Des-acyl Ghrelin Concentrations Research Articles

Measurement of Ghrelin as a Marker of Appetite Dysregulation in Cats with and without Chronic Kidney Disease.

Appetite abnormalities and weight loss are important comorbidities in the treatment of chronic kidney disease (CKD) in cats. Ghrelin, a key hormone involved in the regulation of appetite and metabolism, is a potential marker of appetite dysregulation in cats with CKD. The aim of this study was to compare the plasma concentrations of acylated, desacyl, and total ghrelin in normal cats and cats with CKD. Storage methodology was investigated prior to evaluating ghrelin concentrations in normal and CKD cats to facilitate clinical sample collection. Twelve normal cats and twelve cats with CKD were enrolled. Plasma acylated and total ghrelin concentrations were measured using radioimmunoassay. Desacyl ghrelin was calculated (total ghrelin minus acylated ghrelin). Cats with CKD had significantly increased total ghrelin and calculated desacyl ghrelin concentrations in comparison to normal cats (p < 0.0001 and p = 0.0001). There was no significant difference in active ghrelin concentrations between groups. Both total ghrelin and calculated desacyl ghrelin were significantly correlated with serum creatinine concentrations (p < 0.0001, r = 0.70 and p < 0.0001, r = 0.73). Elevated plasma desacyl ghrelin concentrations in cats with CKD provides evidence for dysregulation of appetite in feline CKD.

Liver-Expressed Antimicrobial Peptide 2 Is a Hepatokine That Predicts Weight Loss and Complete Remission of Type 2 Diabetes Mellitus after Vertical Sleeve Gastrectomy in Japanese Individuals

Introduction: Vertical sleeve gastrectomy (VSG) is considered one of the most effective treatments for sustained weight loss and complete remission of type 2 diabetes mellitus (CR-T2DM). Liver-expressed antimicrobial peptide 2 (LEAP2), a ghrelin receptor antagonist peptide, is a metabolic hormone regulated by VSG. However, it is unknown whether LEAP2 can be used to predict the outcomes of VSG. This study aimed to evaluate LEAP2 as a predictive factor for weight loss and CR-T2DM after VSG. Methods: This retrospective study included 39 Japanese participants with obesity who underwent VSG. Serum LEAP2, des-acyl ghrelin (DAG), and other metabolic and anthropometric parameters were studied before and at 12 months after VSG. Receiver operating characteristics (ROC) curve was generated to evaluate predictive score for weight loss with cut-off value of >50 percent excess weight loss. ROC curve was also generated to assess CR-T2DM. Results: Serum LEAP2 levels were significantly higher in participants with body mass index (BMI) 32–50 kg/m² than in those with normal weight. Participants with BMI >50 kg/m² had lower serum LEAP2 concentrations than those with BMI 32–50 kg/m². VSG caused a significant reduction in serum DAG concentrations, but it did not affect serum LEAP2 concentrations in either male or female participants. Preoperative serum LEAP2 concentration of 2.88 pmol/mL was the optimal cutoff value for predicting weight loss after VSG, with sensitivity of 80.0% and specificity of 75.9%. Preoperative serum LEAP2 level higher than 4.67 pmol/mL predicted CR-T2DM after VSG with sensitivity of 100% and specificity of 58.8%. Conclusion: Preoperative serum LEAP2 could predict weight loss and CR-T2DM as outcomes of VSG.

Circulating acyl and des-acyl ghrelin levels in obese adults: a systematic review and meta-analysis

Ghrelin is the only known orexigenic gut hormone, and its synthesis, secretion and degradation are affected by different metabolic statuses. This meta-analysis aimed to investigate the potential differences in plasma acyl ghrelin (AG) and des-acyl ghrelin (DAG) concentrations between normal weight and obese adults. Systematic literature searches of PubMed, Embase and Web of Science through October 2021 were conducted for articles reporting AG or DAG levels in obesity and normal weight, and 34 studies with 1863 participants who met the eligibility criteria were identified. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to evaluate group differences in circulating AG and DAG levels. Pooled effect size showed significantly lower levels of baseline AG (SMD: − 0.85; 95% CI: − 1.13 to − 0.57; PSMD < 0.001) and DAG (SMD: − 1.06; 95% CI: − 1.43 to − 0.69; PSMD < 0.001) in obese groups compared with healthy controls, and similar results were observed when subgroup analyses were stratified by the assay technique or storage procedure. Postprandial AG levels in obese subjects were significantly lower than those in controls when stratified by different time points (SMD 30 min: − 0.85, 95% CI: − 1.18 to − 0.53, PSMD < 0.001; SMD 60 min: − 1.00, 95% CI: − 1.37 to − 0.63, PSMD < 0.001; SMD 120 min: − 1.21, 95% CI: − 1.59 to − 0.83, PSMD < 0.001). In healthy subjects, a postprandial decline in AG was observed at 120 min (SMD: − 0.42; 95% CI: − 0.77 to − 0.06; PSMD = 0.021) but not in obese subjects (SMD: − 0.28; 95% CI: − 0.60 to 0.03; PSMD = 0.074). The mean change in AG concentration was similar in both the obese and lean health groups at each time point (ΔSMD30min: 0.31, 95% CI: − 0.35 to 0.97, PSMD = 0.359; ΔSMD60min: 0.17, 95% CI: − 0.12 to 0.46, PSMD = 0.246; ΔSMD120min: 0.21, 95% CI: − 0.13 to 0.54, PSMD = 0.224). This meta-analysis strengthens the clinical evidence supporting the following: lower baseline levels of circulating AG and DAG in obese individuals; declines in postprandial circulating AG levels, both for the healthy and obese individuals; a shorter duration of AG suppression in obese subjects after meal intake. These conclusions have significance for follow-up studies to elucidate the role of various ghrelin forms in energy homeostasis.

Effectiveness of Tongue cleaning as a component of Oral care on the fasting Plasma Desacyl Ghrelin concentration in very elderly individuals: Six-Week Randomized controlled trial

To investigate whether tongue cleaning as a component of oral care affects the fasting plasma desacyl ghrelin concentrations in elderly people with the peak expiratory flow (PEF) as the measure of coughing ability. This randomized controlled trial was conducted in Kitakyushu, Japan from July 2017 to November 2018. We randomly assigned 52 enrolled Japanese subjects from three nursing care facilities to a routine oral care group (control group) and an oral care with twice-daily tongue cleaning group (intervention group). Before and after 6 weeks of each version of oral care, the PEF of each subject was measured and blood was collected. A final total of 48 subjects (39 females, 9 males, mean ± SD age 88.4 ± 7.5 years) was analyzed. The PEF increased significantly in the intervention group (1.62 ± 0.89 L/s to 2.07 ± 1.09 L/s) but not in the control group (1.76 ± 1.05 L/s to 1.53 ± 0.67 L/s). The fasting plasma desacyl ghrelin concentrations in the intervention group did not change significantly (181 ± 102 fmol/mL to 175 ± 98 fmol/mL) whereas those in the control group decreased significantly (168 ± 114 fmol/mL to 142 ± 72 fmol/mL). The change of the plasma desacyl ghrelin concentration was significantly correlated with the change in albumin (correlation coefficient = 0.292, p<0.05), but not with that in PEF. Tongue cleaning accompanied by improved coughing ability seemed to help prevent the decrease in the fasting plasma desacyl ghrelin concentration in very elderly individuals.

Dietary macronutrient regulation of acyl and desacyl ghrelin concentrations in children with Prader-Willi syndrome (PWS).

The effects of dietary macronutrients on orexigenic and anorexigenic hormones in children are poorly understood. 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). 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 6.63years; BMI z 1.05); experiment 2 had seven HC (median age 12.54years; BMI z 0.95). Blood samples were collected at baseline and at 60-minute intervals for 4hours. Independent linear mixed models were adjusted for age, sex and BMI z-score. 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. 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.

Metabolic state and value-based decision-making in acute and recovered female patients with anorexia nervosa

Patients with anorexia nervosa forgo eating despite emaciation and severe health consequences. Such dysfunctional decision-making might be explained by an excessive level of self-control, alterations in homeostatic and hedonic regulation, or an interplay between these processes. We aimed to understand value-based decision-making in anorexia nervosa and its association with the gut hormone ghrelin. Besides its homeostatic function, ghrelin has been implicated in the hedonic regulation of appetite and reward via the modulation of phasic dopamine signalling. In a cross-sectional design, we studied acutely underweight (n = 94) and recovered (n = 37) patients with anorexia nervosa of the restrictive subtype, as well as healthy control participants (n = 119). We assessed plasma concentrations of desacyl ghrelin and parameters of delay discounting, probability discounting for gains and losses, and loss aversion. Recovered patients displayed higher risk aversion for gains, but we observed no group differences for the remaining decision-making parameters. Desacyl ghrelin was higher in acutely underweight and recovered participants with anorexia nervosa relative to healthy controls. Moreover, we found a significant group × desacyl ghrelin interaction in delay discounting, indicating that in contrast to healthy controls, acutely underweight patients with anorexia nervosa who had high desacyl ghrelin concentrations preferably chose the delayed reward option. We probed decision-making using monetary rewards, but patients with anorexia nervosa may react differently to disorder-relevant stimuli. Furthermore, in contrast to acyl ghrelin, the functions of desacyl ghrelin are unclear. Therefore, the interpretation of the results is preliminary. The propensity for risk aversion as found in recovered patients with anorexia nervosa could help them successfully complete therapy, or it could reflect sequelae of the disorder. Conversely, ghrelin findings might be related to a mechanism contributing to disease maintenance; that is, in acutely underweight anorexia nervosa, a hungry state may facilitate the ability to forgo an immediate reward to achieve a (dysfunctional) long-term goal.

Effect of desacyl-ghrelin on food anticipatory activity in a mouse model of chronic food restriction

Background The physiological mechanisms involved in the adaptation to chronic food restriction are largely unknown. Anorexia nervosa (AN) is characterized by elevated plasma concentrations of ghrelin, a gut orexigenic hormone. AN patients maintain a restricted feeding behavior, usually associated with elevated physical activity in meal anticipation called food anticipatory activity (FAA). Ghrelin exists in two forms: acylghrelin (AG), carrying an octanoyl group, and des-acylghrelin (DAG) which predominates in plasma and having an opposite action on energy homeostasis. The respective role of AG and DAG in the initiation of FAA remains unknown. Objectives We used a mouse model, which combined chronic food restriction and voluntary activity mimicking most of the alterations of AN1. We evaluated: – the change in plasma AG and/or DAG concentrations in relation with FAA; – determine whether injections of AG and/or DAG elicit FAA and interact on hypothalamic (ARC: energy homeostasis) and mesolimbic (VTA: reward/motivation) neurons. Methods Eight-week old female mice were placed in a cage containing a running wheel in free access for 20 days. Mice were exposed to a progressive food restriction (FRW, n = 24) compared to ad libitum fed condition (ALW, n = 24). On D10, blood samples were collected before the onset of FAA (9 a.m.) and during FAA (5 p.m). AG and DAG were measured with selective immunoassays. On D20, AG (10 nmol/10 g BW), DAG (10 nmol/10 g BW), AG + DAG (respectively 10 and 20 nmol/10 g BW), or saline solution were injected subcutaneously both in ALW and FRW mice (n = 6/group); followed by 2 h of the evaluation of physical activity. Immunocytochemical detection of c-Fos protein, a marker of neuronal activation, was obtained in the ARC and VTA. Data were analyzed with a One-Way ANOVA test (Statview software, P Results FRW mice displayed a stable FAA from D6 of restriction. Plasma concentrations of AG and DAG significantly increased between 9 a.m and 5 p.m in FRW mice compared to ALW mice. AG and DAG concentrations were the highest in mice displaying the highest FAA. Interestingly, only the injection of DAG was able to elicit: – an increase in physical activity (P = 0.06) associated with significant neuronal activation in the VTA (P – to decrease glycemia (P = 0.06) and low neuronal activation in the ARC contrary to AG (P Conclusion These results suggest that DAG might have an unexpected function in the induction of physical activity in meal anticipation.

Effects of Testosterone Supplementation on Ghrelin and Appetite During and After Severe Energy Deficit in Healthy Men.

Severe energy deficits cause interrelated reductions in testosterone and fat free mass. Testosterone supplementation may mitigate those decrements, but could also reduce circulating concentrations of the orexigenic hormone ghrelin, thereby exacerbating energy deficit by suppressing appetite. To determine whether testosterone supplementation during severe energy deficit influences fasting and postprandial ghrelin concentrations and appetite. Secondary analysis of a randomized, double-blind trial that determined the effects of testosterone supplementation on body composition changes during and following severe energy deficit in nonobese, eugonadal men. Phase 1 (PRE-ED): 14-day run-in; phase 2: 28 days, 55% energy deficit with 200 mg testosterone enanthate weekly (TEST; n = 24) or placebo (PLA; n = 26); phase 3: free-living until body mass recovered (end-of-study; EOS). Fasting and postprandial acyl ghrelin and des-acyl ghrelin concentrations and appetite were secondary outcomes measured during the final week of each phase. Fasting acyl ghrelin concentrations, and postprandial acyl and des-acyl ghrelin concentrations increased in PLA during energy deficit then returned to PRE-ED values by EOS, but did not change in TEST (phase-by-group, P < 0.05). Correlations between changes in free testosterone and changes in fasting acyl ghrelin concentrations during energy deficit (ρ = -0.42, P = 0.003) and body mass recovery (ρ = -0.38; P = 0.01) were not mediated by changes in body mass or body composition. Transient increases in appetite during energy deficit were not affected by testosterone treatment. Testosterone supplementation during short-term, severe energy deficit in healthy men prevents deficit-induced increases in circulating ghrelin without blunting concomitant increases in appetite. www.clinicaltrials.gov NCT02734238 (registered 12 April 2016).

Plasma Peptide Concentrations and Peptide-Reactive Immunoglobulins in Patients with Eating Disorders at Inclusion in the French EDILS Cohort (Eating Disorders Inventory and Longitudinal Survey).

Eating disorders (EDs) are increasingly frequent. Their pathophysiology involves disturbance of peptide signaling and the microbiota–gut–brain axis. This study analyzed peptides and corresponding immunoglobulin (Ig) concentrations in groups of ED. In 120 patients with restrictive (R), bulimic (B), and compulsive (C) ED, the plasma concentrations of leptin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin were analyzed by Milliplex and those of acyl ghrelin (AG), des-acyl ghrelin (DAG), and α-melanocyte-stimulating hormone (α-MSH) by ELISA kits. Immunoglobulin G (in response to an antigen) concentrations were analyzed by ELISA, and their affinity for the respective peptide was measured by surface plasmon resonance. The concentrations of leptin, insulin, GLP-1, and PYY were higher in C patients than in R patients. On the contrary, α-MSH, DAG, and AG concentrations were higher in R than in C patients. After adjustment for body mass index (BMI), differences among peptide concentrations were no longer different. No difference in the concentrations of the IgG was found, but the IgG concentrations were correlated with each other. Although differences of peptide concentrations exist among ED subtypes, they may be due to differences in BMI. Changes in the concentration and/or affinity of several anti-peptide IgG may contribute to the physiopathology of ED or may be related to fat mass.

Sleep Deprivation Selectively Upregulates an Amygdala-Hypothalamic Circuit Involved in Food Reward.

Sleep loss is associated with increased obesity risk, as demonstrated by correlations between sleep duration and change in body mass index or body fat percentage. Whereas previous studies linked this weight gain to disturbed endocrine parameters after sleep deprivation or restriction, neuroimaging studies revealed upregulated neural processing of food rewards after sleep loss in reward-processing areas such as the anterior cingulate cortex, ventral striatum, and insula. To address this ongoing debate between hormonal versus hedonic factors underlying sleep-loss-associated weight gain, we rigorously tested the association between sleep deprivation and food cue processing using high-resolution fMRI and assessment of hormones. After taking blood samples from 32 lean, healthy, human male participants, they underwent fMRI while performing a neuroeconomic, value-based decision-making task with snack food and trinket rewards following a full night of habitual sleep and a night of sleep deprivation in a repeated-measures crossover design. We found that des-acyl ghrelin concentrations were increased after sleep deprivation compared with habitual sleep. Despite similar hunger ratings due to fasting in both conditions, participants were willing to spend more money on food items only after sleep deprivation. Furthermore, fMRI data paralleled this behavioral finding, revealing a food-reward-specific upregulation of hypothalamic valuation signals and amygdala-hypothalamic coupling after a single night of sleep deprivation. Behavioral and fMRI results were not significantly correlated with changes in acyl, des-acyl, or total ghrelin concentrations. Our results suggest that increased food valuation after sleep loss might be due to hedonic rather than hormonal mechanisms.SIGNIFICANCE STATEMENT Epidemiological studies suggest an association between overweight and reduced nocturnal sleep, but the relative contributions of hedonic and hormonal factors to overeating after sleep loss are a matter of ongoing controversy. Here, we tested the association between sleep deprivation and food cue processing in a repeated-measures crossover design using fMRI. We found that willingness to pay increased for food items only after sleep deprivation. fMRI data paralleled this behavioral finding, revealing a food-reward-specific upregulation of hypothalamic valuation signals and amygdala-hypothalamic coupling after a single night of sleep deprivation. However, there was no evidence for hormonal modulations of behavioral or fMRI findings. Our results suggest that increased food valuation after sleep loss is due to hedonic rather than hormonal mechanisms.

Effects of ghrelin agonist and antagonist on endogenous desacyl-ghrelin content in the brain limbical structures under psychoemotional stress in rats

Background. During last years it has been shown the ghrelin signaling system not only regulates energy balance and food intake. It also takes part in reinforcement mechanisms and addiction formation. So the ghrelin system may be considered as possible molecular target to study addiction treatment and post-stressor pharmacological modulation.&#x0D; The aim of this work was to study the effects of ghrelin agonist and antagonist administration on des-acyl ghrelin (DAG) content in the brain structures under stress exposure in Wistar rats.&#x0D; Methods. The acute psychoemotional stress was realized by means of exposure of experimental rats to predator, a tiger python. Ghrelin or ghrelin antagonist D-Lys3-GHRP-6 (Tocris, UK) 10 µg in 20 µl administered intranasally for 7 days after stress exposure. Then brain structures were obtained, homogenized with cryogenic system “Cryomill 200” (Retsch, Germany) and investigated with high-sensitive ELISA (SP-BIO, France). Results. DAG have been detected in every brain structures studied. That are amygdala, hippocampus and hypothalamus. In control group of animals the DAG concentration in hypothalamus was 3-fold more comparning to hippocampus and 2-fold more conparning to amygdala content. The acute stress have dramatically 8-12-fold decrease of DAG concentrations in every brain structures studied. The pharmacological actions on GHSR receptor by ghrelin agonist and antagonist have not affect significant changes in DAG concentrations in every brain structures.&#x0D; Conclusions. The different concentrations of DAG in brain structures in control gtoup supports the view about ghrelin releasing neurons in the hypothalamus. Intranasal administration of ghrelin agonist and antagonist changes the levels of DAG in the hippocampus and the hypothalamus but not in the amygdala nucleus. Our data confirm the opinion about ghrelin-releasing neurons in hypothalamus. The experiments showed the acute stress had caused great depression of ghrelin system in various brain structures. The response of ghrelin system to acute stress occur possibly besides GHSR receptor pathway. The last have been suggested by absence of significant response to ghrelin agonist and antagonist administration.

Ghrelin Octanoylation Is Completely Stabilized in Biological Samples by Alkyl Fluorophosphonates.

Ghrelin is a peptide hormone involved in multiple physiological processes related to energy homeostasis. This hormone features a unique posttranslational serine octanoylation modification catalyzed by the enzyme ghrelin O-acyltransferase, with serine octanoylation essential for ghrelin to bind and activate its cognate receptor. Ghrelin deacylation rapidly occurs in circulation, with both ghrelin and desacyl ghrelin playing important roles in biological signaling. Understanding the regulation and physiological impact of ghrelin signaling requires the ability to rapidly protect ghrelin from deacylation in biological samples such as blood serum or cell lysates to preserve the relative concentrations of ghrelin and desacyl ghrelin. In in vitro ghrelin O-acyltransferase activity assays using insect microsomal protein fractions and mammalian cell lysate and blood serum, we demonstrate that alkyl fluorophosphonate treatment provides rapid, complete, and long-lasting protection of ghrelin acylation against serine ester hydrolysis without interference in enzyme assay or ELISA analysis. Our results support alkyl fluorophosphonate treatment as a general tool for stabilizing ghrelin and improving measurement of ghrelin and desacyl ghrelin concentrations in biochemical and clinical investigations and suggest current estimates for active ghrelin concentration and the ghrelin to desacyl ghrelin ratio in circulation may underestimate in vivo conditions.

Metabolic Benefit of Chronic Caloric Restriction and Activation of Hypothalamic AGRP/NPY Neurons in Male Mice Is Independent of Ghrelin.

Aging is associated with attenuated ghrelin signaling. During aging, chronic caloric restriction (CR) produces health benefits accompanied by enhanced ghrelin production. Ghrelin receptor (GH secretagogue receptor 1a) agonists administered to aging rodents and humans restore the young adult phenotype; therefore, we tested the hypothesis that the metabolic benefits of CR are mediated by endogenous ghrelin. Three month-old male mice lacking ghrelin (Ghrelin-/-) or ghrelin receptor (Ghsr-/-), and their wild-type (WT) littermates were randomly assigned to 2 groups: ad libitum (AL) fed and CR, where 40% food restriction was introduced gradually to allow Ghrelin-/- and Ghsr-/- mice to metabolically adapt and avoid severe hypoglycemia. Twelve months later, plasma ghrelin, metabolic parameters, ambulatory activity, hypothalamic and liver gene expression, as well as body composition were measured. CR increased plasma ghrelin and des-acyl ghrelin concentrations in WT and Ghsr-/- mice. CR of WT, Ghsr-/-, and Ghrelin-/- mice markedly improved metabolic flexibility, enhanced ambulatory activity, and reduced adiposity. Inactivation of Ghrelin or Ghsr had no effect on AL food intake or food anticipatory behavior. In contrast to the widely held belief that endogenous ghrelin regulates food intake, CR increased expression of hypothalamic Agrp and Npy, with reduced expression of Pomc across genotypes. In the AL context, ablation of ghrelin signaling markedly inhibited liver steatosis, which correlated with reduced Pparγ expression and enhanced Irs2 expression. Although CR and administration of GH secretagogue receptor 1a agonists both benefit the aging phenotype, we conclude the benefits of chronic CR are a consequence of enhanced metabolic flexibility independent of endogenous ghrelin or des-acyl ghrelin signaling.

Plasma ghrelin and liquid gastric emptying in children with functional dyspepsia consistent with post-prandial distress syndrome.

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. 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 (13) C-sodium acetate. Pain severity, liquid GE utilizing exhaled (13) CO2 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. 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 (13) CO2 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. 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.

Desacyl ghrelin is influenced by changes in insulin concentration during an insulin tolerance test

ObjectiveGhrelin, a gut-brain peptide, regulates energy homeostasis and glucose metabolism and is present in acylated and nonacylated form in the circulation. Although desacyl ghrelin (DAG), the predominant form of ghrelin, is associated with insulin sensitivity and improved metabolic state, not much is known about its direct regulation by insulin. We aimed to assess changes in DAG in response to the rapid increase in insulin concentration during an insulin tolerance test (ITT) in normal weight and obese subjects. DesignWe performed an observational single center study. An ITT was assessed in eight subjects (four males), median age of 29.9 years (range 19.6–42.0). DAG concentrations were measured at 20, 40, 60 and 90min after insulin infusion. Homeostatic Model Assessment (HOMA) was calculated from fasting insulin and glucose. Body mass index (BMI) and waist circumference were assessed. ResultsThree subjects were obese (BMI≥30kg/m2), one subject was overweight (BMI=25–30kg/m2) and four subjects had normal weight (BMI=18.5–25kg/m2). Median DAG decreased after insulin infusion (90pg/mL, p=0.028), especially in normal weight subjects. Baseline DAG was lower in subjects with higher BMI (ρ=−0.76, p=0.028) and higher fasting insulin (ρ=−0.76, p=0.030). DAG changes correlated with fasting insulin levels (ρ=−0.85, p=0.007), HOMA (ρ=−0.86, p=0.007), BMI (ρ=−0.83, p=0.010) and waist circumference (ρ=−0.93, p<0.001). ConclusionDAG levels rapidly decreased in response to insulin administration in normal subjects, but not in insulin-resistant obese who are in a state of relative DAG deficiency.

EFFECT OF EXERCISE ON APPETITE-REGULATING HORMONES IN OVERWEIGHT WOMEN

Over the past decade, our knowledge of how homeostatic systems regulate food intake and body weight has increased with the discovery of circulating peptides such as leptin, acyl ghrelin, des-acyl ghrelin and obestatin. These hormones regulate the appetite and food intake by sending signals to the brain regarding the body's nutritional status. The purpose of this study was to investigate the response of appetite-regulating hormones to exercise. Nine overweight women undertook two 2 h trials in a randomized crossover design. In the exercise trial, subjects ran for 60 min at 50% of maximal oxygen uptake followed by a 60 min rest period. In the control trial, subjects rested for 2 h. Obestatin, acyl ghrelin, des-acyl ghrelin and leptin concentrations were measured at baseline and at 20, 40, 60, 90 and 120 min after baseline. A two-way ANOVA revealed a significant (P < 0.05) interaction effect for leptin and acyl ghrelin. However, changes in obestatin and des-acyl ghrelin concentration were statistically insignificant (P > 0.05). The data indicated that although acute treadmill exercise resulted in a significant change in acyl ghrelin and leptin levels, it had no effect on plasma obestatin and des-acyl ghrelin levels.

Ghrelin, leptin and insulin in cirrhotic children and adolescents: Relationship with cirrhosis severity and nutritional status

ObjectiveGhrelin, leptin, and insulin concentrations are involved in the control of food intake and they seem to be associated with anorexia–cachexia in cirrhotic patients. The present study aimed to investigate the relationship between the nutritional status and fasting ghrelin, leptin and insulin concentrations in pediatric cirrhotic patients. MethodsThirty-nine patients with cirrhosis and 39 healthy controls aged 0–15years matched by sex and age were enrolled. Severity of liver disease was assessed by Child–Pugh classification, and Pediatric for End Stage Liver Disease (PELD) or Model for End-stage Liver Disease (MELD) scores. Blood samples were collected from patients and controls to assay total ghrelin, acyl ghrelin, leptin and insulin by using a commercial ELISA kit. Anthropometry parameters used were standard deviation score of height-for-age and triceps skinfold thickness-for-age ratio. A multiple linear regression analysis was used to determine the correlation between dependent and independent variables. ResultsAcyl ghrelin was significantly lower in cirrhotic patients than in controls [142 (93–278) pg/mL vs 275 (208–481) pg/mL, P=0.001]. After multiple linear regression analysis, total ghrelin and acyl ghrelin showed an inverse correlation with age; acyl ghrelin was associated with the severity of cirrhosis and des-acyl ghrelin with PELD or MELD scores ≥15. Leptin was positively correlated with gender and anthropometric parameters. Insulin was not associated with any variable. ConclusionLow acyl ghrelin and high des-acyl ghrelin concentrations were associated with cirrhosis severity, whereas low leptin concentration was associated with undernourishment in children and adolescents with cirrhosis.

Plasma ghrelin isoforms and gastric ghrelin O-acyltransferase expression are influenced by Helicobacter pylori status

ObjectiveHelicobacter pylori is known to affect the host’s nutritional status. This study was performed to elucidate the relationship between H. pylori status and the dynamics of the ghrelin system, in the context of ghrelin O-acyltransferase (GOAT) expression. MethodsWe conducted a clinical study of 30 subjects focusing on the following points: 1) the effects of H. pylori infection on the concentrations of circulating ghrelin isoforms and on ghrelin and GOAT mRNA expression in the gastric mucosa, and 2) the effects of H. pylori eradication on the same parameters. ResultsThe plasma acyl-ghrelin and desacyl-ghrelin concentrations of 16 H. pylori positive participants were significantly lower than those of 14 H. pylori negative controls. The acyl-ghrelin/desacyl-ghrelin ratio was not significantly different between the H. pylori positive and H. pylori negative participants. The levels of ghrelin and GOAT mRNA in the gastric mucosa were significantly lower in the H. pylori positive participants than in the H. pylori negative controls. In 11 subjects in whom H. pylori eradication was successful, their plasma acyl-ghrelin levels tended to increase after H. pylori eradication, but the difference was not significant; however, their plasma desacyl-ghrelin levels were significantly reduced. Although gastric ghrelin mRNA expression increased significantly after H. pylori eradication, gastric GOAT mRNA expression tended to increase but was not significantly altered. ConclusionH. pylori status might affect the host’s nutritional status through changes in the plasma levels of ghrelin isoforms and the gastric expression levels of ghrelin and GOAT mRNA.

Potential New Treatment to Alleviate Chemotherapy Anorexia

atry 2009, 65:748-759), on decreased food intake, body weight, and muscle weight in a cachexia model with chronic respiratory disturbance in mice. Methods: For the induction of pulmonary fibrosis, 10-week-old male C57BL/6J mice received a single dose of bleomycin sulfate (3.0 mg/kg) by endotracheal instillation. Rikkunshito (1.0 g/kg body weight), dissolved in distilled water, was administered orally once a day. Body weight, food intake, and locomotor activity were measured as indicators of cachexia. After the 14-day program and food deprivation for 24 h, the mice were dissected, and subsequently the weight of the gastrocnemius muscle was measured. Plasma acyl ghrelin and des-acyl ghrelin concentrations were measured by ELISA. The onset of, and the improvement in, pulmonary fibrosis were histopathologically investigated. Results: Body weight, food intake, and gastrocnemius muscle weight had significantly decreased in the pulmonary fibrotic mice compared with the control mice. Locomotor activity had decreased with the development of pneumonitis and lung fibrosis. In these mice, the acyl ghrelin concentration had significantly increased after compared with the level of the control mice. As a result of the administration of rikkunshito, the decrease in body weight and food intake was significantly inhibited, and muscle weight (absolute and relative) was maintained at the same level as that in the control mice. The plasma acyl ghrelin level was also found to be at the same level as that in the control mice. Histopathological examination revealed that pulmonary fibrosis and interstitial pneumonia were ameliorated by the administration of rikkunshito. Conclusion: In the cachexia model of pulmonary fibrosis, the administration of the ghrelin enhancer rikkunshito significantly reversed the decreased food intake and body weight and prevented muscle wasting. These results suggest that rikkunshito possesses the potential to ameliorate impaired exercise capacity and improve the quality of life of cachectic patients with chronic respiratory disturbance.

Significant lowering of plasma ghrelin but not des-acyl ghrelin in response to acute exercise in men

Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and growth hormone (GH) secretion via interaction with the GH secretagogue receptor. Ghrelin molecules are present in two major endogenous forms, an acylated form (ghrelin) and a des-acylated form (des-acyl ghrelin). Recent studies indicated that aerobic exercise did not change plasma total ghrelin levels, however, dynamics of circulating ghrelin and des-acyl ghrelin during aerobic exercise remains unclear. The purpose of this study is to examine the effects of moderate intensity exercise on plasma ghrelin and des-acyl ghrelin concentrations, and to investigate the relationship between ghrelin molecules and other hormonal and metabolic parameters during exercise. Nine healthy males (25.2 ± 0.5 years) exercised for 60 min at 50% of their maximal oxygen consumptions. We measured the plasma concentrations of ghrelin, des-acyl ghrelin, GH, norepinephrine (NE), epinephrine (E), dopamine (DA), insulin, and glucose. Plasma ghrelin level significantly decreased during exercise, whereas plasma des-acyl ghrelin and total ghrelin levels did not change. Plasma NE, E, DA and GH levels were significantly increased during exercise. Plasma insulin level significantly decreased during exercise, and plasma glucose levels remained steady during exercise. NE, E, DA, and GH were correlated negatively with plasma ghrelin levels. These findings suggest that acute moderate exercise may suppress ghrelin release from the stomach, decrease ghrelin O-acyltransferase activity, and/or activate ghrelin utilization in peripheral tissues and that exercise-induced ghrelin suppression may be mediated by activated adrenergic system.