties including regulating the hypothalamic-pituitary-adrenal (HPA) axis response to psychological stress and being a potent anti-inflammatory agent. Ghrelin's HPA axis and anti-inflammatory actions have previously been identified as principally due to the acylated form (AG). However, our recent work has also suggested a role for des-acylated ghrelin (DAG) in these functions. Here we hypothesized ghrelin's anti-inflammatory activity is mediated by the HPA axis and this effect is differentially executed by AG and DAG. We gave adult male Wistar rats a concomitant injection of AG or DAG and lipopolysaccharide (LPS) and measured their effects on circulating cytokines, stress hormones and neuronal activation of the paraventricular nucleus of the hypothalamus (PVN). AG, but not DAG significantly suppressed the pro- and anti-inflammatory cytokine response induced by LPS in vivo. DAG also had no effects on any components of the HPA axis. AG, despite stimulating neuronal activation in the PVN in vivo and stimulating ACTH release from the pituitary in vitro , did not affect the HPA axis response to LPS. These findings suggest AG's anti-inflammatory effects are independent of its actions on the HPA axis and have implications for the potential use of this peptide for treatment of inflammatory conditions without compromising HPA axis activity. [ABSTRACT FROM AUTHOR]

Introduction: The mechanism underlying beneficial outcomes of bariatric surgery still remains unclear. Especially little is known about hormonal and metabolic changes induced by the novel bariatric procedure mini gastric bypass (MGB). Aim: To evaluate pre- and post-prandial changes in both ghrelin isoforms in obese patients without diabetes and cardiovascular complications treated with MGB, sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) surgery. Material and methods: From 45 patients initially enrolled in the study, 23 persons completed a one-year follow-up period. Venous blood for acyl and desacyl ghrelin (AG and DAG) as well as other metabolic assays was collected 3 months before and 6 and 12 months after bariatric surgery (MGB, RYGB, SG) - in the fasting state and 2 h after the consumption of a standard 300 kcal-mixed meal (Nutridrink standard, Nutricia). Results: AG and DAG levels (both fasting and prandial) as well as AG/DAG ratio did not change after 6 and 12 months in MGB and RYGB groups. In the SG group we observed a significant decrease in fasting and postprandial DAG levels and consecutively an increase in the fasting AG/DAG ratio after 6 and 12 months. Six months after surgery we observed some differences between carbohydrate metabolism measures in the MGB group (lower HbA1c, HOMA-IR and fasting insulinaemia) in comparison to the rest of the participants, but 12 months after each type of surgery body mass index and indices of carbohydrate and lipid metabolism did not differ. Conclusions: The results of our study demonstrate that all studied bariatric procedures can successfully reduce overall body weight and suggest also that the mechanisms of weight loss and improvement in carbohydrate and lipid metabolism after all three types of surgery are independent of ghrelin and the acyl/desacyl ghrelin ratio. [ABSTRACT FROM AUTHOR]

Introduction: Different physical exercises play an important role in energy balance and weight control through affecting the appetite-regulating hormones. The aim of this study was to determine the effect of different resistance training modes on appetite and appetite-related hormones among sedentary healthy males. Subjects & Methods: This study was conducted on 40 healthy males with the mean age of 22.15±0.7 years and body mass index of 24.12±3.5 kg/m2 . The study population was randomly assigned into four groups of control group (n=10), upper-body resistance training (n=10), lower-body resistance training, and full body resistance training. Trainings were performed three sessions a week for eight weeks. The fasting blood samples were obtained from the antecubital vein before and 48 h after the last session of the resistance training for the evaluation of plasma growth hormone, orexin, ghrelin, acyl ghrelin, and neuropeptide Y (NPY) using ELISA method. In addition, the desire to eat was measured by means of the appetite questionnaire. Results: According to the results, plasma growth hormone, orexin, ghrelin, and acyl ghrelin were increased significantly after lower-body and full body resistance trainings, compared to the pre-intervention stage. Meanwhile, the upper-body resistance training just resulted in the elevation of NPY (P=0.049). The enhancement of orexin level was more significant in the lower-body training group in comparison to that in the control group (P=0.001). Furthermore, the enhancement of ghrelin level was more significant in the full body (P=0.021) and lower-body (P=0.001) training groups than in the control group. On the other hand, the three intervention groups showed a higher elevation in NPY as compared to the control group. Additionally, desire to eat was increased after the three modes of training; however, there was no significant difference among the three training groups in this regard. Conclusion: As the findings indicated, resistance training, especially lowerbody and full body resistance trainings, regulated appetite through the elevation of growth hormone, orexin, ghrelin, and NPY. Moreover, the type of resistance training affected the amount of appetite changes after adjusting to resistance training. [ABSTRACT FROM AUTHOR]

Preproghrelin is a prohormone producing several preproghrelin-derived peptides with structural and functional heterogeneity: acyl ghrelin (AG), desacyl ghrelin (DAG), and obestatin. The absence of selective and reliable assays to measure these peptides simultaneously in biological samples has been a limitation to assess their real proportions in tissues and plasma in physiological and pathological conditions. We aimed at reliably measure the ratio between the different preproghrelin-derived peptides in murine tissues using selective immunoassays combined with a highly sensitive mass spectrometry method. AG-, DAG-, and obestatin-immunopositive fractions from the gastrointestinal tract of adult wild-type and ghrelin-deficient mice were processed for analysis by mass spectrometry (MS) with a Triple Quadrupole mass spectrometer. We found that DAG was predominant in mouse plasma, however it only represented 50% of total ghrelin (AG+DAG) production in the stomach and duodenum. Obestatin plasma levels accounted for about 30% of all circulating preproghrelin-derived peptides, however, it represented

Sows are usually restricted fed during pregnancy to maximize their reproductive efficiency, which may predispose sows to a state of hunger. However, an objective measurement of hunger status has not been established. In the present study, we examined the correlation of plasma hormones and NEFA and selected the best predictors for hunger status using pregnant gilts. Three different levels of feed intake (0.5, 1.0 and 2.0 × maintenance energy intake [0.5M, 1.0M and 2.0M, respectively]) were imposed from Day 28 to 34 of gestation to create different hunger statuses in pregnant gilts. Plasma hormones related to energy homeostasis and NEFA were analyzed to quantify their response to different levels of feed intake. A total of 18 gilts (197.53 ± 6.41 kg) were allotted to 1 of 3 dietary treatments using a completely randomized design. Results showed that BW change, ADG, and G:F from Day 28 to 34 of gestation were higher (P < 0.01) for gilts on the 2.0M feeding level than for gilts on the 0.5M feeding level. Plasma acyl ghrelin concentrations showed a relatively flat pattern during the 24-h period. Plasma acyl ghrelin and NEFA concentrations and areas under the curve (AUC) were greater (P < 0.05) in gilts on the 0.5M level of feed intake than in those on the 2.0M level of feed intake. No differences were observed among the 3 feeding levels in terms of plasma glucagon-like peptide 1 and leptin concentrations. Additionally, consumption time for 1.82 kg feed on Day 35 of gestation was longer (P < 0.01) in gilts fed the 2.0M level of feed intake from Day 28 to 34 of gestation than in those on the 0.5M level of feed intake. Simple linear regression results showed that the AUC of acyl ghrelin was the best predictor for consumption time (R2 = 0.82), whereas the AUC of NEFA was the best predictor for BW (R² = 0.55) or backfat change (R2 = 0.42) from Day 28 to 34 of gestation. In conclusion, our data suggested that a relative flat pattern existed in pregnant gilts in terms of the diurnal plasma profile of acyl ghrelin and that the level of feed intake of pregnant gilts was negatively correlated with plasma concentrations of acyl ghrelin and NEFA, which, in turn, were negatively associated with feed consumption time. The AUC of acyl ghrelin and NEFA seemed to be the best predictors for hunger status of pregnant gilts. [ABSTRACT FROM AUTHOR]

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1-40 (Aβ1-40) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aβ1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y-maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aβ1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aβ1-40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aβ1-40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium-binding adapter expressing microglial in the rostral hippocampus. Finally, Aβ1-40 blocked long-term potentiation induced by high-frequency stimulation and this effect could be acutely blocked with co-administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD. [ABSTRACT FROM AUTHOR]

Preproghrelin is a prohormone producing several preproghrelin-derived peptides with structural and functional heterogeneity: acyl ghrelin (AG), desacyl ghrelin (DAG), and obestatin. The absence of selective and reliable assays to measure these peptides simultaneously in biological samples has been a limitation to assess their real proportions in tissues and plasma in physiological and pathological conditions. We aimed at reliably measure the ratio between the different preproghrelin-derived peptides in murine tissues using selective immunoassays combined with a highly sensitive mass spectrometry method. AG-, DAG-, and obestatin-immunopositive fractions from the gastrointestinal tract of adult wild-type and ghrelin-deficient mice were processed for analysis by mass spectrometry (MS) with a Triple Quadrupole mass spectrometer. We found that DAG was predominant in mouse plasma, however it only represented 50% of total ghrelin (AG+DAG) production in the stomach and duodenum. Obestatin plasma levels accounted for about 30% of all circulating preproghrelin-derived peptides, however, it represented <1% of total preproghrelin-derived peptides production (AG+DAG+Obestatin) in the stomach. Assays were validated in ghrelin-deficient mice since neither ghrelin nor obestatin immunoreactivities were detected in their stomach, duodenum nor plasma. MS analyses confirmed that obestatin-immunoreactivity in stomach corresponded to the C-terminal amidated form of the peptide but not to des(1-10)-obestatin, nor to obestatin-Gly. In conclusion, specificity of ghrelin and obestatin immunoreactivities in gastrointestinal tissues using selective immunoassays was validated by MS. Obestatin was less abundant than AG or DAG in these tissues. Whether this is due to inefficient processing rate of preproghrelin into mature obestatin in gastrointestinal mouse tissues remains elusive. [ABSTRACT FROM AUTHOR]

Maintenance of body temperature (T b) at various ambient temperatures (T a) during fasting is important for homeotherms. Fasting decreases T b in thermoneutral and cold conditions and facilitates thermoregulatory behavior in the cold in rats; however, the mechanism is unknown. We focused on ghrelin, a hormone secreted by the stomach during fasting, in two circulatory forms: acyl ghrelin (AG) and des-acyl ghrelin (DAG). AG is called active ghrelin, while DAG, the non-active ghrelin, was unknown for a long time before its many functions were recently clarified. In the present review, we present the modulation of AG and DAG on autonomic and behavioral thermoregulation at various T a and discuss the differences between their modulation on thermoregulation. AG decreases T b in thermoneutral and cold conditions but does not affect the thermoregulatory behavior of rodents in cold conditions. The DAG decreases T b in thermoneutral and hot conditions, but it does not affect T b and facilitates the thermoregulatory behavior of rodents in the cold. These findings indicate that the actions of AG and DAG on thermoregulation are similar in thermoneutral conditions but are different in cold conditions. • The modulation of thermoregulation at various ambient temperatures by acyl and des-acyl ghrelin was reviewed. • Acyl-ghrelin decreases body temperature, but does not affect thermoregulatory behavior in the cold. • Des-acyl ghrelin decreases body temperature in the hot, and facilitates thermoregulatory behavior in the cold. • The actions of acyl ghrelin and des-acyl ghrelin on thermoregulation are different in the cold. [ABSTRACT FROM AUTHOR]

Background: Ghrelin, an orexigenic hormone, has multiple favorable functions including protein anabolism enhancement, anti-inflammatory actions, and cardiovascular protection. A low plasma ghrelin level is associated with increased mortality in patients treated with hemodialysis (HD). However, it is unclear whether the plasma ghrelin level in HD patients correlates with the severity of gastric mucosal atrophy and Helicobacter pylori status.Methods: Seventy-eight maintenance HD patients and 51 non-dialysis patients with chronic kidney disease were evaluated for severity of gastric mucosal atrophy by gastroduodenoscopy and for H. pylori status using an anti-H. pylori-antibody and rapid urease test. Plasma acyl and des-acyl ghrelin levels were measured and their associations with relevant clinical parameters were investigated.Results: Des-acyl ghrelin level in HD patients was significantly higher than that in patients with kidney function preserved. Although acyl and des-acyl ghrelin levels were similar between current H. pylori positive and negative HD patients, both levels decreased significantly with the progress of endoscopic gastric mucosal atrophy in HD patients. Serum pepsinogen (PG) I level and PG I/II ratio decreased significantly according to the severity of atrophy in HD patients and positively significantly correlated with both ghrelin levels. Multiple regression analysis showed significant positive correlations between acyl ghrelin and PG I levels (β = 0.738, p < 0.001) and significant negative correlations between ghrelin and age, albumin, and creatinine levels.Conclusions: Gastric atrophy is the major determinant of ghrelin level in HD patients. Management practices, such as H. pylori eradication, before advanced atrophy may be required to prevent the decrease of ghrelin levels and improve the prognosis of HD patients. [ABSTRACT FROM AUTHOR]

Background A significant problem to be solved for patients after liver transplantation (LT) is malnutrition with anorexia in the early posttransplant period. We hypothesized that this problem was due to the change in ghrelin metabolism during LT. The aim of this study was to examine the balance of acyl ghrelin (AG) and desacyl ghrelin and the dependence of the regulation mechanism on hepatic-related enzymes in patients during LT. Materials and methods AG, desacyl ghrelin, and acyl/total ghrelin (A/T) concentrations in blood samples were measured in 15 patients with liver failure (LF), 15 patients after LT, and 10 controls. The correlations between the participants' ghrelin profiles and hepatic function–related data, including liver enzymes, were evaluated. In vitro assays using synthetic AG for assessment of deacylation activity in serum were performed. Results AG and A/T ratio were significantly higher in the LF patients than the patients after LT and controls (AG: 25.9 ± 12.6 versus 16.4 ± 12.6 and 9.8 ± 7.6 fmol/mL, P < 0.05; A/T ratio: 17.4 ± 4.1 versus 12.2 ± 5.5 and 11.8% ± 5.9%, P < 0.05). The serum cholinesterase level was inversely correlated with AG and A/T ratio ( P < 0.01). In vitro assays showed that deacylation activity was significantly lower in patients with LF than controls (10.5% versus 42.4%, 90 min; P < 0.01). Degradation of AG was partially suppressed by a cholinesterase inhibitor. Conclusions Deacylation activity was lower in LF patients, which could cause elevation of AG levels. Serum cholinesterase may be responsible for deacylation in humans. [ABSTRACT FROM AUTHOR]

Background Adult studies indicate a role for ghrelin in functional dyspepsia ( FD) mediated through ghrelin's effect on gastric emptying ( GE). This study examines the relationship between ghrelin, liquid GE, and pain in children with FD. Methods Thirteen FD patients reporting symptoms consistent with post-prandial distress syndrome ( PDS) and 17 healthy controls were enrolled. All participants received a liquid meal containing 13C-sodium acetate. Pain severity, liquid GE utilizing exhaled 13CO2 from the sodium acetate breath tests ( ABT), plasma acyl ghrelin ( AG), and des-acyl ghrelin concentrations were measured at specific intervals over 240 min following ingestion. Key Results FD- PDS patients demonstrated lower mean baseline AG (14.8 ± 9.7 vs 27.2 ± 14.0 fmol/mL; p = 0.013), AG Cmax (24.6 ± 8.2 vs 40.5 ± 16.8 fmol/mL; p = 0.007), and AG flux (18.2 ± 7.8 vs 32.7 ± 17.3 fmol/mL; p = 0.015) than controls. The time to reach maximum exhaled 13CO2 concentration (T max) was longer in FD patients than controls (47.5 ± 18.5 vs 35.8 ± 11.8 min; p = 0.046). Significant relationships between ghrelin analyte ratios and ABT parameters were largely confined to control participants. Conclusions & Inferences FD- PDS in children is associated with lower fasting and maximum AG concentrations, and dampened AG flux. These data suggest a possible role for altered ghrelin physiology in the pathogenesis of PDS. [ABSTRACT FROM AUTHOR]