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Ghrelin is an endogenous orexigenic hormone mainly produced by stomach cells and is reported to influence appetite, gastrointestinal motility and growth hormone secretion. We observed that enzymatic digest of wheat gluten stimulated ghrelin secretion from mouse ghrelinoma 3‐1, a ghrelin‐releasing cell line. Further on, we characterized the ghrelin‐releasing peptides present in the digest by comprehensive peptide analysis using liquid chromatography–mass spectrometry and structure–activity relationship. Among the candidate peptides, we found that SQQQQPVLPQQPSF, LSVTSPQQVSY and YPTSL stimulated ghrelin release. We then named them wheat‐ghretropin A, B and C, respectively. In addition, we observed that wheat‐ghretropin A increased plasma ghrelin concentration and food intake in mice after oral administration. Thus, we demonstrated that wheat‐ghretropin stimulates ghrelin release both in vitro and in vivo. To the best of our knowledge, this is the first report of a wheat‐derived exogenous bioactive peptide that stimulates ghrelin secretion., By using peptide comprehensive analysis of the gluten digest and by peptide homology comparison with already known ghrelin‐releasing peptides, we discovered three novel peptides that we name wheat‐ghretropins A, B and C. We observed that wheat‐ghretropin A increased food intake and serum ghrelin levels after oral administration in mice. To the best of our knowledge, this is the first report of a wheat‐derived exogenous bioactive peptide that stimulates ghrelin secretion.

Objective The mechanism of action of intragastric balloons in the treatment of obesity is not fully understood. One of the hypotheses is that balloons might have an effect on the fundus, the area of ghrelin production. Methods Participants were randomized to a 13‐week period of sham or balloon treatment followed by a 13‐week period of balloon therapy in everyone. Blood samples for ghrelin levels were taken in the fasting state and after a breakfast at the start, after 13 and 26 weeks. Biopsies for ghrelin cell immunohistochemistry were taken from the fundus at endoscopy. Results Seven participants entered the balloon–balloon (BB) group and 11 the sham–balloon (SB) group. Despite a considerable weight loss, a median −17.9 kg (interquartile ranges −23.8 to −0.5) in the BB group and −18.3 kg (−22.7 to −14.7) in the SB group, fasting ghrelin and meal‐induced ghrelin response did not change. In the SB group, the number of ghrelin cells increased significantly (p 0.001) from 110.6 (83.6–118.9) to 160.2 (128.5–223.0) while on sham treatment and returned to initial levels, 116.3 (91.7–146.9) (p 0.001), when they received their first balloon. No significant changes in ghrelin cell numbers were observed in the BB group. Conclusion In participants without a balloon, weight loss induced an increase in ghrelin cell numbers in the fundus, which was annulled by the subsequent placement of a balloon. The effect of a balloon might be explained by effects on ghrelin cell numbers or ghrelin cell activity.

Objective. Considering the importance of ghrelin in stress-induced hyperphagia and a role of antioxidants in decreasing body weight, in the present study, the effect of vitamin C (VitC) on ghrelin secretion and food intake following chronic social isolation (CIS) was evaluated in rats. Methods. Thirty two male Wistar rats (200–220g) were randomly divided into: control, VitC, CIS, and CIS + VitC groups. Animals received VitC (500 mg/kg/day)/saline by gavage for 3 weeks. For 24 h cumulative and post 18–20 h fasting food intake, fasting plasma ghrelin level, and body weight were measured. Gastric histopathology was also evaluated. Results. Results showed a marked increase in fasting plasma ghrelin and food intake in stressed rats compared to controls. VitC prevented the increases in stressed rats. Histological assessment indicated a positive effect of VitC on gastric glandular cells compared to control, an effect that might partially be a reason of significant increase of plasma ghrelin levels in VitC rats. Elevated plasma ghrelin in VitC group was even higher than that one in stressed group, whereas there were no significant changes in the food intake. Assessment of the percentage of changes in body weight during 21 days showed a significant increase in stressed rats compared to controls. Vitamin C treatment prevented this increase. Stressed rats also displayed depression-like behavior as indicated by sucrose test, whereas VitC ameliorated it. Conclusions. The data of the present study indicate that VitC may overcome ghrelin-induced hyperphagia and improve the abnormal feeding and depressive behavior in CIS rats.

Mechanisms underlying postprandial and obesity-associated plasma ghrelin reductions are incompletely understood. Here, using ghrelin cell-selective insulin receptor-KO (GhIRKO) mice, we tested the impact of insulin, acting via ghrelin cell-expressed insulin receptors (IRs), to suppress ghrelin secretion. Insulin reduced ghrelin secretion from cultured gastric mucosal cells of control mice but not from those of GhIRKO mice. Acute insulin challenge and insulin infusion during both hyperinsulinemic-hypoglycemic clamps and hyperinsulinemic-euglycemic clamps lowered plasma ghrelin in control mice but not GhIRKO mice. Thus, ghrelin cell-expressed IRs are required for insulin-mediated reductions in plasma ghrelin. Furthermore, interventions that naturally raise insulin (glucose gavage, refeeding following fasting, and chronic high-fat diet) also lowered plasma ghrelin only in control mice - not GhIRKO mice. Thus, meal- and obesity-associated increases in insulin, acting via ghrelin cell-expressed IRs, represent a major, direct negative modulator of ghrelin secretion in vivo, as opposed to ingested or metabolized macronutrients. Refed GhIRKO mice exhibited reduced plasma insulin, highlighting ghrelin's actions to inhibit insulin release via a feedback loop. Moreover, GhIRKO mice required reduced glucose infusion rates during hyperinsulinemic-hypoglycemic clamps, suggesting that suppressed ghrelin release resulting from direct insulin action on ghrelin cells usually limits ghrelin's full potential to protect against insulin-induced hypoglycemia.

Physiological changes including altered nutritional status influence disease progression and survival in patients with amyotrophic lateral sclerosis (ALS). Ghrelin affects the nutritional status by regulating appetite and energy expenditure, and also has neuroprotective effects. To investigate the association between ghrelin and ALS prognosis, we analyzed plasma acylated-ghrelin levels in 33 patients with ALS. Compared among ALS patients, male had lower plasma ghrelin levels than female, although disease specificity is unknown. ALS patients, especially male ALS patients, with low plasma ghrelin levels (

We performed a comprehensive analysis of ghrelin release-modulating activity of a dipeptide library using MGN3-1, a ghrelin-producing cell line. We found that most dipeptides suppress ghrelin secretion, whereas the N-terminal Ser-containing dipeptides and a few others stimulate it. N-terminal amino acid residues, but not C-terminal residues, play a dominant role in the effects of dipeptides. Among dipeptides, Leu-Ile (LI) and Ser-Val (SV) most strongly suppress and stimulate ghrelin secretion, respectively. LI activates Gi signaling and SV acts via the MAPK pathway. Orally administered LI and SV reduce and increase plasma ghrelin levels and food intake in mice, respectively. In conclusion, LI and SV, found based on the comprehensive screening of a dipeptide library, modulate ghrelin secretion in vitro and in vivo.

It is known that gastrointestinal microbiota, probiotics and heat-killed microbes can regulate intestinal immunity; however, their effect on the secretion of gastrointestinal hormones is unclear. The secretion of gastrointestinal hormones can be mediated by the elevation of intracellular Ca2+ concentration, suggesting that these hormones may act through common mechanisms. We have previously shown that heat-killed Lactobacillus brevis SBC8803 (hk-SBC8803) induced the secretion of serotonin and elevated intracellular Ca2+ concentration in serotonin-producing RIN-14B cells, suggesting that hk-SBC8803 could potentially cause the same effect on other gastrointestinal hormones, including hunger hormone ghrelin. Here, we tested this hypothesis by treating cultured cells and experimental animals with hk-SBC8803 and assessing ghrelin secretion, expression of ghrelin-related genes, and food intake. The results indicated that hk-SBC8803 treatment for 30 min significantly upregulated the secretion of acyl ghrelin (active form) (P=0.046) and mRNA expression of the Syt3 (synaptotagmin 3) gene related to ghrelin exocytosis (P

Damage to podocytes is a key event in glomerulopathies. While energy dense food can contribute to kidney damage, the role of the orixegenic hormone "ghrelin" in podocyte biology is still unknown. In the present study, we investigated the effect of ghrelin on podocyte survival as well as the signalling pathways mediating ghrelin effect in immortalized cultured rat podocytes. RT-PCR analysis revealed that GHS-R1 is expressed in rat podocytes. Western blot analysis showed that ghrelin upregulated COX-2 protein expression in a time and dose-dependent manner. Additionally, ghrelin activated P38 MAPK, AKT, and ERK1/2 pathways and also induced P38 MAPK phosphorylation in high glucose conditions. Ghrelin induced ROS release and dose dependently reduced podocyte survival. Ghrelin mediated podocyte cell death was partially reversed by pharmacologically inhibiting P38 MAPK or phospholipase C (PLC). Furthermore, PLC inhibitor (U73122) inhibited ghrelin induced P38 MAPK activation. While PI3K inhibitor (LY294002) was without effect on cell survival or P38 MAPK activation, it inhibited ghrelin induced ERK1/2 phosphorylation. Finally, ghrelin induced TAU phosphorylation was reversed by pharmacologic inhibitors of either P38 MAPK or PKA. In conclusion, ghrelin activated harmful molecular pathways in podocytes that can be damaging to the glomerular filtration barrier SIGNIFICANCE OF THE STUDY: Endocrine derangements secondary to obesity are major players in the aetiology of renal injuries. Furthermore, energy dense diet is thought to be the major element in developing obesity. Appetite and increase in energy intake are regulated by complex hormonal pathways which mainly include the orexigenic hormone "ghrelin" in addition to leptin. To date no study have highlighted a significant role for ghrelin in kidney biology, and therefore, it is thought that its endocrine effect is mostly limited to adipose tissue metabolism and appetite regulation. In this study, we first showed that ghrelin receptor is expressed on glomerular podocytes. Also, ghrelin showed negative impact on podocyte survival through modulating signalling pathways such as P38 MAPK and AKT known to play a key role in podocyte health. Moreover, the negative effects of ghrelin on podocytes were further exacerbated in hyperglycemic conditions. Of note, podocytes contribute to the formation and the maintenance of the glomerular filtration barrier and thus are important for normal renal function. Therefore, ghrelin secretion in the context of obesity could be involved in the aetiology of kidney injury, a well-known hallmark found in obese patients.

Much effort has been directed at studying the orexigenic actions of administered ghrelin and the potential effects of the endogenous ghrelin system on food intake, food reward, body weight, adiposity, and energy expenditure. Although endogenous ghrelin’s actions on some of these processes remain ambiguous, its glucoregulatory actions have emerged as well-recognized features during extreme metabolic conditions. The blood glucose–raising actions of ghrelin are beneficial during starvation-like conditions, defending against life-threatening falls in blood glucose, but they are seemingly detrimental in obese states and in certain monogenic forms of diabetes, contributing to hyperglycemia. Also of interest, blood glucose negatively regulates ghrelin secretion. This article reviews the literature suggesting the existence of a blood glucose–ghrelin axis and highlights the factors that mediate the glucoregulatory actions of ghrelin, especially during metabolic extremes such as starvation and diabetes.

Ghrelin, one of the most important appetite regulating peptides, is involved in the regulation of energy homeostasis. The anorexia effect of ghrelin in chickens is contrary to that of ghrelin in mammals. In the present study, the effects of feeding status and dietary energy level on plasma total ghrelin levels and expression were studied in broilers. The gene expression of ghrelin and its receptor GHS-R1a were measured in the hypothalamus, proventriculus, duodenum, liver, and abdominal fat pad. The results showed that ghrelin mRNA and GHS-R1a mRNA are moderately expressed in liver and abdominal fat. Ghrelin secretion was increased by fasting and refeeding. The gene expression of ghrelin and GHS-R1a in the hypothalamus, proventriculus, liver, and abdominal fat pad were changed by feeding status and dietary energy level. The results suggest that ghrelin is a signal of energy utilization in chickens. The abundant expression of ghrelin and GHS-R1a in liver and abdominal fat pad may be associated with energy balance.

Chemosensory signaling in organs such as the mouth and gut contributes to the mechanisms that control metabolism. We investigated the chemosensory pathways that regulate secretion of the hunger hormone ghrelin in response to neurotransmitters, bitter and sweet tastants at the cellular level in the human gut mucosa, and the disturbances in this regulatory pathway induced by obesity. Obesity impaired ghrelin protein production and adrenalin-induced ghrelin secretion in fundic cells, which was counterbalanced by somatostatin. Bitter agonists selective for taste receptor type 2 (TAS2Rs), TAS2R5 and TAS2R10 stimulated ghrelin secretion in fundic cells. The stimulatory effect of the broadly tuned bitter agonist, denatonium benzoate, was selectively blunted by obesity in the small intestine but not in the fundus. Luminal glucose concentrations inhibited ghrelin secretion via sodium-dependent glucose cotransporter and taste receptor type 1 member 3. Obesity altered the sensitivity of the ghrelin cell to glucose in the small intestine but not in the fundus. Sweet taste receptor activation inhibited bitter taste signaling of the ghrelin cell. In conclusion, obesity impairs the sympathetic drive that controls ghrelin release in the fundus and affects the sensitivity of the ghrelin cell to bitter and sweet stimuli in the small intestine but not in the fundus. Region-selective targeting of gut taste receptors in obesity is indicated.-Wang, Q., Liszt, K. I., Deloose, E., Canovai, E., Thijs, T., Farré, R., Ceulemans, L. J., Lannoo, M., Tack, J., Depoortere, I. Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut. ispartof: FASEB JOURNAL vol:33 issue:4 pages:4907-4920 ispartof: location:United States status: published

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.

Under severe calorie restriction (CR), the ghrelin-growth hormone axis in mice is involved in the maintenance of plasma glucose levels. Ghrelin, a stomach-derived acylated peptide, is up-regulated by the sympathetic nerve in the negative energy status. Central corticotrophin-releasing factor receptor (CRF-R) signalling stimulates the sympathetic tone. The present study aimed to examine the effect of central CRF-R signalling on the maintenance of plasma glucose concentrations in severe calorie-restricted mice with the involvement of ghrelin. Intracerebroventricular injections of urocorin-1 and urocorin-2, which are natural ligands for CRF-R1 and CRF-R2, elevated plasma ghrelin concentrations and ghrelin elevation with an i.c.v. injection of urocorin-1 was cancelled by atenolol (β1 adrenergic receptor antagonist) administration. We then established a mice model of 60% CR and found that the administration of [d-Lys3]-GHRP-6 (a ghrelin receptor antagonist) in mice under 60% CR reduced the plasma glucose concentration more compared to the vehicle mice. Similarly, the atenolol injection in mice under 60% CR significantly reduced the plasma glucose concentration, which was rescued by the co-administration of ghrelin. An i.c.v. injection of the alpha helical CRH, a non-selective corticotrophin-releasing factor receptor antagonist, in mice under 60% CR significantly reduced the plasma glucose concentration, although the co-administration of α-helical CRH with ghrelin maintained plasma glucose levels. These results suggest that central CRF-R signalling is involved in the maintenance of plasma glucose levels in mice under severe CR via the sympathetic-ghrelin pathway.

This study aims to examine the changes of glucose metabolism, glucose variability (GV), and ghrelin secretion within 1 week following SG in Chinese patients with obesity. Forty-nine patients with obesity (15 with type 2 diabetes) were enrolled to undergo SG. Within 1 week before and after surgery, liquid meal tests were performed in all subjects, and continuous glucose monitoring (CGM) was performed in diabetic patients. Blood samples were collected at 0, 15, 30, 45, 60, 120, and 180 min for glucose, C-peptide, insulin, and ghrelin analysis in liquid meal test. Mean amplitude of glucose excursions (MAGE), standard deviations (SD), and percent time-in-range (%TIR) determined by CGM were analyzed. Both in diabetic and non-diabetic groups, significant decrease was observed in glucose, insulin, C-peptide, and ghrelin. Homeostasis model assessment-insulin resistance and liver fat content was decreased. In diabetic group, MAGE and SD were decreased significantly, and the percent time-in-range was higher. The decrease in blood glucose was positively correlated with the decrease in ghrelin concentration in non-diabetic group. Within 1 week after SG, both glucose metabolism and glucose variability were improved significantly. Suppression of ghrelin secretion postoperatively might be a driver of this early improved glycemia homeostasis.

Ghrelin is a gastric hormone with multiple physiological functions, including the stimulation of food intake and adiposity. It is well established that circulating ghrelin levels are closely associated with feeding patterns, rising strongly before a meal and lowering upon food intake. However, the mechanisms underlying the modulation of ghrelin secretion are not fully understood. The purpose of this review is to discuss current knowledge on the circadian oscillation of circulating ghrelin levels, the neural mechanisms stimulating fasting ghrelin levels and peripheral mechanisms modulating postprandial ghrelin levels. Furthermore, the therapeutic potential of targeting the ghrelin pathway is discussed in the context of the treatment of various metabolic disorders, including obesity, type 2 diabetes, diabetic gastroparesis and Prader-Willi syndrome. Moreover, eating disorders including anorexia nervosa, bulimia nervosa and binge-eating disorder are also discussed.

Metabolic surgery modulates the enterohormone profile, which leads, among other effects, to changes in food intake. Bitter taste receptors (TAS2Rs) have been identified in the gastrointestinal tract and specific stimulation of these has been linked to the control of ghrelin secretion. We hypothesize that optimal stimulation of TAS2Rs could help to modulate enteroendocrine secretions and thus regulate food intake. To determine this, we have assayed the response to specific agonists for hTAS2R5, hTAS2R14 and hTAS2R39 on enteroendocrine secretions from intestinal segments and food intake in rats. We found that hTAS2R5 agonists stimulate glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), and reduce food intake. hTAS2R14 agonists induce GLP1, while hTASR39 agonists tend to increase peptide YY (PYY) but fail to reduce food intake. The effect of simultaneously activating several receptors is heterogeneous depending on the relative affinity of the agonists for each receptor. Although detailed mechanisms are not clear, bitter compounds can stimulate differentially enteroendocrine secretions that modulate food intake in rats.

The stomach is the primary source of the orexigenic and adiposity-promoting hormone, ghrelin. There is emerging evidence on the nutrient-mediated modulation of gastric ghrelin secretion. However, limited information is available on gastric nutrient-sensing mechanisms in high-fat diet (HFD)-induced obesity. This study investigated the impact of HFD-induced obesity on the expression of nutrient chemosensors in mouse stomach, particularly ghrelin cells. Male C57BL/6 mice were fed either a standard laboratory diet (SLD) or HFD for 12 weeks. The expression of ghrelin, enzymes involved in ghrelin production (PC1/3, GOAT) and nutrient chemosensors (CD36, FFAR2&amp, 4, GPR93, CaSR, mGluR4 and T1R3) was determined by quantitative RT-PCR in the mouse corpus and antrum. Immunohistochemistry assessed the protein expression of CaSR and ghrelin in the corpus and antrum. Antral mRNA levels of CaSR and PC1/3 were increased in HFD compared to SLD mice, while mRNA levels of all other nutrient chemosensors examined remained unchanged. CaSR immunolabelling was observed in the gastric antrum only. Nearly 80% of antral ghrelin cells expressed CaSR, with a similar cell density and co-expression in SLD and HFD mice. In conclusion, HFD-induced obesity increased CaSR mRNA expression in mouse antrum. However, the high antral co-expression of CaSR and ghrelin was unaltered in HFD compared to SLD mice.

Background The ability of the gut to detect nutrients is critical to the regulation of gut hormone secretion, food intake, and postprandial blood glucose control. Ingested nutrients are detected by specific gut chemosensors. However, knowledge of these chemosensors has primarily been derived from the intestine, while available information on gastric chemosensors is limited. This study aimed to investigate the nutrient-sensing repertoire of the mouse stomach with particular emphasis on ghrelin cells. Methods Quantitative RT-PCR was used to determine mRNA levels of nutrient chemosensors (protein: G protein-coupled receptor 93 [GPR93], calcium-sensing receptor [CaSR], metabotropic glutamate receptor type 4 [mGluR4]; fatty acids: CD36, FFAR2&4; sweet/umami taste: T1R3), taste transduction components (TRPM5, GNAT2&3), and ghrelin and ghrelin-processing enzymes (PC1/3, ghrelin O-acyltransferase [GOAT]) in the gastric corpus and antrum of adult male C57BL/6 mice. Immunohistochemistry was performed to assess protein expression of chemosensors (GPR93, T1R3, CD36, and FFAR4) and their co-localization with ghrelin. Key results Most nutrient chemosensors had higher mRNA levels in the antrum compared to the corpus, except for CD36, GNAT2, ghrelin, and GOAT. Similar regional distribution was observed at the protein level. At least 60% of ghrelin-positive cells expressed T1R3 and FFAR4, and over 80% expressed GPR93 and CD36. Conclusions and inferences The cellular mechanisms for the detection of nutrients are expressed in a region-specific manner in the mouse stomach and gastric ghrelin cells. These gastric nutrient chemosensors may play a role modulating gastrointestinal responses, such as the inhibition of ghrelin secretion following food intake.

Ghrelin is a predominantly stomach-derived peptide hormone with many actions including regulation of food intake, body weight, and blood glucose. Plasma ghrelin levels are robustly regulated by feeding status, with its levels increasing upon caloric restriction and decreasing after food intake. At least some of this regulation might be due to direct responsiveness of ghrelin cells to changes in circulating nutrients, including glucose. Indeed, oral and parental glucose administration to humans and mice lower plasma ghrelin. Also, dissociated mouse gastric mucosal cell preparations, which contain ghrelin cells, decrease ghrelin secretion when cultured in high ambient glucose. Here, we used primary cultures of mouse gastric mucosal cells in combination with an array of pharmacological tools to examine the potential role of changed intracellular oxidative stress in glucose-restricted ghrelin secretion. The antioxidants resveratrol, SRT1720, and curcumin all markedly increased ghrelin secretion. Furthermore, three different selective activators of Nuclear factor erythroid-derived-2-like 2 (Nrf2), a master regulator of the antioxidative cellular response to oxidative stress, increased ghrelin secretion. These antioxidant compounds blocked the inhibitory effects of glucose on ghrelin secretion. Therefore, we conclude that lowering oxidative stress within ghrelin cells stimulates ghrelin secretion and blocks the direct effects of glucose on ghrelin cells to inhibit ghrelin secretion.

Objective To compare appetite markers in reduced-obese individuals with a nonobese control group. Methods A total of 34 adults with obesity who lost 17% body weight at week 13 and maintained this weight loss (WL) at 1 year were compared with 33 nonobese controls matched for body composition. Basal and postprandial subjective appetite ratings and appetite-related hormone concentrations (ghrelin, total peptide YY, peptide YY3-36, total and active glucagon-like peptide 1, and cholecystokinin) were measured in all participants and repeated at week 13 and 1 year in the weight-reduced group. Results WL led to a reduction in prospective food consumption and an increase in feelings of hunger, fullness, and ghrelin secretion (basal and postprandial), but these new ratings were no different from those seen in controls. Postprandial concentrations of active glucagon-like peptide 1, total peptide YY, and cholecystokinin were lower in individuals with obesity at all time points compared with controls. Conclusion The increased drive to eat (both subjective feelings of hunger and ghrelin concentrations) seen in reduced-obese individuals, both after acute and sustained WL, reflects a normalization toward a lower body weight. Overall, WL does not have a sustained negative impact on satiety peptide secretion, despite a blunted secretion in individuals with obesity compared with nonobese controls.

Hunger is defined as a craving or urgent need for food. Abundant evidence now indicates that homeostatic and cognitive mechanisms promote the sensation of hunger. Communication between the gastrointestinal (GI) tract and the central nervous system (CNS) regulate both homeostatic and cognitive mechanisms to control feeding behavior. In this context the GI derived feeding peptide ghrelin, targets the CNS to promote food anticipation, learning, hedonic feeding and motivation for food. Importantly meal expectation following nutrient deprivation or satiation is associated with elevation of plasma ghrelin, highlighting the propensity of each mechanism to stimulate GI ghrelin secretion. It is well established that multiple physiological processes control ghrelin secretion from the GI tract. For example activation of descending sympathetic and parasympathetic pathways, GI feeding peptides, metabolic factors and endocannabinoid signaling mechanisms all regulate ghrelin secretion. In parallel, activation of the CNS ghrelin receptor (GHSR-1a) controls food anticipation, food-based learning, spatial learning and the rewarding properties of food. Notably GHSR-1a is expressed within a network of CNS regions that regulate diverse aspects of feeding behavior. These examples suggest a redundancy regarding mechanisms that control GI ghrelin secretion and complexity for GHSR-1a-mediated regulation of food intake. Based on this collective data, we suggest that learned information linked to the receipt of food is transmitted from the CNS to the GI tract to stimulate ghrelin release. We further postulate that GI ghrelin release and ghrelin-GHSR-1a interactions adapt over time, metabolic status and environment to direct feeding behavior.

Bacground & aim: Pinolenic acid, a major component (~20%) of pine nut oil, is a dual agonist of the free fatty acid receptors, FFA1 and FFA4, which may regulate release of incretins and ghrelin from the gut. Here, we investigated the acute effects of hydrolyzed pine nut oil (PNO-FFA), delivered to the small intestine by delayed-release capsules, on glucose tolerance, insulin, incretin and ghrelin secretion, and appetite. Methods: In two cross-over studies, we evaluated 3 g unhydrolyzed pine nut oil (PNO-TG) or 3 g PNO-FFA versus no oil in eight healthy, non-obese subjects (study 1), and 3 g PNO-FFA or 6 g PNO-FFA versus no oil in ten healthy, overweight/obese subjects (study 2) in both studies given in delayed-release capsules 30 min prior to a 4-h-oral glucose tolerance test (OGTT). Outcomes were circulating levels of glucose, insulin, GLP-1, GIP, ghrelin, appetite and gastrointestinal tolerability during OGTT. Results: Both 3 g PNO-FFA in study 1 and 6 g PNO-FFA in study 2 markedly increased GLP-1 levels (p < 0.001) and attenuated ghrelin levels (p < 0.001) during the last 2 h of the OGTT compared with no oil. In study 2, these effects of PNO-FFA were accompanied by an increased satiety and fullness (p < 0.03), and decreased prospective food consumption (p < 0.05). PNO-FFA caused only small reductions in glucose and insulin levels during the first 2 h of the OGTT. Conclusions: Our results provide evidence that PNO-FFA delivered to the small intestine by delayed-release capsules may reduce appetite by augmenting GLP-1 release and attenuating ghrelin secretion in the late postprandial state. Clinical trial registry numbers: NCT03062592 and NCT03305367.

ContextThe mechanisms regulating the postprandial suppression of ghrelin secretion remain unclear, but recent observations in rats indicate that an increase in duodenal osmolarity is associated with a reduction in ghrelin levels. Several hormones have been implicated in the regulation of ghrelin.ObjectiveWe hypothesized that intraduodenal infusion of a hyperosmolar solution would lower plasma ghrelin concentrations.Design, Setting, Participants, and InterventionsEighteen healthy young men were studied after an overnight fast on two occasions in a randomized double-blinded fashion. A nasoduodenal catheter was positioned and isoosmolar (300 mOsm/L) or hyperosmolar (1500 mOsm/L) saline was infused intraduodenally (4 mL/min, t = 0 to 45 minutes). Venous blood was sampled at t = −45, −30, −15, 0, 15, 30, 45, 60, 75, 90, 120, and 180 minutes.Main Outcome MeasuresPlasma concentrations of ghrelin, glucagonlike peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glucagon, pancreatic polypeptide (PP), neurotensin (NT), peptide YY (PYY), motilin, and glucose.ResultsGhrelin concentrations were suppressed with hyperosmolar when compared with isoosmolar saline, and remained lower until t = 180 minutes. CCK, NT, GLP-1, PYY, and glucagon all increased during hyperosmolar, but not isoosmolar, saline infusion (P < 0.01 for all), whereas GIP, PP, and motilin levels were not affected by either infusion.ConclusionsPlasma ghrelin concentrations are lowered, whereas CCK, GLP-1, PYY, NT, and glucagon concentrations are augmented, by hyperosmolar duodenal content in healthy individuals. These observations have implications for the evaluation of studies comparing the effects of different types and loads of nutrients and chemicals on gut hormone secretion.

The mycotoxin deoxynivalenol (DON) generally exists in cereals and affects human and animal health. The aim of this study is to analyze the impacts of DON in naturally contaminated feed on piglet growth performance and intestinal hormone secretion in the short term. We randomly divided 5-week-old piglets into four groups: Control, DON 1,000, DON 2,000 and DON 3,000 groups. Piglets received a feed naturally contaminated with DON (approximately 400, 1,000, 2,000 or 3,000 μg/kg) for 21 days. Body weight showed no significant difference following exposure to DON. The balance of anti-oxidation and oxidation was disrupted by DON after 21 days. The concentration of tumor necrosis factor-alpha (TNF-α) and cyclooxgenase-2 (COX-2) significantly increased (p

Background Recent data suggest that ghrelin is involved in the pathophysiology of alcohol use disorders, affecting alcohol self-administration and craving. Gastric ghrelin secretion is reduced by stomach distension. We now tested the hypothesis whether the clinically well-known effects of high-volume water intake on craving reduction in alcoholism is mediated by acute changes in ghrelin secretion. Methods In this randomized human laboratory study, we included 23 alcohol-dependent male inpatient subjects who underwent alcohol cue exposure. Participants of the intervention group drank 1000 ml of mineral water within 10 min directly thereafter, compared to the participants of the control group who did not. Craving and plasma concentrations of acetylated ghrelin were measured ten times during the 120 min following the alcohol cue exposure session. Results In the intervention group, a significant decrease in acetylated ghrelin in plasma compared to the control group was observed. This decrease was correlated to a reduction in patients’ subjective level of craving. In the control group, no decrease of acetylated ghrelin in plasma and no association between alcohol craving and changes in plasma concentrations of acetylated ghrelin were observed. Conclusions Our results present new evidence that the modulation in the ghrelin system by oral water intake mediates the effects of volume intake with craving reduction in alcohol use disorders. Hence, in addition to pharmacological interventions with ghrelin antagonists, the reduction of physiological ghrelin secretion might be a target for future interventions in the treatment of alcohol craving.

Some probiotics have been shown to alleviate age-related muscle atrophy via the gut-muscle axis. The aim of this study was to investigate the effects of live or heat-killed Lactobacillus paracasei PS23 (PS23) on muscle health in D-galactose-induced aging mice. Administration of D-galactose significantly reduced the strength, size, and levels of phosphorylated Akt in the muscle of mice. These effects were ameliorated by both live and heat-killed PS23 supplementation. Ghrelin is a multifaceted gut hormone with the ability to improve muscle atrophy. The levels of ghrelin in the serum and stomach of the aging mice were also significantly reduced and could be rescued by heat-killed but not live PS23. Furthermore, heat-killed PS23 greatly stimulated ghrelin secretion in the KATO III human gastric cell line. In conclusion, PS23 is a potential dietary supplement that can alleviate age-related muscle loss and dysfunction by regulating ghrelin secretion.

Purpose: Ghrelin is found as an endogenous ligand for growth hormone secretagogue receptor (GHSR). Several studies have reported an association between plasma ghrelin and GHRL-single nucleotide polymorphism, namely the Leu72Met polymorphism, with Body mass Index, type 2 diabetes mellitus, and insulin resistance. The role of gene variant of GHRL Leu72Met in obesity is still unclear. The aim of the present study was to examine the associations of Leu72Met with ghrelin levels, insulin secretion, and obesity among Javanese subjects. Materials and methods: All subjects were measured with anthropometry, and fasting blood glucose was measured by the glucose oxidase-phenol and 4 aminophenazone method. Plasma insulin and ghrelin were measured using ELISA. Insulin secretion was calculated using HOMA analysis. The Leu72Met genetic variant of the ghrelin gene was screened using PCR-RFLP. Results: Plasma ghrelin concentrations were lower in the obese group than the lean group (P < 0.05). Fasting plasma ghrelin was negatively correlated with body mass index and insulin secretion. Subjects with the Met72 allele carried a higher risk of obesity than the subjects with the Leu72 allele (OR = 4.928 [95% CI = 2.424–10.01]). Conclusion: The conclusion of this study is Leu72Met polymorphisms increases the risk of obesity in Javanese ethnicity, but this polymorphism does not play a role in plasma ghrelin secretion and plasma insulin secretion.

Ghrelin, an endogenous peptide isolated from the stomach, is known to stimulate food intake after peripheral administration. We found that the enzymatic digest of β-lactoglobulin decreases ghrelin secretion from the ghrelin-producing cell line MGN3-1. The peptides present in the digest were comprehensively analyzed using the nanoLC-OrbitrapMS. Among them, we identified that the nonapeptide LIVTQTMKG, corresponding to β-lactoglobulin(1-9), suppresses ghrelin secretion from MGN3-1 cells. We named LIVTQTMKG 'lacto-ghrestatin'. We found that lacto-ghrestatin decreases intracellular cAMP levels and mRNA expression levels of ghrelin production-related genes in MGN3-1 cells. Orally administered lacto-ghrestatin decreases plasma ghrelin levels and food intake in fasted mice. Lacto-ghrestatin is the first food-derived peptide to suppress ghrelin secretion in vitro and in vivo.

It is known that exists a relationship between listening to music and food intake. Hypothalamus appears to integrate the orexigenic properties of a novel peptide, ghrelin (Ghre) that induces food intake through neuropeptide Y (NPY). Ghre stimulates appetite by acting on the ventral hypothalamus, which controls food intake. Ghre is secreted from the stomach and circulates in the bloodstream under fasting conditions, sending a hunger signal from the periphery to the Central Nervous System. The aim of this study was to evaluate, in the rat, the effects of different musical frequencies (432 and 440 Hz) on the Ghre and NPY expression in the hypothalamic neurons through immunohistochemistry; in addition, we investigated on the different production of Ghre in the serum through Western blot assay (Wb), in relation to the body weight of animals. Ghre-immunopositive cells were counted, showing a significant increase in music-treated compared to the control (CTR) group. Similarly, music-treated rats showed increased levels of Ghre in the serum compared to CTR animals. Finally, the body weight of animals was affected by music. In particular, music exposure was able to stimulate the body weight increase and, interestingly, the increase was higher when animals were exposed to music at 440 Hz. Together, the results strongly support the hypothesis that different musical frequencies could affect food intake by modulating the hypothalamic Ghre expression and its release.

Background Previous studies have provided conflicting results regarding whether the serum ghrelin concentration can reflect the severity of acute pancreatitis (AP). The present study examined the correlation between the serum ghrelin concentration and AP severity in animal models and investigated whether altered ghrelin expression in pancreatic acinar cells influences IKKβ/NF-κB signaling and pro-inflammatory cytokine production. Methods Mild or severe AP was induced in rats by intraperitoneal injection of cerulein or retrograde cholangiopancreatic duct injection of sodium taurocholate, respectively. After successful model induction, serum ghrelin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) concentrations were determined by enzyme-linked immunosorbent assay, and IKKβ/NF-κB activation was assessed by immunohistochemistry. Subsequently, stable overexpression or knockdown of ghrelin in AR42J cells was achieved by lentiviral transfection. After transfected cells and control cells were treated with cerulein for 24 h, the TNF-α and IL-1β levels in the supernatants were determined by enzyme-linked immunosorbent assay, and the expression levels of p-p65, IKKβ, and p-IKKβ were detected by Western blotting. Results In rat AP models, AP severity was correlated with increased IKKβ/NF-κB activation, pro-inflammatory cytokine production, and ghrelin secretion. The levels of pro-inflammatory cytokines TNF-α and IL-1β as well as IKKβ/NF-κB signaling activity were increased upon knockdown of ghrelin in the AP acinar cell model and decreased with ghrelin overexpression. Conclusions Serum ghrelin is related to the severity of AP. Ghrelin may play a protective role in the pathogenesis of AP by inhibiting the pro-inflammatory cytokines and the activation of the IKKβ/NF-κB signaling pathway.

cope : Grape-seed phenolic compounds have recently been described as satiating agents in rats when administered as a whole phenolic extract (GSPE). This satiating effect may involve the release of satiating gut hormones such as GLP-1, although a short-term increase in the orexigenic hormone ghrelin was also reported. In this study we investigated the short and long-term effects of GSPE in rats, focusing on the role of the main grape-seed phenolics in ghrelin secretion. Methods and results : GSPE produced a short-term increase in plasma ghrelin in rats after an acute treatment. A mouse ghrelinoma cell line was used to test the effects of the main pure grape-seed phenolic compounds on ghrelin release. Monomeric flavanols stimulated ghrelin secretion by activating bitter taste receptors. In contrast, gallic acid (GA) and oligomeric flavanols inhibited ghrelin release. The ghrelin-inhibiting effects of GA were confirmed in rats and in rat duodenal segments. One day after the last dose of a subchronic treatment, GSPE decreased plasma ghrelin in rats, ghrelin secretion in intestinal segments and ghrelin mRNA expression in stomach. Conclusion : The sustained satiating effects of GSPE are related to a long-term decrease in ghrelin expression. GA and oligomeric flavanols play a ghrelin-inhibiting role in this process. This article is protected by copyright. All rights reserved

Gut hormones send information about incoming nutrients to the rest of the body and thereby control many aspects of metabolism. The secretion of ghrelin and glucagon-like protein (GLP)-1, two hormones with opposite secretory patterns and opposite actions on multiple targets, is controlled by a limited number of G-protein coupled receptors (GPCRs); half of which recognize and bind dietary nutrient metabolites, metabolites generated by gut microbiota, and metabolites of the host's intermediary metabolism. Most metabolite GPCRs controlling ghrelin secretion are inhibitory, whereas all metabolite receptors controlling GLP-1 secretion are stimulatory. This dichotomy in metabolite sensor function, which is obtained through a combination of differential expression and cell-dependent signaling bias, offers pharmacological targets to stimulate GLP-1 and inhibit ghrelin through the same mechanism.

Feeding is a highly complex behavior that is influenced by learned associations between external and internal cues. The type of excessive feeding behavior contributing to obesity onset and metabolic deficit may be based, in part, on conditioned appetitive and ingestive behaviors that occur in response to environmental and/or interoceptive cues associated with palatable food. Therefore, there is a critical need to understand the neurobiology underlying learned aspects of feeding behavior. The stomach-derived “hunger” hormone, ghrelin, stimulates appetite and food intake and may function as an important biological substrate linking mnemonic processes with feeding control. The current review highlights data supporting a role for ghrelin in mediating the cognitive and neurobiological mechanisms that underlie conditioned feeding behavior. We discuss the role of learning and memory on food intake control (with a particular focus on hippocampal-dependent memory processes) and provide an overview of conditioned cephalic endocrine responses. A neurobiological framework is provided through which conditioned cephalic ghrelin secretion signals in neurons in the hippocampus, which then engage orexigenic neural circuitry in the lateral hypothalamus to express learned feeding behavior.

We investigated exogenous secretagogues of ghrelin, which is an orexigenic hormone isolated from the stomach. We found that the tryptic digest of soy β-conglycinin stimulated ghrelin secretion by the ghrelin-producing cell line, MGN3-1. We then identified a 22-amino acid peptide corresponding to the β-conglycinin α-subunit(192-213) [βCGα(192-213)] from an active fraction separated by HPLC. The N-terminal undecapeptide of βCGα(192-213), NKNPFLFGSNR, exhibited ghrelin-releasing activity at a lower dose than that of βCGα(192-213). We named NKNPFLFGSNR 'soy-ghretropin', which corresponds to βCGα(192-202). Neither [des-N(1) K(2) ]-soy-ghretropin nor [des-R(11) ]-soy-ghretropin stimulated ghrelin secretion; hence, both the N- and C-terminal structures of soy-ghretropin were indispensable. Orally administered soy-ghretropin increased plasma ghrelin levels and food intake in vivo. Soy-ghretropin is the first exogenous ghrelin-releasing peptide derived from food protein.

Obesity, insulin resistance and the metabolic syndrome are associated with changes to the gut microbiota; however, the mechanism by which modifications to the gut microbiota might lead to these conditions is unknown. Here we show that increased production of acetate by an altered gut microbiota in rodents leads to activation of the parasympathetic nervous system, which, in turn, promotes increased glucose-stimulated insulin secretion, increased ghrelin secretion, hyperphagia, obesity and related sequelae. Together, these findings identify increased acetate production resulting from a nutrient-gut microbiota interaction and subsequent parasympathetic activation as possible therapeutic targets for obesity.

Ghrelin is a metabolic hormone that promotes energy conservation by regulating appetite and energy expenditure. Although some studies suggest that antagonizing ghrelin function attenuates body weight gain and glucose intolerance on a high calorie diet, there is little information about the metabolic actions of ghrelin in the obese state. In this review, we discuss the novel concept of obesity-induced central ghrelin resistance in neural circuits regulating behavior, and impaired ghrelin secretion from the stomach. Interestingly, weight loss restores ghrelin secretion and function, and we hypothesize that ghrelin resistance is a mechanism designed to protect a higher body weight set-point established during times of food availability, to maximize energy reserves during a time of food scarcity.

In this study we compare the interaction of three protein sources&mdash, insect, beef, and almond&mdash, with the gastrointestinal tract. We measured the enterohormone secretion ex vivo in human and pig intestine treated with in vitro digestions of these foods. Insect and beef were the most effective in inducing the secretion of CCK, while almond was the most effective in inducing PYY in pig duodenum. In the human colon, almond was also the most effective in inducing PYY, and GLP-1 levels were increased by insect and beef. The three digested proteins reduced ghrelin secretion in pig duodenum, while only insect reduced ghrelin secretion in human colon. We also found that food intake in rats increased in groups fed a raw insect pre-load and decreased when fed raw almond. In conclusion, the insect Alphitobius diaperinus modulates duodenal and colonic enterohormone release and increases food intake in rats. These effects differ from beef and almond.

Background: Blood concentration of many hormones fluctuates during a 24-hour period and sleep deprivation affects this circadian rhythm. The ghrelin hormone is secreted from gastric cells and stimulates hunger. There are a few studies regarding the 24-hour ghrelin secretion pattern in normal subjects, but no studies have addressed the effects of sleep deprivation on this pattern. Objectives: To assess the 24-hour ghrelin secretion pattern and the effect of sleep deprivation on this pattern. Methods: This work was conducted on 16 young soldiers (age: 19 - 23 years old) who served in AJA University of Medical Sciences. The participants were divided into two groups. The first group had regular sleep-wake cycle (n = 8). The second group did not have normal arousal cycle (n = 8). Six blood samples were taken from each subject within 24 hours. The samples were centrifuged and serum was frozen to -20°C until the various assays were performed. Serum cortisol and ghrelin levels were measured by the enzyme-linked immunosorbent assay (ELISA). Results: Cortisol showed a diurnal rhythm with a peak at 06.00 A.M. in the normal and disrupted sleep subjects. However, ghrelin did not show a significant diurnal rhythm in neither group. Sleep deprivation did not have a significant effect on the time pattern of the cortisol and ghrelin secretion. Conclusions: It seems that in real life, ghrelin does not show a circadian rhythm and sleep deprivation does not impact this rhythm.

Ghrelin is a stomach‐derived hormone that regulates several metabolic functions including growth hormone release, appetite, adiposity, and gastric motility. Nutrients, the autonomic nervous system, and other metabolic hormones have all been implicated in the regulation of ghrelin secretion. Despite this, ongoing efforts to develop modulators of ghrelin secretion in human diseases are still underway. Hydrogen sulfide (H2S) is a gaseous signaling molecule that is produced both endogenously in many tissues and by the gut microbiome. H2S has established roles in cardiovascular and immune health, however, more recently H2S has been implicated in the regulation of metabolic hormone secretion. We hypothesized that H2S is able to directly regulate ghrelin secretion and in turn, regulate appetite. We first demonstrated that GYY4137 (an H2S donor molecule) directly suppresses ghrelin secretion in rat primary gastric culture, in part through the activation of the protein kinase B (AKT) pathway. We then demonstrated the colocalization of ghrelin‐positive gastric cells with the H2S producing enzyme cystathionine‐γ‐lyase (CSE). While GYY4137 suppressed ghrelin secretion, inhibition of CSE caused a stimulation in ghrelin secretion in primary gastric culture. In mice, GYY4137 treatment prolonged the postprandial drop of circulating ghrelin and caused reduced food consumption up to 4 h after treatment. These results demonstrate for the first time a role for H2S in the regulation of ghrelin and appetite. Modulating H2S levels may be a novel approach to regulate ghrelin secretion in the treatment of metabolic diseases.

Introduction: Ghrelin has been recognized to have a major influence on energy balance. Hence, the discovery of various regulatory factors that control ghrelin secretion may have major implications for the development of drugs and diet control. This study aims to analyze differences in ghrelin secretion pattern and prevention of hunger in the provision of breakfast in low-calorie breakfast, low energy density and high energy density in obese female adolescents. Methods: Subjects were female students aged 18-22 years with a BMI=25 kg/m², receiving low-calorie breakfast with low (n=8) and high energy density (n=8). Before the breakfast, subjects fasted for 12 hours and were subjected to plasma ghrelin level and hunger measurement using visual analog scale (VAS). Breakfast was done at 08.00, divided into three parts and each was taken for 5 minutes. Measurement of plasma ghrelin was carried out again post prandial ( PP ) at 2 hours and 4 hours. VAS filling was done 1 hour PP , 2 hours PP , 3 hours PP , and 4 hours PP . Result: There were differences in plasma ghrelin level, but not significant. VAS 1 analysis of hunger (p=0.040) at 4 hours PP and VAS 3 of satiety (p=0.025) was significantly different at 3 hours PP. Conclusion: Food density did not affect the plasma ghrelin levels. Low density foods are more effective to prevent hunger in 4 hours PP and increases satiety in 3 hours PP .

Ghrelin is one of the most important appetite regulating peptides, involved in the regulation of energy homeostasis. The role of ghrelin on the appetite and fat metabolism in chickens is different from that of ghrelin in mammals. Glucocorticoids and insulin are important hormones and work differently in energy regulation of body. In this study, the effects of dexamethasone (DEX, 2.0 mg/kg BW), subcutaneous insulin injection (40 µg/kg BW), and glucose load on ghrelin secretion and expression were determined in broilers. DEX treatment increased circulating ghrelin concentration in broiler fed with either a low-energy diet (11.05 MJ/kg of metabolizable energy) or a high-energy diet (14.44 MJ/kg of metabolizable energy). The expression levels of ghrelin were increased while both ghrelin and its receptor GHS-R1a expression levels were stimulated by DEX. A single subcutaneous insulin injection (40 µg/kg BW) or oral glucose infusion (2 g/kg BW) rise circulating ghrelin level. Ghrelin expression in the proventriculus was increased by insulin treatment but unchanged by glucose load. DEX had no detectable influence on ghrelin and GHS-R1a expression in the hypohtalamus, whereas insulin suppressed their expression. In conclusion, both insulin and glucocorticoid stimulate ghrelin secretion in chickens, in contrast to mammals. Glucocorticoids evoke peripheral ghrelin/GHS-R1a system while insulin increases peripheral ghrelin expression and suppress the activation of central ghrelin/GHS-R1a system. The result suggests that ghrelin involved in the modulating network of energy homeostasis in concert with glucocorticoids and insulin.

In two experiments, we studied (a) the changes of LH secretion in heifers under different feeding schedules and (b) total ghrelin concentration at oestrus in cows and heifers. In experiment one, synchronized heifers were allocated in three groups (R, regularly fed controls; F, fasted; and F-F fasted-fed). One day after the completion of the oestrous induction protocol, group F and F-F animals stayed without feed for 24 hr; thereafter, feed was provided to R and F-F cattle; 2 hr later, GnRH was administered to all animals. Blood samples were collected for ghrelin, progesterone, LH and cortisol concentrations. Fasting caused increased ghrelin concentrations in groups F and F-F, while in response to GnRH, LH surge was significantly attenuated in groups F and F-F compared to R. In experiment 2, lactating cows and heifers were used. On day 9 of a synchronized cycle, PGF2α was administered, and blood samples were collected twice daily until the third day after oestrus and analysed for progesterone, estradiol, ghrelin, glucose and BHBA concentrations. No difference was recorded between groups in steroids and BHBA concentrations. In comparison to mid-luteal values, ghrelin concentrations significantly increased at perioestrual period in cows, but not in heifers. This study provides evidence that starving-induced elevated ghrelin concentrations can have suppressing effect on LH secretion, even after ghrelin's restoration to basal values and that during oestrus, ghrelin secretion is differently regulated in cows and heifers, likely being independent from oestradiol concentrations. Further research is required to identify the determining factors that drive the different regulation of ghrelin secretion in cows and heifers.

Food consumption is supposed to affect the onset of functional gastrointestinal disorder (FGID), particularly functional dyspepsia (FD). Many secretory fluids and digestive enzymes are secreted from digestive organs in response to food consumption and are then combined with the crushed and mixed food and transported, thereby inducing gastrointestinal motility. Gastrointestinal hormones are active substances that promote these digestive and absorptive functions. Furthermore, in recent years, many gastrointestinal hormones were found to have appetite-regulatory activity, and the abnormal secretion of gastrointestinal hormones and changes in their physiological activity have been suggested to contribute to FD onset. Although some gastrointestinal hormones have anorexic effects, only ghrelin have an orexigenic action and it also stimulates gastric motility. This short review presents the physiological activity of ghrelin as well as the regulatory mechanisms underlying appetite, acid secretion, and gastric motility via the brain–gut axis. In this review, we present the action of ghrelin on the secretion of gastric acid and its mechanism. We found that histamine mediates the stimulatory action of ghrelin on acid secretion through the mechanism based on brain–gut axis. Furthermore, we discussed the relationship between FD and ghrelin, and pathophysiology for FD in the state of stress that was simulated through animal experiments with intracerebroventricular (icv) injection of stress-related peptide urocortin 1 (UCN1). Our study has elucidated that UCN1 decreases plasma ghrelin level through CRF receptor 2. The inhibition of ghrelin secretion is mediated by sympathetic nerve through α2-adrenergic receptor in periphery. The mechanism may explain pathophysiology for FD inducing dyspepsia symptoms such as abdominal distension, fullness, and anorexia.

Dopamine is well recognized to regulate feeding via hypothalamic circuits in the brain.However, the mechanism by which dopamine controls food intake through hypothalamic pathways remains largely unknown. Recent findings propose that metabolic circuit and especially peripheral orexigenic/anorexigenic signals may play a critical role in the regulation of food intake. Therefore, in the present study, we hypothesized that ghrelin might modulate the orexigenic effect of ventromedial hypothalamic (VMH) dopamine receptors. To address this issue, we assessed the effects of intraventromedial administration of dopamine D2 receptors agonist, Quinpirrole, and anatagonist, Sulpiride, on plasma levels of ghrelin in 20-h fasted rats. Results showed that the pharmacological activation of D2 receptors increases the plasma ghrelin level persisted over 1h. This stimulatory effect of dopamine receptor activation on ghrelin was reduced by D2 receptors blockade in the VMH. In some experiments, atropine (cholinergic antagonist; 1 mg ⁄ kg s.c.) was administered 30 min before drug or saline injections which resulted in a marked suppression of fasted and stimulated ghrelin secretion. Together, our novel data implicates ghrelin in the orexigenic action of VMH D2 receptors signaling with a possible functional role of vagal pathway in the control of dopamine-evoked appetite (ghrelin) induction.

Background Ghrelin is a growth hormone secretagogue. It is a potent regulator of energy homeostasis. Ghrelin concentration is down-regulated in humans with hypersomatotropism (HS) and increases after successful treatment. Additionally, ghrelin secretion seems impaired in human diabetes mellitus (DM). Hypothesis Serum ghrelin concentration is down-regulated in cats with HS-induced DM (HSDM) compared to healthy control cats or cats with DM unrelated to HS and increases after radiotherapy. Animals Cats with DM (n = 20) and with HSDM (n = 32), 13 of which underwent radiotherapy (RT-group); age-matched controls (n = 20). Methods Retrospective cross-sectional study. Analytical performance of a serum total ghrelin ELISA was assessed and validated for use in cats. Differences in serum ghrelin, fructosamine, IGF-1 and insulin were evaluated. Results Ghrelin was significantly higher (P

Ghrelin is a stomach-derived orexigenic hormone with a wide range of physiological functions. Elucidation of the regulation of the circulating ghrelin level would lead to a better understanding of appetite control in body energy homeostasis. Earlier studies revealed that circulating ghrelin levels are under the control of both acute and chronic energy status: at the acute scale, ghrelin levels are increased by fasting and decreased by feeding, whereas at the chronic scale, they are high in obese subjects and low in lean subjects. Subsequent studies revealed that nutrients, hormones, or neural activities can influence circulating ghrelin levels in vivo. Recently developed in vitro assay systems for ghrelin secretion can assess whether and how individual factors affect ghrelin secretion from cells. In this review, on the basis of numerous human, animal, and cell-based studies, we summarize current knowledge on the regulation of circulating ghrelin levels and enumerate the factors that influence ghrelin levels.

Electroacupuncture (EA) accelerates intestinal functional recovery in sepsis. The present study investigated ghrelin and ghrelin receptor (GSH-R) levels during EA in rats with acute bowel injury (ABI). Rats were grouped into four groups: Sham, ABI, ABI+EA and ABI+GHRA+EA (n=12 per group). ABI was induced by cecal ligation and puncture (CLP). EA on bilateral Zusanli acupoints was performed following CLP. GSH-R blocker (GHRA) was used following CLP but prior to EA for ABI+GHRA+EA rats. Rats were sacrificed 12 h following CLP. Serum ghrelin, tumor necrosis factor-α (TNF-α) and high mobility group box 1 (HMGB1) levels, as well as ghrelin and GSH-R protein expression, water content, pathological changes and myeloperoxidase (MPO) and diamine oxidase (DAO) activities in the bowel tissues, were measured. ABI rats, compared with the sham rats, had significantly lower levels of ghrelin and GSH-R in the serum and bowel tissue, and higher Chiu's score (all P

Ghrelin is a peptide hormone with a unique structure comprising a medium chain fatty acid modification. Ghrelin cells are known to be abundantly localized in the gastric mucosa and are released into the blood stream to exert their multifunctional physiological effects. To elucidate the regulatory mechanisms of ghrelin secretion and acyl-modification, we developed novel ghrelin-producing cell lines. Using ghrelinoma cell lines, we focused on the mechanisms of ghrelin secretion and found that several GPCRs were highly expressed in ghrelin cells. Then, we showed that noradrenaline treatment stimulated ghrelin secretion via β1-adrenergic receptor, and fasting-induced ghrelin elevation was completely inhibited by the β1-adrenergic receptor antagonist in mice. In addition, we demonstrated that long chain fatty acids, glucose, and L-glutamate significantly inhibited ghrelin secretion. Furthermore, we recently revealed that the genes involved in fatty acid synthesis and long chain fatty acid metabolism were expressed in ghrelin cells, and that CPT-1 inhibitor treatment dramatically decreased the levels of acyl-modified ghrelin. Here, we introduce the current knowledge of the mechanisms involving ghrelin secretion and its acyl-modification.

Objective To assess possible changes in leptin and ghrelin secretion due to etanercept in juvenile idiopathic arthritis (JIA). Methods 50 patients with JIA and 16 age-matched controls were enrolled into this prospective, cross-sectional study. Serum leptin, total and acyl ghrelin were measured in addition to white blood cell (WBC) and lymphocyte counts. Results 25 patients received etanercept and 25 conventional therapies (including methotrexate) for JIA. There was no difference between treatment and control groups in leptin or ghrelin levels and no evidence of a relationship between leptin and ghrelin in patients with JIA. In all children with JIA there was a correlation between leptin and body mass index (BMI). However, compared with children in the conventional treatment group, children in the etanercept group showed a positive correlation between total ghrelin and BMI and those with a low BMI showed a negative correlation between acyl ghrelin and BMI. Conclusion No differences in leptin and ghrelin concentrations were found when patients with JIA and controls were compared or when patients who received etanercept were compared with those who received conventional treatment for JIA.

The gut–brain axis maintains energy homeostasis through signaling of the membrane receptors for ghrelin, leptin, α-melanocyte-stimulating hormone (α-MSH), and cannabinoids. Signaling that emanates from these receptors in the stomach and the hypothalamus results in interregulation of the actions of these receptors and maintenance of physiological body weight, with imbalances leading to positive metabolism or obesity. The appetite-regulating ghrelin promotes food intake and fat storage, leptin inhibits appetite through its actions on α-MSH to reduce body weight, while signaling through the cannabinoid 1 receptor (CB1R) controls ghrelin secretion by the stomach and mediates the actions of both ghrelin and leptin in the hypothalamus. In rat obesity models, sleeve gastrectomy, a bariatric surgery performed in humans to manage obesity, imposes transcriptional reprogramming in the acyl–ghrelin–CB1R axis to lower body weight in the long term. Thus, peripheral intervention into this axis should be considered as a therapeutic target for human obesity.