ABSTRACT
BACKGROUND: Cancer cachexia is a syndrome characterized by anorexia and decreased body weight. This study evaluated the efficacy and safety of anamorelin, an orally active, selective ghrelin receptor agonist, in patients with cancer cachexia and a low body mass index (BMI). METHODS: This multicenter, open-label, single-arm study enrolled Japanese patients with non-small cell lung cancer or gastrointestinal cancer with cancer cachexia (BMI < 20 kg/m2 , involuntary weight loss > 2% in the last 6 months, and anorexia). Patients were administered 100 mg of anamorelin once daily for up to 24 weeks. The primary end point was a composite clinical response (CCR) at 9 weeks, which was defined as an increase in body weight of ≥5% from the baseline, an increase of ≥2 points in the score of the 5-item Anorexia Symptom Scale of the Functional Assessment of Anorexia/Cachexia Therapy, and being alive. RESULTS: One hundred two patients were eligible and enrolled. The means and standard deviations for age and BMI were 71.0 ± 8.2 years and 17.47 ± 1.48 kg/m2 , respectively. The CCR rate at 9 weeks was 25.9% (95% confidence interval [CI], 18.3%-35.3%), which met the primary end point with a lower 95% CI exceeding the prespecified minimum of 8%. Improvements in body weight and anorexia were durable and were accompanied by improvements in patients' global impression of change for appetite/eating-related symptoms and overall condition. Adverse drug reactions occurred in 37 of 101 treated patients (36.6%), with the most common being glycosylated hemoglobin increases, constipation, and peripheral edema. CONCLUSIONS: Anamorelin improved body weight and anorexia-related symptoms in patients with cancer cachexia and a low BMI with durable efficacy and favorable safety and tolerability. LAY SUMMARY: Anamorelin is a drug that stimulates appetite and promotes weight gain. This clinical trial was aimed at determining its efficacy and safety in Japanese cancer patients with a low body mass index and cachexia, a syndrome associated with anorexia and weight loss. Anamorelin was found to improve body weight and anorexia-related symptoms in these patients, and these effects were durable for up to 24 weeks. Moreover, anamorelin was generally well tolerated. These findings suggest that anamorelin is a valuable treatment option for patients with cancer cachexia and a low body mass index.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Anorexia/drug therapy , Anorexia/etiology , Body Mass Index , Body Weight , Cachexia/drug therapy , Cachexia/etiology , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/drug therapy , Ghrelin/analogs & derivatives , Humans , Hydrazines , Lung Neoplasms/drug therapy , OligopeptidesABSTRACT
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.
Subject(s)
Ghrelin/analogs & derivatives , Obesity/blood , Acylation , Adult , Biomarkers/blood , Ghrelin/blood , HumansABSTRACT
Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy-drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post-mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.) alcohol administration; (4) effect of alcohol on ghrelin secretion from gastric mucosa cells ex vivo and GOAT enzymatic activity in vitro; and (5) ghrelin levels in rats following i.p. alcohol administration versus a calorically equivalent non-alcoholic sucrose solution. Acyl- and total-ghrelin levels decreased following acute alcohol administration in humans, but AUD was not associated with changes in central expression of ghrelin system genes in post-mortem tissue. In rats, alcohol decreased acyl-ghrelin, but not des-acyl-ghrelin, in both Ghsr knockout and wild-type rats. No dose-dependent effects of alcohol were observed on acyl-ghrelin secretion from gastric mucosa cells or on GOAT acylation activity. Lastly, alcohol and sucrose produced distinct effects on ghrelin in rats despite equivalent caloric value. Our findings suggest that alcohol acutely decreases peripheral ghrelin concentrations in vivo, but not in proportion to alcohol's caloric value or through direct interaction with ghrelin-secreting gastric mucosal cells, the ghrelin receptor, or the GOAT enzyme.
Subject(s)
Ethanol/metabolism , Ghrelin/metabolism , Receptors, Ghrelin/metabolism , Animals , Blood Glucose/metabolism , Ghrelin/analogs & derivatives , Humans , Male , Rats , Signal TransductionABSTRACT
BACKGROUND: Resistance to platinum-based chemotherapy is one of the crucial problems in ovarian cancer treatment. Ghrelin, a widely distributed peptide hormone, participates in a series of cancer progression. The aim of this study is to determine whether ghrelin influences the sensitivity of ovarian cancer to cisplatin, and to demonstrate the underlying mechanism. METHODS: The anti-tumor effects of ghrelin and cisplatin were evaluated with human ovarian cancer cells HO-8910 PM in vitro or in vivo. Cell apoptosis and cell cycle were analyzed via flow cytometry assay. The signaling pathway and the expression of cell cycle protein were analyzed with Western Blot. RESULTS: Our results showed that treatment with ghrelin specifically inhibited cell proliferation of HO-8910 PM and sensitized these cells to cisplatin via S phase cell cycle arrest, and enhanced the inhibitory effect of cisplatin on tumor growth of HO-8910 PM derived xenografts in vivo. Treatment with ghrelin inhibited the expression of p-Erk1/2 and p-p38, which was opposite the effect of cisplatin. However, under the treatment of ghrelin, cisplatin treatment exhibited a stronger effect on inhibiting P21 expression, upregulating p-CDK1 and cyclin B1 expression, and blocking cell cycle progression. Mechanistically, ghrelin promoted S phase cell cycle arrest and upregulated p-CDK1 and cyclin B1 expression induced by cisplatin via inhibition of p38. CONCLUSION: This study revealed a specifically inhibitory effect of ghrelin on platinum-resistance via suppressing p-P38 and subsequently promoting p-CDK1 mediated cell cycle arrest in HO-8910 PM.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , Drug Resistance, Neoplasm/drug effects , Ghrelin/analogs & derivatives , Ovarian Neoplasms/drug therapy , Animals , Antineoplastic Agents/therapeutic use , CDC2 Protein Kinase/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/therapeutic use , Enzyme Inhibitors/pharmacology , Female , Ghrelin/pharmacology , Ghrelin/therapeutic use , Humans , Mice , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Signal Transduction/drug effects , Xenograft Model Antitumor Assays , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
AIMS: This study investigated the nutrient-mediated modulation of total ghrelin (TG) and acyl ghrelin (AG) secretion from the mouse gastric mucosa, and the role of long-chain fatty acid chemosensors, FFAR4 and CD36, in lipid-mediated modulation of TG and AG release. METHODS: Ex-vivo experiments were conducted using mouse gastric mucosa to examine the effects of nutrients (D-glucose, L-phenylalanine, peptone (mixture of oligopeptides & single amino acids), D-mannitol, α-linolenic acid and fat emulsion (intralipid)) on TG and AG secretion. Additionally, inhibition of FFAR4 and CD36 on α-linolenic acid and intralipid-mediated regulation of TG and AG secretion was assessed. RESULTS: TG and AG secretion were unaffected by glucose and D-mannitol. Peptone stimulated the release of TG and AG. In contrast, L-phenylalanine reduced AG secretion only. Intralipid reduced TG secretion and stimulated AG secretion, and α-linolenic acid reduced AG release, without affecting TG mobilisation. Modulation of ghrelin secretion by lipids occurred in an FFAR4 and CD36-independent manner. CONCLUSION: Ghrelin secretion is modulated in a nutrient-specific manner by proteins and lipids, with TG and AG displaying independent responses to the same stimuli. In addition, FFAR4 and CD36 do not participate in modulation of TG and AG secretion by α-linolenic acid and intralipid.
Subject(s)
CD36 Antigens/metabolism , Gastric Mucosa/metabolism , Ghrelin/analogs & derivatives , Lipids/analysis , Receptors, G-Protein-Coupled/metabolism , Animals , Ghrelin/blood , Ghrelin/metabolism , Male , Mice , Mice, Inbred C57BLABSTRACT
OBJECTIVE: The hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a recently identified antagonist and an inverse agonist of the growth hormone secretagogue receptor (GHSR). GHSR's other well-known endogenous ligand, acyl-ghrelin, increases food intake, body weight, and GH secretion and is lowered in obesity but elevated upon fasting. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is found elevated in obesity but lowered upon fasting. Thus, the plasma LEAP2/acyl-ghrelin molar ratio could be a key determinant modulating GHSR signaling in response to changes in body mass and feeding status. In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion. METHODS: We generated the first known LEAP2-KO mouse line. Food intake, GH secretion, and cellular activation (c-fos induction) in different brain regions following s.c. acyl-ghrelin administration in LEAP2-KO mice and wild-type littermates were determined. LEAP2-KO mice and wild-type littermates were submitted to a battery of tests (such as measurements of body weight, food intake, and body composition; indirect calorimetry, determination of locomotor activity, and meal patterning while housed in metabolic cages) over the course of 16 weeks of high-fat diet and/or standard chow feeding. Fat accumulation was assessed in hematoxylin & eosin-stained and oil red O-stained liver sections from these mice. RESULTS: LEAP2-KO mice were more sensitive to s.c. ghrelin. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0.5 mg/kg BW in standard chow-fed LEAP2-KO mice while a 2× higher dose was required by wild-type littermates. Also, acyl-ghrelin stimulated food intake at a dose of 1 mg/kg BW in high-fat diet-fed LEAP2-KO mice while not even a 10× higher dose was effective in wild-type littermates. Acyl-ghrelin induced a 90.9% higher plasma GH level and 77.2-119.7% higher numbers of c-fos-immunoreactive cells in the arcuate nucleus and olfactory bulb, respectively, in LEAP2-KO mice than in wild-type littermates. LEAP2 deletion raised body weight (by 15.0%), food intake (by 18.4%), lean mass (by 6.1%), hepatic fat (by 42.1%), and body length (by 1.7%) in females on long-term high-fat diet as compared to wild-type littermates. After only 4 weeks on the high-fat diet, female LEAP2-KO mice exhibited lower O2 consumption (by 13%), heat production (by 9.5%), and locomotor activity (by 49%) than by wild-type littermates during the first part of the dark period. These genotype-dependent differences were not observed in high-fat diet-exposed males or female and male mice exposed for long term to standard chow diet. CONCLUSIONS: LEAP2 deletion sensitizes lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion. LEAP2 deletion increases body weight in females chronically fed a high-fat diet as a result of lowered energy expenditure, reduced locomotor activity, and increased food intake. Furthermore, in female mice, LEAP2 deletion increases body length and exaggerates the hepatic fat accumulation normally associated with chronic high-fat diet feeding.
Subject(s)
Antimicrobial Cationic Peptides/metabolism , Ghrelin/analogs & derivatives , Secretagogues/metabolism , Animals , Antimicrobial Cationic Peptides/deficiency , Antimicrobial Cationic Peptides/genetics , Diet, High-Fat/adverse effects , Female , Ghrelin/administration & dosage , Ghrelin/metabolism , Growth Hormone , Male , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Anorexia nervosa (AN) is a severe eating disorder where caloric restriction, excessive physical activity and metabolic alterations lead to life-threatening situations. Despite weight restoration after treatment, a significant part of patients experience relapses. In this translational study, we combined clinical and preclinical approaches. We describe preliminary data about the effect of weight gain on the symptomatology of patients suffering from acute AN (n = 225) and partially recovered (n = 41). We measured more precisely physical activity with continuous cardiac monitoring in a sub-group (n = 68). Using a mouse model, we investigated whether a long-term food restriction followed by nutritional recovery associated or not with physical activity may differentially impact peripheral and central homeostatic regulation. We assessed the plasma concentration of acyl ghrelin, desacyl ghrelin and leptin and the mRNA expression of hypothalamic neuropeptides and their receptors. Our data show an effect of undernutrition history on the level of physical activity in AN. The preclinical model supports an important role of physical activity in the recovery process and points out the leptin system as one factor that can drive a reliable restoration of metabolic variables through the hypothalamic regulation of neuropeptides involved in feeding behavior.
Subject(s)
Anorexia Nervosa/metabolism , Anorexia Nervosa/rehabilitation , Exercise , Adolescent , Adult , Animals , Anorexia Nervosa/blood , Body Mass Index , Body Weight , Feeding Behavior , Female , Ghrelin/analogs & derivatives , Ghrelin/blood , Ghrelin/metabolism , Heart Rate , Humans , Hypothalamus/metabolism , Leptin/blood , Mice , Mice, Inbred C57BL , Models, Animal , Neuropeptides/metabolism , RNA, Messenger/metabolism , Recurrence , Weight Gain , Young AdultABSTRACT
OBJECTIVE: To assess the post-meal response in appetite-regulating hormones acyl-ghrelin and insulin after fermented soybean (tempeh) consumption in girls with obesity. METHODS: A randomized counter-balanced crossover study was conducted using a breakfast (307 kcal, protein: 28%, fat: 23%, and carbohydrate: 55%) containing fermented soybean or isocaloric non-fermented soybean among 13 females (aged 18-20 y; BMI 25-30) after an overnight fast. The outcome variables were plasma acyl-ghrelin, insulin, arginine and score of the visual analog scale (VAS) appetite questionnaire. RESULTS: While no change was observed after the non-fermented soybean meal, plasma acyl-ghrelin decreased by 35% at 30 min and remained below baseline until 120 min after the fermented soybean meal (P < 0.05). Plasma insulin increased after consumption of both meals and fermented soybean meal-induced 30% greater response in insulin at 120 min than non-fermented soybean meal (P < 0.05). Circulating arginine levels were slightly greater (24%) at 120 min after the fermented soybean meal than the non-fermented soybean meal (P < 0.05). No difference in subjective appetite was observed between the fermented soybean meal and the non-fermented soybean meal. CONCLUSIONS: Fermented soybean meal induced greater response in appetite-regulating hormones compared with non-fermented soybean meal. No difference in post-meal satiety feeling between fermented and non-fermented soybean meal suggests poor sensitivity of the brain to the appetite-regulating hormones among girls with obesity.
Subject(s)
Appetite , Fermented Foods , Blood Glucose , Cross-Over Studies , Ghrelin/analogs & derivatives , Humans , Indonesia , Obesity , Glycine maxABSTRACT
ABSTRACT: This study investigated the protective effect of acylated ghrelin (AG) against l-thyroxin (l-Thy)-induced cardiac damage in rats and examined possible mechanisms. Male rats were divided into five intervention groups of 12 rats/group: control, control + AG, l-Thy, l-Thy + AG, and l-Thy + AG + [D-Lys3]-GHRP-6 (AG antagonist). l-Thy significantly reduced the levels of AG and des-acyl ghrelin and the AG to des-acyl ghrelin ratio. Administration of AG to l-Thy-treated rats reduced cardiac weights and levels of reactive oxygen species and preserved the function and structure of the left ventricle. In addition, AG also reduced the protein levels of cleaved caspase-3 and cytochrome c and prevented mitochondrial permeability transition pore opening. In the left ventricle of both control + AG-treated and l-Thy + AG-treated rats, AG significantly increased left ventricular levels of manganese superoxide dismutase (SOD2), total glutathione (GSH), and Bcl2. It also reduced the levels of malondialdehyde, tumor necrosis factor-α (TNF-α), interleukin-6, and Bax and the nuclear activity of nuclear factor-kappa B. Concomitantly, in both treated groups, AG reduced the mRNA and protein levels of NADPH oxidase 1, angiotensin (Ang) II type 1 receptor, and Ang-converting enzyme 2. All the beneficial effects of AG in l-Thy-treated rats were prevented by the coadministration of [D-Lys3]-GHRP-6, a selective growth hormone secretagogue receptor subtype 1a antagonist. In conclusion, AG protects against hyperthyroidism-induced cardiac hypertrophy and damage, which is mainly due to its antioxidant and anti-inflammatory potentials and requires the activation of GHS-R1a.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Ghrelin/analogs & derivatives , Hypertrophy, Left Ventricular/prevention & control , Myocytes, Cardiac/drug effects , Renin-Angiotensin System/drug effects , Acylation , Animals , Disease Models, Animal , Ghrelin/metabolism , Ghrelin/pharmacology , Hyperthyroidism/chemically induced , Hyperthyroidism/metabolism , Hypertrophy, Left Ventricular/chemically induced , Hypertrophy, Left Ventricular/metabolism , Hypertrophy, Left Ventricular/pathology , Inflammation Mediators/metabolism , Male , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Mitochondria, Heart/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Reactive Nitrogen Species/metabolism , Thyroxine , Ventricular Function, Left/drug effectsABSTRACT
OBJECTIVE: Acyl-ghrelin regulates eating, body weight, blood glucose, and GH secretion upon binding to its receptor GHSR (growth hormone secretagogue receptor; ghrelin receptor). GHSR is distributed in several brain regions and some peripheral cell-types including pituitary somatotrophs. The objective of the current study was to determine the functional significance of acyl-ghrelin's action on GHSR-expressing somatotrophs in mediating GH secretion and several of acyl-ghrelin's metabolic actions. METHODS: GH-IRES-Cre mice and loxP-flanked (floxed) GHSR mice were newly developed and then crossed to one another to generate mice that lacked GHSR selectively from somatotrophs. Following validation of mice with somatotroph-selective GHSR deletion, metabolic responses of these mice and control littermates were assessed following both acute and chronic acyl-ghrelin administration, a 24-h fast, and a prolonged 60% chronic caloric restriction protocol modeling starvation. RESULTS: In mice with somatotroph-selective GHSR deletion, a single peripheral injection of acyl-ghrelin failed to induce GH secretion or increase food intake, unlike wild-type and other littermate control groups. However, the usual acute blood glucose increase in response to the acyl-ghrelin bolus was preserved. Similarly, chronic s.c. acyl-ghrelin administration to mice with somatotroph-selective GHSR deletion failed to increase plasma GH, food intake, or body weight. Physiologically elevating plasma acyl-ghrelin via a 24-h fast also failed to raise plasma GH and resulted in a limited hyperphagic response upon food reintroduction in mice with somatotroph-selective GHSR deletion, although those mice nonetheless did not exhibit an exaggerated reduction in blood glucose. Physiologically elevating plasma acyl-ghrelin via a 15-day caloric restriction protocol which provided only 40% of usual daily calories failed to raise plasma GH in mice with somatotroph-selective GHSR deletion, although those mice did not exhibit life-threatening hypoglycemia. CONCLUSIONS: These results reveal that direct engagement of GHSR-expressing somatotrophs is required for a peripheral ghrelin bolus to acutely stimulate GH secretion and the actions of chronic acyl-ghrelin delivery and physiological plasma acyl-ghrelin elevations to increase plasma GH. These results also suggest that actions of acyl-ghrelin to increase food intake and body weight are reliant on direct activation of GHSRs expressed on somatotrophs. Furthermore, these results suggest that the glucoregulatory actions of acyl-ghrelin - in particular, its actions to raise blood glucose when acutely administered, prevent small blood glucose drops following a 24-h fast, and avert life-threatening hypoglycemia during an acute-on-chronic caloric restriction protocol - do not depend on GHSR expression by somatotrophs.
Subject(s)
Ghrelin/metabolism , Growth Hormone/metabolism , Animals , Blood Glucose/metabolism , Ghrelin/analogs & derivatives , Mice , Receptors, Ghrelin/deficiency , Receptors, Ghrelin/genetics , Receptors, Ghrelin/metabolismABSTRACT
Anorexia nervosa (AN) is a severe psychiatric condition associated with high mortality and chronicity. The hunt for state, trait, subtyping, and prognostic biomarkers is ongoing and the orexigenic hormone ghrelin and its different forms, acyl ghrelin and desacyl ghrelin, have been proposed to be increased in AN, especially in the restrictive subtype. A systematic literature search was performed using established databases up to 30 November 2020. Forty-nine studies met inclusion criteria for cross-sectional and longitudinal meta-analyses on total ghrelin, acyl ghrelin, and desacyl ghrelin. All forms of ghrelin were increased in the acute stage of anorexia nervosa during fasting compared to healthy controls. Previous notions on differences in ghrelin levels between AN subtypes were not supported by current data. In addition, a significant decrease in total ghrelin was observed pre-treatment to follow-up. However, total ghrelin levels at follow-up were still marginally elevated compared to healthy controls, whereas for acyl ghrelin, no overall effect of treatment was observed. Due to heterogeneity in follow-up designs and only few data on long-term recovered patients, longitudinal results should be interpreted with caution. While the first steps towards a biomarker in acute AN have been completed, the value of ghrelin as a potential indicator of treatment success or recovery status or its use in subtype differentiation are yet to be established.
Subject(s)
Anorexia Nervosa/blood , Bulimia/blood , Fasting/blood , Ghrelin/blood , Acute Disease , Adolescent , Adult , Biomarkers/blood , Cross-Sectional Studies , Female , Ghrelin/analogs & derivatives , Humans , Longitudinal Studies , Male , Phenotype , Young AdultABSTRACT
The aim for this study was to elucidate how the hypothalamic hunger-inducing hormone acyl-ghrelin (AG), which is also produced in the pancreas, affects ß-cell function, with particular attention to the role of ATP-sensitive K+ (KATP) channels and the exact site of action of the hormone. AG hyperpolarized the membrane potential and decreased cytoplasmic calcium concentration [Ca2+]c and glucose-stimulated insulin secretion (GSIS). These effects were abolished in ß-cells from SUR1-knockout (KO) mice. AG increased KATP current but only in a configuration with intact metabolism. Unacylated ghrelin counteracted the effects of AG. The influence of AG on membrane potential and GSIS could only be averted in the combined presence of a ghrelin receptor (GHSR1a) antagonist and an inverse agonist. The inhibition of GSIS by AG could be prevented by dibutyryl cyclic-cAMP or 3-isobutyl-1-methylxanthine and the somatostatin (SST) receptor 2-5 antagonist H6056. These data indicate that AG indirectly opens KATP channels probably by interference with the cAMP/cAMP-dependent protein kinase pathway, resulting in a decrease of [Ca2+]c and GSIS. The experiments with SUR1-KO ß-cells point to a direct effect of AG on ß-cells and not, as earlier suggested, to an exclusive effect by AG-induced SST release from δ-cells. Nevertheless, SST receptors may be involved in the effect of AG, possibly by heteromerization of AG and SST receptors.
Subject(s)
Ghrelin/analogs & derivatives , Insulin Secretion/drug effects , Insulin-Secreting Cells/drug effects , KATP Channels/metabolism , Animals , Calcium/metabolism , Ghrelin/pharmacology , Glucose/pharmacology , Insulin-Secreting Cells/metabolism , Mice , Receptors, Somatostatin/metabolism , Signal Transduction/drug effects , Somatostatin/metabolismABSTRACT
CONTEXT: Fructose compared to glucose has adverse effects on metabolic function, but endocrine responses to oral sucrose vs glucose is not well understood. OBJECTIVE: We investigated how oral sucrose vs glucose affected appetite-regulating hormones, and how biological factors (body mass index [BMI], insulin sensitivity, sex) influence endocrine responses to these 2 types of sugar. DESIGN: Sixty-nine adults (29 men; 23.22â ±â 3.74 years; BMI 27.03â ±â 4.96 kg/m2) completed the study. On 2 occasions, participants consumed 300-mL drinks containing 75 g of glucose or sucrose. Blood was sampled at baseline, 10, 35, and 120 minutes post drink for plasma glucose, insulin, glucagon-like peptide (GLP-1)(7-36), peptide YY (PYY)total, and acyl-ghrelin measures. Hormone levels were compared between conditions using a linear mixed model. Interaction models were performed, and results were stratified to assess how biological factors influence endocrine responses. RESULTS: Sucrose vs glucose ingestion provoked a less robust rise in glucose (Pâ <â .001), insulin (Pâ <â .001), GLP-1 (Pâ <â .001), and PYY (Pâ =â .02), whereas acyl-ghrelin suppression was similar between the sugars. We found BMI status by sugar interactions for glucose (Pâ =â .01) and PYY (Pâ =â .03); obese individuals had smaller increases in glucose and PYY levels after consuming sucrose vs glucose. There were interactions between insulin sensitivity and sugar for glucose (Pâ =â .003) and insulin (Pâ =â .04), and a sex by sugar interaction for GLP-1 (Pâ =â .01); men demonstrated smaller increases in GLP-1 in response to oral sucrose vs glucose. CONCLUSION: Sucrose is less efficient at signaling postprandial satiation than glucose, and biological factors influence differential hormone responses to sucrose vs glucose consumption.
Subject(s)
Appetite Regulation/drug effects , Glucose/pharmacology , Sucrose/pharmacology , Administration, Oral , Adolescent , Adult , Appetite/drug effects , Appetite/physiology , Blood Glucose/drug effects , Blood Glucose/metabolism , Body Mass Index , Down-Regulation/drug effects , Eating/physiology , Female , Ghrelin/analogs & derivatives , Ghrelin/blood , Glucagon-Like Peptide 1/blood , Glucose/administration & dosage , Glucose Tolerance Test , Humans , Insulin Resistance/physiology , Male , Obesity/blood , Peptide YY/blood , Satiation/drug effects , Satiation/physiology , Sex Characteristics , South Carolina , Sucrose/administration & dosage , Young AdultABSTRACT
BACKGROUND: The hormone ghrelin stimulates food intake, promotes adiposity, increases body weight, and elevates blood glucose. Consequently, alterations in plasma ghrelin levels and the functioning of other components of the broader ghrelin system have been proposed as potential contributors to obesity and diabetes. Furthermore, targeting the ghrelin system has been proposed as a novel therapeutic strategy for obesity and diabetes. SCOPE OF REVIEW: The current review focuses on the potential for targeting ghrelin and other proteins comprising the ghrelin system as a treatment for obesity and diabetes. The main components of the ghrelin system are introduced. Data supporting a role for the endogenous ghrelin system in the development of obesity and diabetes along with data that seemingly refute such a role are outlined. An argument for further research into the development of ghrelin system-targeted therapeutic agents is delineated. Also, an evidence-based discussion of potential factors and contexts that might influence the efficacy of this class of therapeutics is provided. MAJOR CONCLUSIONS: It would not be a "leap to" conclusions to suggest that agents which target the ghrelin system - including those that lower acyl-ghrelin levels, raise LEAP2 levels, block GHSR activity, and/or raise desacyl-ghrelin signaling - could represent efficacious novel treatments for obesity and diabetes.
Subject(s)
Antimicrobial Cationic Peptides/metabolism , Blood Proteins/metabolism , Diabetes Mellitus/metabolism , Ghrelin/metabolism , Obesity/metabolism , Obesity/therapy , Adiposity , Animals , Blood Glucose/metabolism , Body Weight , Eating , Ghrelin/analogs & derivatives , Ghrelin/pharmacology , Ghrelin/therapeutic use , Humans , Receptors, GhrelinABSTRACT
We had reported that orally administered ghrelin-containing salmon stomach extract prevents doxorubicin (DOX)-induced cardiotoxicity. In this study, we investigated the binding affinity of salmon ghrelin to rat ghrelin receptor and the cardioprotective effects of subcutaneous (sc) injected synthetic salmon ghrelin in rats with DOX-induced acute heart failure in order to clarify the potential efficacy of salmon ghrelin. Intracellular calcium mobilization assay was performed on rat GHS-R1a-expressing CHO cells to reveal ghrelin activity. Rats were divided into five groups; the normal control (I), and toxic control (II) groups were given saline (sc, twice daily), and the salmon acyl-ghrelin (sAG) (III), salmon unacylated-ghrelin (sUAG) (IV), and rat acyl-ghrelin (rAG) (V) groups were given corresponding synthetic ghrelins (sc, twice daily), respectively. After seven days of treatment, DOX (20 mg/kg BW) or saline was administered to the corresponding groups by intraperitoneal injection. The toxic control group was the negative control group for the DOX-induced cardiotoxicity groups. While sAG displayed similar affinity to rAG upon application to GHS-R1a-expressing cells, and also decreased DOX-induced apoptosis and increased food intake, sUAG did not. Both sAG and rAG improved DOX-induced deterioration, showing anti-oxidative activity. The anti-oxidative activity of sAG might contribute to the protective effects on cardiomyocytes. The results also suggest that, similar to rAG, sAG is a potent protectant against DOX-induced cardiotoxicity and a potential functional component in orally administered ghrelin-containing salmon stomach extract, which prevented DOX-induced cardiotoxicity in our previous study.
Subject(s)
Cardiotoxicity/prevention & control , Doxorubicin/adverse effects , Eating/drug effects , Ghrelin/analogs & derivatives , Animals , Apoptosis/drug effects , CHO Cells , Cardiotoxicity/etiology , Cardiotoxicity/pathology , Cricetulus , Doxorubicin/pharmacology , Ghrelin/pharmacology , Heart/drug effects , Heart/physiopathology , Humans , Myocardium/pathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Oxidative Stress/drug effects , Rats , SalmonABSTRACT
BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) procedures are becoming more popular in the world of bariatric surgery. OBJECTIVES: This study investigates how LSG and LRYGB affect gut hormones and examines their differences. SETTING: Systematic review and meta-analysis. METHODS: The literature was retrieved from PubMed, Web of Science, Embase, and the Cochrane Library database before April 2020. RESULTS: We included 53 articles in our meta-analysis. After bariatric surgery, the patients' ghrelin, fasting acyl-ghrelin, fasting peptide YY (PYY), and their AUC in the LSG group were significantly lower than those in LRYGB group. Fasting ghrelin levels were significantly reduced in patients who received LSG. After LRYGB, the postoperative fasting PYY was higher than at baseline, and the results were statistically significant. Additionally, we found an increase in fasting ghrelin levels after LRYGB. Lastly, insulin levels were both reduced after LSG and LRYGB with no significant difference. CONCLUSIONS: In terms of gut hormones, ghrelin decreased significantly after LSG, while PYY increased after LRYGB. However, the impacts caused by the change in gut hormones after undergoing either LSG and LRYGB on patients are complicated, therefore, the results should be interpreted cautiously.
Subject(s)
Gastric Bypass , Laparoscopy , Obesity, Morbid , Gastrectomy , Ghrelin/analogs & derivatives , Humans , Obesity, Morbid/surgery , Treatment OutcomeABSTRACT
Blood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin-O-acyl transferase-null (GOAT-/-) mice that lack acyl-ghrelin (AG) but have high levels of UAG were rescued by acyl-ghrelin. Acyl-ghrelin-mediated neurogenesis in vitro was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice. To determine relevance in humans, we analyzed circulating AG:UAG in Parkinson disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. Notably, plasma AG:UAG was only reduced in PDD. Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT+ cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia.
Subject(s)
Acyltransferases/genetics , Ghrelin/analogs & derivatives , Ghrelin/genetics , Hippocampus/metabolism , Membrane Proteins/genetics , Parkinson Disease/genetics , Supranuclear Palsy, Progressive/genetics , Acyltransferases/deficiency , Animals , Brain-Derived Neurotrophic Factor/genetics , Brain-Derived Neurotrophic Factor/metabolism , Cognition/physiology , Disease Models, Animal , Female , Gene Expression Regulation , Ghrelin/metabolism , Hippocampus/pathology , Humans , Male , Membrane Proteins/deficiency , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurogenesis/genetics , Neuronal Plasticity/genetics , Neurons/metabolism , Neurons/pathology , Parkinson Disease/metabolism , Parkinson Disease/pathology , Primary Cell Culture , Rats , Signal Transduction , Spatial Memory/physiology , Supranuclear Palsy, Progressive/metabolism , Supranuclear Palsy, Progressive/pathologyABSTRACT
Human ghrelin receptor (GHSR) is a recognized prospective target in the diagnosis and therapy of multiple cancer types. To gain a better understanding of this receptor signaling system, we have synthesized a novel full-length ghrelin analog that is fluorescently labeled at the side-chain of a C-terminal cysteine extension. This analog exhibited nanomolar affinity and potency for the ghrelin receptor. It shows comparable efficacy with that of endogenous ghrelin. The fluorescently-labeled ghrelin analog is a valuable tool for in vitro imaging of cell lines that express ghrelin receptor.
Subject(s)
Ghrelin/analogs & derivatives , Ghrelin/chemical synthesis , Luminescent Proteins/chemical synthesis , Luminescent Proteins/metabolism , Fluorescence , HEK293 Cells , Humans , Luminescent Proteins/chemistry , Receptors, Ghrelin/metabolismSubject(s)
Ghrelin/analogs & derivatives , Psychological Trauma/complications , Stress Disorders, Post-Traumatic , Adolescent , Cross-Sectional Studies , Ghrelin/blood , Humans , Stress Disorders, Post-Traumatic/blood , Stress Disorders, Post-Traumatic/epidemiology , Stress Disorders, Post-Traumatic/etiologyABSTRACT
Fasting increases ghrelin that is a peptide hormone with two circulating isoforms, acyl and des-acyl ghrelin. We reported that fasting or des-acyl ghrelin facilitates behavioral thermoregulation in the cold in rats assessed by tail-hiding behavior that was the indicator of rats' thermoregulatory behavior in the cold; however, the effect of acyl-ghrelin on the same process remains to be elucidated. We investigated the effect of acyl-ghrelin on thermoregulatory behavior in the cold in rats. The animals received an intraperitoneal saline or 24⯵gâ¯acyl-ghrelin injection and were exposed to 27⯰C or 15⯰C for 2â¯h, while their body temperature, tail skin temperature, and tail-hiding behavior were constantly monitored. cFos immunoreactive (cFos-IR) cells in the median preoptic area, medial preoptic area, paraventricular nucleus (PVN), and arcuate nucleus were counted. Body temperature and the duration of thermoregulatory behavior did not show a significant difference between the acyl-ghrelin-treated and control groups at 15⯰C; however, tail skin temperature in the acyl-ghrelin-treated group was higher than that in the control group. The number of cFos-IR cells in the PVN was greater in the control group than that in the acyl-ghrelin-treated group at 27⯰C. These results indicate that acyl-ghrelin did not affect behavioral thermoregulation but might affect tail skin temperature in rats in the cold.