Acyl Ghrelin Research Articles

Post-prandial acyl ghrelin infusion in heart failure patients increases gastric emptying rate

Abstract Background Acyl ghrelin (ghrelin) increases cardiac output (CO) and contractility in patients with heart failure with reduced ejection fraction (HFrEF). In healthy humans, ghrelin increases gastric emptying rate (GER) and hunger, a potential add-on benefit for HFrEF patients suffering from cachexia with symptoms of delayed gastric emptying and loss of appetite. Aim Determine if post-prandial ghrelin infusion increases GER and hunger in HFrEF patients; compare to CO. Methods This study was a component of a double-blind placebo-controlled trial of acyl ghrelin vs. placebo in HFrEF. Patients (n=29) arrived fasted and received a 500 kcal breakfast and 1.5 g paracetamol. They next received placebo (vehicle, n=15) or ghrelin infusion (0.1 µg/kg/min, n=14) for 120 min. Blood was tapped for plasma at 0, 30, 60, 120 and 150 min into the meal. Plasma concentration of paracetamol was measured to assess GER of a liquid bolus. Hunger scores and CO were recorded. Mann-Whitney rank sum test was used for statistics. Results Paracetamol peaked at 30 min in 8 of 14 (57%) in the ghrelin treatment group versus 1 of 15 (7%) in the placebo group (P=0.004, Fig 1). Remaining patients peaked at later time points. There were no anomalous peaks at 0 min baseline or 2880 min (2 days). The ghrelin treatment group data was segregated into rapid (peak at 30 min, n=8) and slow (peak >30 min, n=6) GER subgroups. The rapid subgroup had a ghrelin treatment effect on CO (one-way repeat measures) (P<0.001, Fig 2). Baseline (t=0) CO for the rapid GER subgroup was 4.06 ±1.41 L/min (median ±SD) and 3.95 ±0.62 L/min for the slow GER subgroup (P=0.31). Data points shown are median ± SEM, each patient normalized to own baseline (100%); * P<0.05, ** P<0.01, *** P<0.001, pairwise comparison to baseline. Hunger gradually increased. The greatest increase in hunger was at 150 min, at which time median fold increase in hunger relative baseline was 1.6 (placebo), 1.7 (ghrelin, slow GER) and 2.3 (ghrelin, rapid GER). These hunger differences between groups did not reach significance. However, this trend was consistent with ghrelin induction of hunger, especially in those with potent GER and CO responses. Conclusions Ghrelin increases GER, and potentially hunger, in HFrEF patients in addition to increasing CO. Some HFrEF patients may benefit from this add-on effect.Fig 1.Time of paracetamol peak.Fig 2.Cardiac output.

Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.

Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.

The GHSR1a antagonist LEAP2 regulates islet hormone release in a sex-specific manner.

LEAP2, a liver-derived antagonist for the ghrelin receptor, GHSR1a, counteracts effects of ghrelin on appetite and energy balance. Less is known about its impact on blood glucose-regulating hormones from pancreatic islets. Here we investigate whether acyl-ghrelin (AG) and LEAP2 regulate islet hormone release in a cell type- and sex-specific manner. Hormone content from secretion experiments with isolated islets from male and female mice was measured by radioimmunoassay and mRNA expression by qPCR. LEAP2 enhanced insulin secretion in islets from males (p<0.01) but not females (p<0.2), whilst AG-stimulated somatostatin release was significantly reversed by LEAP2 in males (p<0.001) but not females (p<0.2). Glucagon release was not significantly affected by AG and LEAP2. Ghsr1a, Ghrelin, Leap2, Mrap2, Mboat4 and Sstr3 islet mRNA expression did not differ between sexes. In control male islets maintained without 17-beta oestradiol (E2), AG exerted an insulinostatic effect (p<0.05), with a trend towards reversal by LEAP2 (p=0.06). Both were abolished by 72h E2 pre-treatment (10 nmol/l, p<0.2). AG-stimulated somatostatin release was inhibited by LEAP2 from control (p<0.001) but not E2-treated islets (p<0.2). LEAP2 and AG did not modulate insulin secretion from MIN6 beta cells and Mrap2 was downregulated (P<0.05) and Ghsr1a upregulated (P<0.0001) in islets from Sst-/- mice. Our findings show that AG and LEAP2 regulate insulin and somatostatin release in an opposing and sex-dependent manner, which in males can be modulated by E2. We suggest that regulation of SST release is a key starting point for understanding the role of GHSR1a in islet function and glucose metabolism.

Intraperitoneal administration of α-melanocyte stimulating hormone (α-MSH) suppresses food intake and induces anxiety-like behavior via the brain MC4 receptor-signaling pathway in goldfish.

α-Melanocyte stimulating hormone (α-MSH) is a peptide hormone released from the intermediate lobe of the pituitary which regulates body pigmentation. In addition to the pituitary, α-MSH is also produced in the midbrain, and exerts both anorexigenic and an anxiogenic actions. Acyl ghrelin and cholecystokinin are peripheral hormones derived from the digestive tract which affect the brain to control food intake and feeding behavior in vertebrates. In the present study, hypothesizing that plasma α-MSH may also stimulate the brain and exert central effects, we examined whether peripherally administered α-MSH affects food intake and psychomotor activity using a goldfish model. Intraperitoneal (IP) administration of α-MSH at 100 pmol g-1 body weight (BW) reduced food consumption and enhanced thigmotaxis. These α-MSH-induced actions were blocked by intracerebroventricular administration of HS024, an antagonist of the melanocortin 4 receptor (MC4R), at 50 pmol g-1 BW, whereas these actions were not attenuated by pretreatment with an IP-injected excess amount of capsaicin, a neurotoxin that destroys primary sensory (vagal and splanchnic) afferents, at 160 nmol g-1 BW. Transcripts for the MC4R showed higher expression in the diencephalon in other regions of the brain. These results suggest that, in goldfish, IP administered α-MSH is taken up by the brain, and also acts as anorexigenic and anxiogenic factor via the MC4R signaling pathway.

A review of frequently used Kampo prescriptions. Part 5. Rikkunshito

AbstractBackgroundThe source of rikkunshito (RKT) is thought to be Yixuezhengzhuan by Yu Tuan. RKT was originally designed for many patients to treat gastrointestinal symptoms such as abdominal bloating, discomfort, nausea, and anorexia.Key FindingsRKT consists of eight types of crude drugs. Clinical studies including randomized clinical trials (RCT) for patients with non‐erosive reflux disease (NERD) refractory to proton‐pump inhibitor (PPI) have demonstrated that RKT improves not only acid‐related dysmotility symptoms, but also extra‐esophageal symptoms, and with RCT trial for functional dyspepsia (FD), RKT can simultaneously treat gastrointestinal and psychological symptoms. Moreover, RKT was recently applied to the day‐to‐day conditions, post‐operative management, and chemotherapy in cancer patients. Preclinical studies have also reported that various pharmacological functions of RKT such as its protective effect on mucosal injuries and its prokinetic effect on gastrointestinal tract motility have been elucidated. RKT was considered to increase plasma ghrelin levels by the inhibition of 5‐HT2B and 5‐HT2C receptor activities, enhanced ghrelin‐mediated signaling, inhibited degradation of acylated ghrelin to suppress decreases in plasma ghrelin levels by inhibiting the rate of degradation of acyl ghrelin to des‐acyl ghrelin, and inhibited PDE III activity. The incidence of adverse events associated with RKT was only 1.2%, and almost all adverse drug reactions were non‐serious reactions.ConclusionRKT is one of the very good candidates for beneficial medicines especially for patients presenting with intractable symptoms caused by gastrointestinal diseases such as disorders of gut–brain interaction or cancers.

Ghrelin Improves Glucolipotoxicity-Induced Pancreatic β-Cellular Dysfunction and Apoptosis by Inhibiting Endoplasmic Reticulum Stress-Induced IRE1/JNK Pathway.

Glucose and fatty acid overload-induced glucolipid toxicity of pancreatic β-cells is associated with the development of diabetes. Endoplasmic reticulum stress (ERS) plays an essential role in this process. Ghrelin, a peptide secreted by the pancreas, negatively correlates with oxidative stress. The study aimed to investigate ghrelin's role in glycolipid-induced β-cell dysfunction and its possible mechanism. Mouse insulinoma β-cell, NIT-1 cells, were stimulated with high fat and high glucose to induce glucolipid toxicity. High fat and high glucose-induced NIT-1 cells were treated with acylated ghrelin (AG) or [d-Lys3]-growth hormone releasing peptide (GHRP)-6. Flow cytometry and Cell Counting Kit-8 (CCK-8) assay were performed to assess apoptosis and cell viability. The protein expression related to apoptosis, inositol-requiring kinase 1 (IRE1)/c-Jun N-terminal kinase (JNK) signaling, and ERS were investigated using western blot. Enzyme-linked immunosorbent assay (ELISA) was adopted to examine insulin's synthesis and secretion levels. Ghrelin treatment improved cell viability while inhibiting cell glucolipotoxicity-induced NIT-1 cell apoptosis. Ghrelin can promote the synthesis and secretion of insulin in NIT-1 cells. Mechanistically, ghrelin attenuates ERS and inhibits the IRE1/JNK signaling pathway in NIT-1 cells induced by glucolipotoxicity. Ghrelin improves β-cellular dysfunction induced by glucolipotoxicity by inhibiting the IRE1/JNK pathway induced by ERS. It could be an effective treatment for β-cellular dysfunction.

Kandungan Antioksidan pada Suplemen Daun Kelor terhadap Kadar Acyl Ghrelin pada Subjek Obesitas

This study aims to explore the effect of antioxidant content on acyl ghrelin levels in obese subjects. This research method is a systematic literature review approach by searching for journal articles in the PubMed database. Inclusion criteria were articles published in the last 10 years using RCT methods on experimental animals and humans with obese nutritional status and providing Moringa leaf intervention. The research results showed that of 69 articles identified, only 7 articles met the inclusion criteria. The findings obtained indicate that the high antioxidant content of Moringa leaves has great potential as a functional food source and is beneficial for body health. The conclusion of the research is that the antioxidant content in Moringa leaves has an effect on obesity and still needs to be studied for its effect on acyl ghrelin. Keywords: Acyl ghrelin, Moringa Leaf Supplements, Antioxidants, Obesity

N-Terminal Pro-Brain Natriuretic Peptide Correlates with Ghrelin and Acyl-Ghrelin in Pre-Dialysis Chronic Kidney Disease.

Pro-B amino-terminal natriuretic peptide (NT-proBNP) is a diagnostic marker for heart failure (HF), a severe complication of chronic kidney disease (CKD). However, its significance in CKD is not clear, as other factors, such as renal function, may also have an impact. Recent studies have shown that ghrelin treatment is effective in HF in the general population, but the impact of ghrelin on cardiac function in CKD patients is still unknown. Our study aimed to investigate the factors associated with NT-proBNP in pre-dialysis CKD patients and to evaluate the correlation between NT-proBNP and ghrelin and acyl-ghrelin, molecules determined using ELISA methods. In a cross-sectional observational study, we included 80 patients with pre-dialysis CKD, with a mean age of 68 years and 50% men. The median values for NT-proBNP were 351.8 pg/mL, for acyl ghrelin 16.39 pg/mL, and for ghrelin 543.32 pg/mL. NT-proBNP was correlated with ghrelin (p = 0.034, r = 0.24), acyl-ghrelin (p = 0.033, r = -0.24), estimated glomerular filtration rate (p = 0.027, r = -0.25), serum urea (p = 0.006, r = 0.31), and ferritin (p = 0.041, r = 0.28). In multivariate analysis, ghrelin (p = 0.040) and blood urea (p = 0.040) remained significant predictors for NT-proBNP levels. NT-proBNP was a significant predictor for acyl-ghrelin (p = 0.036). In conclusion, in pre-dialysis CKD patients, a high value of NT-proBNP was associated with a high value of total ghrelin and a low value of acyl-ghrelin.

Impact of nocturnal hypoxia on glycaemic control, appetite, gut microbiota and inflammation in adults with type 2 diabetes mellitus: A single-blind cross-over trial.

High altitude residents have a lower incidence of type 2 diabetes mellitus (T2DM). Therefore, we examined the effect of repeated overnight normobaric hypoxic exposure on glycaemic control, appetite, gut microbiota and inflammation in adults with T2DM. Thirteen adults with T2DM [glycated haemoglobin (HbA1c): 61.1±14.1mmolmol-1; aged 64.2±9.4years; four female] completed a single-blind, randomised, sham-controlled, cross-over study for 10 nights, sleeping when exposed to hypoxia (fractional inspired O2 [ ]=0.155; ∼2500m simulated altitude) or normoxic conditions ( =0.209) in a randomised order. Outcome measures included: fasted plasma [glucose]; [hypoxia inducible factor-1α]; [interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]; [heat shock protein 70]; [butyric acid]; peak plasma [glucose] and insulin sensitivity following a 2h oral glucose tolerance test; body composition; appetite indices ([leptin], [acyl ghrelin], [peptide YY], [glucagon-like peptide-1]); and gut microbiota diversity and abundance [16S rRNA amplicon sequencing]. During intervention periods, accelerometers measured physical activity, sleep duration and efficiency, whereas continuous glucose monitors were used to assess estimated HbA1c and glucose management indicator and time in target range. Overnight hypoxia was not associated with changes in any outcome measure (P>0.05 with small effect sizes) except fasting insulin sensitivity and gut microbiota alpha diversity, which exhibited trends (P=0.10; P=0.08 respectively) for a medium beneficial effect (d=0.49; d=0.59 respectively). Ten nights of overnight moderate hypoxic exposure did not significantly affect glycaemic control, gut microbiome, appetite, or inflammation in adults with T2DM. However, the intervention was well tolerated and a medium effect-size for improved insulin sensitivity and reduced alpha diversity warrants further investigation. KEY POINTS: Living at altitude lowers the incidence of type 2 diabetes mellitus (T2DM). Animal studies suggest that exposure to hypoxia may lead to weight loss and suppressed appetite. In a single-blind, randomised sham-controlled, cross-over trial, we assessed the effects of 10 nights of hypoxia (fractional inspired O2 ∼0.155) on glucose homeostasis, appetite, gut microbiota, inflammatory stress ([interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]) and hypoxic stress ([hypoxia inducible factor 1α]; heat shock protein 70]) in 13 adults with T2DM. Appetite and inflammatory markers were unchanged following hypoxic exposure, but an increased insulin sensitivity and reduced gut microbiota alpha diversity were associated with a medium effect-size and statistical trends, which warrant further investigation using a definitive large randomised controlled trial. Hypoxic exposure may represent a viable therapeutic intervention in people with T2DM and particularly those unable or unwilling to exercise because barriers to uptake and adherence may be lower than for other lifestyle interventions (e.g. diet and exercise).

Ghrelin is associated with an elevated mood after an overnight fast in depression

BackgroundMajor depressive disorder (MDD) comprises subtypes with distinct symptom profiles. For example, patients with melancholic and atypical MDD differ in the direction of appetite and body weight changes as well as mood reactivity. Despite reported links to altered energy metabolism, the role of circulating neuropeptides from the gut in modulating such symptoms remains largely elusive. MethodsWe collected data from 103 participants, including 52 patients with MDD and 51 healthy control participants (HCP). After an overnight fast, we measured plasma levels of (acyl and des-acyl) ghrelin and participants reported their current metabolic and mood states using visual analog scales (VAS). Furthermore, they completed symptom-related questionnaires (i.e., STAI-T). ResultsPatients with atypical versus melancholic MDD reported less negative affect (p = 0.025). Higher levels of acyl ghrelin (corrected for BMI) were associated with improved mood (p = 0.012), specifically in patients with MDD. These associations of ghrelin were not mood-item specific and exceeded correlations with trait markers of negative affectivity. In contrast to associations with mood state, higher levels of ghrelin were not associated with increased hunger per se or changes in appetite in patients with MDD. LimitationsThe study is limited by the cross-sectional design without an intervention. ConclusionsOur results reveal potentially mood-enhancing effects of ghrelin in fasting individuals that exceed associations with metabolic state ratings. These associations with circulating neuropeptides might help explain anti-depressive effects of fasting interventions and could complement conventional treatments in patients with melancholic MDD.

Substituting carbohydrate at lunch for added protein increases fat oxidation during subsequent exercise in healthy males.

How pre-exercise meal composition influences metabolic and health responses to exercise later in the day is currently unclear. Examine the effects of substituting carbohydrate for protein at lunch on subsequent exercise metabolism, appetite, and energy intake. Twelve healthy males completed three trials in randomized, counterbalanced order. Following a standardized breakfast (779 ± 66 kcal; ∼08:15), participants consumed a lunch (1186 ± 140 kcal; ∼13:15) containing either 0.2 g·kg-1 carbohydrate and ∼2 g·kg-1 protein (LO-CARB), 2 g·kg-1 carbohydrate and ∼0.4 g·kg-1 protein (HI-CARB), or fasted (FAST). Participants later cycled at ∼60% V̇O2peak for 1 h (∼16:15) and post-exercise ad-libitum energy intake was measured (∼18:30). Substrate oxidation, subjective appetite, and plasma concentrations of glucose, insulin, non-esterified fatty acids (NEFA), peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and acylated ghrelin (AG) were measured for 5 h post-lunch. Fat oxidation was greater during FAST (+11.66 ± 6.63 g) and LO-CARB (+8.00 ± 3.83 g) than HI-CARB (p < 0.001), with FAST greater than LO-CARB (+3.67 ± 5.07 g; p < 0.05). NEFA were lowest in HI-CARB and highest in FAST, with insulin demonstrating the inverse response (all p < 0.01). PYY and GLP-1 demonstrated a stepwise pattern, with LO-CARB greatest and FAST lowest (all p < 0.01). AG was lower during HI-CARB and LO-CARB versus FAST (p < 0.01). Energy intake in LO-CARB was lower than FAST (-383 ± 233 kcal; p < 0.001) and HI-CARB (-313 ± 284 kcal; p < 0.001). Substituting carbohydrate for protein in a pre-exercise lunch increased fat oxidation, suppressed subjective and hormonal appetite, and reduced post-exercise energy intake.

Ghrelin regulates the endoplasmic reticulum stress signalling pathway in gestational diabetes mellitus

ObjectiveWe aimed to investigate the effects and mechanisms of the ghrelin-regulated endoplasmic reticulum stress (ERS) signalling pathway in gestational diabetes mellitus (GDM). MethodsPregnant female C57BL/6 mice were randomly divided into a normal group, GDM group (high-fat diet + STZ), GDM + ghrelin group (acyl ghrelin), and GDM + ghrelin + ghrelin inhibitor group ([D-lys3]-GHRP-6). We measured body weight, the intake of water and food, glucose, cholesterol, triglyceride and fasting insulin levels in each group. HE staining was used to observe the morphological changes in the pancreas. The TUNEL method was used to detect the apoptosis rate of islet cells. qPCR and Western boltting were performed to detect the relative expression levels of PERK, ATF6, IREIα, GRP78, CHOP and caspase-12, which are related to the ERS signalling pathway in the pancreas. Then, NIT-1 cells were cultured to verify whether ghrelin regulates ERS under high-glucose or tunicamycin conditions. ResultsCompared with the GDM group, the GDM + ghrelin group showed improved physical conditions and significantly decreased the fasting blood glucose, glucose tolerance, cholesterol, triglyceride and fasting insulin levels. Damaged islet areas were inhibited by ghrelin in the GDM group. The GDM + ghrelin group showed reduced β-cell apoptosis compared to the GDM and GDM + ghrelin + ghrelin inhibitor groups. ERS-associated factors (PERK, ATF6, IREIα, GRP78, CHOP and caspase-12) mRNA and protein levels were obviously lower in the GDM + ghrelin group than in the GDM group, while expression levels were restored in the inhibitor group. Ghrelin treatment improved the high-glucose or tunicamycin-induced apoptosis, increased insulin levels and upregulation of GRP78, CHOP and caspase-12 in NIT-1 cells. ConclusionGhrelin suppressed ERS signalling and apoptosis in GDM mice and in NIT-1 cells. This study established a link between ghrelin and GDM, and the targeting of ERS with ghrelin represents a promising therapeutic strategy for GDM.

Zinc Alpha-2 Glycoprotein, Acylated Ghrelin, and Zinc Levels in Prediabetics.

Prediabetic stages of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) exhibit differences in the sites of insulin resistance. Serum Zinc α-2 glycoprotein (ZAG), acylated ghrelin (AG), and zinc (Zn) levels can affect IFG, IGT, and diabetic glucose tolerance (DGT) differently. This study examined the importance of ZAG, AG, and serum Zn levels in prediabetic individuals with IFG, IGT, and DGT, compared to those with normal glucose levels. The study was conducted at İstanbul University Cerrahpaşa-Cerrahpaşa Faculty of Medicine. A total of n=151 volunteers were classified according to the WHO criteria for diabetes after undergoing an oral glucose tolerance test. Plasma and serum samples were measured by Inductively Coupled Plasma Optical Emission Spectroscopy, ELISA, and immunoassay. Prediabetic conditions became more prominent with the decrease in ZAG levels. ZAG levels showed a negative correlation with acylated ghrelin and Homeostatic Model Assessment for assessing beta-cell function and insulin resistance. Zinc levels were significantly lower in DGT. ZAG levels have regulatory effects on insulin resistance and plasma glucose levels are mediated by zinc and acylated ghrelin.

The New Trends in Physiological and Pathological Actions of Ghrelin (Brain-Heart Axis) on the Heart and Cardiovascular System

Background: Ghrelin increased significantly the Left Ventriculus Eject Fraction and end-systolic volume after 30 minutes of intra-venous injection and without alterations heart rate and blood pressure. Ghrelin was discovered in 1999 as an only one 28 amino acid peptides (with octanoyl serine group) located on the short arm of chromosome 3 (position 3p25-26) having six exons, two are noncoding and four introns and encodes a 511 bp mRNA. Ghrelin is synthesized by the endocrine X/A-like cells located from the gastric fundus mucosa through the whole mucosa of the medium right vertical side of the stomach until to the 1 inch before anatomical pylorus. These cells are responsible to produced 80% of the whole ghrelin produced in the human body. Furthermore, other place of this production occurs at the hypothalamus, the pituitary, second portion of duodenum, pancreas, heart and other tissues. Bibliographic references also demonstrate the importance of ghrelin’s action in the main cardiovascular activities. Related to cardiovascular activities, ghrelin plays multitudinous beneficial and thereby help during cardiovascular diseases. Several studies demonstrated that ghrelin cause an anti-inflammatory activity by the inhibition of proinflammatory cytokines which can diminish inflammatory diseases in the heart, pericardium and specific innervations, for instance, vagus nerve and inhibited sympathetic nerves. Outcomes of this review emphasize these important actions of ghrelin. Methods: A systematic review of ghrelin activities over the heart and cardiovascular system with the inclusion of papers in review involved the physiological and physio pathological activities of ghrelin in vivo and in vitro studies. Results: Ghrelin is a natural tide with the growth hormone secretagogue (GHS) receptor (GHS-R) which cloned in 1996. The processes which generate this peptide and ghrelin-related peptides are transcriptional, translational and posttranslational. Homo and heterodimers of GHS-R and other yet unidentified receptors mediate the biological actions of acyl ghrelin and desacyl ghrelin. However, the main biological functions of ghrelin involve the secretion of growth hormone, stimulation of appetite and food intake at the hypothalamus, modulate acid secretion and motility, endocrine and exocrine pancreas secretion, blockaded insulin activity, heart functions and cardiovascular responses and other. Conclusion: One of the main occurrences in acute heart infarction is an increase activation of cardiac sympathetic nerve activity (CSNA) which is one of the causes of chronic cardiac dysfunction (CCD). Ghrelin is an effective for obtain a better cardiac function and by the suppression of renal sympathetic nerve activity which also have an important benefit to the acute myocardial infarction. Therefore, the physiological effects of ghrelin are very important to the body homeostasis even in the grave heart and cardiovascular diseases and in the immunological system.

Suboptimal Weight Loss 13 Years After Roux-en-Y Gastric Bypass Is Associated with Blunted Appetite Response

PurposeBariatric surgery remains the most efficient treatment to achieve a sustained weight loss. However, a large proportion of patients experience suboptimal weight loss (SWL). The exact mechanisms involved remain to be fully elucidated, but the homeostatic appetite control system seems to be involved. The aim of this study was, therefore, to compare the plasma concentration of gastrointestinal hormones, and appetite ratings, between those experiencing SWL and optimal weight loss (OWL) after Roux-en-Y gastric bypass (RYGB).Materials and MethodsFifty participants from the Bariatric Surgery Observation Study (BAROBS) experiencing either SWL or OWL (< or ≥ 50% of excess weight loss (EWL), respectively) > 13 years post-RYGB were compared to 25 non-surgical controls. Plasma concentrations of acylated ghrelin (AG), total glucagon-like peptide-1 (GLP-1), total peptide YY (PYY), cholecystokinin (CCK), and subjective ratings of hunger, fullness, desire to eat (DTE), and prospective food consumption (PFC) were assessed in the fasting and postprandial (area under the curve (AUC)) states.ResultsThose experiencing OWL presented with higher basal AG and GLP-1 iAUC, and lower AG iAUC compared with SWL and controls. Additionally, both bariatric groups presented with higher PYY and CCK iAUC compared to controls. PFC tAUC was also lower in OWL compared to the SWL group. Total weight loss was positively correlated with GLP-1 tAUC and negatively correlated with fasting and tAUC DTE and PFC tAUC.ConclusionsSWL > 13 years post-RYGB is associated with lower basal ghrelin, as well as a weaker satiety response to a meal. Future studies should investigate the causality of these associations.Graphical

Acylated Ghrelin Activates PI3K/mTOR Signaling Pathway by Promoting ThPOK Acetylation to Promote Milk Fat Synthesis in Bovine Mammary Epithelial Cells.

Ghrelin regulates diverse physiological activities. However, the effects of this hormone on the milk fat synthesis remain unknown. This study aimed to investigate the effect of acylated ghrelin (AG) on milk fat synthesis by modifying the expression (knockdown or overexpression) of growth hormone secretagogue receptor 1a (GHSR1a) and Th-inducing POK (ThPOK) in primary bovine mammary epithelial cells (BMECs). The results showed that AG significantly increased the triglyceride relative content from 260.83 ± 9.87 to 541.67 ± 8.38 in BMECs via GHSR1a. ThPOK functions as a key regulatory target downstream of AG, activating the PI3K and mTOR signaling pathways to promote milk fat synthesis in BMECs. Moreover, AG-regulated ThPOK by increasing the EP300 activity, which promoted ThPOK acetylation to protect it from proteasomal degradation. In conclusion, AG increases ThPOK acetylation and stabilizes ThPOK through GHSR1a, thereby activating the PI3K/mTOR signaling pathway and ultimately promoting the milk fat synthesis in BMECs.

Octanoic acid-rich enteral nutrition attenuated hypercatabolism through the acylated ghrelin-POMC pathway in endotoxemic rats

ObjectivesMetabolic disorders and no response to intravenous nutrition because of sepsis have been urgent problems for clinical nutrition support. Enteral nutrition (EN) has been an important clinical therapeutic measure in septic patients; however, simple EN has not demonstrated good performance. This study aimed to investigate the effects of different concentrations of octanoic acid (OA)-rich EN on hypercatabolism in endotoxemic rats and test whether OA-rich EN could attenuate hypercatabolism through the acylated ghrelin-proopiomelanocortin (POMC) pathway. MethodsRats were randomly divided into six groups: sham, lipopolysaccharide (LPS), LPS + EN and LPS + EN + OA (0.25, 0.5, and 1 g/kg, respectively) groups to investigate the effects of different concentrations of OA-rich EN on hypercatabolism in endotoxemic rats. The rats were then randomly divided into four groups: sham, LPS, LPS + OA, and LPS + OA + Go-CoA-Tat, to test whether OA-rich EN attenuated hypercatabolism through the acylated ghrelin-POMC pathway. Rats received nutrition support via a gastric tube for 3 d (100 kcal/kg daily). Insulin resistance, muscle protein synthesis and atrophy, inflammatory cytokines, ghrelin in circulation and hypothalamus, ghrelin O-acyltransferase (GOAT), and the adenosine 5′-monophosphate-activated protein kinase (AMPK)-autophagy-POMC pathway were measured. ResultsCompared with simple EN, OA-rich EN promoted the acylation of ghrelin in a dose-dependent manner and attenuated POMC-mediated hypercatabolism in endotoxemic rats. Inhibition of GOAT activity decreased the level of acylated ghrelin and aggravated POMC-mediated hypercatabolism conferred by OA-rich EN. ConclusionsOA-rich EN could increase the level of acylated ghrelin and attenuate hypercatabolism through the acylated ghrelin-POMC pathway compared with simple EN in endotoxemic rats.

Regulation of hormonal receptors of the hypothalamic-pituitary-gonadal axis by ghrelin in ovary of grass carp (Ctenopharyngodon idella)

Ghrelin has been well known as an orexigenic hormone that regulates appetite and energy metabolism in animals. Recent studies imply the regulatory function of ghrelin on ovary development, however, the mechanism about the effects of ghrelin on key hormonal receptors in ovary is far away from systematically understood. The present study aimed to analyze the tissue distribution of ghrelin and related genes and elucidate the regulation of ghrelin on key hormonal receptors in ovary of grass carp (Ctenopharyngodon idella). High expression of ghrelin and ghrelin O-acyltransferase (GOAT) was found in the ovary compared to heart, kidney, spleen, muscle, brain, liver, gill and intestine. To understand the regulatory function of ghrelin on ovarian development, the effects of ghrelin on the key hormone receptors participated in ovarian maturation were determined by ghrelin, acyl-ghrelin and octanoic acid (substrate in the ghrelin acylation system) treatments with 1, 10 and 100 nM concentration. The in vivo study showed that all the 1, 10 and 100 nM ghrelin treatment stimulated follicle-stimulating hormone receptor (FSHR) expression compared to the control. Estrogen Receptor-α (ERα) was depressed by 10 nM acyl-ghrelin compared to the control, while ERβ1 and ERβ2 could be inhibited by 1 nM and 10 nM octanoic acid treatment compared to the control, respectively. The present results for the first time provided novel information about the regulatory role of ghrelin on key hormonal receptors in ovarian of grass carp providing potential new ideas for cultivating of grass carp broodstock.

Acyl ghrelin increases cardiac output and preserves right ventricular-pulmonary arterial coupling in patients with heart failure

Abstract Background Pulmonary hypertension and right ventricular (RV) failure are common in heart failure with reduced ejection fraction (HFrEF). Acyl ghrelin improves cardiac output (CO) in HFrEF but when CO increases there is a risk of increased pulmonary vascular resistance (PVR). This may impair the right ventricular-pulmonary artery coupling (RVPAC) and in the long term further harm the afterload sensitive RV in HFrEF or in patients with pulmonary arterial hypertension (WHO group 1). Animal data suggest that acyl ghrelin has beneficial effects on the pulmonary vasculature. Purpose To investigate if grehlin increases CO without worsening the right-sided hemodynamics in HFrEF assessed by RVPAC measured as the non-invasive surrogate tricuspid annular plane systolic excursion/tricuspid regurgitation velocity (TAPSE/TRV). Methods The Karolinska Acyl Ghrelin Trial (ClinicalTrials.gov NCT05277415) was a double-blind placebo-controlled trial of acyl ghrelin vs. placebo in HFrEF. In this secondary analysis we assessed RVPAC. Patients (n = 15+15) received either acyl ghrelin 30 pmol/kg/min or placebo (normal saline) intravenously during 120 min. Echocardiography exams at baseline and 120 min were assessed for RV parameters and patients were included if both TAPSE and TRV could be assessed at both time-points. Changes within groups (acyl ghrelin and placebo) at baseline vs. 120 min were analysed by Wilcoxon rank sign test. Analysis of variance was used to test for difference in change acyl ghrelin vs. placebo, adjusted for baseline values. Results A total of 22 patients (acyl ghrelin n = 12, placebo = 10) were included. Clinical characteristics were similar [median (IQR) acyl ghrelin vs. placebo): age 71 (65-77) vs. 74 (72-77) years, EF 29 (20-35) vs. 18 (13-36) %. 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 it 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. Similarly, TAPSE remained unchanged in the acyl ghrelin group 18.0 (14.8-20.5) to 17.5 (13.8-19.3), p = 0.188, while it decreased in the placebo group 14.5 (13.0-17.5) to 13.5 (11.3-15.0), p = 0.028. There were no differences in TRV. When comparing the changes between groups adjusted for baseline, CO increased in the acyl ghrelin group vs. placebo (p = 0.036) while there were no significant differences in RVPAC or TRV (Figure 1). Conclusion These preliminary findings indicate that acyl ghrelin may preserve or even improve RVPAC without increasing the RV pressure gradient. This may be due to acyl ghrelin causing improved contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF and suggest potentially beneficial effects also in patients with isolated or combined pre- and post-capillary pulmonary hypertension.

Weight-loss Independent Clinical and Metabolic Biomarkers Associated with Type 2 Diabetes Remission Post-bariatric/metabolic Surgery

PurposeRemission of type 2 diabetes (T2D) can be achieved by many, but not all, people following bariatric/metabolic surgery. The mechanisms underlying T2D remission remain incompletely understood. This observational study aimed to identify novel weight-loss independent clinical, metabolic and genetic factors that associate with T2D remission using comprehensive phenotyping.Materials and MethodsTen patients without T2D remission (non-remitters) were matched to 10 patients with T2D remission (remitters) for age, sex, type of surgery, body weight, BMI, post-operative weight loss, duration from surgery and duration of T2D. Detailed body composition assessed using magnetic resonance imaging, gut hormones, serum metabolomics, insulin sensitivity, and genetic risk scores for T2D and anthropometric traits were assessed.ResultsRemitters had significantly greater β-cell function and circulating acyl ghrelin levels, but lower visceral adipose tissue (VAT): subcutaneous adipose tissue (SAT) ratio than non-remitters. Branched-chain amino acids (BCAAs) and VLDL particle size were the most discriminant metabolites between groups. A significant positive correlation between, VAT area, VAT:SAT ratio and circulating levels of BCAAs was observed, whereas a significant negative correlation between BCAAs and β-cell function was revealed.ConclusionWe highlight a potentially novel relationship between VAT and BCAAs, which may play a role in glucoregulatory control. Improvement in β-cell function, and the role ghrelin plays in its recovery, is likely another key factor influencing T2D remission post-surgery. These findings suggest that adjunctive approaches that target VAT loss and restoration of BCAA metabolism might achieve higher rates of long-term T2D remission post-surgery.Graphical