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Sample records for acylated ghrelin level

  1. Total and acylated ghrelin levels in children with poor growth.

    PubMed

    Pinsker, Jordan E; Ondrasik, Deborah; Chan, Debora; Fredericks, Gregory J; Tabisola-Nuesca, Eludrizza; Fernandez-Aponte, Minela; Focht, Dean R; Poth, Merrily

    2011-06-01

    Ghrelin, an enteric hormone with potent appetite stimulating effects, also stimulates growth hormone release. We hypothesized that altered levels of total ghrelin (TG) or acylated ghrelin (AG) could affect growth by altering growth hormone secretion, subsequently affecting insulin-like growth factor-1 (IGF-1) generation or by altering appetite and food intake. After institutional review board approval, 52 children presenting for evaluation of chronic gastrointestinal symptoms (group 1), poor weight gain (group 2), or poor linear growth (group 3) were evaluated for fasting TG and AG levels in addition to their regular evaluation. Serum ghrelin, IGF-1, and prealbumin were compared between groups. No difference was observed for mean fasting TG between groups. However, mean fasting AG was highest in patients in group 2 (465 ± 128 pg/mL) versus group 1 (176 ± 37 pg/mL) and group 3 (190 ± 34 pg/mL). IGF-1 was lowest in patients in group 2 despite similar prealbumin levels among the three groups. We conclude that serum AG levels are highest in children with isolated poor weight gain compared with children with short stature or chronic gastrointestinal symptoms, suggesting the possibility of resistance to AG in underweight children. Additional studies are needed to further clarify ghrelin's role in growth and appetite.

  2. Neural correlates of plasma acylated ghrelin level in individuals with major depressive disorder.

    PubMed

    Matsuo, Koji; Nakano, Masayuki; Nakashima, Mami; Watanuki, Toshio; Egashira, Kazuteru; Matsubara, Toshio; Watanabe, Yoshifumi

    2012-09-14

    Anhedonic symptoms, which include loss of pleasure, appetite and motivation, are key symptoms of major depressive disorder (MDD) and are thought to depend on a neural circuit of the mesolimbic system. The neuropeptide ghrelin plays a crucial role in appetite and reward. Little is known, however, about the role of ghrelin in MDD. We examined the association between morphometric change and plasma ghrelin levels in patients with MDD. Twenty-four patients with MDD and 24 healthy control subjects were studied. Plasma concentration of acylated ghrelin was measured after a period of fasting. Using voxel-based morphometry, we found a main effect of ghrelin on the volume of several brain regions. We then compared these regional volumes in patients with MDD versus healthy subjects. We also compared brain volumes between the two groups, controlling for ghrelin level. There was no significant difference in plasma acylated ghrelin level between patients with MDD and healthy subjects. In the MDD group, ghrelin levels positively correlated with the severity of reduced appetite. Ghrelin levels negatively correlated with gray matter volume of the ventral tegmental area (VTA) in the total sample. The patients with MDD showed significantly smaller VTA gray matter volume compared to healthy subjects. Controlling for the plasma acylated ghrelin level, patients with MDD showed significantly smaller gray matter volume of right substantia nigra compared to healthy subjects. Our findings suggest that plasma acylated ghrelin is associated with neural abnormalities of the pleasure/reward system and may be involved in the pathophysiology of MDD.

  3. Impact of intracerebroventricular obestatin on plasma acyl ghrelin, des-acyl ghrelin and nesfatin-1 levels, and on gastric emptying in rats.

    PubMed

    Chen, Chih-Yen; Lee, Wei-Jei; Chong, Keong; Lee, Shou-Dong; Liao, You-Di

    2012-07-01

    Obestatin, which is a putative 23-amino-acid peptide, is derived from the C-terminal part of the mammalian preproghrelin gene. Nesfatin-1 mRNA is co-expressed with ghrelin in gastric endocrine X/A-like cells; therefore, nesfatin-1 may also interact with preproghrelin gene products in the stomach. In this study, we investigated the impact of obestatin on the plasma levels of acyl ghrelin, des-acyl ghrelin and nesfatin-1, and on the gastric emptying of a solid nutrient meal 2 h after an intracerebroventricular (ICV) injection in conscious, fasted rats. The rats were implanted with ICV catheters. Plasma levels of acyl ghrelin, des-acyl ghrelin and nesfatin-1, expected to be co-expressed with obestatin, were measured, whereas the human/rat corticotropin-releasing factor (h/rCRF) was applied as an inhibitor of gastric emptying. The ICV administration of obestatin (0.1, 0.3 and 1.0 nmol/rat) did not modify the plasma acyl ghrelin and des-acyl ghrelin levels, the acyl ghrelin/des-acyl ghrelin ratio and nesfatin-1 concentrations. The ICV acute administration of obestatin had no influence on the 2-h rate of gastric emptying of a solid nutrient meal, but the ICV h/rCRF injection delayed it. The weight of food ingested 1 h before ICV injection significantly, but negatively correlated with the gastric emptying of a solid nutrient meal. Our study indicates that the ICV injection of obestatin does not change the 2-h rate of gastric emptying of a solid nutrient meal and the relatively weak interrelationships between ghrelin gene products and nesfatin-1. However, the weight of the ingested food negatively affects the gastric emptying of a solid nutrient meal in conscious, fasted rats.

  4. The Level of Circulating Octanoate Does Not Predict Ghrelin O-Acyl Transferase (GOAT)-Mediated Acylation of Ghrelin During Fasting

    PubMed Central

    Nikolayev, Alexander; Liu, Jianhua; Pezzoli, Suzan S.; Farhy, Leon S.; Patrie, James; Gaylinn, Bruce D.; Heiman, Mark; Thorner, Michael O.

    2015-01-01

    Background: Acyl-ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin O-acyl transferase (GOAT) attaches an 8-carbon medium-chain fatty acid (MCFA) (octanoate) to serine 3 of ghrelin. This acylation is necessary for the activity of ghrelin. Animal data suggest that MCFAs provide substrate for GOAT and an increase in nutritional octanoate increases acyl-ghrelin. Objectives: To address the question of the source of substrate for acylation, we studied whether the decline in ghrelin acylation during fasting is associated with a decline in circulating MCFAs. Methods: Eight healthy young men (aged 18–28 years, body mass index range, 20.6–26.2 kg/m2) had blood drawn every 10 minutes for acyl- and desacyl-ghrelin and every hour for free fatty acids (FFAs) during the last 24 hours of a 61.5-hour fast and during a fed day. FFAs were measured by a highly sensitive liquid chromatography-mass spectroscopy method. Acyl- and desacyl-ghrelin were measured in an in-house assay; the results were published previously. Ghrelin acylation was assessed by the ratio of acyl-ghrelin to total ghrelin. Results: With the exception of MCFAs C8 and C10, all other FFAs, the MCFAs (C6 and C12), and the long-chain fatty acids (C14–C18) significantly increased with fasting (P < .05). There was no significant association between the fold change in ghrelin acylation and circulating FFAs. Conclusions: These results suggest that changes in circulating MCFAs are not linked to the decline in ghrelin acylation during fasting and support the hypothesis that acylation of ghrelin depends at least partially on the availability of gastroluminal MCFAs or the regulation of GOAT activity. PMID:25337923

  5. Ethanol affects acylated and total ghrelin levels in peripheral blood of alcohol-dependent rats.

    PubMed

    Szulc, Michal; Mikolajczak, Przemyslaw L; Geppert, Bogna; Wachowiak, Roman; Dyr, Wanda; Bobkiewicz-Kozlowska, Teresa

    2013-07-01

    There is a hypothesis that ghrelin could take part in the central effects of alcohol as well as function as a peripheral indicator of the changes which occur during long-term alcohol consumption. The aim of this study was to determine a correlation between alcohol concentration and acylated and total form of ghrelin after a single administration of alcohol (intraperitoneal, i.p.) (experiment 1) and prolonged ethanol consumption (experiment 2). The study was performed using Wistar alcohol preferring (PR) and non-preferring (NP) rats and rats from inbred line (Warsaw High Preferring, WHP; Warsaw Low Preferring, WLP). It was found that ghrelin in ethanol-naive WHP animals showed a significantly lower level when compared with the ethanol-naive WLP or Wistar rats. After acute ethanol administration in doses of 1.0; 2.0 and 4.0 g/kg, i.p., the simple (WHP) or inverse (WLP and Wistar) relationship between alcohol concentration and both form of ghrelin levels in plasma were found. Chronic alcohol intake in all groups of rats led to decrease of acylated ghrelin concentration. PR and WHP rats, after chronic alcohol drinking, had lower levels of both form of ghrelin in comparison with NP and WLP rats, respectively, and the observed differences in ghrelin levels were in inverse relationship with their alcohol intake. In conclusion, it is suggested that there is a strong relationship between alcohol administration or intake, ethanol concentration in blood and both active and total ghrelin level in the experimental animals, and that ghrelin plasma concentration can be a marker of alcohol drinking predisposition.

  6. Ghrelin acylation and metabolic control.

    PubMed

    Al Massadi, O; Tschöp, M H; Tong, J

    2011-11-01

    Since its discovery, many physiologic functions have been ascribed to ghrelin, a gut derived hormone. The presence of a median fatty acid side chain on the ghrelin peptide is required for the binding and activation of the classical ghrelin receptor, the growth hormone secretagogue receptor (GHSR)-1a. Ghrelin O-acyl transferase (GOAT) was recently discovered as the enzyme responsible for this acylation process. GOAT is expressed in all tissues that have been found to express ghrelin and has demonstrated actions on several complex endocrine organ systems such as the hypothalamus-pituitary-gonadal, insular and adrenal axis as well as the gastrointestinal (GI) tract, bone and gustatory system. Ghrelin acylation is dependent on the function of GOAT and the availability of substrates such as proghrelin and short- to medium-chain fatty acids (MCFAs). This process is governed by GOAT activity and has been shown to be modified by dietary lipids. In this review, we provided evidence that support an important role of GOAT in the regulation of energy homeostasis and glucose metabolism by modulating acyl ghrelin (AG) production. The relevance of GOAT and AG during periods of starvation remains to be defined. In addition, we summarized the recent literature on the metabolic effects of GOAT specific inhibitors and shared our view on the potential of targeting GOAT for the treatment of metabolic disorders such as obesity and type 2 diabetes.

  7. Effects of acute resistance exercise on acyl-ghrelin and obestatin levels in hemodialysis patients: a pilot study.

    PubMed

    Moraes, Cristiane; Borges, Natália A; Barboza, Jorge; Barros, Amanda F; Mafra, Denise

    2015-11-01

    Chronic physical exercises may be beneficial to modulate appetite hormones as acyl-ghrelin (orexigenic) and obestatin (anorexigenic) in chronic kidney disease (CKD) patients; however, there are no data about the effects of acute exercises on these hormones. Thus, the aim of the present study was to assess the effect of acute resistance exercise on appetite hormones (acyl-ghrelin and obestatin) of patients undergoing hemodialysis (HD). Twenty-five patients (44.7 ± 12.9 years, 68% women) on regular HD program were enrolled into two groups, 16 patients performed exercises and 9 patients comprised the control group. The patients performed the exercises in both lower limbs with ankle-cuffs and elastic bands, 30 min after the initiation of hemodialysis session. Blood samples of both the groups were drawn in the morning before and after 30 min with exercise session (exercise group) and, before and after the same time without exercise (control group). Acyl-ghrelin and obestatin plasma levels were measured using an enzyme immunometric assay. Acyl-ghrelin plasma levels did not change in both the groups. However, when stratified by gender the acyl-ghrelin increased significantly right after exercise in men [32.1 pg/mL (25.6-41.2) to 46.0 pg/mL (39.0-59.5)] (p = 0.04). Obestatin plasma levels reduced after a single bout of exercise and changes remained significantly when the sample was stratified by gender. There was no change in obestatin plasma levels in control group. A single bout of resistance exercise seems to modulate the levels of appetite hormones in HD patients.

  8. Combined effects of aerobic exercise and high-carbohydrate meal on plasma acylated ghrelin and levels of hunger.

    PubMed

    Becker, Geórgia Franco; Macedo, Rodrigo Cauduro Oliveira; Cunha, Giovani Dos Santos; Martins, Jocelito Bijoldo; Laitano, Orlando; Reischak-Oliveira, Alvaro

    2012-02-01

    The present study investigated the effect of an aerobic exercise bout associated with a high-carbohydrate (CHO) meal on plasma levels of acylated ghrelin and hunger sensation. Eight healthy males performed an exercise (ET) and a control (CT) trial. In ET, participants performed a 60-min cycling exercise (∼70% of maximal oxygen uptake) after consuming a high-CHO meal. In the CT, participants remained at rest throughout the whole period after consuming the high-CHO meal. Hunger sensation was assessed and blood samples were taken to determine the levels of acylated ghrelin, glucose, insulin, total cholesterol (TC), and triglycerides (TG). There was suppression of hunger after consuming the meal in ET and CT (p = 0.028 and p = 0.011, respectively). Hunger increased in CT in the period correspondent to the exercise session (p = 0.017) and remained suppressed in the ET. The area under the curve for acylated ghrelin showed that its levels were lower in the ET compared with CT in the period of the exercise plus the immediate period (1 h) postexercise (60.7 vs. 96.75 pg·mL(-1)·2 h(-1), respectively; p = 0.04). Inverse correlations between acylated ghrelin levels and insulin, TC, and TG levels at different time points were observed. In conclusion, these findings suggest that 1 bout of aerobic exercise maintains the meal-induced suppression of hunger. The mechanism underlying this effect may involve the exercise-induced suppression of acylated ghrelin. These results implicate that the combination of a high-CHO meal and aerobic exercise may effectively improve appetite control and body weight management.

  9. Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males.

    PubMed

    Broom, David R; Batterham, Rachel L; King, James A; Stensel, David J

    2009-01-01

    Resistance (muscle strengthening) exercise is a key component of exercise recommendations for weight control, yet very little is known about the effects of resistance exercise on appetite. We investigated the effects of resistance and aerobic exercise on hunger and circulating levels of the gut hormones acylated ghrelin and peptide YY (PYY). Eleven healthy male students: age 21.1 +/- 0.3 yr, body mass index 23.1 +/- 0.4 kg/m(2), maximum oxygen uptake 62.1 +/- 1.8 ml.kg(-1).min(-1) (means +/- SE) undertook three, 8-h trials, 1) resistance exercise: a 90-min free weight lifting session followed by a 6.5-h rest period, 2) aerobic exercise: a 60-min run followed by a 7-h rest period, 3) control: an 8-h rest, in a randomized crossover design. Meals were provided 2 and 5 h into each trial. Hunger ratings and plasma concentrations of acylated ghrelin and PYY were measured throughout. Two-way ANOVA revealed significant (P < 0.05) interaction effects for hunger, acylated ghrelin, and PYY, indicating suppressed hunger and acylated ghrelin during aerobic and resistance exercise and increased PYY during aerobic exercise. A significant trial effect was observed for PYY, indicating higher concentrations on the aerobic exercise trial than the other trials (8 h area under the curve: control 1,411 +/- 110, resistance 1,381 +/- 97, aerobic 1,750 +/- 170 pg/ml 8 h). These findings suggest ghrelin and PYY may regulate appetite during and after exercise, but further research is required to establish whether exercise-induced changes in ghrelin and PYY influence subsequent food intake.

  10. Administration of exogenous acylated ghrelin or rikkunshito, an endogenous ghrelin enhancer, improves the decrease in postprandial gastric motility in an acute restraint stress mouse model

    PubMed Central

    Nahata, M; Saegusa, Y; Sadakane, C; Yamada, C; Nakagawa, K; Okubo, N; Ohnishi, S; Hattori, T; Sakamoto, N; Takeda, H

    2014-01-01

    Background Physical or psychological stress causes functional disorders in the upper gastrointestinal tract. This study aims to elucidate the ameliorating effect of exogenous acylated ghrelin or rikkunshito, a Kampo medicine which acts as a ghrelin enhancer, on gastric dysfunction during acute restraint stress in mice. Methods Fasted and postprandial motor function of the gastric antrum was wirelessly measured using a strain gauge force transducer and solid gastric emptying was detected in mice exposed to restraint stress. Plasma corticosterone and ghrelin levels were also measured. To clarify the role of ghrelin on gastrointestinal dysfunction in mice exposed to stress, exogenous acylated ghrelin or rikkunshito was administered, then the mice were subjected to restraint stress. Key Results Mice exposed to restraint stress for 60 min exhibited delayed gastric emptying and increased plasma corticosterone levels. Gastric motility was decreased in mice exposed to restraint stress in both fasting and postprandial states. Restraint stress did not cause any change in plasma acylated ghrelin levels, but it significantly increased the plasma des-acyl ghrelin levels. Administration of acylated ghrelin or rikkunshito improved the restraint stress-induced delayed gastric emptying and decreased antral motility. Ameliorating effects of rikkunshito on stress-induced gastric dysfunction were abolished by simultaneous administration of a ghrelin receptor antagonist. Conclusions & Inferences Plasma acylated/des-acyl ghrelin imbalance was observed in acute restraint stress. Supplementation of exogenous acylated ghrelin or enhancement of endogenous ghrelin signaling may be useful in the treatment of decreased gastric function caused by stress. PMID:24684160

  11. Ghrelin levels in chronic periodontitis patients.

    PubMed

    Yılmaz, Gülin; Kırzıoğlu, Fatma Yeşim; Doğuç, Duygu Kumbul; Koçak, Havva; Orhan, Hikmet

    2014-01-01

    Ghrelin is a peptide hormone that has modulatory effects on the immune system. This study was designed to evaluate plasma ghrelin levels in patients with chronic periodontitis and to investigate if a relationship exists between ghrelin and periodontal parameters, serum cytokines, and bone turnover markers. Thirty-five chronic periodontitis patients (CP) and periodontal healthy individuals (C) were included in this study. Periodontal parameters were recorded. Blood samples were obtained to determine the levels of total and acylated ghrelin, interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), the soluble receptor activator nuclear factor kappaB ligand (sRANKL), alkaline phosphatase (ALP), and osteocalcin (OSC). Plasma levels of total and acylated ghrelin were significantly elevated in the CP group compared with the C group (p < 0.05). The difference was significant only between males in the two groups (groups were compared with respect to gender) (p < 0.05). There was no difference between the groups regarding the levels of serum sRANKL, TNF-α, and ALP. A relative increase in the serum levels of IL-1β and a decrease in the serum levels of OSC of the CP group were observed (p < 0.05). In addition, positive correlations between total ghrelin/ALP and total ghrelin/acylated ghrelin were discovered. We found no direct correlation between ghrelin levels and periodontal parameters. Our results indicate an increase of total and acylated ghrelin levels in patients with chronic periodontitis. Further, studies in larger populations (which could include ghrelin levels in gingival tissue, gingival crevicular fluid, and saliva) are needed in order to confirm the role of ghrelin in periodontal disease.

  12. Des-acyl ghrelin prevents heatstroke-like symptoms in rats exposed to high temperature and high humidity.

    PubMed

    Inoue, Yoshiyuki; Hayashi, Yujiro; Kangawa, Kenji; Suzuki, Yoshihiro; Murakami, Noboru; Nakahara, Keiko

    2016-02-26

    We have shown previously that des-acyl ghrelin decreases body temperature in rats through activation of the parasympathetic nervous system. Here we investigated whether des-acyl ghrelin ameliorates heatstroke in rats exposed to high temperature. Peripheral administration of des-acyl ghrelin significantly attenuated hyperthermia induced by exposure to high-temperature (35°C) together with high humidity (70-80%). Although biochemical analysis revealed that exposure to high temperature significantly increased hematocrit and the serum levels of aspartate amino transferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), creatinine and electrolytes (Na(+), K(+), Cl(-)), most of these heatstroke-associated reactions were significantly reduced by treatment with des-acyl ghrelin. The level of des-acyl ghrelin in plasma was also found to be significantly increased under high-temperature conditions. These results suggest that des-acyl ghrelin could be useful for preventing heatstroke under high temperature condition.

  13. Effects of ghrelin and des-acyl ghrelin on neurogenesis of the rat fetal spinal cord

    SciTech Connect

    Sato, Miho; Nakahara, Keiko; Goto, Shintaro; Kaiya, Hiroyuki; Miyazato, Mikiya . E-mail: a0d201u@cc.miyazaki-u.ac.jp; Date, Yukari; Nakazato, Masamitsu; Kangawa, Kenji; Murakami, Noboru

    2006-11-24

    Expressions of the growth hormone secretagogue receptor (GHS-R) mRNA and its protein were confirmed in rat fetal spinal cord tissues by RT-PCR and immunohistochemistry. In vitro, over 3 nM ghrelin and des-acyl ghrelin induced significant proliferation of primary cultured cells from the fetal spinal cord. The proliferating cells were then double-stained using antibodies against the neuronal precursor marker, nestin, and the cell proliferation marker, 5-bromo-2'-deoxyuridine (BrdU), and the nestin-positive cells were also found to be co-stained with antibody against GHS-R. Furthermore, binding studies using [{sup 125}I]des-acyl ghrelin indicated the presence of a specific binding site for des-acyl ghrelin, and confirmed that the binding was displaced with unlabeled des-acyl ghrelin or ghrelin. These results indicate that ghrelin and des-acyl ghrelin induce proliferation of neuronal precursor cells that is both dependent and independent of GHS-R, suggesting that both ghrelin and des-acyl ghrelin are involved in neurogenesis of the fetal spinal cord.

  14. Ghrelin, des-acyl ghrelin and obestatin on the gastrointestinal motility.

    PubMed

    Fujimiya, Mineko; Ataka, Koji; Asakawa, Akihiro; Chen, Chih-Yen; Kato, Ikuo; Inui, Akio

    2011-11-01

    Ghrelin, des-acyl ghrelin and obestatin are derived from a common prohormone, preproghrelin by posttranslational processing, originating from endocrine cells in the stomach. Ghrelin exerts stimulatory effects on the motility of antrum and duodenum in both fed and fasted state of animals. On the other hand, des-acyl ghrelin exerts inhibitory effects on the motility of antrum but not on the motility of duodenum in the fasted state of animals. Obestatin exerts inhibitory effects on the motility of antrum and duodenum in the fed state but not in the fasted state of animals. NPY Y2 and Y4 receptors in the brain may mediate the action of ghrelin, CRF type 2 receptor in the brain may mediate the action of des-acyl ghrelin, whereas CRF type 1 and type 2 receptors in the brain may mediate the action of obestatin.

  15. Acylation type determines ghrelin's effects on energy homeostasis in rodents.

    PubMed

    Heppner, Kristy M; Chaudhary, Nilika; Müller, Timo D; Kirchner, Henriette; Habegger, Kirk M; Ottaway, Nickki; Smiley, David L; Dimarchi, Richard; Hofmann, Susanna M; Woods, Stephen C; Sivertsen, Bjørn; Holst, Birgitte; Pfluger, Paul T; Perez-Tilve, Diego; Tschöp, Matthias H

    2012-10-01

    Ghrelin is a gastrointestinal polypeptide that acts through the ghrelin receptor (GHSR) to promote food intake and increase adiposity. Activation of GHSR requires the presence of a fatty-acid (FA) side chain on amino acid residue serine 3 of the ghrelin molecule. However, little is known about the role that the type of FA used for acylation plays in the biological action of ghrelin. We therefore evaluated a series of differentially acylated peptides to determine whether alterations in length or stability of the FA side chain have an impact on the ability of ghrelin to activate GHSR in vitro or to differentially alter food intake, body weight, and body composition in vivo. Fatty acids principally available in the diet (such as palmitate C16) and therefore representing potential substrates for the ghrelin-activating enzyme ghrelin O-acyltransferase (GOAT) were used for dose-, time-, and administration/route-dependent effects of ghrelin on food intake, body weight, and body composition in rats and mice. Our data demonstrate that altering the length of the FA side chain of ghrelin results in the differential activation of GHSR. Additionally, we found that acylation of ghrelin with a long-chain FA (C16) delays the acute central stimulation of food intake. Lastly, we found that, depending on acylation length, systemic and central chronic actions of ghrelin on adiposity can be enhanced or reduced. Together our data suggest that modification of the FA side-chain length can be a novel approach to modulate the efficacy of pharmacologically administered ghrelin.

  16. The Effects of Exercise on Food Intake and Hunger: Relationship with Acylated Ghrelin and Leptin

    PubMed Central

    Vatansever-Ozen, Serife; Tiryaki-Sonmez, Gul; Bugdayci, Guler; Ozen, Guclu

    2011-01-01

    This study investigated the effects of a long bout of aerobic exercise on hunger and energy intake and circulating levels of leptin and acylated ghrelin. Ten healthy male subjects undertook two, 4 h trials in a randomized crossover design. In the exercise trial subjects ran for 105 min at 50% of maximal oxygen uptake and the last 15 min at 70% of maximal oxygen uptake followed by a 120 min rest period. In the control trial, subjects rested for 4 h. Subjects consumed a buffet test meal at 180 min during each trial. Hunger ratings, acylated ghrelin, leptin, glucose and insulin concentrations were measured at 0, 1, 2, 3 and 4 h. No differences were found at baseline values for hunger, acylated ghrelin, leptin, insulin and glucose for both trials (p > 0.05). The estimated energy expenditure of the exercise trial was 1550 ± 136 kcal. Exercise did not change subsequent absolute energy intake, but produced a significant decrease (p < 0.05) in relative energy intake. A two-way ANOVA revealed a significant (p < 0. 05) interaction effect for hunger and acylated ghrelin. In conclusion, this exercise regimen had a positive effect on reducing appetite which is related to reduced acylated ghrelin responses over time. This finding lends support for a role of exercise in weight management. Key points Physical exercise is a strategy used to counteract obesity, since it lowers the energetic balance by increasing energy expenditure. However, because any energy expended in exercise elevates the intensity of hunger and drives food consumption, it is pertinent to ask how effective exercise could be in helping people to lose weight or to prevent weight gain. The effects of exercise on hunger sensations and food intake are fairly controversial and depend on the intensity and duration of exercise. 120 min prolonged treadmill exercise with mix intensity, temporarily decreased hunger sensations, acylated ghrelin and relative energy intake. Variations in exercise intensity should

  17. Assessment of serum and urine ghrelin levels in patients with acute stroke

    PubMed Central

    Seyhanli, Eyyup Sabri; Lok, Ugur; Gulacti, Umut; Buyukaslan, Hasan; Atescelik, Metin; Yildiz, Mustafa; Onur, Mehmet Ruhi; Goktekin, Mehmet Cagri; Aydın, Suleyman

    2015-01-01

    Introduction: Ghrelin is a novel brain-gut peptide hormone consisted of 28 amino-acid. In the plasma, it exists in two major molecular forms, acylated and des-acyled ghrelin, filtered in glomeruli or secreted by nephrons. Primary biological effects of hormones are regulating appetite, foods intake and energy metabolism. We investigated the changing and relationships between serum and urine ghrelin levels in acute stroke patients to provide more information whether diagnostic parameter. Methods: Thirty acute stroke patients and thirty consecutive volunteers included in study prospectively. To analyze serum and urine ghrelin levels, at the time of diagnose, all of participant blood and fresh urine (1 ml serum, 2 ml urine respectively) samples were obtained. Serum ghrelin levels analyzed ELISA technique, and urine ghrelin levels studied by validation technique. To compare quantitative data student’s t test, and for qualitative data chi-square and Fisher’s Exact Chi-square test was used. P<0.05 was considered statistically significant. Results: Urine acyl ghrelin levels found statistically significant between patient and control groups (P=0.001), but there were no statistically significant differences between both groups (P>0.05) in serum acyl gherelin, des-acyl ghrelin and urine des-acyle ghrelin levels. Conclusions: The results indicate that urine acyl ghrelin levels may be considered as a diagnostic parameter in acute ischemic stroke patients. Further studies delineating the mechanism of these observed results are warranted. PMID:25785049

  18. Elevated circulating acylated and total ghrelin concentrations along with reduced appetite scores in infants with failure to thrive.

    PubMed

    Tannenbaum, Gloria Shaffer; Ramsay, Maria; Martel, Chantal; Samia, Marwan; Zygmuntowicz, Catherine; Porporino, Mafalda; Ghosh, Shuvo

    2009-05-01

    Failure to thrive (FTT) is a term used to describe inadequate growth in infants. The immediate cause is undernutrition. Ghrelin is a potent orexigenic hormone that induces a positive energy balance and enhances appetite. There is no information regarding the possible role of ghrelin in infants with FTT. The aim of this study was 2-fold: 1) to examine circulating ghrelin levels in FTT infants, compared with those of normally growing infants; and 2) to evaluate appetitive behaviors in the two groups. Plasma acylated and total ghrelin concentrations were measured in nine FTT and five normally growing infants (age range, 9-18 mo). Appetite was assessed using three novel appetite measures. Both acylated and total ghrelin levels were significantly elevated in FTT infants compared with controls (p = 0.03 or less). Infants with FTT scored significantly lower than control infants on all appetite measures (p = 0.002 or less). Ghrelin levels were inversely related to appetite, weight velocity, weight/length z-scores, and weight z-score. These findings provide the first evidence that infants with FTT have higher circulating ghrelin concentrations but paradoxically lower appetite scores. Increased ghrelin secretion may reflect an adaptive mechanism attempting to increase appetite and preserve energy balance in response to poor nutritional state.

  19. Changes in acyl and total ghrelin concentrations and their association with dry matter intake, average daily gain, and feed efficiency of finishing beef steers and heifers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is a peptide hormone produced in the gut that is implicated in signaling appetite and regulating DMI. The objective of this experiment was to determine the change in acyl ghrelin, total ghrelin, and the ghrelin ratio (acyl ghrelin/total ghrelin) over an 84-d DMI and ADG measurement period a...

  20. Meal anticipatory rise in acylated ghrelin at dark onset is blunted after long-term fasting in rats.

    PubMed

    Zizzari, P; Hassouna, R; Longchamps, R; Epelbaum, J; Tolle, V

    2011-09-01

    Ghrelin is a 28 amino acid acylated peptide originally characterised for its capacity to stimulate growth hormone secretion. Ghrelin is also an orexigenic and adipogenic hormone and is thought to be a signal to increase locomotor activity in anticipation of a scheduled meal. Although ghrelin is considered to be up-regulated during fasting, there are still conflicting data regarding the impact of starvation on ghrelin secretion. To test whether the secretory pattern of acylated ghrelin is altered during fasting, plasma levels were monitored every 20 min for 6 h in freely-behaving rats at the light/dark cycle transition, when animals initiate feeding and activity and use preferentially free fatty acids (FFA) as a source of energy. Rats were fed ad lib. or fasted at dark onset for 24, 48 or 72 h, with or without refeeding rate. The anticipatory rise in ghrelin levels, as well as home-cage activity at the onset of darkness, was significantly reduced from 48 h of fasting compared to ad lib. conditions. A delayed ghrelin peak, sensitive to renutrition, was observed in fasted animals. Although their motivation to eat appeared to be intact, rats fasted for 72 h showed the smallest compensatory refeeding rate after fasting, possibly reflecting altered gut function. Expression of agouti-related protein and neuropeptide Y, was significantly increased in 48- and 72-h fasted animals. Thus, following fasting, a blunted acylated ghrelin secretion at dark onset (i.e. a period when animals depend on FFA as a source of energy) is associated with reduced locomotor activity and refeeding and an up-regulation of anabolic neuropeptides. Such changes could be interpreted as compensatory mechanisms for helping to conserve energy under conditions where food is not available.

  1. d-Lys-GHRP-6 does not modify the endocrine response to acylated ghrelin or hexarelin in humans.

    PubMed

    Benso, A; Prodam, F; Lucatello, B; Gramaglia, E; Riganti, F; Schneider, H; van der Lely, A J; Muccioli, G; Ghigo, E; Broglio, F

    2007-02-01

    Acylated ghrelin exerts numerous endocrine and non-endocrine activities via the GH Secretagogue receptor type 1a (GHS-R1a). D-Lys-GHRP-6 has been widely studied in vitro and in vivo in animal studies as GHS-R1a antagonist; its action in humans has, however, never been tested so far. Aim of our study was to verify the antagonistic action of D-Lys-GHRP-6 on the endocrine responses to acylated ghrelin and hexarelin, a peptidyl synthetic GHS, in humans. The effects of different doses of D-Lys-GHRP-6 (2.0microg/kg iv as bolus or 2.0microg/kg/h iv as infusion) on both spontaneous and acylated ghrelin- or hexarelin (1.0microg/kg iv as bolus) -stimulated GH, PRL, ACTH and cortisol levels were studied in six normal volunteers (age [mean+/-SEM]: 25.4+/-1.2yr; BMI: 22.3+/-1.0kg/m(2)). The effects of D-Lys-GHRP-6 (2.0microg/kg iv as bolus+4.0microg/kg/h iv) on the GH response to 0.25microg/kg iv as bolus acylated ghrelin was also studied. During saline, spontaneous ACTH and cortisol decrease was observed while non changes occurred in GH and PRL levels. Acylated ghrelin and hexarelin stimulated (p<0.05) GH, PRL, ACTH and cortisol secretions. D-Lys-GHRP-6 administered either as bolus or a continuous infusion did not modify both spontaneous and acylated ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. D-Lys-GHRP-6 did not modify even the GH response to 0.25microg/kg iv acylated ghrelin. In conclusion, D-Lys-GHRP-6 does not affect the neuroendocrine response to both ghrelin and hexarelin. These findings question D-Lys-GHRP-6 as an effective GHS-R1a antagonist for human studies.

  2. Acylated and desacyl ghrelin are associated with hepatic lipogenesis, β-oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats

    PubMed Central

    Ezquerro, Silvia; Méndez-Giménez, Leire; Becerril, Sara; Moncada, Rafael; Valentí, Víctor; Catalán, Victoria; Gómez-Ambrosi, Javier; Frühbeck, Gema; Rodríguez, Amaia

    2016-01-01

    Bariatric surgery improves non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the potential role of ghrelin isoforms in the resolution of hepatic steatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure, in diet-induced obese rats. Male Wistar rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal (ND) or a high-fat (HFD) diet or pair-fed]. Obese rats developed hepatosteatosis and showed decreased circulating desacyl ghrelin without changes in acylated ghrelin. Sleeve gastrectomy induced a dramatic decrease of desacyl ghrelin, but increased the acylated/desacyl ghrelin ratio. Moreover, sleeve gastrectomy reduced hepatic triglyceride content and lipogenic enzymes Mogat2 and Dgat1, increased mitochondrial DNA amount and induced AMPK-activated mitochondrial FFA β-oxidation and autophagy to a higher extent than caloric restriction. In primary rat hepatocytes, the incubation with both acylated and desacyl ghrelin (10, 100 and 1,000 pmol/L) significantly increased TG content, triggered AMPK-activated mitochondrial FFA β-oxidation and autophagy. Our data suggest that the decrease in the most abundant isoform, desacyl ghrelin, after sleeve gastrectomy contributes to the reduction of lipogenesis, whereas the increased relative acylated ghrelin levels activate factors involved in mitochondrial FFA β-oxidation and autophagy in obese rats, thereby ameliorating NAFLD. PMID:28008992

  3. Acylated and desacyl ghrelin are associated with hepatic lipogenesis, β-oxidation and autophagy: role in NAFLD amelioration after sleeve gastrectomy in obese rats.

    PubMed

    Ezquerro, Silvia; Méndez-Giménez, Leire; Becerril, Sara; Moncada, Rafael; Valentí, Víctor; Catalán, Victoria; Gómez-Ambrosi, Javier; Frühbeck, Gema; Rodríguez, Amaia

    2016-12-23

    Bariatric surgery improves non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the potential role of ghrelin isoforms in the resolution of hepatic steatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure, in diet-induced obese rats. Male Wistar rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal (ND) or a high-fat (HFD) diet or pair-fed]. Obese rats developed hepatosteatosis and showed decreased circulating desacyl ghrelin without changes in acylated ghrelin. Sleeve gastrectomy induced a dramatic decrease of desacyl ghrelin, but increased the acylated/desacyl ghrelin ratio. Moreover, sleeve gastrectomy reduced hepatic triglyceride content and lipogenic enzymes Mogat2 and Dgat1, increased mitochondrial DNA amount and induced AMPK-activated mitochondrial FFA β-oxidation and autophagy to a higher extent than caloric restriction. In primary rat hepatocytes, the incubation with both acylated and desacyl ghrelin (10, 100 and 1,000 pmol/L) significantly increased TG content, triggered AMPK-activated mitochondrial FFA β-oxidation and autophagy. Our data suggest that the decrease in the most abundant isoform, desacyl ghrelin, after sleeve gastrectomy contributes to the reduction of lipogenesis, whereas the increased relative acylated ghrelin levels activate factors involved in mitochondrial FFA β-oxidation and autophagy in obese rats, thereby ameliorating NAFLD.

  4. Ghrelin O-Acyl Transferase in Zebrafish Is an Evolutionarily Conserved Peptide Upregulated During Calorie Restriction

    PubMed Central

    Hatef, Azadeh; Yufa, Roman

    2015-01-01

    Abstract Ghrelin is a multifunctional orexigenic hormone with a unique acyl modification enabled by ghrelin O-acyl transferase (GOAT). Ghrelin is well-characterized in nonmammals, and GOAT sequences of several fishes are available in the GenBank. However, endogenous GOAT in non-mammals remains poorly understood. In this research, GOAT sequence comparison, tissue-specific GOAT expression, and its regulation by nutrient status and exogenous ghrelin were studied. It was found that the bioactive core of zebrafish GOAT amino acid sequence share high identity with that of mammals. GOAT mRNA was most abundant in the gut. GOAT-like immunoreactivity (i.r.) was found colocalized with ghrelin in the gastric mucosa. Food deprivation increased, and feeding decreased GOAT and preproghrelin mRNA expression in the brain and gut. GOAT and ghrelin peptides in the gut and brain showed corresponding decrease in food-deprived state. Intraperitoneal injection of acylated fish ghrelin caused a significant decrease in GOAT mRNA expression, suggesting a feedback mechanism regulating its abundance. Together, these results provide the first in-depth characterization of GOAT in a non-mammal. Our results demonstrate that endogenous GOAT expression is responsive to metabolic status and availability of acylated ghrelin, providing further evidences for GOAT in the regulation of feeding in teleosts. PMID:26226634

  5. Differential effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circulating acyl-ghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans.

    PubMed

    Yousseif, Ahmed; Emmanuel, Julian; Karra, Efthimia; Millet, Queensta; Elkalaawy, Mohamed; Jenkinson, Andrew D; Hashemi, Majid; Adamo, Marco; Finer, Nicholas; Fiennes, Alberic G; Withers, Dominic J; Batterham, Rachel L

    2014-02-01

    Laparoscopic Roux-en-Y gastric bypass (LRYGBP) reduces appetite and induces significant and sustainable weight loss. Circulating gut hormones changes engendered by LRYGBP are implicated in mediating these beneficial effects. Laparoscopic sleeve gastrectomy (LSG) is advocated as an alternative to LRYGBP, with comparable short-term weight loss and metabolic outcomes. LRYGBP and LSG are anatomically distinct procedures causing differential entero-endocrine cell nutrient exposure and thus potentially different gut hormone changes. Studies reporting the comparative effects of LRYGBP and LSG on appetite and circulating gut hormones are controversial, with no data to date on the effects of LSG on circulating peptide YY3-36 (PYY3-36) levels, the specific PYY anorectic isoform. In this study, we prospectively investigated appetite and gut hormone changes in response to LRYGBP and LSG in adiposity-matched non-diabetic patients. Anthropometric indices, leptin, fasted and nutrient-stimulated acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), PYY3-36 levels and appetite were determined pre-operatively and at 6 and 12 weeks post-operatively in obese, non-diabetic females, with ten undergoing LRYGBP and eight adiposity-matched females undergoing LSG. LRYGBP and LSG comparably reduced adiposity. LSG decreased fasting and post-prandial plasma acyl-ghrelin compared to pre-surgery and to LRYGBP. Nutrient-stimulated PYY3-36 and active GLP-1 concentrations increased post-operatively in both groups. However, LRYGBP induced greater, more sustained PYY3-36 and active GLP-1 increments compared to LSG. LRYGBP suppressed fasting hunger compared to LSG. A similar increase in post-prandial fullness was observed post-surgery following both procedures. LRYGBP and LSG produced comparable enhanced satiety and weight loss. However, LSG and LRYGBP differentially altered gut hormone profiles.

  6. Acyl ghrelin acts in the brain to control liver function and peripheral glucose homeostasis in male mice.

    PubMed

    Stark, Romana; Reichenbach, Alex; Lockie, Sarah H; Pracht, Corinna; Wu, Qunli; Tups, Alexander; Andrews, Zane B

    2015-03-01

    Recent evidence suggests that peripheral ghrelin regulates glucose metabolism. Here, we designed experiments to examine how central acyl ghrelin infusion affects peripheral glucose metabolism under pair-fed or ad libitum feeding conditions. Mice received intracerebroventricular (icv) infusion of artificial cerebrospinal fluid (aCSF), ghrelin, and allowed to eat ad libitum (icv ghrelin ad lib) or ghrelin and pair-fed to the aCSF group (icv ghrelin pf). Minipumps delivered acyl ghrelin at a dose of 0.25 μg/h at 0.5 μL/h for 7 days. There was no difference in daily blood glucose, insulin, glucagon, triglycerides, or nonesterified fatty acids. Body weight gain and food intake was significantly higher in icv ghrelin ad lib mice. However, both icv ghrelin ad lib and icv ghrelin pf groups exhibited heavier white adipose mass. Icv ghrelin pf mice exhibited better glucose tolerance than aCSF or icv ghrelin ad lib mice during a glucose tolerance test, although both icv ghrelin ad lib and icv ghrelin pf increased insulin release during the glucose tolerance test. Central acyl ghrelin infusion and pair feeding also increased breakdown of liver glycogen and triglyceride, and regulated genes involved in hepatic lipid and glucose metabolism. Icv ghrelin pf mice had an increase in plasma blood glucose during a pyruvate tolerance test relative to icv ghrelin ad lib or aCSF mice. Our results suggest that under conditions of negative energy (icv ghrelin pf), central acyl ghrelin engages a neural circuit that influences hepatic glucose function. Metabolic status affects the ability of central acyl ghrelin to regulate peripheral glucose homeostasis.

  7. Carob pulp preparation rich in insoluble dietary fiber and polyphenols enhances lipid oxidation and lowers postprandial acylated ghrelin in humans.

    PubMed

    Gruendel, Sindy; Garcia, Ada L; Otto, Baerbel; Mueller, Corinna; Steiniger, Jochen; Weickert, Martin O; Speth, Maria; Katz, Norbert; Koebnick, Corinna

    2006-06-01

    Ghrelin is an orexigenic hormone that may affect substrate utilization in humans. Ghrelin is influenced by macronutrients, but the effects of insoluble dietary fiber and polyphenols are unknown. We investigated the effects of a polyphenol-rich insoluble dietary fiber preparation from carob pulp (carob fiber) on postprandial ghrelin responses and substrate utilization. Dose-dependent effects of the consumption of carob fiber were investigated in a randomized, single-blind, crossover study in 20 healthy subjects, aged 22-62 y. Plasma total and acylated ghrelin, triglycerides, and serum insulin and nonesterified fatty acids (NEFA) levels were repeatedly assessed before and after ingestion of an isocaloric standardized liquid meal with 0, 5, 10, or 20 g of carob fiber over a 300-min period. The respiratory quotient (RQ) was determined after consumption of 0 or 20 g of carob fiber. Carob fiber intake lowered acylated ghrelin to 49.1%, triglycerides to 97.2%, and NEFA to 67.2% compared with the control meal (P < 0.001). Total ghrelin and insulin concentrations were not affected by consumption of a carob fiber-enriched liquid meal. Postprandial energy expenditure was increased by 42.3% and RQ was reduced by 99.9% after a liquid meal with carob fiber compared with a control meal (P < 0.001). We showed that the consumption of a carob pulp preparation, an insoluble dietary fiber rich in polyphenols, decreases postprandial responses of acylated ghrelin, triglycerides, and NEFA and alters RQ, suggesting a change toward increased fatty acid oxidation. These results indicate that carob fiber might exert beneficial effects in energy intake and body weight.

  8. Genetic manipulation of the ghrelin signaling system in male mice reveals bone compartment specificity of acylated and unacylated ghrelin in the regulation of bone remodeling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin receptor-deficient (Ghsr-/-) mice that lack acylated ghrelin (AG) signaling retain a metabolic response to unacylated ghrelin (UAG). Recently, we showed that Ghsr-deficiency affects bone metabolism. The aim of this study was to further establish the impact of AG and UAG on bone metabolism. W...

  9. Ghrelin and feedback systems.

    PubMed

    Nonogaki, Katsunori

    2008-01-01

    Ghrelin is produced primarily in the stomach in response to hunger, and circulates in the blood. Plasma ghrelin levels increase during fasting and decrease after ingesting glucose and lipid, but not protein. The efferent vagus nerve contributes to the fasting-induced increase in ghrelin secretion. Ghrelin secreted by the stomach stimulates the afferent vagus nerve and promotes food intake. Ghrelin also stimulates pituitary gland secretion of growth hormone (GH) via the afferent vagus nerve. GH inhibits stomach ghrelin secretion. These findings indicate that the vagal circuit between the central nervous system and stomach has a crucial role in regulating plasma ghrelin levels. Moreover, body mass index modulates plasma ghrelin levels. In a lean state and anorexia nervosa, plasma ghrelin levels are increased, whereas in obesity, except in Prader-Willi syndrome, plasma ghrelin levels are decreased and the feeding- and sleeping-induced decline in plasma ghrelin levels is disrupted. There are two forms of ghrelin: active n-octanoyl-modified ghrelin and des-acyl ghrelin. Fasting increases both ghrelin types compared with the fed state. Hyperphagia and obesity are likely to decrease plasma des-acyl ghrelin, but not n-octanoyl-modified ghrelin levels. Hypothalamic serum and glucocorticoid-inducible kinase-1 and serotonin 5-HT2C/1B receptor gene expression levels are likely to be proportional to plasma des-acyl ghrelin levels during fasting, whereas they are likely to be inversely proportional to plasma des-acyl ghrelin levels in an increased energy storage state such as obesity. Thus, a dysfunction of the ghrelin feedback systems might contribute to the pathophysiology of obesity and eating disorders.

  10. Increased acylated plasma ghrelin, but improved lipid profiles 24-h after consumption of carob pulp preparation rich in dietary fibre and polyphenols.

    PubMed

    Gruendel, Sindy; Garcia, Ada L; Otto, Baerbel; Wagner, Karen; Bidlingmaier, Martin; Burget, Lukas; Weickert, Martin O; Dongowski, Gerhard; Speth, Maria; Katz, Norbert; Koebnick, Corinna

    2007-12-01

    We have recently shown that a polyphenol-rich insoluble dietary fibre preparation from carob pulp (Ceratonia siliqua L; carob fibre) decreased postprandial acylated ghrelin, TAG and NEFA during an acute liquid meal challenge test. However, delayed effects of carob fibre consumption are unknown. Therefore, a randomized controlled crossover study in nineteen healthy volunteers consuming foods with or without 50 g carob fibre was conducted. On the subsequent day (day 2), glucose, TAG, total and acylated ghrelin as well as insulin, NEFA and leptin were assessed at baseline and at timed intervals for 300 min after ingestion of standardized bread. Consumption of carob fibre-enriched foods did not affect fasting concentrations of glucose, TAG, total ghrelin, NEFA, insulin and leptin. Fasting acylated ghrelin was increased on the day subsequent to carob fibre consumption compared with control (P = 0.046). After consumption of the standard bread on day 2, glucose response (P = 0.029) was increased, and TAG (P = 0.033) and NEFA (P < 0.001) responses were decreased compared with control. Postprandial responses of total and acylated ghrelin, insulin and leptin on day 2 were unaffected by carob fibre consumption the previous day. In conclusion, an increase in total and acylated plasma ghrelin accompanied by enhanced lipid metabolism after carob fibre consumption suggests higher lipid utilization and suppressed lipolysis on the day subsequent to carob fibre consumption. However, elevated glucose levels after carob fibre consumption need to be addressed in future studies.

  11. Dietary Caprylic Acid (C8:0) Does Not Increase Plasma Acylated Ghrelin but Decreases Plasma Unacylated Ghrelin in the Rat

    PubMed Central

    Lemarié, Fanny; Beauchamp, Erwan; Dayot, Stéphanie; Duby, Cécile; Legrand, Philippe; Rioux, Vincent

    2015-01-01

    Focusing on the caprylic acid (C8:0), this study aimed at investigating the discrepancy between the formerly described beneficial effects of dietary medium chain fatty acids on body weight loss and the C8:0 newly reported effect on food intake via ghrelin octanoylation. During 6 weeks, Sprague-Dawley male rats were fed with three dietary C8:0 levels (0, 8 and 21% of fatty acids) in three experimental conditions (moderate fat, caloric restriction and high fat). A specific dose-response enrichment of the stomach tissue C8:0 was observed as a function of dietary C8:0, supporting the hypothesis of an early preduodenal hydrolysis of medium chain triglycerides and a direct absorption at the gastric level. However, the octanoylated ghrelin concentration in the plasma was unchanged in spite of the increased C8:0 availability. A reproducible decrease in the plasma concentration of unacylated ghrelin was observed, which was consistent with a decrease in the stomach preproghrelin mRNA and stomach ghrelin expression. The concomitant decrease of the plasma unacylated ghrelin and the stability of its acylated form resulted in a significant increase in the acylated/total ghrelin ratio which had no effect on body weight gain or total dietary consumption. This enhanced ratio measured in rats consuming C8:0 was however suspected to increase (i) growth hormone (GH) secretion as an increase in the GH-dependent mRNA expression of the insulin like growth Factor 1 (IGF-1) was measured (ii) adipocyte diameters in subcutaneous adipose tissue without an increase in the fat pad mass. Altogether, these results show that daily feeding with diets containing C8:0 increased the C8:0 level in the stomach more than all the other tissues, affecting the acylated/total ghrelin plasma ratio by decreasing the concentration of circulating unacylated ghrelin. However, these modifications were not associated with increased body weight or food consumption. PMID:26196391

  12. Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: evidence for target cell-induced acylation

    PubMed Central

    Hopkins, Anna L.; Nelson, Timothy A. S.; Guschina, Irina A.; Parsons, Lydia C.; Lewis, Charlotte L.; Brown, Richard C.; Christian, Helen C.; Davies, Jeffrey S.; Wells, Timothy

    2017-01-01

    Despite being unable to activate the cognate ghrelin receptor (GHS-R), unacylated ghrelin (UAG) possesses a unique activity spectrum that includes promoting bone marrow adipogenesis. Since a receptor mediating this action has not been identified, we re-appraised the potential interaction of UAG with GHS-R in the regulation of bone marrow adiposity. Surprisingly, the adipogenic effects of intra-bone marrow (ibm)-infused acylated ghrelin (AG) and UAG were abolished in male GHS-R-null mice. Gas chromatography showed that isolated tibial marrow adipocytes contain the medium-chain fatty acids utilised in the acylation of UAG, including octanoic acid. Additionally, immunohistochemistry and immunogold electron microscopy revealed that tibial marrow adipocytes show prominent expression of the UAG-activating enzyme ghrelin O-acyl transferase (GOAT), which is located in the membranes of lipid trafficking vesicles and in the plasma membrane. Finally, the adipogenic effect of ibm-infused UAG was completely abolished in GOAT-KO mice. Thus, the adipogenic action of exogenous UAG in tibial marrow is dependent upon acylation by GOAT and activation of GHS-R. This suggests that UAG is subject to target cell-mediated activation – a novel mechanism for manipulating hormone activity. PMID:28361877

  13. Ghrelin plasmatic levels in patients with fibromyalgia.

    PubMed

    Otero, Miguel; Nogueiras, Ruben; Lago, Francisca; Meijide, Juan; Amarelo, Juan; Mera, Antonio; Gomez-Reino, Juan; Gualillo, Oreste

    2005-01-01

    Ghrelin is a recently discovered 28 amino acid peptide that regulates GH secretion and energy homeostasis. In fibromyalgia (FM) there are alterations in the pituitary-hypothalamic axis, particularly in the growth hormone (GH) secretion pattern. Whether this anomalous secretion of GH pertains to abnormal levels of ghrelin is still unknown. The purpose of this study was to investigate plasma ghrelin levels in patients with fibromyalgia (FM) compared with healthy controls. Plasmatic ghrelin concentrations were determined by a double antibody radioimmunoassay in 19 patients with FM and 14 healthy controls. Compared with controls, patients with FM did not show any significant differences of ghrelin plasmatic levels. In conclusion, FM is not associated with deviation in ghrelin concentrations. Existing alterations in FM with respect to GH are unlikely due to circulating ghrelin.

  14. Acylated ghrelin as provocative test for the diagnosis of ACTH deficiency in patients with hypothalamus-pituitary disease.

    PubMed

    Gasco, Valentina; Berton, Alessandro; Caprino, Mirko Parasiliti; Karamouzis, Ioannis; Maccario, Mauro; Ghigo, Ezio; Grottoli, Silvia

    2015-11-01

    The insulin tolerance test (ITT) is the gold standard to evaluate adrenocorticotropic hormone (ACTH) insufficiency. However, alternative tests have been proposed such as metyrapone, glucagon, and ACTH stimulation test. We determined the diagnostic reliability of testing with ghrelin, the natural GH secretagogue that is a potent stimulus exploring the integrity of hypothalamic-pituitary-adrenal axis. We studied the ACTH and cortisol response to acylated ghrelin in 49 patients with history of pituitary disease. The best cortisol and ACTH cut offs to ghrelin test, defined as those with the best sensitivity (SE) and specificity (SP), were identified using the ROC analysis. We also compared accuracy of ghrelin test with that of a simple and cheap test like basal cortisol and ACTH levels. The best cortisol and ACTH cut offs to ghrelin test were ≤11.6 µg/dl (SE 86.4%, SP 77.8%) and ≤32.5 pg/ml (SE 72.7%, SP 51.9%), respectively; the best basal cortisol and ACTH cut offs were ≤10.7 µg/dl (SE 90.9%, SP 70.4%) and ≤25.0 pg/ml (SE 85%, SP 37%), respectively. The diagnostic accuracy was 81.6, 60.9, 79.6, and 57.4%, respectively. A comparison between ROC AUC showed a great diagnostic power for cortisol, both stimulated and basal, versus ACTH, both stimulated and basal, but no difference between stimulated and basal cortisol evaluation. Our data show that testing with acylated ghrelin is not a useful diagnostic tool for the diagnosis of central hypocortisolism; particularly ghrelin test adds no more information that basal cortisol evaluation in the diagnosis of ACTH deficiency in patients with hypothalamus-pituitary disease.

  15. Characterization of pericardial and plasma ghrelin levels in patients with ischemic and non-ischemic heart disease.

    PubMed

    Sax, Balazs; Merkely, Béla; Túri, Katalin; Nagy, Andrea; Ahres, Abdelkrim; Hartyánszky, István; Hüttl, Tivadar; Szabolcs, Zoltán; Cseh, Károly; Kékesi, Violetta

    2013-09-10

    Ghrelin is an endocrine regulatory peptide with multiple functions including cardioprotective effects. It is produced in various tissues among others in the myocardium. Pericardial fluid has been proven to be a biologically active compartment of the heart that communicates with the myocardial interstitium. Thus, pericardial level of certain agents may reflect their concentration in the myocardium well. In our study we measured acylated (active) and total (acylated and non-acylated) pericardial and plasma ghrelin levels of patients with ischemic and non-ischemic heart disease. Pericardial fluid and plasma samples were obtained from patients with coronary artery disease (ISCH, n=54) or valvular heart disease (VHD, n=41) undergoing cardiac surgery. Acylated pericardial ghrelin concentrations were found to be significantly higher in patients with ischemic heart disease (ISCH vs. VHD, 32±3 vs. 16±2pg/ml, p<0.01), whereas plasma levels of the peptide showed no difference between patient groups. Pericardial-to-plasma ratio, an index abolishing systemic effects on local ghrelin level was also significantly higher in ISCH group for both acylated and total ghrelin. Plasma total ghrelin showed negative correlation to BMI, plasma insulin and insulin resistance index HOMA-A. Pericardial acylated and total ghrelin concentrations were negatively correlated with posterior wall thickness (R=-0.31, p<0.05 and R=-0.35, p<0.01, respectively). Plasma insulin concentration and HOMA-A showed significant negative correlation with pericardial ghrelin levels. In conclusion, increased pericardial active ghrelin content and higher pericardial-to-plasma ghrelin ratio were found in ischemic heart disease as compared to non-ischemic patients suggesting an increased ghrelin production of the chronically ischemic myocardium. According to our results, pericardial ghrelin content is negatively influenced by left ventricular hypertrophy and insulin resistance.

  16. Evaluation of ghrelin level and appetite regulation in patients with acute exacerbations of chronic obstructive pulmonary disease

    PubMed Central

    Wang, Ye; Shen, Yongchun; Zuo, Qiunan; Zhao, Li; Wan, Chun; Tian, Panwen; Chen, Lei; Wen, Fuqiang

    2014-01-01

    Background Appetite reduction is a major cause of cachexia in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). This study tested the correlation of appetite and circulating levels of acylated ghrelin in patients with AECOPD. Methods Thirty-six patients with AECOPD and 23 healthy adults were enrolled in this study. Circulating total ghrelin, acylated ghrelin, and obestatin levels, Simplified Nutritional Appetite Questionnaire (SNAQ) score, and caloric intake were compared in patients and healthy controls. Additionally, the above parameters were compared between admission and discharge in the patients with AECOPD. Results Compared with healthy controls, SNAQ scores and caloric intake were significantly lower in patients with AECOPD, but there were no significant differences in total ghrelin, acyl ghrelin, or obestatin levels. In patients with AECOPD, the total ghrelin level was significantly higher at admission than on discharge, the SNAQ score and caloric intake were significantly increased at discharge when compared with admission, and there was no significant difference in acylated ghrelin level between admission and discharge. Conclusion We demonstrated lower appetite scores and caloric intake in patients with AECOPD, but could not confirm that these effects were caused by insufficient levels of the orexigenic peptide, acyl ghrelin. Further studies are needed to confirm our findings and to determine the mechanism regulating appetite in patients with AECOPD. PMID:25152618

  17. Acute aerobic exercise differentially alters acylated ghrelin and perceived fullness in normal-weight and obese individuals.

    PubMed

    Heden, Timothy D; Liu, Ying; Park, Youngmin; Dellsperger, Kevin C; Kanaley, Jill A

    2013-09-01

    Adiposity alters acylated ghrelin concentrations, but it is unknown whether adiposity alters the effect of exercise and feeding on acylated ghrelin responses. Therefore, the purpose of this study was to determine whether adiposity [normal-weight (NW) vs. obese (Ob)] influences the effect of exercise and feeding on acylated ghrelin, hunger, and fullness. Fourteen NW and 14 Ob individuals completed two trials in a randomized counterbalanced fashion, including a prior exercise trial (EX) and a no exercise trial (NoEX). During the EX trial, the participants performed 1 h of treadmill walking (55-60% peak O2 uptake) during the evening, 12 h before a 4-h standardized mixed meal test. Frequent blood samples were taken and analyzed for acylated ghrelin, and a visual analog scale was used to assess perceived hunger and fullness. In NW individuals, EX, compared with NoEX, reduced fasting acylated ghrelin concentrations by 18% (P = 0.03), and, in response to feeding, the change in acylated ghrelin (P = 0.02) was attenuated by 39%, but perceived hunger and fullness were unaltered. In Ob individuals, despite no changes in fasting or postprandial acylated ghrelin concentrations with EX, postprandial fullness was attenuated by 46% compared with NoEX (P = 0.05). In summary, exercise performed the night before a meal suppresses acylated ghrelin concentrations in NW individuals without altering perceived hunger or fullness. In Ob individuals, despite no changes in acylated ghrelin concentrations, EX reduced the fullness response to the test meal. Acylated ghrelin and perceived fullness responses are differently altered by acute aerobic exercise in NW and Ob individuals.

  18. Transitional change in rat fetal cell proliferation in response to ghrelin and des-acyl ghrelin during the last stage of pregnancy

    SciTech Connect

    Inoue, Yoshiyuki; Nakahara, Keiko; Kangawa, Kenji; Murakami, Noboru

    2010-03-12

    Expression of mRNA for the ghrelin receptor, GHS-R1a, was detected in various peripheral and central tissues of fetal rats, including skin, bone, heart, liver, gut, brain and spinal cord, on embryonic day (ED)15 and ED17. However, its expression in skin, bone, heart and liver, but not in gut, brain and spinal cord, became relatively weak on ED19 and disappeared after birth (ND2). Ghrelin and des-acyl ghrelin facilitated the proliferation of cultured fetal (ED17, 19), but not neonatal (ND2), skin cells. On the other hand, with regard to cells from the spinal cord and hypothalamus, the proliferative effect of ghrelin continued after birth, whereas the effect of des-acyl ghrelin on neurogenesis in these tissues was lost at the ED19 fetal and ND2 neonatal stages. Immunohistochemistry revealed that the cells in the hypothalamus induced to proliferate by ghrelin at the ND2 stage were positive for nestin and glial fibrillary acidic protein. These results suggest that in the period immediately prior to, and after birth, rat fetal cells showing proliferation in response to ghrelin and des-acyl ghrelin are at a transitional stage characterized by alteration of the expression of GHS-R1a and an undefined des-acyl ghrelin receptor, their responsiveness varying among different tissues.

  19. Plasma acylated and plasma unacylated ghrelin: useful new biomarkers in patients with neuroendocrine tumors?

    PubMed Central

    van Adrichem, Roxanne C S; van der Lely, Aart Jan; Huisman, Martin; Kramer, Piet; Feelders, Richard A; Delhanty, Patric J D

    2016-01-01

    To date, the value of fasting plasma acylated ghrelin (AG) and unacylated ghrelin (UAG) as potential novel biomarkers in patients with neuroendocrine tumors (NETs) is unknown. The aims of this study are to (i) compare fasting AG and UAG levels between nonobese, nondiabetic NET patients (N=28) and age- (±3 years) and sex-matched nonobese, nondiabetic controls (N=28); and (ii) study the relationship between AG, UAG, and AG/UAG ratios and biochemical (chromogranin-A (CgA) and neuron-specific enolase (NSE) levels) and clinical parameters (age at diagnosis, sex, primary tumor location, carcinoid syndrome, ENETS TNM classification, Ki-67 proliferation index, grading, prior incomplete surgery) in NET patients. Fasting venous blood samples (N=56) were collected and directly stabilized with 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride after withdrawal. Plasma AG and UAG levels were determined by ELISA. Expression of ghrelin was examined in tumor tissue by immunohistochemistry. There were no significant differences between NET patients and controls in AG (median: 62.5 pg/mL, IQR: 33.1–112.8 vs median: 57.2pg/mL, IQR: 26.7–128.3, P=0.66) and UAG in levels (median: 76.6pg/mL, IQR: 35.23–121.7 vs median: 64.9, IQR: 27.5–93.1, P=0.44). No significant correlations were found between AG, UAG, and AG/UAG ratios versus biochemical and clinical parameters in NET patients with the exception of age at diagnosis (AG: ρ= −0.47, P=0.012; AG/UAG ratio: ρ= −0.50, P=0.007) and baseline chromogranin-A levels (AG/UAG ratio: ρ= −0.44, P=0.019). In our view, fasting plasma acylated and unacylated ghrelin appear to have no value as diagnostic biomarkers in the clinical follow-up of patients with NETs. PMID:27215920

  20. Abnormal relationships between the neural response to high- and low-calorie foods and endogenous acylated ghrelin in women with active and weight-recovered anorexia nervosa

    PubMed Central

    Holsen, Laura M.; Lawson, Elizabeth A.; Christensen, Kara; Klibanski, Anne; Goldstein, Jill M.

    2014-01-01

    Evidence contributing to the understanding of neurobiological mechanisms underlying appetite dysregulation in anorexia nervosa draws heavily on separate lines of research into neuroendocrine and neural circuitry functioning. In particular, studies consistently cite elevated ghrelin and abnormal activation patterns in homeostatic (hypothalamus) and hedonic (striatum, amygdala, insula) regions governing appetite. The current preliminary study examined the interaction of these systems, based on research demonstrating associations between circulating ghrelin levels and activity in these regions in healthy individuals. In a cross-sectional design, we studied 13 women with active anorexia nervosa (AN), 9 women weight-recovered from AN (AN-WR), and 12 healthy-weight control women using a food cue functional magnetic resonance imaging paradigm, with assessment of fasting levels of acylated ghrelin. Healthy-weight control women exhibited significant positive associations between fasting acylated ghrelin and activity in the right amygdala, hippocampus, insula, and orbitofrontal cortex in response to high-calorie foods, associations which were absent in the AN and AN-WR groups. Women with AN-WR demonstrated a negative relationship between ghrelin and activity in the left hippocampus in response to high-calorie foods, while women with AN showed a positive association between ghrelin and activity in the right orbitofrontal cortex in response to low-calorie foods. Findings suggest a breakdown in the interaction between ghrelin signaling and neural activity in relation to reward responsivity in AN, a phenomenon that may be further characterized using pharmacogenetic studies. PMID:24862390

  1. Acyl Ghrelin Induces Insulin Resistance Independently of GH, Cortisol, and Free Fatty Acids

    PubMed Central

    Vestergaard, Esben T.; Jessen, Niels; Møller, Niels; Jørgensen, Jens Otto Lunde

    2017-01-01

    Ghrelin produced in the gut stimulates GH and ACTH secretion from the pituitary and also stimulates appetite and gastric emptying. We have shown that ghrelin also induces insulin resistance via GH-independent mechanisms, but it is unknown if this effect depends on ambient fatty acid (FFA) levels. We investigated the impact of ghrelin and pharmacological antilipolysis (acipimox) on insulin sensitivity and substrate metabolism in 8 adult hypopituitary patients on stable replacement with GH and hydrocortisone using a 2 × 2 factorial design: Ghrelin infusion, saline infusion, ghrelin plus short-term acipimox, and acipimox alone. Peripheral and hepatic insulin sensitivity was determined with a hyperinsulinemic euglycemic clamp in combination with a glucose tracer infusion. Insulin signaling was assayed in muscle biopsies. Peripheral insulin sensitivity was reduced by ghrelin independently of ambient FFA concentrations and was increased by acipimox independently of ghrelin. Hepatic insulin sensitivity was increased by acipimox. Insulin signaling pathways in skeletal muscle were not consistently regulated by ghrelin. Our data demonstrate that ghrelin induces peripheral insulin resistance independently of GH, cortisol, and FFA. The molecular mechanisms remain elusive, but we speculate that ghrelin is a hitherto unrecognized direct regulator of substrate metabolism. We also suggest that acipimox per se improves hepatic insulin sensitivity. PMID:28198428

  2. Plasma concentrations of acyl-ghrelin are associated with average daily gain and feeding behavior in grow-finish pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Feeding behavior is an important component of growth and feed efficiency in swine. Acyl-ghrelin is a peptide produced in the stomach that is orexigenic. The role of ghrelin in regulating feeding behavior in swine under commercial conditions is unknown. The objectives of this study were to determine ...

  3. Increased peptide YY blood concentrations, not decreased acyl-ghrelin, are associated with reduced hunger and food intake in healthy older women: Preliminary evidence.

    PubMed

    Hickson, Mary; Moss, Charlotte; Dhillo, Waljit S; Bottin, Jeanne; Frost, Gary

    2016-10-01

    With ageing there is frequently a loss of appetite, termed anorexia of ageing, which can result in under-nutrition. We do not know how appetite control alters with ageing. The objective of this study was to investigate whether differences in the release of, and response to, gastrointestinal appetite hormones is altered in young compared to old healthy volunteers. We hypothesised that an increase in PYY and GLP-1 or a decrease ghrelin may result in a decreased appetite. A comparative experimental design, using a cross-sectional sample of ages from a healthy population, matched for sex and BMI was used. The study compared total ghrelin, acyl-ghrelin, PYY, GLP-1 and subjective appetite responses to ingestion of a standardised 2781kj (660 kcal) test meal. 31 female volunteers aged between 21 and 92yrs took part. Multiple linear regression showed that both age and sex had an independent effect on energy intake. Subjective appetite scores showed that hunger, pleasantness to eat, and prospective food intake were significantly lower in the older age groups. PYY incremental area under the curve (IAUC) was greater in the oldest old compared to younger ages f(3,27) = 2.9, p = 0.05. No differences in GLP-1, ghrelin or acyl-ghrelin were observed in the older compared to younger age groups. Our data suggest that there may be increases in postprandial PYY(3-36) levels in female octogenarians, potentially resulting in reduced appetite. There does not appear to be any change in ghrelin or acyl-ghrelin concentrations with ageing.

  4. Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity.

    PubMed

    Wiedemann, Tobias; Bielohuby, Maximilian; Müller, Timo D; Bidlingmaier, Martin; Pellegata, Natalia S

    2016-02-01

    Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.

  5. The influence of vigorous running and cycling exercise on hunger perceptions and plasma acylated ghrelin concentrations in lean young men.

    PubMed

    Wasse, Lucy K; Sunderland, Caroline; King, James A; Miyashita, Masashi; Stensel, David J

    2013-01-01

    Vigorous running suppresses plasma acylated ghrelin concentrations but the limited literature on cycling suggests that acylated ghrelin is unchanged, perhaps because body mass is supported during cycling. It is important from a research and applied perspective to determine whether acylated ghrelin and hunger responses are exercise-mode specific. This study sought to examine this. Eleven recreationally active males fasted overnight and completed three 4-h trials: control, running, and cycling, in a random order. Participants rested throughout the control trial and ran or cycled at 70% of mode-specific maximal oxygen uptake for the first hour during exercise trials, resting thereafter. Hunger was measured every 0.5 h using visual analogue scales. Eight venous blood samples were collected to determine acylated ghrelin concentrations and a standardised meal was consumed at 3 h. Compared with the control trial, acylated ghrelin concentrations were suppressed to a similar extent at 0.5 and 1 h during the running (p < 0.005) and cycling (p < 0.001) trials. Area under the curve values for ghrelin concentration over time were lower during exercise trials versus control (Control: 606 ± 379; Running: 455 ± 356; Cycling: 448 ± 315 pg·mL(-1)·4 h(-1); mean ± SD, p < 0.05). Hunger values did not differ significantly between trials but an interaction effect (p < 0.05) indicated a tendency for hunger to be suppressed during exercise. Thus, at similar relative exercise intensities, plasma acylated ghrelin concentrations are suppressed to a similar extent during running and cycling.

  6. Ghrelin-related peptides do not modulate vasodilator nitric oxide production or superoxide levels in mouse systemic arteries.

    PubMed

    Ku, Jacqueline M; Sleeman, Mark W; Sobey, Christopher G; Andrews, Zane B; Miller, Alyson A

    2016-04-01

    The ghrelin gene is expressed in the stomach where it ultimately encodes up to three peptides, namely, acylated ghrelin, des-acylated ghrelin and obestatin, which all have neuroendocrine roles. Recently, the authors' reported that these peptides have important physiological roles in positively regulating vasodilator nitric oxide (NO) production in the cerebral circulation, and may normally suppress superoxide production by the pro-oxidant enzyme, Nox2-NADPH oxidase. To date, the majority of studies using exogenous peptides infer that they may have similar roles in the systemic circulation. Therefore, this study examined whether exogenous and endogenous ghrelin-related peptides modulate NO production and superoxide levels in mouse mesenteric arteries and/or thoracic aorta. Using wire myography, it was found that application of exogenous acylated ghrelin, des-acylated ghrelin or obestatin to mouse thoracic aorta or mesenteric arteries failed to elicit a vasorelaxation response, whereas all three peptides elicited vasorelaxation responses of rat thoracic aorta. Also, none of the peptides modulated mouse aortic superoxide levels as measured by L-012-enhanced chemiluminescence. Next, it was found that NO bioactivity and superoxide levels were unaffected in the thoracic aorta from ghrelin-deficient mice when compared with wild-type mice. Lastly, using novel GHSR-eGFP reporter mice in combination with double-labelled immunofluorescence, no evidence was found for the growth hormone secretagogue receptor (GHSR1a) in the throracic aorta, which is the only functional ghrelin receptor identified to date. Collectively these findings demonstrate that, in contrast to systemic vessels of other species (e.g. rat and human) and mouse cerebral vessels, ghrelin-related peptides do not modulate vasodilator NO production or superoxide levels in mouse systemic arteries.

  7. Intracerebroventricular urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats

    PubMed Central

    Yeh, Chun; Ting, Ching-Heng; Doong, Ming-Luen; Chi, Chin-Wen; Lee, Shou-Dong; Chen, Chih-Yen

    2016-01-01

    Purpose Urocortin 3 is a key neuromodulator in the regulation of stress, anxiety, food intake, gut motility, and energy homeostasis, while ghrelin elicits feeding behavior and enhances gastric emptying, adiposity, and positive energy balance. However, the interplays between urocortin 3 and ghrelin on food intake and gastric emptying remain uninvestigated. Methods We examined the differential effects of central O-n-octanoylated ghrelin, des-Gln14-ghrelin, and urocortin 3 on food intake, as well as on charcoal nonnutrient semiliquid gastric emptying in conscious rats that were chronically implanted with intracerebroventricular (ICV) catheters. The functional importance of corticotropin-releasing factor (CRF) receptor 2 in urocortin 3-induced responses was examined by ICV injection of the selective CRF receptor 2 antagonist, astressin2-B. Results ICV infusion of urocortin 3 opposed central acyl ghrelin-elicited hyperphagia via CRF receptor 2 in satiated rats. ICV injection of O-n-octanoylated ghrelin and des-Gln14-ghrelin were equally potent in accelerating gastric emptying in fasted rats, whereas ICV administration of urocortin 3 delayed gastric emptying. In addition, ICV infusion of urocortin 3 counteracted central acyl ghrelin-induced gastroprokinetic effects via CRF receptor 2 pathway. Conclusion ICV-infused urocortin 3 counteracts central acyl ghrelin-induced hyperphagic and gastroprokinetic effects via CRF receptor 2 in rats. Our results clearly showed that enhancing ghrelin and blocking CRF receptor 2 signaling in the brain accelerated gastric emptying, which provided important clues for a new therapeutic avenue in ameliorating anorexia and gastric ileus found in various chronic wasting disorders. PMID:27757017

  8. Teaghrelins, unique acylated flavonoid tetraglycosides in Chin-shin oolong tea, are putative oral agonists of the ghrelin receptor.

    PubMed

    Lo, Yuan-Hao; Chen, Ying-Jie; Chang, Chi-I; Lin, Yi-Wen; Chen, Chung-Yu; Lee, Maw-Rong; Lee, Viola S Y; Tzen, Jason T C

    2014-06-04

    Chin-shin oolong tea, a popular tea in Taiwan, was empirically perceived to induce hunger and accelerate gastric emptying in a manner similar to the physiological effects of ghrelin, an endogenous acylated peptide known as the hunger hormone. Two unique acylated flavonoid tetraglycosides previously identified in Chin-shin oolong tea were demonstrated to induce hunger of rats in a food intake assay and, thus, named teaghrelin-1 and teaghrelin-2. Similar to GHRP-6, a synthetic analogue of ghrelin, teaghrelin-1 stimulated growth hormone secretion of rat primary anterior pituitary cells in a dose-dependent manner, and the stimulation was inhibited by [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]-substance P, an antagonist of the ghrelin receptor. While teaghrelin-2 remained unmodified, a meta-O-methylated metabolite of teaghrelin-1 was detected in bile of rats after intravenous injection. Presumably, teaghrelins are promising oral agonists of the ghrelin receptor.

  9. Changes in appetite hormone (ghrelin) levels of saliva and serum in acute appendicitis cases before and after operation.

    PubMed

    Cetinkaya, Ziya; Aydin, Suleyman; Cerrahoglu, Yusuf Z; Ayten, Refik; Erman, Fazilet; Aygen, Erhan

    2009-02-01

    This study was designed to measure the levels of serum and saliva ghrelin concentrations before and after surgery in an attempt to clarify whether this hormone plays any significant roles in acute appendicitis and cholelithiasis patients when compared with healthy controls. Samples were obtained from 20 patients with appendicitis, 10 patients with cholelithiasis before and after operation, and 16 healthy controls. The levels of ghrelin (acylated) were measured by means of a RIA assay. The results revealed that preoperative levels of ghrelin in saliva and serum were significantly decreased with respect to post-op in patients undergoing appendectomy, and control levels. This was also the case when the preoperative ghrelin concentrations in patients with appendicitis were compared with those having choelithiasis. Taken together, decreased ghrelin concentration in preoperative appendicitis might be a causative factor for the "loss of appetite" observed in an acute inflammatory condition such as acute appendicitis. However, further studies are necessary to reveal the exact mechanisms behind this observation.

  10. Age, sex, and lactating status regulate ghrelin secretion and GOAT mRNA levels from isolated rat stomach.

    PubMed

    Al-Massadi, O; Crujeiras, A B; González, R C; Pardo, M; Diéguez, C; Casanueva, F F; Seoane, L M

    2010-09-01

    Ghrelin is a stomach derivate peptide involved in energy homeostasis regulation, and ghrelin O-acyltransferase (GOAT) is the enzyme responsible for ghrelin acylation. Puberty is a period characterized by profound changes in the metabolic requirements and notable variations of sexual hormone levels. On the other hand, the weaning process is a fundamental modification of the diet, which implicates several adaptations of the gastrointestinal tract physiology. Until now the direct secretion of ghrelin by the stomach in these conditions, without interferences from other organs, has never been studied. The main objective of this article was to investigate how the stomach modulates ghrelin production and secretion as well as GOAT expression on these periods of life. Gastric ghrelin secretion is regulated through postnatal life in an independent way of gastric expression and circulating levels of this hormone. The present work shows a strong regulation of gastric ghrelin secretion by estrogens. The weaning strongly regulates gastric ghrelin secretion. Animals subjected to delayed weaning present a lower body weight than the corresponding controls. For the first time, it is shown that a noticeable decrease in circulating levels of testosterone and estrogens is associated with delay of weaning. GOAT mRNA levels in the stomach are strongly regulated by age, breastfeeding, and testosterone. In conclusion, the stomach itself regulates ghrelin and GOAT production to adapt the organism to the metabolic requirements demanded through each stage of life.

  11. Ghrelin reverses experimental diabetic neuropathy in mice

    SciTech Connect

    Kyoraku, Itaru; Shiomi, Kazutaka; Kangawa, Kenji; Nakazato, Masamitsu

    2009-11-20

    Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. We investigated the pharmacological potential of ghrelin in the treatment of polyneuropathy in uncontrolled streptozotocin (STZ)-induced diabetes in mice. Ghrelin or desacyl-ghrelin was administered daily for 4 weeks after STZ-induced diabetic polyneuropathy had developed. Ghrelin administration did not alter food intake, body weight gain, blood glucose levels, or plasma insulin levels when compared with mice given saline or desacyl-ghrelin administration. Ghrelin administration ameliorated reductions in motor and sensory nerve conduction velocities in diabetic mice and normalized their temperature sensation and plasma concentrations of 8-isoprostaglandin {alpha}, an oxidative stress marker. Desacyl-ghrelin failed to have any effect. Ghrelin administration in a mouse model of diabetes ameliorated polyneuropathy. Thus, ghrelin's effects represent a novel therapeutic paradigm for the treatment of this otherwise intractable disorder.

  12. Ghrelin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The gut hormone ghrelin was discovered in 1999. In the last 15 years, ample data have been generated on ghrelin. Bedsides its hallmark function as an appetite stimulator, ghrelin also has many other important functions. In this review, we discussed ghrelin's functions in learning and memory, gut mov...

  13. Effect of enalapril maleate on ghrelin levels in metabolic syndrome in rats.

    PubMed

    Aygen, Bilge; Kucuksu, Mehmet; Aydin, Suleyman; Ozercan, Ibrahim Hanifi

    2015-05-01

    We have explored how enalapril affects ghrelin levels in serum and renal tissues of rats with fructose-induced MetS, using 5-week-old Wistar albino male rats weighing 220 ± 20 g. They divided into 5 groups: (i) control (CT), no fructose supplement fed on standard rat pellet and tap water for 60 days, (ii) metabolic syndrome (MetS) fed with 10% fructose for 60 days, (iii) rats after metabolic syndrome developed treated with enalapril over 30 days (MetS+E30), (iv) rats in which only enalapril was administered for 60 days (E60), and (v) MetS-treated with enalapril for 60 days (MetS+E60). Enalapril maleate was given at 20mg/kg per day by gavage. Fasting serum insulin, uric acid, triglyceride, low-density lipoprotein cholesterol and total cholesterol levels were significantly higher, and the amount of high density lipoprotein cholesterol, and acylated and desacyl ghrelin levels was significantly lower in the MetS groups. Ghrelins were significantly lower in all 3 groups, which were administered enalapril than that of MetS and the control group. Immunohistochemical staining showed that the density of ghrelin was parallel to the serum levels of the peptide. Ghrelin immunoreactivity in the kidneys was of moderate density in the distal and collecting tubules, mild density in the proximal tubule and glomeruli, whereas the density decreased in the MetS group and other enalapril-treated groups. In conclusion, ghrelin levels in MetS groups were significantly lower than control group, and thus Enalapril treatment improves components of MetS and has direct effects on serum ghrelin levels that are independent of MetS.

  14. Central acylated ghrelin improves memory function and hippocampal AMPK activation and partly reverses the impairment of energy and glucose metabolism in rats infused with β-amyloid.

    PubMed

    Kang, Suna; Moon, Na Rang; Kim, Da Sol; Kim, Sung Hoon; Park, Sunmin

    2015-09-01

    Ghrelin is a gastric hormone released during the fasting state that targets the hypothalamus where it induces hunger; however, emerging evidence suggests it may also affect memory function. We examined the effect of central acylated-ghrelin and DES-acetylated ghrelin (native ghrelin) on memory function and glucose metabolism in an experimentally induced Alzheimer's disease (AD) rat model. AD rats were divided into 3 groups and Non-AD rats were used as a normal-control group. Each rat in the AD groups had intracerebroventricular (ICV) infusion of β-amyloid (25-35; 16.8nmol/day) into the lateral ventricle for 3 days, and then the pumps were changed to infuse either acylated-ghrelin (0.2nmol/h; AD-G), DES-acylated ghrelin (0.2nmol/h; AD-DES-G), or saline (control; AD-C) for 3 weeks. The Non-AD group had ICV infusion of β-amyloid (35-25) which does not deposit in the hippocampus. During the next 3 weeks memory function, food intake, body weight gain, body fat composition, and glucose metabolism were measured. AD-C exhibited greater β-amyloid deposition compared to Non-AD-C, and AD-G suppressed the increased β-amyloid deposition and potentiated the phosphorylation AMPK. In addition, AD-G increased the phosphorylation GSK and decreased the phosphorylation of Tau in comparison to AD-C and AD-DES-G. Cognitive function, measured by passive avoidance and water maze tests, was much lower in AD-C than Non-AD-C whereas AD-G but not AD-DES-G prevented the decrease (p<0.021). Body weight gain was lower in AD-C group than Non-AD-C group without changing epididymal fat mass. AD-G reversed the decrease in body weight which was due to increased energy intake and decreased energy expenditure. The AD-G group exhibited a decrease in the second part of serum glucose levels during an oral glucose tolerance test (OGTT) compared to the AD-C and AD-DES-G group (p<0.009). However, area under the curve of insulin during the first part of OGTT was higher in AD-DES-G than other groups

  15. Effects of sire breed, gender, and postnatal litter size on plasma concentrations of acyl ghrelin and its relationship with growth traits and feeding behavior in swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Feeding behavior is an important component of growth and feed efficiency in swine. Acyl ghrelin is a peptide produced in the stomach that is orexigenic. The role of ghrelin in regulating feeding behavior in swine under commercial conditions is unknown. The objective of this study was to determine th...

  16. Ghrelin and Breast Cancer: Emerging Roles in Obesity, Estrogen Regulation, and Cancer

    PubMed Central

    Au, CheukMan Cherie; Furness, John B.; Brown, Kristy A.

    2017-01-01

    Local and systemic factors have been shown to drive the growth of breast cancer cells in postmenopausal obese women, who have increased risk of estrogen receptor-positive breast cancer. Estrogens, produced locally in the breast fat by the enzyme aromatase, have an important role in promoting cancer cell proliferation. Ghrelin, a 28-amino acid peptide hormone, may also influence cancer growth. This peptide is produced in the stomach and acts centrally to regulate appetite and growth hormone release. Circulating levels of ghrelin, and its unacylated form, des-acyl ghrelin, are almost always inversely correlated with obesity, and these peptide hormones have recently been shown to inhibit adipose tissue aromatase expression. Ghrelin and des-acyl ghrelin have also been shown to be produced by some tumor cells and influence tumor growth. The ghrelin/des-acyl ghrelin–cancer axis is complex, one reason being that tumor cells have been shown to express splice variants of ghrelin, and ghrelin and des-acyl ghrelin might act at receptors other than the cognate ghrelin receptor, growth hormone secretagogue receptor 1a, in tumors. Effects of ghrelin and des-acyl ghrelin on energy homeostasis may also affect tumor development and growth. This review will summarize our current understanding of the role of ghrelin and des-acyl ghrelin in hormone-dependent cancers, breast cancer in particular. PMID:28119851

  17. Elevated ratio of acylated to unacylated ghrelin in children and young adults with Prader-Willi syndrome.

    PubMed

    Kuppens, R J; Diène, G; Bakker, N E; Molinas, C; Faye, S; Nicolino, M; Bernoux, D; Delhanty, P J D; van der Lely, A J; Allas, S; Julien, M; Delale, T; Tauber, M; Hokken-Koelega, A C S

    2015-12-01

    Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. Hyperghrelinemia may be involved in the underlying mechanisms of the switch. The purpose of this study is to evaluate acylated ghrelin (AG) and unacylated ghrelin (UAG) levels in PWS and investigate their associations with hyperphagia. This is a cross-sectional clinical study conducted in three PWS expert centers in the Netherlands and France. Levels of AG and UAG and the AG/UAG ratio were determined in 138 patients with PWS (0.2-29.4 years) and compared with 50 age-matched obese subjects (4.3-16.9 years) and 39 healthy controls (0.8-28.6 years). AEBSF was used to inhibit deacylation of AG. As a group, PWS patients had higher AG but similar UAG levels as healthy controls (AG 129.1 vs 82.4 pg/ml, p = 0.016; UAG 135.3 vs 157.3 pg/ml, resp.), resulting in a significantly higher AG/UAG ratio (1.00 vs 0.61, p = 0.001, resp.). Obese subjects had significantly lower AG and UAG levels than PWS and controls (40.3 and 35.3 pg/ml, resp.), but also a high AG/UAG ratio (1.16). The reason for the higher AG/UAG ratio in PWS and obese was, however, completely different, as PWS had a high AG and obese a very low UAG. PWS patients without weight gain or hyperphagia had a similar AG/UAG ratio as age-matched controls, in contrast to those with weight gain and/or hyperphagia who had an elevated AG/UAG ratio. The switch to excessive weight gain in PWS seems to coincide with an increase in the AG/UAG ratio, even prior to the start of hyperphagia.

  18. Ghrelin and obestatin levels in end-stage renal disease.

    PubMed

    Aygen, B; Dogukan, A; Dursun, F E; Aydin, S; Kilic, N; Sahpaz, F; Celiker, H

    2009-01-01

    Malnutrition is fairly common in end-stage renal disease (ESRD) patients, persistent lack of appetite being a major symptom. Ghrelin and obestatin are two hormones that are involved in appetite and energy homeostasis. The present study examined ghrelin and obestatin levels in 24 ESRD patients undergoing haemodialysis and 24 age-matched healthy controls. Serum and saliva ghrelin and obestatin levels in the ESRD patients were significantly higher compared with controls, while saliva ghrelin and obestatin levels in all study participants were significantly higher than serum levels. Saliva ghrelin correlated with serum ghrelin and saliva obestatin correlated with serum obestatin in all study participants, although there was no correlation between ghrelin and obestatin levels. In conclusion, the results suggest that the kidneys may have a role in the metabolism and/or clearance of obestatin, as they do for ghrelin. Further studies are needed to determine if elevated levels of these hormones in ESRD patients contribute to the malnutrition that is common in these patients.

  19. Ghrelin/obestatin ratio in two populations with low bodyweight: constitutional thinness and anorexia nervosa.

    PubMed

    Germain, Natacha; Galusca, Bogdan; Grouselle, Dominique; Frere, Delphine; Tolle, Virginie; Zizzari, Philippe; Lang, François; Epelbaum, Jacques; Estour, Bruno

    2009-04-01

    Constitutional thinness (CT) and anorexia nervosa (AN) are two categories of severely underweight subjects. Some appetite-regulating hormones display opposite levels in AN and CT. While levels of ghrelin, an orexigenic hormone, fit with the normal food intake in CT, the lack of efficacy of increased ghrelin levels in AN is not clear. Obestatin is a recently described peptide derived from the preproghrelin gene, reported to inhibit appetite in contrast to ghrelin. The aim of this study was to determine whether the circadian profile of obestatin, total and acylated ghrelin levels is different in CT subjects when compared with AN patients. Six-points circadian profiles of plasma obestatin, acylated ghrelin, total ghrelin and other hormonal and nutritional parameters were evaluated in four groups of young women: 10 CT, 15 restricting-type AN, 7 restored from AN and 9 control subjects. Obestatin circadian levels were significantly higher in AN (p<0.0001) while no difference was found between CT and control subjects. Acylated and total ghrelin were found increased in AN. Acylated ghrelin/obestatin and total ghrelin/obestatin were found decreased in AN compared to CT or C subjects (p<0.05). The percentage of acylated ghrelin was found decreased in CT group (p<0.05). The decreased ghrelin/obestatin ratio found in AN might participate in the restraint in nutriment intake of these patients. In contrast, in CT a lower percentage of acylated over total ghrelin might be considered in the aetiology of this condition.

  20. D-Lys(3)-GHRP-6 antagonizes the effect of unacylated but not of acylated ghrelin on the growth of HECa10 murine endothelial cells.

    PubMed

    Polowinczak-Przybylek, Joanna; Siejka, Agnieszka; Melen-Mucha, Gabriela

    2012-12-01

    Recent studies demonstrate that ghrelin can be an endogenous regulator of angiogenesis. We studied direct effects of human acylated (hAG) and unacylated (hUAG) ghrelin, as well as of rat acylated ghrelin (rAG) on the growth of HECa10 murine endothelial cells. Ghrelin was applied separately or together with D-Lys(3)-GHRP-6, which is commonly used as an antagonist of ghrelin receptor type 1a - GHS-R1a. The growth of HECa10 cells was assessed with Mosmann and in selected study conditions also with BrdU and TUNEL methods. Both hAG and hUAG (10(-5) M to 10(-12) M) inhibited the growth of HECa10 cells in 24h and 72 h cultures. Similarly, rAG decreased the growth of the cells after 24h (10(-7) M and 10(-11) M), and after 72 h (10(-7) M, 10(-8) M and 10(-11) M). Unexpectedly, D-Lys(3)-GHRP-6 itself also inhibited the growth of these cells at 10(-4) to 10(-6) M in 24h, 48 h (dose-response effect) and 72 h cultures. D-Lys(3)-GHRP-6 did not modify the inhibitory effect of rAG. However, D-Lys(3)-GHRP-6 at the concentration of 10(-4) M diminished, abolished or even reversed the inhibitory effect of hUAG in 72 h culture and this was dependent on ghrelin concentrations. These data indicate that both AG and UAG have antiangiogenic properties at least at the level of endothelial growth, through decreased metabolic activity of the cells or stimulation of apoptosis. D-Lys(3)-GHRP-6 (inhibitor of GHS-R1a) seems not to be an appropriate antagonist in this experimental condition. Similar effects of these substances on HECa10 cells suggest that they are not mediated by GHS-R1a.

  1. Intravenous injection of urocortin 1 induces a CRF2 mediated increase in circulating ghrelin and glucose levels through distinct mechanisms in rats.

    PubMed

    Wang, Lixin; Stengel, Andreas; Goebel-Stengel, Miriam; Shaikh, Almaas; Yuan, Pu-Qing; Taché, Yvette

    2013-01-01

    Urocortins (Ucns) injected peripherally decrease food intake and gastric emptying through peripheral CRF(2) receptors in rodents. However, whether Ucns influence circulating levels of the orexigenic and prokinetic hormone, ghrelin has been little investigated. We examined plasma levels of ghrelin and blood glucose after intravenous (iv) injection of Ucn 1, the CRF receptor subtype involved and underlying mechanisms in ad libitum fed rats equipped with a chronic iv cannula. Ucn 1 (10 μg/kg, iv) induced a rapid onset and long lasting increase in ghrelin levels reaching 68% and 219% at 0.5 and 3h post injection respectively and a 5-h hyperglycemic response. The selective CRF(2) agonist, Ucn 2 (3 μg/kg, iv) increased fasting acyl (3h: 49%) and des-acyl ghrelin levels (3h: 30%) compared to vehicle while the preferential CRF(1) agonist, CRF (3 μg/kg, iv) had no effect. Ucn 1's stimulatory actions were blocked by the selective CRF(2) antagonist, astressin(2)-B (100 μg/kg, iv). Hexamethonium (10 mg/kg, sc) prevented Ucn 1-induced rise in total ghrelin levels while not altering the hyperglycemic response. These data indicate that systemic injection of Ucns induces a CRF(2)-mediated increase in circulating ghrelin levels likely via indirect actions on gastric ghrelin cells that involves a nicotinic pathway independently from the hyperglycemic response.

  2. Serum ghrelin levels in patients with Behcet’s disease

    PubMed Central

    Erden, Ilker; Demir, Betül; Cicek, Demet; Dertlioğlu, Selma Bakar; Aydin, Suleyman; Ozturk, Savas

    2016-01-01

    Introduction Behcet’s disease (BD) is a chronic, relapsing, systemic vasculitis of unknown etiology. Aim To measure serum ghrelin levels in BD patients and healthy controls and to investigate its association with metabolic syndrome (MetS). Material and methods Thirty BD patients and 30 healthy individuals were enrolled in the study. Ghrelin levels were measured in blood samples using ELISA. Results The mean serum ghrelin level in BD patients (28.57 ±14.04) was significantly lower compared to healthy controls (40.72 ±23.21) (p = 0.01). The mean serum ghrelin level in BD patients who had MetS (24.18 ±12.73) was lower compared to BD patients who did not have MetS (30.77 ±14.45), but this difference was not significant (p > 0.05). Conclusions Ghrelin levels were lower in BD patients compared to healthy controls. There was no association between reduced ghrelin levels and MetS; however, there was a negative correlation between ghrelin levels and disease activity. PMID:28035223

  3. Effects of intraamygdaloid microinjections of acylated-ghrelin on liquid food intake of rats.

    PubMed

    Tóth, Krisztián; László, Kristóf; Bagi, Eva Eszter; Lukács, Edit; Lénárd, László

    2008-09-30

    Ghrelin (Ghr) has two main forms in the blood: the acylated (A-Ghr) and non-acylated (NA-Ghr) Ghr. A-Ghr was discovered as a potent growth hormone (GH) secretion increasing substance acting on GH secretagouge receptor (GHS-R) type 1a. A-Ghr facilitates food intake after its i.p., i.c.v. or direct hypothalamic application. Immunohistological assays identified projections of ghrelinergic neurons to the basolateral nucleus (ABL) of the amygdala (AMY). A-Ghr injected into the hypothalamus caused c-Fos overexpression in the AMY area that has an important role in food intake and body weight regulation. In separate experiments, liquid food intake of male wistar rats was measured after bilateral intraamygdalar or bilateral i.c.v. administration of A-Ghr (25, 50, 100, 250, and 500 ng/side or 500 and 1000 ng/side, A-Ghr dissolved in 0.15 M sterile NaCl/0.4 microl or 1 microl, respectively). In the ABL, A-Ghr microinjections in the 50-250 ng dose range resulted in significant decrease of food intake. The 25 and 500 ng had no effect. Action of 50 ng (14.83 pmol) or 100 ng (30.16 pmol) A-Ghr was eliminated by 15 ng (16.13 pmol) or 30 ng (32.25 pmol) GHS-R antagonist (D-Lys3-GHRP-6) pretreatment. The administration of 30 ng D-Lys3-GHRP-6 in itself had no influence on feeding. I.c.v. applied 1000 ng A-Ghr increased liquid food intake. Our results are the first ones reporting that A-Ghr injected into the ABL resulted in a decrease of liquid food consumption, within a limited dose range. This is a receptor-linked effect because it was eliminated by a GHS-R specific antagonist.

  4. Obestatin is present in saliva: alterations in obestatin and ghrelin levels of saliva and serum in ischemic heart disease.

    PubMed

    Ozbay, Yilmaz; Aydin, Suleyman; Dagli, A Ferda; Akbulut, Mehmet; Dagli, Necati; Kilic, Nermin; Rahman, Ali; Sahin, Ibrahim; Polat, Veli; Ozercan, H Ibrahim; Arslan, Nadi; Sensoy, Dogan

    2008-01-31

    Ghrelin and obestatin are a single gene products and are a multiple functional peptides that regulates energy homeostasis, and food intake. In the present work, we studied the secretion of ghrelin and its co-secreted peptide obestatin in 44 patients with ischemic heart disease with that of 27 healthy matched controls. Here we first conducted using an immunohistochemistry assay to screen whether human salivary glands have any obestatin immunoreactivity. Then, serum and saliva obestatin and acylated ghrelin levels were determined by using Radioimmunoassay. Our immunohistochemical analysis demonstrated that obestatin was localized in the striated and excretory duct of human salivary gland. We also report for the first time that obestatin, like ghrelin, is present in human salivary gland and saliva. No evidence of the role of obestatin or ghrelin saliva levels in the context of ischemic heart disease was found. Salivary ghrelin and obestatin levels are correlated in controls with the blood levels. Determination of salivary values could represent a non-invasive alternative to serum ones that can be useful in clinical practice.

  5. Recent Advances in Potential Clinical Application of Ghrelin in Obesity

    PubMed Central

    Delporte, Christine

    2012-01-01

    Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelin O-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets. PMID:22523666

  6. Plasma ghrelin and obestatin levels are increased in spontaneously hypertensive rats.

    PubMed

    Li, Zhao-Feng; Guo, Zhi-Fu; Cao, Jiang; Hu, Jian-Qiang; Zhao, Xian-Xian; Xu, Rong-Liang; Huang, Xin-Miao; Qin, Yong-Wen; Zheng, Xing

    2010-02-01

    Obestatin, encoded by the same gene as ghrelin, was first described as a physiological opponent of ghrelin. We investigated fasting plasma ghrelin and obestatin levels in spontaneously hypertensive rats and Wistar-Kyoto rats. We found that ghrelin levels, obestatin levels and the ratio of ghrelin to obestatin were significantly higher in spontaneously hypertensive rats than Wistar-Kyoto rats. Systolic blood pressure and diastolic blood pressure were positively correlated; however, heart period and baroreflex sensitivity were negatively correlated with ghrelin levels. Systolic blood pressure was positively correlated, whereas baroreflex sensitivity was negatively correlated with obestatin levels. In addition, systolic blood pressure was a significantly independent variable of ghrelin levels, obestatin levels, and the ghrelin to obestatin ratio in a multiple regression analysis. Our data suggests that there is a disturbance of ghrelin and obestatin in the circulation of spontaneously hypertensive rats and the ghrelin/obestatin system might play a role in blood pressure regulation.

  7. The opposing effects of ghrelin on hypothalamic and systemic inflammatory processes are modulated by its acylation status and food intake in male rats.

    PubMed

    García-Cáceres, Cristina; Fuente-Martín, Esther; Díaz, Francisca; Granado, Miriam; Argente-Arizón, Pilar; Frago, Laura M; Freire-Regatillo, Alejandra; Barrios, Vicente; Argente, Jesús; Chowen, Julie A

    2014-08-01

    Ghrelin is an endogenous hormone that stimulates appetite and adipose tissue accrual. Both the acylated (AG) and non-acylated (DAG) isoforms of this hormone are also reported to exert anti-inflammatory and protective effects systemically and in the central nervous system. As inflammatory processes have been implicated in obesity-associated secondary complications, we hypothesized that this natural appetite stimulator may protect against negative consequences resulting from excessive food intake. Adult male Wistar rats were treated icv (5 μg/day) with AG, DAG, the ghrelin mimetic GH-releasing peptide (GHRP)-6, AG, and pair-fed with controls (AG-pf) or saline for 14 days. Regardless of food intake AG increased visceral adipose tissue (VAT) and decreased circulating cytokine levels. However, AG reduced cytokine production in VAT only in rats fed ad libitum. Hypothalamic cytokine production was increased in AG-treated rats fed ad libitum and by DAG, but intracellular inflammatory signaling pathways associated with insulin and leptin resistance were unaffected. Gliosis was not observed in response to any treatment as glial markers were either reduced or unaffected. AG, DAG, and GHRP-6 stimulated production of hypothalamic insulin like-growth factor I that is involved in cell protective mechanisms. In hypothalamic astrocyte cell cultures AG decreased tumor necrosis factorα and DAG decreased interleukin-1β mRNA levels, suggesting direct anti-inflammatory effects on astrocytes. Thus, whereas ghrelin stimulates food intake and weight gain, it may also induce mechanisms of cell protection that help to detour or delay systemic inflammatory responses and hypothalamic gliosis due to excess weight gain, as well as its associated pathologies.

  8. Ghrelin Regulates Glucose and Glutamate Transporters in Hypothalamic Astrocytes

    PubMed Central

    Fuente-Martín, Esther; García-Cáceres, Cristina; Argente-Arizón, Pilar; Díaz, Francisca; Granado, Miriam; Freire-Regatillo, Alejandra; Castro-González, David; Ceballos, María L.; Frago, Laura M.; Dickson, Suzanne L.; Argente, Jesús; Chowen, Julie A.

    2016-01-01

    Hypothalamic astrocytes can respond to metabolic signals, such as leptin and insulin, to modulate adjacent neuronal circuits and systemic metabolism. Ghrelin regulates appetite, adiposity and glucose metabolism, but little is known regarding the response of astrocytes to this orexigenic hormone. We have used both in vivo and in vitro approaches to demonstrate that acylated ghrelin (acyl-ghrelin) rapidly stimulates glutamate transporter expression and glutamate uptake by astrocytes. Moreover, acyl-ghrelin rapidly reduces glucose transporter (GLUT) 2 levels and glucose uptake by these glial cells. Glutamine synthetase and lactate dehydrogenase decrease, while glycogen phosphorylase and lactate transporters increase in response to acyl-ghrelin, suggesting a change in glutamate and glucose metabolism, as well as glycogen storage by astrocytes. These effects are partially mediated through ghrelin receptor 1A (GHSR-1A) as astrocytes do not respond equally to desacyl-ghrelin, an isoform that does not activate GHSR-1A. Moreover, primary astrocyte cultures from GHSR-1A knock-out mice do not change glutamate transporter or GLUT2 levels in response to acyl-ghrelin. Our results indicate that acyl-ghrelin may mediate part of its metabolic actions through modulation of hypothalamic astrocytes and that this effect could involve astrocyte mediated changes in local glucose and glutamate metabolism that alter the signals/nutrients reaching neighboring neurons. PMID:27026049

  9. Ghrelin Regulates Glucose and Glutamate Transporters in Hypothalamic Astrocytes.

    PubMed

    Fuente-Martín, Esther; García-Cáceres, Cristina; Argente-Arizón, Pilar; Díaz, Francisca; Granado, Miriam; Freire-Regatillo, Alejandra; Castro-González, David; Ceballos, María L; Frago, Laura M; Dickson, Suzanne L; Argente, Jesús; Chowen, Julie A

    2016-03-30

    Hypothalamic astrocytes can respond to metabolic signals, such as leptin and insulin, to modulate adjacent neuronal circuits and systemic metabolism. Ghrelin regulates appetite, adiposity and glucose metabolism, but little is known regarding the response of astrocytes to this orexigenic hormone. We have used both in vivo and in vitro approaches to demonstrate that acylated ghrelin (acyl-ghrelin) rapidly stimulates glutamate transporter expression and glutamate uptake by astrocytes. Moreover, acyl-ghrelin rapidly reduces glucose transporter (GLUT) 2 levels and glucose uptake by these glial cells. Glutamine synthetase and lactate dehydrogenase decrease, while glycogen phosphorylase and lactate transporters increase in response to acyl-ghrelin, suggesting a change in glutamate and glucose metabolism, as well as glycogen storage by astrocytes. These effects are partially mediated through ghrelin receptor 1A (GHSR-1A) as astrocytes do not respond equally to desacyl-ghrelin, an isoform that does not activate GHSR-1A. Moreover, primary astrocyte cultures from GHSR-1A knock-out mice do not change glutamate transporter or GLUT2 levels in response to acyl-ghrelin. Our results indicate that acyl-ghrelin may mediate part of its metabolic actions through modulation of hypothalamic astrocytes and that this effect could involve astrocyte mediated changes in local glucose and glutamate metabolism that alter the signals/nutrients reaching neighboring neurons.

  10. Plasma ghrelin levels in patients with Familial Mediterranean Fever.

    PubMed

    Keskin, Göksal; Inal, Ali; Ilikçi, Rahşan; Baysal, Ozan

    2009-01-01

    Familial mediterranean fever (FMF) is a familial disease characterized by recurrent episodes of febrile serositis, peritonitis, arthritis and pleuritis. Many studies have been performed is an attempt to understand the basis of the inflammatory attacts in FMF. Ghrelin, a recently described orexigene peptide is predominantly produced by stomach. Ghrelin also exerts multiple regulatory effects on immune system. It has reported that grelin has anti-inflammatory effects. There is currently no published evidence demonstrating a role for anti-inflammatory effects of ghrelin in FMF. For this reason, we investigated the role of plasma ghrelin levels in patients with FMF. Thirty seven patients with FMF and 10 healthy controls (5 female, 5 male; mean age 35.4 +/- 5.6 years) were enrolled in this study. Twenty-one patients were in active stage (10 female, 11 male, mean age; 31.0 +/- 5.4 years, mean disease duration 7.2 +/- 3.3 years) and 16 patients were in inactive stage (7 female,9 male, mean age; 33.0 +/- 6.0 years, mean disease duration; 8.7 +/- 3.2 years). Plasma ghrelin levels were determined by EIA. The mean plasma ghrelin levels were 158.4 +/- 52.9 pg/ml in patients with FMF and 56.7 +/- 7.5 pg/ml in healthy controls. The mean plasma ghrelin levels were 190.5 +/- 49.4 pg/ml in the active patients and 116.2 +/- 11.7 pg/ml in the inactive patients. Plasma ghrelin levels were significantly high in patients with FMF compared to healthy controls (p<0.001). Plasma ghrelin levels were significantly high in the active patients compared to in the inactive patients and healthy controls (p<0.001 and p<0.001 respectively). There was significantly difference between in active and inactive patients with FMF (p<0.001). As a results; Plasma ghrelin levels were high both in active and inactive patients with FMF. It is showed that ghrelin may play significant role of the pathogenesis of FMF.

  11. Interpersonal Stressors Predict Ghrelin and Leptin Levels in Women

    PubMed Central

    Jaremka, Lisa M.; Belury, Martha A.; Andridge, Rebecca R.; Malarkey, William B.; Glaser, Ronald; Christian, Lisa; Emery, Charles F.; Kiecolt-Glaser, Janice K.

    2014-01-01

    Objective Stressful events enhance risk for weight gain and adiposity. Ghrelin and leptin, two hormones that are implicated in appetite regulation, may link stressful events to weight gain; a number of rodent studies suggest that stressors increase ghrelin production. The present study investigated the links among daily stressors, ghrelin and leptin, and dietary intake in humans. Method Women (N = 50) completed three study appointments that were scheduled at least 2 weeks apart. At each visit, women arrived fasting and ate a standardized breakfast and lunch. Blood samples were collected 45 minutes after each meal. Women completed a self-report version of the Daily Inventory of Stressful Events (DISE) at each appointment. Two composites were created from the DISE data, reflecting the number of stressors that did and did not involve interpersonal tension. Results Women who experienced more stressors involving interpersonal tension had higher ghrelin and lower leptin levels than those who experienced fewer interpersonal stressors. Furthermore, women who experienced more interpersonal stressors had a diet that was higher in calories, fat, carbohydrates, protein, sugar, sodium, and fiber, and marginally higher in cholesterol, vegetables (but not fruits), vitamin A, and vitamin C. Stressors that did not involve interpersonal tension were unrelated to ghrelin and leptin levels or any of the dietary components examined. Conclusions These data suggest that ghrelin and leptin may link daily interpersonal stressors to weight gain and obesity. PMID:25032903

  12. Ghrelin

    PubMed Central

    Müller, T.D.; Nogueiras, R.; Andermann, M.L.; Andrews, Z.B.; Anker, S.D.; Argente, J.; Batterham, R.L.; Benoit, S.C.; Bowers, C.Y.; Broglio, F.; Casanueva, F.F.; D'Alessio, D.; Depoortere, I.; Geliebter, A.; Ghigo, E.; Cole, P.A.; Cowley, M.; Cummings, D.E.; Dagher, A.; Diano, S.; Dickson, S.L.; Diéguez, C.; Granata, R.; Grill, H.J.; Grove, K.; Habegger, K.M.; Heppner, K.; Heiman, M.L.; Holsen, L.; Holst, B.; Inui, A.; Jansson, J.O.; Kirchner, H.; Korbonits, M.; Laferrère, B.; LeRoux, C.W.; Lopez, M.; Morin, S.; Nakazato, M.; Nass, R.; Perez-Tilve, D.; Pfluger, P.T.; Schwartz, T.W.; Seeley, R.J.; Sleeman, M.; Sun, Y.; Sussel, L.; Tong, J.; Thorner, M.O.; van der Lely, A.J.; van der Ploeg, L.H.T.; Zigman, J.M.; Kojima, M.; Kangawa, K.; Smith, R.G.; Horvath, T.; Tschöp, M.H.

    2015-01-01

    Background The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. Scope of review In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. Major conclusions In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism. PMID:26042199

  13. Intracoronary Des-Acyl Ghrelin Acutely Increases Cardiac Perfusion Through a Nitric Oxide-Related Mechanism in Female Anesthetized Pigs.

    PubMed

    Grossini, Elena; Raina, Giulia; Farruggio, Serena; Camillo, Lara; Molinari, Claudio; Mary, David; Walker, Gillian Elisabeth; Bona, Gianni; Vacca, Giovanni; Moia, Stefania; Prodam, Flavia; Surico, Daniela

    2016-06-01

    Des-acyl ghrelin (DAG), the most abundant form of ghrelin in humans, has been found to reduce arterial blood pressure and prevent cardiac and endothelial cell apoptosis. Despite this, data regarding its direct effect on cardiac function and coronary blood flow, as well as the related involvement of autonomic nervous system and nitric oxide (NO), are scarce. We therefore examined these issues using both in vivo and in vitro studies. In 20 anesthetized pigs, intracoronary 100 pmol/mL DAG infusion with a constant heart rate and aortic blood pressure, increased coronary blood flow and NO release, whereas reducing coronary vascular resistances (P < .05). Dose responses to DAG were evaluated in five pigs. No effects on cardiac contractility/relaxation or myocardial oxygen consumption were observed. Moreover, whereas the blockade of muscarinic cholinoceptors (n = 5) or α- and β-adrenoceptors (n = 5 each) did not abolish the observed responses, NO synthase inhibition (n = 5) prevented the effects of DAG on coronary blood flow and NO release. In coronary artery endothelial cells, DAG dose dependently increased NO release through cAMP signaling and ERK1/2, Akt, and p38 MAPK involvement as well as the phosphorylation of endothelial NO synthase. In conclusion, in anesthetized pigs, DAG primarily increased cardiac perfusion through the involvement of NO release. Moreover, the phosphorylation of ERK1/2 and Akt appears to play roles in eliciting the observed NO production in coronary artery endothelial cells.

  14. Association of cord blood des-acyl ghrelin with birth weight, and placental GHS-R1 receptor expression in SGA, AGA, and LGA newborns.

    PubMed

    González-Domínguez, Martha I; Lazo-de-la-Vega-Monroy, Maria-Luisa; Zaina, Silvio; Sabanero, Myrna; Daza-Benítez, Leonel; Malacara, Juan Manuel; Barbosa-Sabanero, Gloria

    2016-07-01

    Although ghrelin in cord blood has been associated to birth weight, its role in fetal and postnatal growth has not been elucidated. The aim of this study was to analyze total ghrelin, acyl ghrelin (AG), and des-acyl ghrelin (DAG) in cord blood of newborns with idiopathic birth weight alterations, and to evaluate protein expression of placental GHS-R1, in order to investigate their correlation with birth weight and placental weight. We performed a cross-sectional comparative study in umbilical cord blood and placentas from healthy mothers of SGA, AGA, and LGA (small, adequate and large for gestational age) term newborns (n = 20 per group). Cord blood total ghrelin, AG, and DAG were measured by ELISA, and placental GHS-R1 expression was evaluated by Western blot. Cord blood DAG was higher in SGA compared to AGA newborns (902.1 ± 109.1 and 597.4 ± 58.2 pg/ml, respectively, p = 0.01) while LGA and AGA showed similar values (627.2 ± 76.4 pg/ml for LGA, p = 0.80). DAG negatively correlated with birthweight (r = -0.31, p = 0.02) and placental weight (r = -0.33, p = 0.02). No differences in AG or total ghrelin were found. GHS-R1 protein in placenta was not differentially expressed among SGA, AGA, and LGA. Our results suggest a role of DAG in intrauterine growth. Further studies are needed in order to elucidate the mechanisms by which DAG participates in fetal growth.

  15. Ghrelin and obestatin levels in type 2 diabetic patients with and without delayed gastric emptying.

    PubMed

    Harsch, Igor A; Koebnick, Corinna; Tasi, Atingwa M; Hahn, Eckhart Georg; Konturek, Peter C

    2009-10-01

    Alterations in the neurohumoral regulation of the upper intestine may change rhythmicity and pattern of ghrelin and obestatin, the latter presumably antagonizing ghrelin effects. Five nongastroparetic diabetic patients and five with gastroparesis were investigated. Over 390 min including breakfast and lunch, ghrelin was significantly lower in patients with gastroparesis compared with in those without (P = 0.015). Ghrelin subsequent to lunch decreased significantly (P = 0.011) in patients without gastroparesis, but not in gastroparetic patients (P = 0.669). Obestatin was similar in both groups and unchanged. No significant differences in ghrelin-to-obestatin ratio were observed (P = 0.530). Loss of rhythmicity in the ghrelin levels of gastroparetic diabetics highlights the importance of integrity of the neurohumoral-intestinal axis. Stable diurnal obestatin levels do not support the concept of interaction between ghrelin and obestatin in terms of regulation of food intake and gastric emptying.

  16. Circulating ghrelin level is higher in HNF1A-MODY and GCK-MODY than in polygenic forms of diabetes mellitus.

    PubMed

    Nowak, Natalia; Hohendorff, Jerzy; Solecka, Iwona; Szopa, Magdalena; Skupien, Jan; Kiec-Wilk, Beata; Mlynarski, Wojciech; Malecki, Maciej T

    2015-12-01

    Ghrelin is a hormone that regulates appetite. It is likely to be involved in the pathophysiology of varying forms of diabetes. In animal studies, the ghrelin expression was regulated by the hepatocyte nuclear factor 1 alpha (HNF1A). Mutations of the HNF1A gene cause maturity onset diabetes of the young (MODY). We aimed to assess the circulating ghrelin levels in HNF1A-MODY and in other types of diabetes and to evaluate its association with HNF1A mutation status. Our cohort included 46 diabetic HNF1A gene mutation carriers, 55 type 2 diabetes (T2DM) subjects, 42 type 1 diabetes (T1DM) patients, and 31 glucokinase (GCK) gene mutation carriers with diabetes as well as 51 healthy controls. Plasma ghrelin concentration was measured using the immunoenzymatic assay with polyclonal antibody against the C-terminal fragment of its acylated and desacylated forms. Ghrelin concentrations were 0.75 ± 0.32, 0.70 ± 0.21, 0.50 ± 0.20, and 0.40 ± 0.16 ng/ml in patients with HNF1A-MODY, GCK-MODY, T1DM, and T2DM, respectively. The ghrelin levels were higher in HNF1A-MODY and GCK-MODY than in T1DM and T2DM (p < 0.001 for all comparisons) but lower than in non-diabetic controls (1.02 ± 0.29 ng/ml, p < 0.001 for both comparisons). In the multivariate linear model, the differences between both MODY groups and common diabetes types remained significant. Analysis by a HNF1A mutation type indicated that ghrelin concentration is similar in patients with different types of sequence differences. Plasma ghrelin level is higher in HNF1A-MODY and GCK-MODY than in the common polygenic forms of diabetes.

  17. Ghrelin and adipokines as circulating markers of disease activity in patients with Takayasu arteritis

    PubMed Central

    2012-01-01

    Introduction The current markers of disease activity in Takayasu arteritis (TA) are insufficient for proper assessment. We investigated circulating levels of unacylated and acylated ghrelin, leptin and adiponectin and their relationships with disease activity in patients with TA. Methods This study included 31 patients with TA and 32 sex-, age- and body mass index-matched healthy controls. Disease activity was assessed in TA patients using various tools, including Kerr's criteria, disease extent index-Takayasu, physician's global assessment, radiological parameters, and laboratory markers. Plasma unacylated and acylated ghrelin, and serum leptin and adiponectin levels were measured using an enzyme-linked immunosorbent assay. Results Unacylated and acylated ghrelin levels were found to be significantly lower in TA patients than that in healthy controls. Patients with active disease had lower unacylated ghrelin levels than those with inactive disease and had lower acylated ghrelin levels than healthy controls. Ghrelin levels were negatively correlated with various parameters of disease activity. The leptin/ghrelin ratio was significantly higher in TA patients than controls. It was positively correlated with disease activity. There was a positive correlation between unacylated and acylated ghrelin and a negative correlation between leptin and ghrelin. There was no statistical difference in adiponectin levels between TA patients and controls. The radiological activity markers were positively correlated with other parameters of disease activity. Conclusions This study suggests that plasma unacylated and acylated ghrelin levels may be useful in monitoring disease activity and planning treatment strategies for patients with TA. The serum leptin level and leptin/ghrelin ratio may also be used to help assess the disease activity. PMID:23259466

  18. Neonatal overfeeding disrupts pituitary ghrelin signalling in female rats long-term; Implications for the stress response

    PubMed Central

    Ziko, Ilvana; Spencer, Sarah J.

    2017-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis responses to psychological stress are exacerbated in adult female but not male rats made obese due to overfeeding in early life. Ghrelin, traditionally known for its role in energy homeostasis, has been recently recognised for its role in coordinating the HPA responses to stress, particularly by acting directly at the anterior pituitary where the growth hormone secretagogue receptor (GHSR), the receptor for acyl ghrelin, is abundantly expressed. We therefore hypothesised that neonatal overfeeding in female rats would compromise pituitary responsiveness to ghrelin, contributing to a hyperactive central stress responsiveness. Unlike in males where hypothalamic ghrelin signalling is compromised by neonatal overfeeding, there was no effect of early life diet on circulating ghrelin or hypothalamic ghrelin signalling in females, indicating hypothalamic feeding and metabolic ghrelin circuitry remains intact. However, neonatal overfeeding did lead to long-term alterations in the pituitary ghrelin system. The neonatally overfed females had increased neonatal and reduced adult expression of GHSR and ghrelin-O-acyl transferase (GOAT) in the pituitary as well as reduced pituitary responsiveness to exogenous acyl ghrelin-induced adrenocorticotropic hormone (ACTH) release in vitro. These data suggest that neonatal overfeeding dysregulates pituitary ghrelin signalling long-term in females, potentially accounting for the hyper-responsive HPA axis in these animals. These findings have implications for how females may respond to stress throughout life, suggesting the way ghrelin modifies the stress response at the level of the pituitary may be less efficient in the neonatally overfed. PMID:28282447

  19. Basal and postprandial plasma levels of PYY, ghrelin, cholecystokinin, gastrin and insulin in women with moderate and morbid obesity and metabolic syndrome.

    PubMed

    Zwirska-Korczala, K; Konturek, S J; Sodowski, M; Wylezol, M; Kuka, D; Sowa, P; Adamczyk-Sowa, M; Kukla, M; Berdowska, A; Rehfeld, J F; Bielanski, W; Brzozowski, T

    2007-03-01

    Metabolic syndrome (MS), defined as central obesity, hyperinsulinemia, insulin resistance, hypertension, dyslipidemia and glucose intolerance, has been associated with inflammatory biomarkers and cardiovascular diseases. This study was carried out on three groups of women; lean controls, moderately obese with MS (OB-MS) and morbidly obese with MS (MOB-MS). The main objectives were: 1. to analyze the plasma levels of total and acylated ghrelin, peptide YY(3-36) (PYY(3-36)), cholecystokinin (CCK), gastrin and insulin levels under basal conditions and in response to a standard mixed meal, and 2. to elucidate the relationship between the plasma levels of these gut peptides and metabolic syndrome parameters. Plasma levels of the gut hormones were measured by radioimmunoassays at time 0 just before the meal and at 30, 60 and 120 min after a meal ingestion. Traditional lipid profile and high-sensitivity C reactive protein (hs-CRP), the strongest biomarker of inflammation were also determined in OB-MS and MOB-MS. When compared to OB-MS, MOB-MS exhibited much higher anthropometric parameters such as waist circumference, higher fat mass and higher plasma levels of low density lipoprotein-cholesterol (LDL-C) and hs-CRP. Both these obese groups revealed significantly higher values of body mass index (BMI), fat mass, total cholesterol (TC), LDL-C, fasting glucose, fasting insulin, insulin resistance (IR) calculated from homeostatic model assessment (HOMA) and hs-CRP compared to the values recorded in lean subjects. Fasting PYY(3-36) level was lower, while fasting acylated ghrelin was higher in MOB-MS than in OB-MS. Plasma total and acylated ghrelin levels were significantly lower in OB-MS compared to lean women. In MOB-MS women the fasting PYY(3-36) levels were lower compared to lean controls and OB-MS, whilst postprandially in both OB-MS and MOB-MS, it was much lower than in lean women. The fasting plasma levels of total and acylated ghrelin and their postprandial decrease

  20. Perinatal Oxidative Stress May Affect Fetal Ghrelin Levels in Humans.

    PubMed

    Luo, Zhong-Cheng; Bilodeau, Jean-François; Nuyt, Anne Monique; Fraser, William D; Julien, Pierre; Audibert, Francois; Xiao, Lin; Garofalo, Carole; Levy, Emile

    2015-12-08

    In vitro cell model studies have shown that oxidative stress may affect beta-cell function. It is unknown whether oxidative stress may affect metabolic health in human fetuses/newborns. In a singleton pregnancy cohort (n = 248), we studied maternal (24-28 weeks gestation) and cord plasma biomarkers of oxidative stress [malondialdehyde (MDA), F2-isoprostanes] in relation to fetal metabolic health biomarkers including cord plasma glucose-to-insulin ratio (an indicator of insulin sensitivity), proinsulin-to-insulin ratio (an indicator of beta-cell function), insulin, IGF-I, IGF-II, leptin, adiponectin and ghrelin concentrations. Strong positive correlations were observed between maternal and cord plasma biomarkers of oxidative stress (r = 0.33 for MDA, r = 0.74 for total F2-isoprostanes, all p < 0.0001). Adjusting for gestational age at blood sampling, cord plasma ghrelin concentrations were consistently negatively correlated to oxidative stress biomarkers in maternal (r = -0.32, p < 0.0001 for MDA; r = -0.31, p < 0.0001 for F2-isoprostanes) or cord plasma (r = -0.13, p = 0.04 for MDA; r = -0.32, p < 0.0001 for F2-isoprostanes). Other fetal metabolic health biomarkers were not correlated to oxidative stress. Adjusting for maternal and pregnancy characteristics, similar associations were observed. Our study provides the first preliminary evidence suggesting that oxidative stress may affect fetal ghrelin levels in humans. The implications in developmental "programming" the vulnerability to metabolic syndrome related disorders remain to be elucidated.

  1. Fasting levels of ghrelin covary with the brain response to food pictures.

    PubMed

    Kroemer, Nils B; Krebs, Lena; Kobiella, Andrea; Grimm, Oliver; Pilhatsch, Maximilian; Bidlingmaier, Martin; Zimmermann, Ulrich S; Smolka, Michael N

    2013-09-01

    Ghrelin figures prominently in the regulation of appetite in normal-weighed individuals. The apparent failure of this mechanism in eating disorders and the connection to addictive behavior in general demand a deeper understanding of the endogenous central-nervous processes related to ghrelin. Thus, we investigated processing of pictures showing palatable food after overnight fasting and following a standardized caloric intake (i.e. a 75-g oral glucose tolerance test) using functional magnetic resonance imaging and correlated it with blood plasma levels of ghrelin. Twenty-six healthy female and male volunteers viewed food and control pictures in a block design and rated their appetite after each block. Fasting levels of ghrelin correlated positively with food-cue reactivity in a bilateral network of visual processing-, reward- and taste-related regions, including limbic and paralimbic regions. Notably, among those regions were the hypothalamus and the midbrain where ghrelin receptors are densely concentrated. In addition, high fasting ghrelin levels were associated with stronger increases of subjective appetite during the food-cue-reactivity task. In conclusion, brain activation and subjective appetite ratings suggest that ghrelin elevates the hedonic effects of food pictures. Thereby, fasting ghrelin levels may generally enhance subjective craving when confronted with reward cues.

  2. Plasma Ghrelin Levels Are Associated with Anorexia but Not Cachexia in Patients with NSCLC

    PubMed Central

    Blauwhoff-Buskermolen, Susanne; Langius, Jacqueline A. E.; Heijboer, Annemieke C.; Becker, Annemarie; de van der Schueren, Marian A. E.; Verheul, Henk M. W.

    2017-01-01

    Background and Aims: The ghrelin receptor is one of the new therapeutic targets in the cancer anorexia-cachexia syndrome. Previous studies revealed that plasma ghrelin levels were high in patients with anorexia nervosa and low in obese subjects. We studied to what extent ghrelin levels are related with anorexia and cachexia in patients with cancer. Materials and Methods: Fasted ghrelin levels were determined as well as anorexia and cachexia in patients with stage III/IV non-small cell lung cancer before chemotherapy. Total plasma ghrelin was measured by radioimmunoassay. Anorexia was measured with the FAACT-A/CS questionnaire (cut-off value ≤ 37). Cachexia was determined as >5% weight loss (WL) in 6 months or >2% WL in 6 months in combination with low BMI or low muscle mass. The Kruskal-Wallis test was performed to assess differences in plasma ghrelin levels between four groups: patients with (+) or without (−) anorexia (A) or cachexia (C). Multiple regression analyses were performed to assess differences in plasma ghrelin levels between patients C+ and C− and patients with A+ and A− (adjusted for age and sex). Results: Forty patients with stage III (33%) or stage IV (68%) were recruited, of which 50% was male. Mean age was 59.6 ± 10.3 years. Sixteen patients had no anorexia or cachexia (A−C−), seven patients had both anorexia and cachexia (A+C+), ten patients had anorexia without cachexia (A+C−) and seven patients had cachexia without anorexia (A−C+). The levels of total plasma ghrelin were significantly different between the four groups of patients with or without anorexia or cachexia (p = 0.032): the A+C− patients had significantly higher ghrelin levels [median (IQR): 1,754 (1,404–2,142) compared to the A−C+ patients 1,026 (952–1,357), p = 0.003]. A+ patients had significantly higher ghrelin levels compared A− patients (C+ and C− combined, β: 304, p = 0.020). Plasma ghrelin levels were not significantly different in C+ patients

  3. Influence of Helicobacter pylori infection on levels of ghrelin and obestatin in human semen.

    PubMed

    Moretti, Elena; Collodel, Giulia; Campagna, Maria Stella; Franci, Maria Beatrice; Iacoponi, Francesca; Mazzi, Lucia; Figura, Natale

    2012-01-01

    Helicobacter pylori (HP) infection might have negative effects on the semen parameters of infertile men. We explored the possibility that this infection can influence systemic and seminal levels of ghrelin and obestatin, hormones mainly produced by the stomach. Ghrelin and obestatin exert many activities, including the regulation of reproductive biology, and are present in many organs and fluids, including human semen. In 78 men, we determined HP infection and cytotoxin-associated gene A protein (CagA) status by enzyme-linked immunosorbent assay and Western blotting, semen quality following World Health Organization guidelines, and ghrelin and obestatin levels in the blood stream (47 subjects) and semen by radioimmunoassay. Twenty-seven men (34.6%) were infected (HP+) and 11 out of 27 infected men (40.7%) were seropositive for CagA (CagA+). Sperm motility was significantly reduced in HP+/CagA+ men compared with HP+/CagA- men (P < .01). Ghrelin semen levels were decreased in HP+ men compared with uninfected individuals (P < .05), whereas they were increased in HP+/CagA+ men compared with HP+/CagA- subjects (P < .01). Ghrelin semen concentrations in HP+/CagA- men were lower than those measured in uninfected subjects (P < .001). Semen obestatin concentration was increased, in a nonsignificant manner, in HP+/CagA+ men. The obestatin levels were approximately 4 times higher than those of ghrelin in semen and approximately half the levels of ghrelin in serum specimens of all the analyzed groups. No significant differences were found in systemic levels of ghrelin and obestatin in HP+ to uninfected individuals. HP infection may influence the ghrelin seminal concentrations, probably as a response to a negative effect of infection on the semen quality.

  4. Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders.

    PubMed

    Tanaka, Muneki; Naruo, Tetsuro; Nagai, Nobuatsu; Kuroki, Nobutaka; Shiiya, Tomomi; Nakazato, Masamitsu; Matsukura, Shigeru; Nozoe, Shin-ichi

    2003-01-01

    Previous studies have reported that fasting plasma ghrelin concentrations play an important role in the pathophysiology of eating disorders. The purpose of this study was to examine the relationship between plasma ghrelin levels and frequency of abnormal eating behaviors, nutritional parameters in eating disorders. Fasting blood samples were obtained in 40 female anorexia nervosa (AN) patients, 21 restricting type (AN-R) and 19 binge-eating/purging type (AN-BP), in 31 bulimia nervosa (BN) patients, 18 purging type (BN-P) and 13 non-purging type (BN-NP), in 15 female healthy volunteers (control) before the initiation of active treatment. The fasting plasma ghrelin concentrations in all subjects were negatively correlated with nutritional parameters such as body mass index, percent body fat and serum cholinesterase concentration. The mean plasma ghrelin level in BN-P was higher than that in both BN-NP and controls despite similar nutritional parameters. The plasma ghrelin levels in both AN-R and AN-BP did not differ from BN-P despite difference of nutritional parameters. For both AN-BP and BN-P patients with habitual binge/purge behavior, there were significant correlations among plasma ghrelin values, frequencies of binge/purge cycles and serum amylase values. In BN-NP, there were no significant correlations among plasma ghrelin values, frequencies of binge-eating episodes and serum amylase values. These results suggest that habitual binge/purge behavior may have some influence on circulating plasma ghrelin levels in both BN-P and AN-BP. Habitual binge/purge cycles with vomiting as opposed to binge-eating episodes without vomiting may have a greater influence on fasting plasma ghrelin concentration in eating disorders.

  5. Treatment with pioglitazone is associated with decreased preprandial ghrelin levels: a randomized clinical trial.

    PubMed

    Taslimi, Shervin; Esteghamati, Alireza; Rashidi, Armin; Tavakkoli, Hosein Moin; Nakhjavani, Manouchehr; Kebriaee-Zadeh, Abbas

    2013-02-01

    The effects of metformin and pioglitazone on ghrelin, a physiologic regulator of appetite and food intake, have not been clearly established. In a randomized clinical trial, we randomly assigned 60 type 2 diabetic patients to either metformin (Group A; n=30) or pioglitazone (Group B; n=30) treatment groups. The groups were similar in their baseline characteristics. A standard fasting 75 g oral glucose tolerance test was performed at time zero before starting metformin or pioglitazone, and 3 months later. After 3 months of treatment, pioglitazone, but not metformin, was significantly associated with weight gain. Both groups experienced a significant reduction in fasting plasma glucose (p<0.01), hemoglobin A1c (p<0.01 in Group A and p<0.05 in Group B), and insulin resistance (p<0.01). The effect of metformin on preprandial ghrelin and its response to glucose challenge was not significant, while the pioglitazone group had a significant reduction in preprandial ghrelin levels after treatment (p<0.05). The effect of pioglitazone on ghrelin was independent of changes in body weight, body mass index, glucose control, insulin resistance, and plasma insulin. In conclusion, treatment with pioglitazone is associated with a decrease in preprandial ghrelin levels and therefore, the weight gain and increased food intake related to pioglitazone use cannot be explained by its effects on ghrelin. The effect of pioglitazone on ghrelin is independent of changes in body weight, body mass index, plasma insulin, insulin resistance, or glucose control.

  6. Ghrelin levels are not regulated by recombinant leptin administration and/or three days of fasting in healthy subjects.

    PubMed

    Chan, Jean L; Bullen, John; Lee, Jennifer H; Yiannakouris, Nikos; Mantzoros, Christos S

    2004-01-01

    Ghrelin, a stomach-derived orexigenic peptide, and leptin, a fat-derived anorexigenic hormone, act primarily in the hypothalamus to regulate energy homeostasis and have been reported to be regulated in opposite directions by acute and chronic changes in nutritional state. Nutritional, anthropometric, and hormonal predictors of circulating ghrelin have not yet been fully elucidated, and whether ghrelin is regulated by leptin in humans remains unknown. To address these questions, we performed cross-sectional and interventional studies. In 120 healthy men and women, ghrelin was negatively associated with leptin as well as overall and central adiposity, but not with total energy or specific macronutrient intake. The sexual dimorphism in ghrelin levels (higher levels in women than in men) and the negative correlation between ghrelin and insulin are largely mediated by central adiposity. In six lean men, complete fasting for 3 d resulted in a low leptin state without a major change in fat mass and abolished the meal-related secretory pattern of ghrelin without increasing 24-h ghrelin levels. In addition, recombinant human leptin administration in physiological and pharmacological doses did not regulate ghrelin over several hours to a few days. These data do not support a role for regulation of circulating ghrelin by leptin levels independently of changes in adiposity and suggest that the leptin and ghrelin systems for energy homeostasis function independently of each other in healthy humans.

  7. Lower Plasma Ghrelin Levels are Found in Women with Diabetes-Complicated Pregnancies

    PubMed Central

    Gómez-Díaz, Rita Angélica; Gómez-Medina, Monica P.; Ramírez-Soriano, Eleazar; López-Robles, Lucio; Aguilar-Salinas, Carlos A.; Saucedo, Renata; Zarate, Arturo; Valladares-Salgado, Adan; Wacher, Niels H.

    2016-01-01

    Objective: To evaluate the associations of glycemic control and gestational age with ghrelin and proinsulin levels in cord blood and mothers’ peripheral blood during pregnancy. Methods: This is a cross-sectional comparative study of twenty-four pregnant women with gestational diabetes (GD), 18 with type 2 diabetes mellitus (T2DM), and 36 without diabetes, as well as their neonates. Levels of proinsulin, ghrelin, and glycated hemoglobin A1c (HbA1c) were measured from maternal blood during the last week before caesarian delivery and in neonatal umbilical cord blood samples. Results: Mothers with GD and T2DM had significantly lower ghrelin levels compared to the healthy mothers (p<0.001). Maternal proinsulin was lower in women with GD than in women without diabetes (p<0.001). Proinsulin was significantly elevated in the neonates of women with GD and in women with HbA1c ≥6.5% (p<0.001). However, maternal ghrelin levels were higher (p=0.031) and neonate proinsulin levels lower in the pre-term offspring of mothers with GD (p=0.033). There was a negative correlation between HbA1c levels and birth weight (r=–0.407, p<0.001). Conclusion: Ghrelin levels were lower in pregnant women with diabetes, although pre-term birth appeared to reverse this trend in GD. Proinsulin levels were also low in pregnant women with diabetes and even lower in pre-term vs. at-term births. Both ghrelin and proinsulin levels were lower in pregnant women with diabetes and HbA1c of <6.5%. Thus, ghrelin participates in the adaptation to the caloric imbalance of diabetic pregnancy and may play a similar role in pregnancy-related complications, since high ghrelin concentrations may be necessary for normal fetal development. PMID:27476441

  8. Ghrelin and the short- and long-term regulation of appetite and body weight.

    PubMed

    Cummings, David E

    2006-08-30

    Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone. Considerable evidence implicates ghrelin in mealtime hunger and meal initiation. Circulating levels decrease with feeding and increase before meals, achieving concentrations sufficient to stimulate hunger and food intake. Preprandial ghrelin surges occur before every meal on various fixed feeding schedules and also among individuals initiating meals voluntarily without time- or food-related cues. Ghrelin injections stimulate food intake rapidly and transiently, primarily by increasing appetitive feeding behaviors and the number of meals. Preprandial ghrelin surges are probably triggered by sympathetic nervous output. Postprandial suppression is not mediated by nutrients in the stomach or duodenum, where most ghrelin is produced. Rather, it results from post-ingestive increases in lower intestinal osmolarity (information probably relayed to the foregut via enteric nervous signaling), as well as from insulin surges. Consequently, ingested lipids suppress ghrelin poorly compared with other macronutrients. Beyond a probable role in meal initiation, ghrelin also fulfills established criteria for an adiposity-related hormone involved in long-term body-weight regulation. Ghrelin levels circulate in relation to energy stores and manifest compensatory changes in response to body-weight alterations. Ghrelin crosses the blood-brain barrier and stimulates food intake by acting on several classical body-weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system. Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader-Willi syndrome and low after gastric bypass

  9. Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease.

    PubMed

    Zhang, Shao-Ren; Fan, Xiao-Ming

    2015-03-21

    Nonalcoholic fatty liver disease (NAFLD) is currently considered as the most common liver disease in Western countries, and is rapidly becoming a serious threat to public health worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. The ghrelin-ghrelin O-acyltransferase (GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis. Ghrelin, the natural ligand of the growth hormone secretagogue receptor, is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT. The ghrelin-GOAT system is involved in insulin resistance, lipid metabolism dysfunction, and inflammation, all of which play important roles in the pathogenesis of NAFLD. A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD. Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied, which provide a new insight into the pathogenesis of NAFLD. This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD, and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.

  10. Differential effects of olanzapine and clozapine on plasma levels of adipocytokines and total ghrelin.

    PubMed

    Lu, Mong-Liang; Wang, Tsu-Nai; Lin, Tsang-Yaw; Shao, Wen-Chuan; Chang, Sheng-Huang; Chou, Jen-Yu; Ho, Yi-Feng; Liao, Yin-To; Chen, Vincent Chin-Hung

    2015-04-03

    Second-generation antipsychotics (SGAs) have been associated with an increased liability for weight gain and metabolic side effects. Among SGAs, clozapine and olanzapine had great liability to induce weight gain and metabolic adverse reactions. Leptin, adiponectin, and total ghrelin play important roles in energy homeostasis and are suggested to be biomarkers of metabolic disturbances. The purpose of the present study was to investigate the differential effects of antipsychotics (olanzapine and clozapine) on the levels of adipocytokines (leptin and adiponectin) and total ghrelin. Three hundred and thirty-three patients with schizophrenia under clozapine or olanzapine monotherapy were recruited. Control participants were recruited from a healthy community population based on a health investigation (N=119). Fasting blood samples for glucose, cholesterol, triglycerides, leptin, adiponectin, and total ghrelin were analyzed. There were significant differences in the levels of cholesterol, triglycerides, and glucose between these three groups. Post hoc comparisons showed that the olanzapine group had the highest levels of cholesterol and triglycerides. The levels of leptin, adiponectin, and total ghrelin were also significantly different between the three groups after controlling age and body mass index (BMI). Post hoc comparisons showed that the olanzapine group had the lowest levels of adiponectin and total ghrelin. The present study found that the uses of olanzapine and clozapine were associated with changes in adipocytokines and total ghrelin, even after adjusting potential confounding factors. Olanzapine had greater influences on adiponectin and total ghrelin than clozapine. The changes in adipocytokines and total ghrelin were a direct effect of antipsychotics on hormonal pathways of energy homeostasis, rather than the result of weight gain.

  11. Ghrelin, leptin, adiponectin, and resistin levels in sleep apnea syndrome: Role of obesity

    PubMed Central

    Ursavas, Ahmet; Ilcol, Yesim Ozarda; Nalci, Nazan; Karadag, Mehmet; Ege, Ercument

    2010-01-01

    AIM: The aim of this study was to investigate the relationship among plasma leptin, ghrelin, adiponectin, resistin levels, and obstructive sleep apnea syndrome (OSAS). METHODS: Fifty-five consecutive newly diagnosed OSAS patients and 15 age-matched nonapneic controls were enrolled in this study. After sleep study between 8:00 AM and 9:00 AM on the morning, venous blood was obtained in the fasting state to measure ghrelin and adipokines. RESULTS: Serum ghrelin levels of OSAS group were significantly (P < 0.05) higher than those of the control group. No significant difference was noted in the levels of leptin, adiponectin, and resistin in OSAS group when compared to controls. There was a significant positive correlation between ghrelin and apnea–hypopnea index (AHI) (r = 0.237, P < 0.05) or the Epworth sleepiness scale (ESS) (r = 0.28, P < 0.05). There was also a significant positive correlation between leptin and body mass index (r = 0.592, P < 0.0001). No significant correlation was observed between leptin, adiponectin, resistin, and any polysomnographic parameters. CONCLUSION: Our findings demonstrated that serum ghrelin levels were higher in OSAS patients than those of control group and correlated with AHI and ESS. Further studies are needed to clarify the complex relation among OSAS, obesity, adipokines, and ghrelin. PMID:20835311

  12. Hypothalamic Ceramide Levels Regulated by CPT1C Mediate the Orexigenic Effect of Ghrelin

    PubMed Central

    Ramírez, Sara; Martins, Luís; Jacas, Jordi; Carrasco, Patricia; Pozo, Macarena; Clotet, Josep; Serra, Dolors; Hegardt, Fausto G.; Diéguez, Carlos; López, Miguel; Casals, Núria

    2013-01-01

    Recent data suggest that ghrelin exerts its orexigenic action through regulation of hypothalamic AMP-activated protein kinase pathway, leading to a decline in malonyl-CoA levels and desinhibition of carnitine palmitoyltransferase 1A (CPT1A), which increases mitochondrial fatty acid oxidation and ultimately enhances the expression of the orexigenic neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY). However, it is unclear whether the brain-specific isoform CPT1C, which is located in the endoplasmic reticulum of neurons, may play a role in this action. Here, we demonstrate that the orexigenic action of ghrelin is totally blunted in CPT1C knockout (KO) mice, despite having the canonical ghrelin signaling pathway activated. We also demonstrate that ghrelin elicits a marked upregulation of hypothalamic C18:0 ceramide levels mediated by CPT1C. Notably, central inhibition of ceramide synthesis with myriocin negated the orexigenic action of ghrelin and normalized the levels of AgRP and NPY, as well as their key transcription factors phosphorylated cAMP-response element–binding protein and forkhead box O1. Finally, central treatment with ceramide induced food intake and orexigenic neuropeptides expression in CPT1C KO mice. Overall, these data indicate that, in addition to formerly reported mechanisms, ghrelin also induces food intake through regulation of hypothalamic CPT1C and ceramide metabolism, a finding of potential importance for the understanding and treatment of obesity. PMID:23493572

  13. Extraordinary level of hormone and number of ghrelin cells in the stomach and duodenum of an obese woman.

    PubMed

    Kasacka, Irena; Arciszewski, Maciej; Łebkowski, Wojciech

    2014-01-01

    Obesity is a major metabolic disorder, in which ghrelin plays a significant role. The objective of this study was to characterize the morphology of ghrelin cells in the stomach and duodenum and the levels of ghrelin and leptin in the serum of a 52-year-old obese woman. Material for the study was obtained from the stomachs and duodenum, of obese and control women. Each subject had been treated at the Intensive Care Unit of the Clinical University Hospital in Białystok, due to brain damage, due to primary cardiac arrest. After brain death was diagnosed and individual death was confirmed by doctors, stomach and duodenum samples were collected from each body. Paraffin sections were stained with hematoxylin and eosin and processed for immunolocalization of ghrelin. The density of ghrelin cells in each part of the gastrointestinal tract was estimated under a light microscope with a digital camera. Ghrelin-IR cells were also analyzed in terms of morphometric features such as length, width and area. The ghrelin and leptin concentrations in each blood sample were measured by ELISA. Immunohistochemical studies revealed a small number of ghrelin cells in the stomach and duodenum which did not reflect the high level of hormone. The obese woman had lower number of ghrelin cells in the stomach and duodenum and elevated ghrelin and leptin levels in serum. It can therefore be assumed that additional source of ghrelin and probably changes in activity of ghrelin o-acylotransferase, are responsible for the high concentration of ghrelin in the obese woman.

  14. Effects of acute ethionine injection on plasma ghrelin and obestatin levels in trained male rats.

    PubMed

    Ghanbari-Niaki, Abbass; Soltani, Rahelah; Shemshaki, Afsaneh; Kraemer, Robert R

    2010-07-01

    Ghrelin and obestatin are orexigenic and anorexigenic peptides, respectively, that are secreted from the stomach mucosa into the circulation. These peptides have opposing actions on food intake, weight gain, and adiposity. It is thought that ghrelin is sensitive to a negative energy environment and also plays a considerable role in short- and long-term energy balance and glucose homeostasis. It has been suggested that the levels of ghrelin and obestatin are upregulated by fasting, hypoglycemic status, and a physical-exercise-induced energy deficit. Ethionine (ETH), the ethyl analogue of methionine, has been shown to increase food intake, decrease adenosine triphosphate (ATP) and glycogen levels, and inhibit protein synthesis in the liver. The purpose of this study was to examine the effect of a single dose of ETH (0.7 mg/g of body weight) injection on resting plasma total ghrelin and obestatin concentrations in male trained rats. Thirty-two adult Wistar male rats weighing 180 to 200 g were randomly assigned to control (n = 16) and training (n =16) groups. The training group was exercised for 10 weeks (25 m/min, 0% grade, 60 minutes, and 5 d/wk). Seventy-two hours after the last exercise session, rats were injected with either saline (NaCl) or ETH and then killed. Ethionine compared with a NaCl injection resulted in significant (P < .013) reductions in resting hepatic ATP and glycogen levels, and in a significant (P < .001) increase in concentrations of plasma total ghrelin but not obestatin. The results indicate that ETH-induced liver ATP and glycogen deficiency could exert a powerful regulatory influence on plasma total ghrelin, but this is not the case for obestatin. Findings demonstrate the short-term energy-regulating capacity of ghrelin.

  15. Central injection of CDP-choline suppresses serum ghrelin levels while increasing serum leptin levels in rats.

    PubMed

    Kiyici, Sinem; Basaran, Nesrin Filiz; Cavun, Sinan; Savci, Vahide

    2015-10-05

    In this study we aimed to test central administration of CDP-choline on serum ghrelin, leptin, glucose and corticosterone levels in rats. Intracerebroventricular (i.c.v.) 0.5, 1.0 and 2.0 µmol CDP-choline and saline were administered to male Wistar-Albino rats. For the measurement of serum leptin and ghrelin levels, blood samples were obtained baseline and at 5, 15, 30, 60 and 120 min following i.c.v. CDP-choline injection. Equimolar doses of i.c.v. choline (1.0 µmol) and cytidine (1.0 µmol) were administered and measurements were repeated throughout the second round of the experiment. Atropine (10 µg) and mecamylamine (50 µg) were injected intracerebroventricularly prior to CDP-choline and measurements repeated in the third round of the experiment. After 1 µmol CDP-choline injection, serum ghrelin levels were suppressed significantly at 60 min (P=0.025), whereas serum leptin levels were increased at 60 and 120 min (P=0.012 and P=0.017 respectively). CDP-choline injections also induced a dose- and time-dependent increase in serum glucose and corticosterone levels. The effect of choline on serum leptin and ghrelin levels was similar with CDP-choline while no effect was seen with cytidine. Suppression of serum ghrelin levels was eliminated through mecamylamine pretreatment while a rise in leptin was prevented by both atropine and mecamylamine pretreatments. In conclusion; centrally injected CDP-choline suppressed serum ghrelin levels while increasing serum leptin levels. The observed effects following receptor antagonist treatment suggest that nicotinic receptors play a role in suppression of serum ghrelin levels,whereas nicotinic and muscarinic receptors both play a part in the increase of serum leptin levels.

  16. Active ghrelin levels across time and associations with leptin and anthropometrics in healthy ache Amerindian women of Paraguay.

    PubMed

    Bribiescas, Richard G; Betancourt, Jaime; Torres, Angélica M; Reiches, Meredith

    2008-01-01

    Active (acylated) ghrelin is a peptide hormone secreted primarily by the stomach, positively associated with fasting, orexigenic, and promotes growth hormone secretion. It is therefore important to energy intake management. The objective of this pilot research was to (1) compare active ghrelin with previous measurements of leptin and anthropometrics; (2) assess the consistency of active ghrelin across time in this population; (3) extend our understanding of potential population variation in active ghrelin. Two serum samples separated by 10 days at the same time between meals were collected from healthy Ache women (n = 12, mean age 32.2 +/- 14.0 SD) to determine consistency over time, associations with leptin, and anthropmetric values. Mean active ghrelin was 72.9 +/- 23.0 pg/ml, highly correlated (r(2) = 0.95, P < 0.0001) between collections, and showed no paired mean differences (P < 0.18). There was no significant correlation with leptin, age, or anthropometric measures. Active ghrelin appears to be consistent over time in this population, perhaps reflecting regimented meal schedules and less interpopulation variation compared to leptin.

  17. Appetite regulation is independent of the changes in ghrelin levels in pregnant rats fed low-protein diet

    PubMed Central

    Gao, Haijun; Tanchico, Daren T; Yallampalli, Uma; Balakrishnan, Meena P; Yallampalli, Chandra

    2015-01-01

    Gestational protein restriction causes hypertension in the adult offspring. Very little is known about the food intake regulation and ghrelin signaling in pregnant dams fed a low-protein (LP) diet. We hypothesized that diet intake and ghrelin signaling are altered in pregnant rats fed the low-protein diet. Sprague–Dawley rats were fed a control (CT) or LP diet from Day 3 of pregnancy. Diet intake and body weight were monitored daily. Expression of ghrelin production-related genes in the stomach and appetite-related genes in the hypothalamus was analyzed by real-time PCR. Plasma levels of total and active ghrelin, growth hormone and leptin were measured by ELISA. Main results include: (1) Daily diet intake was greater in the LP group than in the CT group in early pregnancy, but substantially lower in late pregnancy; (2) Daily gain in body weight was substantially lower in the LP group in late pregnancy; (3) Expression of ghrelin production-related genes in the stomach and plasma total ghrelin levels were increased in LP group in late pregnancy; (4) Plasma active ghrelin levels were elevated in the LP group at mid-late pregnancy, but growth hormone and leptin levels were uncorrelated with active ghrelin in late pregnancy; and (5) Hypothalamic expression of ghrelin-stimulated genes in LP rats was unassociated with the changes in both plasma ghrelin levels and the diet intake. Taken together, the appetite in LP rats is greater in early pregnancy but reduced at late pregnancy, possibly due to ghrelin insensitivity in appetite regulation. PMID:25907788

  18. Role of endogenous cortistatin in the regulation of ghrelin system expression at pancreatic level under normal and obese conditions.

    PubMed

    Chanclón, Belén; Luque, Raúl M; Córdoba-Chacón, José; Gahete, Manuel D; Pozo-Salas, Ana I; Castaño, Justo P; Gracia-Navarro, Francisco; Martínez-Fuentes, Antonio J

    2013-01-01

    Ghrelin-system components [native ghrelin, In1-ghrelin, Ghrelin-O-acyltransferase enzyme (GOAT) and receptors (GHS-Rs)] are expressed in a wide variety of tissues, including the pancreas, where they exert different biological actions including regulation of neuroendocrine secretions, food intake and pancreatic function. The expression of ghrelin system is regulated by metabolic conditions (fasting/obesity) and is associated with the progression of obesity and insulin resistance. Cortistatin (CORT), a neuropeptide able to activate GHS-R, has emerged as an additional link in gut-brain interplay. Indeed, we recently reported that male CORT deficient mice (cort-/-) are insulin-resistant and present a clear dysregulation in the stomach ghrelin-system. The present work was focused at analyzing the expression pattern of ghrelin-system components at pancreas level in cort-/- mice and their control littermates (cort +/+) under low- or high-fat diet. Our data reveal that all the ghrelin-system components are expressed at the mouse pancreatic level, where, interestingly, In1-ghrelin was expressed at higher levels than native-ghrelin. Thus, GOAT mRNA levels were significantly lower in cort-/- mice compared with controls while native ghrelin, In1-ghrelin and GHS-R transcript levels remained unaltered under normal metabolic conditions. Moreover, under obese condition, a significant increase in pancreatic expression of native-ghrelin, In1-ghrelin and GHS-R was observed in obese cort+/+ but not in cort-/- mice. Interestingly, insulin expression and release was elevated in obese cort+/+, while these changes were not observed in obese cort-/- mice. Altogether, our results indicate that the ghrelin-system expression is clearly regulated in the pancreas of cort+/+ and cort -/- under normal and/or obesity conditions suggesting that this system may play relevant roles in the endocrine pancreas. Most importantly, our data demonstrate, for the first time, that endogenous CORT is essential

  19. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters.

    PubMed

    Luque, Raul M; Sampedro-Nuñez, Miguel; Gahete, Manuel D; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D; Castaño, Justo P; Marazuela, Mónica

    2015-08-14

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value.

  20. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters

    PubMed Central

    Gahete, Manuel D.; Ramos-Levi, Ana; Ibáñez-Costa, Alejandro; Rivero-Cortés, Esther; Serrano-Somavilla, Ana; Adrados, Magdalena; Culler, Michael D.; Castaño, Justo P.; Marazuela, Mónica

    2015-01-01

    Ghrelin system comprises a complex family of peptides, receptors (GHSRs), and modifying enzymes [e.g. ghrelin-O-acyl-transferase (GOAT)] that control multiple pathophysiological processes. Aberrant alternative splicing is an emerging cancer hallmark that generates altered proteins with tumorigenic capacity. Indeed, In1-ghrelin and truncated-GHSR1b splicing variants can promote development/progression of certain endocrine-related cancers. Here, we determined the expression levels of key ghrelin system components in neuroendocrine tumor (NETs) and explored their potential functional role. Twenty-six patients with NETs were prospectively/retrospectively studied [72 samples from primary and metastatic tissues (30 normal/42 tumors)] and clinical data were obtained. The role of In1-ghrelin in aggressiveness was studied in vitro using NET cell lines (BON-1/QGP-1). In1-ghrelin, GOAT and GHSR1a/1b expression levels were elevated in tumoral compared to normal/adjacent tissues. Moreover, In1-ghrelin, GOAT, and GHSR1b expression levels were positively correlated within tumoral, but not within normal/adjacent samples, and were higher in patients with progressive vs. with stable/cured disease. Finally, In1-ghrelin increased aggressiveness (e.g. proliferation/migration) of NET cells. Altogether, our data strongly suggests a potential implication of ghrelin system in the pathogenesis and/or clinical outcome of NETs, and warrant further studies on their possible value for the future development of molecular biomarkers with diagnostic/prognostic/therapeutic value. PMID:26124083

  1. Ghrelin accelerates synapse formation and activity development in cultured cortical networks

    PubMed Central

    2014-01-01

    Background While ghrelin was initially related to appetite stimulation and growth hormone secretion, it also has a neuroprotective effect in neurodegenerative diseases and regulates cognitive function. The cellular basis of those processes is related to synaptic efficacy and plasticity. Previous studies have shown that ghrelin not only stimulates synapse formation in cultured cortical neurons and hippocampal slices, but also alters some of the electrophysiological properties of neurons in the hypothalamus, amygdala and other subcortical areas. However, direct evidence for ghrelin’s ability to modulate the activity in cortical neurons is not available yet. In this study, we investigated the effect of acylated ghrelin on the development of the activity level and activity patterns in cortical neurons, in relation to its effect on synaptogenesis. Additionally, we quantitatively evaluated the expression of the receptor for acylated ghrelin – growth hormone secretagogue receptor-1a (GHSR-1a) during development. Results We performed electrophysiology and immunohistochemistry on dissociated cortical cultures from neonates, treated chronically with acylated ghrelin. On average 76 ± 4.6% of the cortical neurons expressed GHSR-1a. Synapse density was found to be much higher in ghrelin treated cultures than in controls across all age groups (1, 2 or 3 weeks). In all cultures (control and ghrelin treated), network activity gradually increased until it reached a maximum after approximately 3 weeks, followed by a slight decrease towards a plateau. During early developmental stages (1–2 weeks), the activity was much higher in ghrelin treated cultures and consequently, they reached the plateau value almost a week earlier than controls. Conclusions Acylated ghrelin leads to earlier network formation and activation in cultured cortical neuronal networks, the latter being a possibly consequence of accelerated synaptogenesis. PMID:24742241

  2. Response of circulating ghrelin levels to insulin therapy in children with newly diagnosed type 1 diabetes mellitus.

    PubMed

    Soriano-Guillén, Leandro; Barrios, Vicente; Lechuga-Sancho, Alfonso; Chowen, Julie A; Argente, Jesús

    2004-05-01

    Ghrelin is secreted primarily by the stomach, although other tissues such as the pancreas synthesize a minor proportion. The discovery of a new cell type that produces ghrelin in the human pancreas and that this organ expresses GHS-R opens new perspectives in the understanding of the control of glucose metabolism. We have studied 22 children with newly diagnosed type 1 diabetes mellitus at four different points: at diagnosis before insulin therapy, after 48-60 h of insulin therapy, and after 1 and 4 mo of insulin treatment. At each point circulating levels of ghrelin, leptin, IGF-I, IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, and glucose were determined. Ghrelin levels were significantly decreased at diagnosis (573 +/- 68 pg/mL, p < 0.01) compared with controls (867 +/- 38 pg/mL) and remained decreased after insulin therapy (d 2: 595 +/- 68 pg/mL; 1 mo: 590 +/- 61 pg/mL; 4 mo: 538 +/- 67 pg/mL) with no differences before or after insulin treatment. There was a negative correlation between ghrelin levels and body mass index at all of the study points, whereas a negative correlation between ghrelin and glucose concentrations was only observed after insulin therapy. No correlation between ghrelin and HbA1c was found at any point. A positive correlation between ghrelin and IGFBP-1 was found after insulin therapy, but no correlation with other members of the IGF system or leptin was found. In conclusion, these data could indicate a possible link between glucose concentrations and ghrelin; hence, the persisting low ghrelin levels in diabetic children may suggest a defensive mechanism against hyperglycemia.

  3. Different responses of circulating ghrelin, obestatin levels to fasting, re-feeding and different food compositions, and their local expressions in rats.

    PubMed

    Guo, Zhi-Fu; Ren, An-Jing; Zheng, Xing; Qin, Yong-Wen; Cheng, Fang; Zhang, Jing; Wu, Hong; Yuan, Wen-Jun; Zou, Lin

    2008-07-01

    Obestatin, a sibling of ghrelin derived from preproghrelin, opposes several physiological actions of ghrelin. Our previous study has demonstrated that both plasma ghrelin and obestatin levels were decreased significantly 2h after food intake in human. To further expand current knowledge, we investigated the temporal profiles of their levels in ad libitum fed rats, 48h fasted rats and 48h fasted rats refed 2h with a standard chow, crude fiber, 50% glucose or water, and their expressions in stomach, liver and pancreatic islets immunohistochemically. Plasma ghrelin and obestatin levels were measured by EIA. Plasma leptin, insulin and glucose levels were also evaluated. Both plasma ghrelin and obestatin levels increased significantly in fasted rats compared with ad libitum fed rats. The ingestion of standard chow produced a profound and sustained suppression of ghrelin levels, whereas plasma obestatin levels decreased significantly but recovered quickly. Intake of crude fiber or 50% glucose, however, produced a more profound and sustained suppression of obestatin levels, though they had relatively less impact on ghrelin levels. Plasma glucose was the only independent predictor of ghrelin levels, obestatin levels, and ghrelin to obestatin ratios. Obestatin immunoreactivity was detected in the fundus of stomach, liver and pancreatic islets, with roughly similar patterns of distribution to ghrelin. These data show quantitative and qualitative differences in circulating ghrelin and obestatin responses to the short-term feeding status and nutrient composition, and may support a role for obestatin in regulating metabolism and energy homeostasis.

  4. A comparison of ghrelin, glucose, alpha-amylase and protein levels in saliva from diabetics.

    PubMed

    Aydin, Suleyman

    2007-01-31

    During the past decade, many salivary parameters have been used to characterize disease states. Ghrelin (GAH) is recently-discovered peptide hormone secreted mainly from the stomach but also produced in a number of other tissues including salivary glands. The aim of this work was to examine the relationship between active (aGAH) and inactive (dGAH) ghrelin in the saliva and other salivary parameters in type II diabetic patients and healthy controls. Salivary parameters were assessed in a single measurement of unstimulated whole saliva from 20 obese and 20 non-obese type II diabetes patients, and in 22 healthy controls. Total protein and alpha-amylase were determined by colorimetric methods, and glucose by the glucose-oxidase method. Saliva aGAH and dGAH levels were measured using a commercial radioimmunoassay (RIA) kit. Salivary concentrations of aGAH and dGAH ghrelin were more markedly decreased in obese diabetic subjects than in the two other groups. Glucose and alpha-amylase levels were higher in diabetic subjects than in controls. Furthermore, there were correlations between GAH levels and BMI, and between GAH and blood pressure. However, there was no marked variability in saliva flow rates among the groups. These results indicate that measurement of salivary GAH and its relationship to other salivary parameters might help to provide insight into the role of ghrelin in diabetes.

  5. Molecular cloning and expression analysis of porcine ghrelin o-acyltransferase.

    PubMed

    Lin, Tonghui; Meng, Qingyong; Sui, Dandan; Peng, Dezhi; Li, Yang; Liu, Xiaofang; Xie, Longfei; Li, Ning

    2011-10-01

    The peptide hormone ghrelin is secreted in the stomach, with unique N-octanoylation at serine 3, which is a requirement for its functionality. These functions include growth hormone release, appetite stimulation, gastrointestinal motility, glucose regulation, and cell proliferation. The enzyme responsible for ghrelin acylation was recently identified as ghrelin O-acyltransferase (GOAT). In this study, porcine GOAT was cloned and characterized. A full-length cDNA of GOAT of 2013 bp was obtained, which included a 70-bp 5' UTR, a 635-bp 3' UTR, and a 1308-bp open reading frame encoding a protein of 415 amino acids. The GOAT and ghrelin mRNAs are co-expressed in stomach, pancreas, and duodenum at high levels. GOAT was also detected in liver, lung, brain, testis, spleen, kidney, heart, muscle, lipid, and ovary. Our results provide an important basis for further research on GOAT function and the relationship between ghrelin and GOAT.

  6. Prognostic Significance of Preoperative and Postoperative Plasma Levels of Ghrelin in Gastric Cancer: 3-Year Survival Study

    PubMed Central

    Soleyman-Jahi, Saeed; Abdirad, Afshin; Fallah, Amir Afraz; Ghasemi, Sevil; Sadeghi, Fatemeh; Heidari, Reza; Mahmoodzadeh, Habibollah; Zendehdel, Kazem

    2017-01-01

    OBJECTIVES: We aimed to investigate prognostic effects of plasma levels of ghrelin before and after gastrectomy in gastric cancer (GC). METHODS: We followed 81 GC patients up to 3 years in this study. They were candidates for curative gastrectomy with or without neoadjuvant chemotherapy. Plasma levels of total and active ghrelins before and after the operation were assessed. Association of plasma levels of ghrelin with survival were assessed and adjusted for other potential prognostic factors using Cox regression analyses. RESULTS: Both total and active ghrelins dropped after gastrectomy (P<0.001 for both). Multiple Cox models revealed worse survival for patients with postoperative total ghrelins below median (hazards ratio (HR)=2.33, 95% confidence interval (CI): 1.01–5.41) or 25th percentile (HR=4.29, 95% CI: 1.48–12.44) compared with patients with higher ghrelin levels. In case of preoperative total ghrelin, patients with either second or third quartiles of plasma ghrelin showed worse survival compared with patients with the lowest quartile (HR=2.67, 95% CI: 1.11–6.38 for second quartile, and HR=2.32, 95% CI: 1.01–5.35 for third quartile vs. the lowest quartile). However, there was no difference between patients with the highest and lowest quartiles (HR=0.78, 95% CI: 0.22–2.73). Similar pattern was observed for preoperative active ghrelin (HR=4.92, 95% CI: 1.80–13.54 for second quartile, and HR=2.87, 95% CI: 1.11–7.38 for third quartile vs. the lowest quartile). Advanced TNM stage (HR=4.88, 95% CI: 1.10–21.77), cachexia (HR=2.99, 95% CI: 1.35–6.63), and receiving no neoadjuvant chemotherapy (HR=2.02, 95% CI: 1.04–3.92) were other poor prognostic factors. CONCLUSIONS: Preoperative and postoperative plasma levels of ghrelin could predict survival of GC patients with different patterns. This prognostic effect was independent of stage and cachexia. Measurement of plasma ghrelin in GC patients could complement conventional staging for more precise

  7. Physiological roles of ghrelin on obesity.

    PubMed

    Sato, Takahiro; Ida, Takanori; Nakamura, Yuki; Shiimura, Yuki; Kangawa, Kenji; Kojima, Masayasu

    2014-01-01

    Ghrelin is a stomach hormone that acts as an endogenous ligand of orphan G-protein coupled receptor. Ghrelin has various physiological functions, such as the stimulation of growth hormone release and of appetite, and fat accumulation. Ghrelin is the only peripheral hormone to transmit satiety signal. Mature ghrelin peptide is consisted of 28 amino acid residues, and is unusual among peptide hormones in that Ser3 is n-octanoylated to obtain. Furthermore, this modification is essential for ghrelin's activity. In order to add this side chain to acyl ghrelin, it is necessary for the recently discovered enzyme, ghrelin-O-acyl transferase (GOAT). Therefore, to understand of ghrelin's functions, it is useful to obtain the knowledge on structures and functions of ghrelin, ghrelin receptor and GOAT. Here, we review our current understanding of the structures and functions of ghrelin, and the relation between obesity and ghrelin. Finally, we referred to the ghrelin and related substances as a drug design target for obesity.

  8. Ghrelin Increases Beta-Catenin Level through Protein Kinase A Activation and Regulates OPG Expression in Rat Primary Osteoblasts

    PubMed Central

    Mrak, Emanuela; Casati, Lavinia; Pagani, Francesca; Rubinacci, Alessandro; Zarattini, Guido; Sibilia, Valeria

    2015-01-01

    Ghrelin, by binding growth hormone secretagogue receptor (GHS-R), promotes osteoblast proliferation but the signaling mechanism of GHS-R on these cells remains unclear. Since canonical Wnt/β-catenin pathway is critically associated with bone homeostasis, we investigated its involvement in mediating ghrelin effects in osteoblasts and in osteoblast-osteoclast cross talk. Ghrelin (10−10M) significantly increased β-catenin levels in rat osteoblasts (rOB). This stimulatory action on β-catenin involves a specific interaction with GHS-R1a, as it is prevented by the selective GHS-R1a antagonist, D-Lys3-GHRP-6 (10−7M). The effect of ghrelin on β-catenin involves the phosphorylation and inactivation of GSK-3β via protein kinase A (PKA). Inhibition of PKA activity reduces the facilitatory action of ghrelin on β-catenin stabilization. Ghrelin treatment of rOB significantly increases the expression of osteoprotegerin (OPG), which plays an important role in the regulation of osteoclastogenesis, and this effect is blocked by D-Lys3-GHRP-6. Furthermore, ghrelin reduced RANKL/OPG ratio thus contrasting osteoclastogenesis. Accordingly, conditioned media from rOB treated with ghrelin decreased the number of multinucleated TRAcP+ cells as compared with the conditioned media from untreated-control rOB. Our data suggest new roles for ghrelin in modulating bone homeostasis via a specific interaction with GHSR-1a in osteoblasts with subsequent enhancement of both β-catenin levels and OPG expression. PMID:25866509

  9. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin

    PubMed Central

    Collden, Gustav; Balland, Eglantine; Parkash, Jyoti; Caron, Emilie; Langlet, Fanny; Prevot, Vincent; Bouret, Sebastien G.

    2014-01-01

    Objective Excess nutrient supply and rapid weight gain during early life are risk factors for the development of obesity during adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Ghrelin is a metabolic hormone secreted from the stomach that acts centrally to promote feeding behavior by binding to growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. Here, we examined whether neonatal overnutrition causes changes in the ghrelin system. Methods We used a well-described mouse model of divergent litter sizes to study the effects of postnatal overfeeding on the central and peripheral ghrelin systems during postnatal development. Results Mice raised in small litters became overweight during lactation and remained overweight with increased adiposity as adults. Neonatally overnourished mice showed attenuated levels of total and acyl ghrelin in serum and decreased levels of Ghrelin mRNA expression in the stomach during the third week of postnatal life. Normalization of hypoghrelinemia in overnourished pups was relatively ineffective at ameliorating metabolic outcomes, suggesting that small litter pups may present ghrelin resistance. Consistent with this idea, neonatally overnourished pups displayed an impaired central response to peripheral ghrelin. The mechanisms underlying this ghrelin resistance appear to include diminished ghrelin transport into the hypothalamus. Conclusions Early postnatal overnutrition results in central resistance to peripheral ghrelin during important periods of hypothalamic development. Because ghrelin signaling has recently been implicated in the neonatal programming of metabolism, these alterations in the ghrelin system may contribute to the metabolic defects observed in postnatally overnourished mice. PMID:25685686

  10. Diurnal Intermittent Fasting during Ramadan: The Effects on Leptin and Ghrelin Levels

    PubMed Central

    Alzoghaibi, Mohammed A.; Pandi-Perumal, Seithikurippu R.; Sharif, Munir M.; BaHammam, Ahmed S.

    2014-01-01

    We aimed to assess the effect of Islamic intermittent fasting, during and outside of Ramadan, on plasma levels of leptin and ghrelin while controlling for several potential confounding variables. Eight healthy male volunteers with a mean age of 26.6±4.9 years reported to the sleep disorders center (SDC) at King Saud University on four occasions: 1) adaptation; 2) 4 weeks before Ramadan while performing Islamic fasting for 1 week (baseline fasting) (BLF); 3) 1 week before Ramadan (non-fasting baseline) (BL); and 4) during the second week of Ramadan while fasting. Plasma leptin and ghrelin levels were measured using enzyme-linked immunoassays at 22:00, 02:00, 04:00, 06:00, and 11:00. During BLF, there were significant reductions in plasma leptin concentrations at 22:00 and 02:00 compared with the baseline concentrations (at 22:00: 194.2±177.2 vs. 146.7±174.5; at 02:00: 203.8±189.5 vs. 168.1±178.1; p<0.05). During Ramadan, there was a significant reduction in plasma leptin levels at 22:00 (194.2±177.2 vs. 132.6±130.4, p<0.05). No significant difference in plasma ghrelin concentrations was detected during the BL, BLF, or Ramadan periods. Cosinor analyses of leptin and ghrelin plasma levels revealed no significant changes in the acrophases of the hormones during the three periods. The nocturnal reduction in plasma leptin levels during fasting may be the result of the changes in meal times during fasting. PMID:24637892

  11. Diurnal intermittent fasting during Ramadan: the effects on leptin and ghrelin levels.

    PubMed

    Alzoghaibi, Mohammed A; Pandi-Perumal, Seithikurippu R; Sharif, Munir M; BaHammam, Ahmed S

    2014-01-01

    We aimed to assess the effect of Islamic intermittent fasting, during and outside of Ramadan, on plasma levels of leptin and ghrelin while controlling for several potential confounding variables. Eight healthy male volunteers with a mean age of 26.6±4.9 years reported to the sleep disorders center (SDC) at King Saud University on four occasions: 1) adaptation; 2) 4 weeks before Ramadan while performing Islamic fasting for 1 week (baseline fasting) (BLF); 3) 1 week before Ramadan (non-fasting baseline) (BL); and 4) during the second week of Ramadan while fasting. Plasma leptin and ghrelin levels were measured using enzyme-linked immunoassays at 22:00, 02:00, 04:00, 06:00, and 11:00. During BLF, there were significant reductions in plasma leptin concentrations at 22:00 and 02:00 compared with the baseline concentrations (at 22:00: 194.2±177.2 vs. 146.7±174.5; at 02:00: 203.8±189.5 vs. 168.1±178.1; p<0.05). During Ramadan, there was a significant reduction in plasma leptin levels at 22:00 (194.2±177.2 vs. 132.6±130.4, p<0.05). No significant difference in plasma ghrelin concentrations was detected during the BL, BLF, or Ramadan periods. Cosinor analyses of leptin and ghrelin plasma levels revealed no significant changes in the acrophases of the hormones during the three periods. The nocturnal reduction in plasma leptin levels during fasting may be the result of the changes in meal times during fasting.

  12. Effects of resistance exercise and obesity level on ghrelin and cortisol in men.

    PubMed

    Thomas, Gwendolyn A; Kraemer, William J; Comstock, Brett A; Dunn-Lewis, Courtenay; Volek, Jeff S; Denegar, Craig R; Maresh, Carl M

    2012-06-01

    Resistance exercise (RE) is increasingly recommended by health organizations as a weight management tool. The purpose of this study was to examine the effects of an acute high-volume, whole-body RE protocol on the glucoregulatory and ghrelin response in sedentary obese and lean men. Five World Health Organization (WHO) class 1 obese (body mass index [BMI], 30.00-34.99) (age, 21.6 ± 2.5 years; height, 176.3 ± 3.7 cm; body mass, 97.8 ± 8.58 kg; body fat, 34.7% ± 2.95%), 5 WHO 2 (BMI, 35-39.99)/WHO 3 (BMI, ≥40) obese (age, 20.0 ± 1.4 years; height, 177.7 ± 5.15 cm; body mass, 120.8 ± 10.49 kg; body fat, 40.5% ± 5.82 %), and 9 lean men (age, 20.1 ± 2.1 years; height, 177.8 ± 8.7 cm; body mass, 71.7 ± 5.8 kg; body fat, 14.7% ± 3.54 %) completed an acute RE testing protocol (6 exercises, 3 sets of 10 repetitions at 85%-95% 10-repetition maximum with 120- and 90-second rest periods); and blood samples were collected pre-, mid-, and immediately postexercise and during recovery (+50, +70, and +110). Resistance exercise produced differences over time in cortisol, insulin, and glucose. Group differences were observed for ghrelin, with the WHO class 2/3 group having significantly greater ghrelin levels than the lean group (d = 0.28, P = .009) and the WHO class 1 group (d = 0.39, P = .002). Higher ghrelin was significantly associated with lower cortisol only in obese individuals. In addition, higher growth hormone was associated with lower ghrelin in lean individuals. Results suggest that glucoregulatory homeostasis is altered with increasing levels of obesity and that these alterations may mediate the response of cortisol and ghrelin in response to RE.

  13. Ghrelin O-acyltransferase (GOAT) and energy metabolism.

    PubMed

    Li, Ziru; Mulholland, Michael; Zhang, Weizhen

    2016-03-01

    Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose- induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.

  14. Correlation of serum ghrelin levels with body mass index and carbohydrate metabolism in patients treated with atypical antipsychotics.

    PubMed

    Palik, E; Birkás, K D; Faludi, G; Karádi, I; Cseh, K

    2005-06-01

    The prevalence of diabetes mellitus and metabolic syndrome is higher in patients with schizophrenia than in the normal population. Atypical antipsychotic drugs are used in psychiatry since the beginning of 1990. These drugs differ from the "typical" antipsychotics used previously, as they have less extrapyramidal side effects, and because of this they are tolerated better, but are associated with weight-gain and disturbances in carbohydrate metabolism. Ghrelin is an orexigen hormone partaking in body weight regulation. It is produced in the enteroendocrine P/D1 cells of the gastric mucosa and secreted to the circulation. The aim of our study was to determine ghrelin levels of atypical antipsychotic-treated patients in relationship with their body mass index (BMI) and carbohydrate metabolism. We measured the fasting serum ghrelin levels in 56 patients (male/female: 16/40, age mean+/-S.D.: 50.6+/-5.6 years) treated with atypical antipsychotics (clozapine, olanzapine, risperidon and quetiapine), and in 75 healthy control subjects, age and gender matched (RIA Linco, USA) in relationship with their BMI and their fasting and 75 g OGTT 120 min blood glucose values. The serum ghrelin levels of the patient group were notably higher (1333+/-659 pg/ml) than in the control group (368+/-103, p<0.0001; Mann-Whitney). We found no difference among the four antipsychotics in weight-gain, diabetes prevalence and the serum ghrelin levels. The BMI of the patient group was significantly higher (29.3+/-7.2 kg/m2 versus 24.3+/-3.7 kg/m2, p<0.0001; Mann-Whitney); 32% of them had blood glucose abnormality (18/56). There was no difference between the ghrelin levels in diabetic and non-diabetic patients. We found a significant negative linear correlation between the serum ghrelin and BMI (r=-0.35, p=0.0078; Spearman), the ghrelin and fasting blood glucose (r=-0.32, p=0.015) and OGTT 75 g 120 min blood glucose levels (r=-0.27, p=0.036). The orexigen effect of elevated serum ghrelin levels can

  15. The ghrelin/obestatin balance in the physiological and pathological control of growth hormone secretion, body composition and food intake.

    PubMed

    Hassouna, R; Zizzari, P; Tolle, V

    2010-07-01

    Ghrelin and obestatin are two gastrointestinal peptides obtained by post-translational processing of a common precursor, preproghrelin. Ghrelin is an orexigenic and adipogenic peptide and a potent growth hormone secretagogue (GHS) modified by the enzyme ghrelin-O-acyl-transferase to bind and activate its receptor, the GHS-R. The ghrelin/GHS-R pathway is complex and the effects of ghrelin on GH secretion, adiposity and food intake appear to be relayed by distinct mechanisms involving different transduction signals and constitutive activity for the GH-R, different cofactors as modulators of endogenous ghrelin signalling and/or alternative ghrelin receptors. The discovery of obestatin in 2005 brought an additional level of complexity to this fascinating system. Obestatin was initially identified as an anorexigenic peptide and as the cognate ligand for GPR39, but its effect on food intake and its ability to activate GPR39 are still controversial. Although several teams failed to reproduce the anorexigenic actions of obestatin, this peptide has been shown to antagonise GH secretion and food intake induced by ghrelin and could be an interesting pharmacological tool to counteract the actions of ghrelin. Ghrelin and obestatin immunoreactivities are recovered in the blood with an ultradian pulsatility and their concentrations in plasma vary with the nutritional status of the body. It is still a matter of debate whether both hormones are regulated by independent mechanisms and whether obestatin is a physiologically relevant peptide. Nevertheless, a significant number of studies show that the ghrelin/obestatin ratio is modified in anorexia nervosa and obesity. This suggests that the ghrelin/obestatin balance could be essential to adapt the body's response to nutritional challenges. Although measuring ghrelin and obestatin in plasma is challenging because many forms of the peptides circulate, more sensitive and selective assays to detect the different preproghrelin

  16. Fasting ghrelin levels in physically active women: relationship with menstrual disturbances and metabolic hormones.

    PubMed

    De Souza, Mary Jane; Leidy, Heather J; O'Donnell, Emma; Lasley, Bill; Williams, Nancy I

    2004-07-01

    Recent findings support a role for ghrelin in the regulation of energy homeostasis and possibly reproductive function. The primary purpose of this study was to test whether differences in fasting ghrelin levels exist in exercising women with differing menstrual and metabolic status. Menstrual cycle status was defined as sedentary ovulatory (SedOvul; n = 10, cycles = 26), exercising ovulatory (ExOvul; n = 11, cycles = 22), exercising luteal phase defect/anovulatory (ExLPD/Anov; n = 11, cycle = 27), and exercising amenorrheic (ExAmen; n = 8, cycle = 16). Subjects were 27.7 +/- 1.2 yr of age, weighed 60.2 +/- 3.3 kg, and had menstrual cycle lengths of 28.4 +/- 0.9 d. Blood was collected during the follicular phase (d 2-9) of each menstrual cycle and analyzed for total ghrelin, insulin, total T(3), and leptin. Ghrelin was significantly elevated by approximately 85% in the ExAmen category (725.5 +/- 40.8 pmol/liter) when compared with all other categories (P < 0.001; SedOvul = 393.6 +/- 32.0 pmol/liter, ExOvul = 418.9 +/- 34.8 pmol/liter, and ExLPD/Anov = 381.1 +/- 314 pmol/liter). Leptin levels were lower in all groups vs. SedOvul (P < 0.001). Insulin was lower in both the ExLPD/Anov and ExAmen categories vs. SedOvul and ExOvul (P < 0.018), and total T(3) was lower in ExAmen compared with all other groups (P < 0.001), with concentrations in ExLPD/Anov and ExOvul exceeding those in SedOvul (P < 0.05). These data clearly indicate a metabolic hormonal profile consistent with chronic energy deficiency in exercising women across a range in menstrual status and introduces ghrelin as a potential supplementary indicator that uniquely discriminates amenorrheic athletes from athletes with other menstrual disturbances.

  17. Acylated and unacylated ghrelin protect MC3T3-E1 cells against tert-butyl hydroperoxide-induced oxidative injury: pharmacological characterization of ghrelin receptor and possible epigenetic involvement.

    PubMed

    Dieci, Elisa; Casati, Lavinia; Pagani, Francesca; Celotti, Fabio; Sibilia, Valeria

    2014-07-01

    Increasing evidence suggests a role for oxidative stress in age-related decrease in osteoblast number and function leading to the development of osteoporosis. This study was undertaken to investigate whether ghrelin, previously reported to stimulate osteoblast proliferation, counteracts tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in MC3T3-E1 osteoblastic cells as well as to characterize the ghrelin receptor (GHS-R) involved in such activity. Pretreatment with ghrelin (10(-7)-10(-11)M) significantly increased viability and reduced apoptosis of MC3T3-E1 cells cultured with t-BHP (250 μM) for three hours at the low concentration of 10(-9)M as shown by MTT assay and Hoechst-33258 staining. Furthermore, ghrelin prevented t-BHP-induced osteoblastic dysfunction and changes in the cytoskeleton organization evidenced by the staining of the actin fibers with Phalloidin-FITC by reducing reactive oxygen species generation. The GHS-R type 1a agonist, EP1572 (10(-7)-10(-11)M), had no effect against t-BHP-induced cytotoxicity and pretreatment with the selective GHS-R1a antagonist, D-Lys(3)-GHRP-6 (10(-7)M), failed to remove ghrelin (10(-9) M)-protective effects against oxidative injury, indicating that GHS-R1a is not involved in such ghrelin activity. Accordingly, unacylated ghrelin (DAG), not binding GHS-R1a, displays the same protective actions of ghrelin against t-BHP-induced cytotoxicity. Preliminary observations indicate that ghrelin increased the trimethylation of lys4 on histones H3, a known epigenetic mark activator, which may regulate the expression of some genes limiting oxidative damage. In conclusion, our data demonstrate that ghrelin and DAG promote survival of MC3T3-E1 cell exposed to t-BHP-induced oxidative damage. Such effect is independent of GHS-R1a and is likely mediated by a common ghrelin/DAG binding site.

  18. Correlation between serum ghrelin levels and cocaine-seeking behaviour triggered by cocaine-associated conditioned stimuli in rats.

    PubMed

    Tessari, Michela; Catalano, Antonio; Pellitteri, Michele; Di Francesco, Carla; Marini, Francesca; Gerrard, Philip A; Heidbreder, Christian A; Melotto, Sergio

    2007-03-01

    Ghrelin is a brain-gut peptide with growth hormone-releasing and appetite-inducing activities. A growing body of evidence suggests that ghrelin may affect the central reward system and modulate the activity of the mesolimbic system. Recent clinical studies also showed a significant positive correlation between plasma ghrelin levels and craving in alcoholics. Accordingly, the present study investigated the potential role of serum ghrelin levels in the reinstatement of cocaine-seeking behaviour triggered by cocaine-associated cues. In addition, serum corticosterone levels were determined in the light of evidence suggesting that corticosterone plays a modulatory role in cocaine-seeking behaviour. Male Lister Hooded rats under a restricted diet regime were first trained to intravenously self-administer cocaine under a fixed ratio-1 schedule of reinforcement. Conditioned stimuli (CS: tone and cue-light on for 5 seconds) were presented contingently with cocaine delivery. Once a stable baseline of cocaine self-administration was observed, lever presses were extinguished to less than 30% of baseline rates by removing both cocaine and CS. Reinstatement of responding was then induced by re-exposure to cocaine-associated CS. Blood samples for the enzyme immunoassay determination of serum ghrelin and the radioimmunoassay determination of serum corticosterone levels were collected 30 minutes before the beginning of reinstatement sessions. Rats significantly reinstated their responding when exposed to CS. A positive and significant correlation was observed between ghrelin levels (r = 0.64; P < 0.05), but not corticosterone (r = 0.37; NS), and the increased active lever presses only in animals exposed to CS. These findings suggest a potential role of ghrelin in the modulation of cue-triggered reinstatement of cocaine-seeking behaviour.

  19. Importance of serum adipokine and ghrelin levels in patients with Crimean-Congo hemorrhagic fever.

    PubMed

    Yilmaz, Gürdal; Mentese, Ahmet; Yilmaz, Hülya; Koksal, İftihar

    2015-02-01

    Crimean-Congo Hemorrhagic Fever (CCHF) may present with a mild clinical course or else exhibit a severe profile with potentially fatal hemorrhaging. The pathogenesis of the disease has not yet been well described. Cytokines have recently been investigated in order to explain the pathogenesis. The latest reports show that adipokines are powerful inflammation modulators. This study investigated the effect of adipokines (resistin, leptin, and adiponectin) and ghrelin on disease severity in CCHF patients by testing their serum levels. This retrospective study was conducted with patients with CCHF hospitalized at the Karadeniz Technical University, Medical Faculty in Turkey. Patients were divided into severe and non-severe groups. Serum adipokine levels of patients with CCHF were measured using enzyme-linked immunosorbent assay (ELISA). Fifty-three patients with confirmed CCHF were investigated. Twenty-five (47.2%) of these patients constituted the severe group. Serum resistin levels in the severe and non-severe groups were 108.9 ± 24.7 ng/ml and 77.5 ± 27.7 ng/ml (P < 0.001), leptin levels 15.5 ± 9.8 and 11.2 ± 5.1 ng/ml (P = 0.074), adiponectin levels 26.8 ± 18.9 and 27.4 ± 16.3 ng/ml (P = 0.903) and ghrelin levels 57.1 ± 48.7 and 200.9 ± 182.7 ng/ml (P = 0.001), all respectively. This study confirms that significant changes in serum levels of resistin and ghrelin take place in severe CCHF.

  20. Improved acylated ghrelin suppression at 2 years in obese patients with type 2 diabetes: effects of bariatric surgery vs standard medical therapy

    PubMed Central

    Malin, SK; Samat, A; Wolski, K; Abood, B; Pothier, CE; Bhatt, DL; Nissen, S; Brethauer, SA; Schauer, PR; Kirwan, JP; Kashyap, SR

    2015-01-01

    OBJECTIVE Roux-en-Y gastric bypass (RYGB) produces more durable glycemic control than sleeve gastrectomy (SG) or intensive medical therapy (IMT). However, the contribution of acylated ghrelin (AG), a gluco-regulatory/appetite hormone, to improve glucose metabolism and body composition in patients with type 2 diabetes (T2D) following RYGB is unknown. DESIGN STAMPEDE (Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently) was a prospective, randomized controlled trial. SUBJECTS Fifty-three (body mass index: 36 ± 3 kg m−2, age: 49 ± 9 years) poorly controlled patients with T2D (HbA1c (glycated hemoglobin): 9.7 ± 2%) were randomized to IMT, IMT + RYGB or IMT + SG and underwent a mixed-meal tolerance test at baseline, 12, and 24 months for evaluation of AG suppression (postprandial minus fasting) and beta-cell function (oral disposition index; glucose-stimulated insulin secretion × Matsuda index). Total/android body fat (dual-energy X-ray absorptiometry) was also assessed. RESULTS RYGB and SG reduced body fat comparably (15–23 kg) at 12 and 24 months, whereas IMT had no effect. Beta-cell function increased 5.8-fold in RYGB and was greater than IMT at 24 months (P < 0.001). However, there was no difference in insulin secretion between SG vs IMT at 24 months (P = 0.32). Fasting AG was reduced fourfold following SG (P < 0.01) and did not change with RYGB or IMT at 24 months. AG suppression improved more following RYGB than SG or IMT at 24 months (P = 0.01 vs SG, P = 0.07 vs IMT). At 24 months, AG suppression was associated with increased postprandial glucagon-like peptide-1 (r = −0.32, P < 0.02) and decreased android fat (r = 0.38; P < 0.006). CONCLUSIONS Enhanced AG suppression persists for up to 2 years after RYGB, and this effect is associated with decreased android obesity and improved insulin secretion. Together, these findings suggest that AG suppression is partly responsible for the improved glucose control after RYGB surgery. PMID

  1. Structure and Physiological Actions of Ghrelin

    PubMed Central

    2013-01-01

    Ghrelin is a gastric peptide hormone, discovered as being the endogenous ligand of growth hormone secretagogue receptor. Ghrelin is a 28 amino acid peptide presenting a unique n-octanoylation modification on its serine in position 3, catalyzed by ghrelin O-acyl transferase. Ghrelin is mainly produced by a subset of stomach cells and also by the hypothalamus, the pituitary, and other tissues. Transcriptional, translational, and posttranslational processes generate ghrelin and ghrelin-related peptides. Homo- and heterodimers of growth hormone secretagogue receptor, and as yet unidentified receptors, are assumed to mediate the biological effects of acyl ghrelin and desacyl ghrelin, respectively. Ghrelin exerts wide physiological actions throughout the body, including growth hormone secretion, appetite and food intake, gastric secretion and gastrointestinal motility, glucose homeostasis, cardiovascular functions, anti-inflammatory functions, reproductive functions, and bone formation. This review focuses on presenting the current understanding of ghrelin and growth hormone secretagogue receptor biology, as well as the main physiological effects of ghrelin. PMID:24381790

  2. Effects of isotretinoin on body mass index, serum adiponectin, leptin, and ghrelin levels in acne vulgaris patients

    PubMed Central

    Ayvaz, Havva Hilal; Ozturk, Gulfer; Ergin, Can; Akıs, Havva Kaya; Gonul, Muzeyyen; Arzuhal, Ercan

    2016-01-01

    Introduction Isotretinoin has been successfully used for the treatment of acne vulgaris. Aim To investigate the effects of isotretinoin on body mass index (BMI), to determine whether isotretinoin causes any changes in serum adiponectin, leptin, and ghrelin levels in acne vulgaris patients, and to correlate variables. Material and methods Thirty-two patients were included in this study. Oral isotretinoin was begun at a dose of 0.5–0.6 mg/kg and raised to 0.6–0.75 mg/kg. Pretreatment and posttreatment third-month BMI and adiponectin, leptin, and ghrelin serum levels were measured. Results The pre- and posttreatment BMI values were not significantly different. In addition, serum adiponectin and leptin levels were significantly increased following isotretinoin therapy while serum ghrelin levels were not different. Conclusions Isotretinoin may exert its anti-inflammatory activity by increasing leptin and adiponectin levels. PMID:27605902

  3. Identification of a ghrelin-like peptide in two species of shark, Sphyrna lewini and Carcharhinus melanopterus.

    PubMed

    Kawakoshi, Akatsuki; Kaiya, Hiroyuki; Riley, Larry G; Hirano, Tetsuya; Grau, E Gordon; Miyazato, Mikiya; Hosoda, Hiroshi; Kangawa, Kenji

    2007-05-01

    In this study, we identified a ghrelin-like peptide (ghrelin-LP) in two elasmobranchs. The peptide, isoforms and cDNA encoding its precursor were isolated from the stomach of two sharks, the hammerhead (HH) shark (Sphyrna lewini) and the black-tip reef (BTR) shark (Carcharhinus melanopterus). The ghrelin-LP isolated from each shark was found to be 25 amino acids in length and exhibit high sequence homology with each other; only three amino acids were different. As has been shown in tetrapod and teleost fish ghrelins, shark ghrelin-LPs possess two forms that are distinguished by having the third serine residue (Ser) acylated by either octanoic or decanoic acid. The N-terminal four residues (GVSF), known as the active core of ghrelin, are not identical to those of other species (GSSF). Nevertheless, shark ghrelin-LP elevated Ca(2+) levels in CHO cell line expressing the growth hormone secretagogue receptor (GHS-R). Unlike teleosts ghrelin's, shark ghrelin-LPs are not amidated at the C-terminus. Messenger RNA of ghrelin-LP in the HH shark was predominantly expressed in the stomach as seen in other species, followed by the brain, intestine, gill, heart and liver. The nucleotide sequence of the ghrelin-LP gene in the HH shark was characterized to compare organization of the ghrelin gene with those in other species. The size of the HH ghrelin-LP gene was 8541 bp, two to ten times larger than that of other species studied to date. The HH ghrelin-LP gene is composed of five exons and four introns, which is the same as ghrelin genes in mammals, chicken and rainbow trout. In conclusion, the shark ghrelin-LPs identified in this study exhibit many characteristics for ghrelin in terms of peptide modifications, GHS-R activation, tissue distribution, and gene organization; however, it is necessary to further clarify their biological properties such as growth hormone-releasing or orexigenic activity before designating these peptides as ghrelin.

  4. Ghrelin O-acyltransferase (GOAT), a specific enzyme that modifies ghrelin with a medium-chain fatty acid.

    PubMed

    Kojima, Masayasu; Hamamoto, Akie; Sato, Takahiro

    2016-10-01

    In the gastric peptide hormone ghrelin, serine 3 (threonine 3 in frogs) is modified, primarily by n-octanoic acid; this modification is essential for ghrelin's activity. The enzyme that transfers n-octanoic acid to Ser3 of ghrelin is ghrelin O-acyltransferase (GOAT). GOAT, the only enzyme known to catalyze acyl modification of ghrelin, specifically modifies serine (or threonine) at the third position and does not modify other serine residues in ghrelin peptides. GOAT prefers n-hexanoyl-CoA over n-octanoyl-CoA as the acyl donor, although in the stomach the n-octanoyl form is the predominant form of acyl-modified ghrelin. GOAT is a promising target for drug development to treat metabolic diseases and eating disorders.

  5. Relationship between ghrelin, Helicobacter pylori and gastric mucosal atrophy in hemodialysis patients

    PubMed Central

    Ichikawa, Hitomi; Sugimoto, Mitsushige; Sakao, Yukitoshi; Sahara, Shu; Ohashi, Naro; Kato, Akihiko; Sugimoto, Ken; Furuta, Takahisa; Andoh, Akira; Sakao, Tadashi; Yasuda, Hideo

    2016-01-01

    AIM To investigate the relationship between plasma ghrelin level, Helicobacter pylori (H. pylori) infection status and the severity of atrophy in hemodialysis patients. METHODS One hundred eights patients who received hemodialysis and 13 non-hemodialysis H. pylori-negative controls underwent gastroduodenoscopy to evaluate the severity of gastric atrophy. Serum levels of pepsinogen (PG) were measured as serum markers of gastric atrophy. H. pylori infection was evaluated by anti-H. pylori IgG antibody, rapid urease test and culture test. We classified H. pylori infection status as non-infection, present infection and past infection. In addition, plasma acyl-ghrelin and desacyl-ghrelin levels were measured by enzyme-linked immunosorbent assay. RESULTS Infection rate of H. pylori was 45.4% (49/108). Acyl-ghrelin level in the non-infection group (39.4 ± 23.0 fmol/mL) was significantly higher than in the past (23.4 ± 19.9 fmol/mL, P = 0.005) and present infection groups (19.5 ± 14.0 fmol/mL, P < 0.001). Furthermore, desacyl-ghrelin level in the non-infection group (353.2 ± 190.2 fmol/mL) was significantly higher than those in the past (234.9 ± 137.5 fmol/mL, P = 0.008) and present infection groups (211.8 ± 124.2 fmol/mL, P < 0.001). Acyl-ghrelin was positively correlated with the PG I level and PG I/II ratio (|R| = 0.484, P < 0.001 and |R| = 0.403, P < 0.001, respectively). Both ghrelins were significantly decreased in accordance with the progress of endoscopic atrophy (both P < 0.001) and acyl-ghrelin was significantly lower in patients with mild, moderate and severe atrophy (24.5 ± 23.1 fmol/mL, 20.2 ± 14.9 fmol/mL and 18.3 ± 11.8 fmol/mL) than in those with non-atrophy (39.4 ± 22.2 fmol/mL, P = 0.039, P = 0.002 and P < 0.001, respectively). CONCLUSION In hemodialysis patients, plasma ghrelin level was associated with the endoscopic and serological severity of atrophy related to H. pylori infection. PMID:28058025

  6. Des-acyl-ghrelin (DAG) normalizes hyperlactacidemia and improves survival in a lethal rat model of burn trauma.

    PubMed

    Sheriff, Sulaiman; Kadeer, Nijiati; Friend, Lou Ann; James, J Howard; Alexander, J Wesley; Balasubramaniam, Ambikaipakan

    2014-10-01

    Critical illness, including burn injury, results in elevated plasma lactate levels. Dysregulation of PI3K/Akt signaling has been shown to play a predominant role in the inactivation of skeletal muscle PDC and, hence, in hyperlactacidemia in rat models of sepsis and endotoxemia. This observation, and our previous finding that DAG can reverse burn-induced skeletal muscle proteolysis through the activation of PI3K/Akt pathway, led us to hypothesize that DAG may also attenuate hyperlactacidemia in burn injury. Our investigations revealed that burn injury significantly elevated both skeletal muscle lactate production and plasma lactate levels. Moreover, this was accompanied in skeletal muscle by a 5-7 fold increase in mRNA expression of pyruvate dehydrogenase kinases (PDK) 2 and 4, and a ∼30% reduction in PDC activity. DAG treatment of burn rats completely normalized not only the mRNA expression of the PDKs and PDC activity, but also hyperlactacidemia within 24h of burn injury. DAG also normalized epinephrine-induced lactate production by isolated skeletal muscles from normal rats. Moreover, DAG also improved survival in a lethal rat model of burn trauma. These findings with DAG may have clinical implications because chances of survival for critically ill patients are greatly improved if plasma lactate levels are normalized within 24h of injury.

  7. Ghrelin is independently associated with anti-mullerian hormone levels in obese but not non-obese women with polycystic ovary syndrome.

    PubMed

    Garin, Margaret C; Butts, Samantha F; Sarwer, David B; Allison, Kelly C; Senapati, Suneeta; Dokras, Anuja

    2017-03-01

    Ghrelin is an endogenous appetite stimulant that may have a role in ovarian function. Women with polycystic ovary syndrome have anovulation and frequently weight management issues; however the associations between ghrelin and hormonal markers in polycystic ovary syndrome have not been well studied. In order to characterize the association between total ghrelin levels and ovarian function and the possible modification of this relationship by obesity, we examined total ghrelin levels and anti-mullerian hormone, total testosterone, and insulin in obese and non-obese women with and without polycystic ovary syndrome. Total ghrelin levels were lower in obese women with polycystic ovary syndrome (n = 45) compared to obese controls (n = 33) (p = 0.005), but similar in non-obese women with polycystic ovary syndrome (n = 20) compared to non-obese controls (n = 21) (p = NS). In the obese polycystic ovary syndrome group, anti-mullerian hormone was associated with ghrelin levels independent of age, insulin, and total testosterone (p = 0.008). There was no association between total ghrelin and anti-mullerian hormone levels in non-obese women with polycystic ovary syndrome, non-obese controls, or obese controls (p = NS). Our results provide evidence for a potential relationship between ghrelin and ovarian function in obese women with polycystic ovary syndrome that was not observed in non-obese women with polycystic ovary syndrome or controls.

  8. Participation of ghrelin signalling in the reciprocal regulation of hypothalamic NPY/POMC-mediated appetite control in amphetamine-treated rats.

    PubMed

    Yu, Ching-Han; Chu, Shu-Chen; Chen, Pei-Ni; Hsieh, Yih-Shou; Kuo, Dong-Yih

    2017-06-01

    Hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) have been documented to participate in amphetamine (AMPH)-induced appetite suppression. This study investigated whether ghrelin signalling is associated with changes in NPY/POMC-mediated appetite control. Rats were given AMPH daily for four days, and changes in food intake, body weight, plasma ghrelin, hypothalamic NPY, melanocortin 3 receptor (MC3R), ghrelin O-acyltransferase (GOAT), acyl ghrelin (AG) and ghrelin receptor (GHSR1a) were examined and compared. Food intake, body weight and NPY expression decreased, while MC3R expression increased and expressed reciprocally to NPY expression during AMPH treatment. Plasma ghrelin and hypothalamic AG/GOAT/GHSR1a expression decreased on Day 1 and Day 2, which was associated with the positive energy metabolism, and returned to normal levels on Day 3 and Day 4, which was associated with the negative energy metabolism; this expression pattern was similar to that of NPY. Infusion with a GHSR1a antagonist or an NPY antisense into the brain enhanced the decrease in NPY and AG/GOAT/GHSR1a expression and the increase in MC3R expression compared to the AMPH-treated group. Peripheral ghrelin and the central ghrelin system participated in the regulation in AMPH-induced appetite control. These results shed light on the involvement of ghrelin signalling in reciprocal regulation of NPY/POMC-mediated appetite control and may prove useful for the development of anti-obesity drugs.

  9. Short-term effect of gastric resection on circulating levels of ghrelin, peptide YY3-36 and obestatin in patients with early gastric cancer.

    PubMed

    Jeon, T Y; Lee, S Y; Kim, H H; Cho, Y H; Cho, A R

    2015-04-01

    The short-term responses of gut hormones and the compensative interaction during a one-week period after subtotal gastrectomy in early gastric cancer (EGC) patients were assessed. Previous studies have reported gut hormonal changes after Roux-en-Y gastric bypass surgery. Blood samples were collected from 40 patients with EGC preoperatively, at 1 h after gastric resection, and on postoperative day (POD) 1, 3, and 7. Levels of active ghrelin, total ghrelin, obestatin, and PYY3-36 were measured. Total ghrelin level rapidly reached a nadir of 69.1%, while active ghrelin level had increased to 135.5% at 1 h after resection. Then, both returned to preoperative level. On the contrary, active/total ghrelin reached its nadir quickly at 1 h after resection and had returned to the preoperative level by POD 3. The nadir PYY3-36 level was 71.4% on POD 1, followed by a gradual recovery, and had increased to 116.5% by POD 7. The same pattern was observed for obestatin. Active ghrelin/obestatin showed an increase on POD 1 while total ghrelin/obestatin showed a decrease on POD 3. Then, both returned to preoperative level. These results suggest that a rapid interactive compensatory mechanism of gut hormones does exist in the remnant gastrointestinal tract after abrupt changes in the production reservoir in nonobese people.

  10. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.

    PubMed

    Kamegai, J; Tamura, H; Shimizu, T; Ishii, S; Sugihara, H; Wakabayashi, I

    2001-11-01

    Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Like the synthetic growth hormone secretagogues (GHSs), ghrelin specifically releases growth hormone (GH) after intravenous administration. Also consistent with the central actions of GHSs, ghrelin-immunoreactive cells were shown to be located in the hypothalamic arcuate nucleus as well as the stomach. Recently, we showed that a single central administration of ghrelin increased food intake and hypothalamic agouti-related protein (AGRP) gene expression in rodents, and the orexigenic effect of this peptide seems to be independent of its GH-releasing activity. However, the effect of chronic infusion of ghrelin on food consumption and body weight and their possible mechanisms have not been elucidated. In this study, we determined the effects of chronic intracerebroventricular treatment with ghrelin on metabolic factors and on neuropeptide genes that are expressed in hypothalamic neurons that have been previously shown to express the GHS-R and to regulate food consumption. Chronic central administration of rat ghrelin (1 microg/rat every 12 h for 72 h) significantly increased food intake and body weight. However, it did not affect plasma insulin, glucose, leptin, or GH concentrations. We also found that chronic central administration of ghrelin increased both neuropeptide Y (NPY) mRNA levels (151.0 +/- 10.1% of saline-treated controls; P < 0.05) and AGRP mRNA levels (160.0 +/- 22.5% of saline-treated controls; P < 0.05) in the arcuate nucleus. Thus, the primary hypothalamic targets of ghrelin are NPY/AGRP-containing neurons, and ghrelin is a newly discovered orexigenic peptide in the brain and stomach.

  11. Ghrelin modulates fatty acid synthase and related transcription factor mRNA levels in a tissue-specific manner in neonatal broiler chicks.

    PubMed

    Buyse, Johan; Janssen, Sara; Geelissen, Sofie; Swennen, Quirine; Kaiya, Hiroyuki; Darras, Veerle M; Dridi, Sami

    2009-07-01

    The endogenous ligand for the growth hormone (GH) secretagogue receptor ghrelin is a peptide secreted by the stomach of mammals and stimulates food intake and enhances adiposity. In avian species, ghrelin is mainly produced by the proventriculus but reduces food intake whereas its effect on lipogenesis in different tissues is unknown. We therefore investigated the effects of a single intravenous injection of 2.8 microg (1 nmol per chick) recombinant chicken ghrelin in neonatal broiler chicks. Besides food intake and plasma corticosterone levels, mRNA levels of the key lipogenic enzyme fatty acid synthase (FAS) and its related transcription factors sterol regulatory element binding protein-1 (SREBP-1) and peroxisome proliferator-activated receptor-gamma (PPARgamma) were determined in diencephalon, liver and quadriceps femoris muscle before, and 15, 30, and 60 min after injection. Chicken ghrelin administration induced a significant short-term (<30 min) reduction in food intake and markedly elevated plasma corticosterone levels. In diencephalon, FAS, SREBP-1 and PPARgamma mRNA levels were significantly increased within 15 min after ghrelin injection. These observations suggest that central fatty acid metabolism is involved in the anorectic effects of ghrelin. In contrast, hepatic mRNA levels of FAS and both transcription factors were significantly reduced within 30 min after ghrelin injection. In muscle, FAS and transcription factor gene expression was very low and not affected by ghrelin. Overall, our results indicate that ghrelin has opposite effects on FAS and transcription factor mRNA amounts with increased levels in diencephalon (central anorectic effect) and decreased levels in liver (peripheral anti-lipogenic effect) in chickens.

  12. Ghrelin and obestatin: different role in fetal lung development?

    PubMed

    Nunes, Susana; Nogueira-Silva, Cristina; Dias, Emanuel; Moura, Rute S; Correia-Pinto, Jorge

    2008-12-01

    Ghrelin and obestatin are two proteins that originate from post-translational processing of the preproghrelin peptide. Various authors claim an opposed role of ghrelin and obestatin in several systems. Preproghrelin mRNA is significantly expressed in airway epithelium throughout lung development, predominantly during the earliest stages. The aim of this study was to evaluate the role of ghrelin and obestatin in fetal lung development in vitro. Immunohistochemistry studies were performed at different gestational ages in order to clarify the expression pattern of ghrelin, GHS-R1a, obestatin and GPR39 during fetal lung development. Fetal rat lung explants were harvested at 13.5 days post-conception (dpc) and cultured during 4 days with increasing doses of total ghrelin, acylated ghrelin, desacyl-ghrelin, ghrelin antagonist (D-Lys(3)-GHRP-6) or obestatin. Immunohistochemistry studies demonstrated that ghrelin, GHS-R1a, obestatin and GPR39 proteins were expressed in primitive rat lung epithelium throughout all studied gestational ages. Total and acylated ghrelin supplementation significantly increased the total number of peripheral airway buds, whereas desacyl-ghrelin induced no effect. Moreover, GHS-R1a antagonist significantly decreased lung branching. Finally, obestatin supplementation induced no significant effect in the measured parameters. The present study showed that ghrelin has a positive effect in fetal lung development through its GHS-R1a receptor, whereas obestatin has no effect on lung branching.

  13. The Ghrelin Axis in Disease; Potential Therapeutic Indications

    PubMed Central

    Nass, Ralf; Gaylinn, Bruce D.; Thorner, Michael O.

    2011-01-01

    Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood main effects of acylated ghrelin administration include anorexic effects, increased appetite and the stimulation of GH secretion. Ghrelin also seems to plays a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease. PMID:21356273

  14. Changes in the ghrelin hormone pathway maybe part of an unusual gastric system in monotremes.

    PubMed

    He, Chuan; Tsend-Ayush, Enkhjargal; Myers, Mark A; Forbes, Briony E; Grützner, Frank

    2013-09-15

    Ghrelin is a growth hormone (GH)-releasing and appetite-regulating peptide predominately released from the stomach. Ghrelin is evolutionarily highly conserved and known to have a wide range of functions including the regulation of metabolism by maintaining an insulin-glucose balance. The peptide is produced as a single proprotein, which is later proteolytically cleaved. Ghrelin exerts its biological function after O-n-octanoylation at residue serine 3, which is catalyzed by ghrelin O-acyl transferase (GOAT) and allows binding to the growth hormone secretagogue receptor (GHS-R 1a). Genes involved in the ghrelin pathway have been identified in a broad range of vertebrate species, however, little is known about this pathway in the basal mammalian lineage of monotremes (platypus and echidna). Monotremes are particularly interesting in this context, as they have undergone massive changes in stomach anatomy and physiology, accompanied by a striking loss of genes involved in gastric function. In this study, we investigated genes in the ghrelin pathway in monotremes. Using degenerate PCR, database searches and synteny analysis we found that genes encoding ghrelin and GOAT are missing in the platypus genome, whilst, as has been reported in other species, the GHSR is present and expressed in brain, pancreas, kidney, intestine, heart and stomach. This is the first report suggesting the loss of ghrelin in a mammal. The loss of this gene may be related to changes to the platypus digestive system and raises questions about the control of blood glucose levels and insulin response in monotreme mammals. In addition, the conservation of the ghrelin receptor gene in platypus indicates that another ligand(s) maybe acting via this receptor in monotremes.

  15. Physiological significance of ghrelin revealed by studies using genetically engineered mouse models with modifications in the ghrelin system.

    PubMed

    Ariyasu, Hiroyuki; Akamizu, Takashi

    2015-01-01

    Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R or ghrelin receptor), is a 28-amino acid acylated peptide mainly produced in the stomach. The pharmacological administration of ghrelin is known to exert diverse effects, such as stimulating GH secretion, promoting food intake, and increasing adiposity. In recent years, genetically engineered mouse models have provided important insights into the physiology of various hormones. In this review, we discuss current knowledge regarding the physiological significance of ghrelin on the basis of studies using genetically engineered mouse models with modifications in the ghrelin system.

  16. Ghrelin and the cardiovascular system.

    PubMed

    Tokudome, Takeshi; Kishimoto, Ichiro; Miyazato, Mikiya; Kangawa, Kenj

    2014-01-01

    Ghrelin is a peptide that was originally isolated from the stomach. It exerts potent growth hormone (GH)-releasing and orexigenic activities. Several studies have highlighted the therapeutic benefits of ghrelin for the treatment of cardiovascular disease. In animal models of chronic heart failure, the administration of ghrelin improved cardiac function and remodeling; these findings were replicated in human patients with heart failure. Moreover, in an animal study, ghrelin administration effectively reduced pulmonary hypertension induced by chronic hypoxia. In addition, repeated administration of ghrelin to cachectic patients with chronic obstructive pulmonary disease had positive effects on overall body function, including muscle wasting, functional capacity and sympathetic activity. The administration of ghrelin early after myocardial infarction (MI) reduced fatal arrhythmia and related mortality. In ghrelin-deficient mice, both exogenous and endogenous ghrelin were protective against fatal arrhythmia and promoted remodeling after MI. Although the mechanisms underlying the effects of ghrelin on the cardiovascular system remain unclear, there are indications that its beneficial effects are mediated through both direct physiological actions, including increased GH levels, improved energy balance and direct actions on cardiovascular cells, and regulation of autonomic nervous system activity. Therefore, ghrelin is a promising novel therapeutic agent for cardiovascular disease.

  17. Basal plasma levels of insulin, leptin, ghrelin, and amylin do not signal adiposity in rats recovering from forced overweight.

    PubMed

    Gloy, Viktoria L; Lutz, Thomas A; Langhans, Wolfgang; Geary, Nori; Hillebrand, Jacquelien J

    2010-09-01

    This study examined how adiposity signals are related to adiposity during recovery from forced overweight (OW). Rats were rendered OW by chronic intragastric overfeeding (OW). Overfeeding was stopped when OW rats reached 126-129% of saline-infused normal-weight (NW) rats. Adipose tissue (AT) mass was estimated by computed tomography, and blood was drawn from chronic atrial cannulas throughout. Basal levels (i.e. after 2-3 h fasts late in the diurnal phase) of the hypothesized adiposity signals insulin, leptin, ghrelin, and amylin were assayed. OW rats gained approximately 130 g more body weight (BW) and approximately 100 g more AT mass during overfeeding. Plasma levels of insulin and leptin increased, whereas those of ghrelin decreased, linearly with AT mass; amylin did not change reliably. During recovery, OW rats' BW and AT mass decreased but were still elevated vs. NW rats after 39 d. OW rats' insulin returned to NW levels on d 1 of recovery and decreased below NW levels thereafter. Leptin was no longer elevated after d 8 of recovery. Ghrelin and amylin did not change reliably during recovery. Although AT mass decreased in OW rats during each intermeasurement interval between d 0 and d 23 of recovery, insulin and leptin did so during only the first interval (d 0-5). Insulin and leptin levels were exponentially related to AT mass during recovery. These data indicate that basal insulin, leptin, ghrelin, and amylin do not encode AT mass in rats dynamically regulating BW and adiposity during recovery from OW.

  18. Ghrelin affects stopover decisions and food intake in a long-distance migrant

    PubMed Central

    Lupi, Sara; Kaiya, Hiroyuki; Cardinale, Massimiliano

    2017-01-01

    Billions of birds migrate long distances to either reach breeding areas or to spend the winter at more benign places. On migration, most passerines frequently stop over to rest and replenish their fuel reserves. To date, we know little regarding how they decide that they are ready to continue their journey. What physiological signals tell a bird’s brain that its fuel reserves are sufficient to resume migration? A network of hormones regulates food intake and body mass in vertebrates, including the recently discovered peptide hormone, ghrelin. Here, we show that ghrelin reflects body condition and influences migratory behavior of wild birds. We measured ghrelin levels of wild garden warblers (Sylvia borin) captured at a stopover site. Further, we manipulated blood concentrations of ghrelin to test its effects on food intake and migratory restlessness. We found that acylated ghrelin concentrations of garden warblers with larger fat scores were higher than those of birds without fat stores. Further, injections of unacylated ghrelin decreased food intake and increased migratory restlessness. These results represent experimental evidence that appetite-regulating hormones control migratory behavior. Our study lays a milestone in migration physiology because it provides the missing link between ecologically dependent factors such as condition and timing of migration. In addition, it offers insights in the regulation of the hormonal system controlling food intake and energy stores in vertebrates, whose disruption causes eating disorders and obesity. PMID:28167792

  19. Inhibitory Effect of Oleic Acid on Octanoylated Ghrelin Production.

    PubMed

    Oiso, Shigeru; Nobe, Miyuki; Iwasaki, Syuhei; Nii, Wakana; Goto, Natsumi; Seki, Yukari; Nakajima, Kensuke; Nakamura, Kazuo; Kariyazono, Hiroko

    2015-01-01

    Ghrelin is a growth hormone-releasing peptide that also displays orexigenic activity. Since serine-3 acylation with octanoylate (octanoylation) is essential for the orexigenic activity of ghrelin, suppression of octanoylation could lead to amelioration or prevention of obesity. To enable the exploration of inhibitors of octanoylated ghrelin production, we developed a cell-based assay system using AGS-GHRL8 cells, in which octanoylated ghrelin concentration increases in the presence of octanoic acid. Using this assay system, we investigated whether fatty acids contained in foods or oils, such as acetic acid, stearic acid, oleic acid, linoleic acid, and α-linolenic acid, have inhibitory effects on octanoylated ghrelin production. Acetic acid did not suppress the increase in octanoylated ghrelin production in AGS-GHRL8 cells, which was induced by the addition of octanoic acid. However, stearic acid, oleic acid, linoleic acid, and α-linolenic acid significantly suppressed octanoylated ghrelin production, with the effect of oleic acid being the strongest. Additionally, oleic acid decreased the serum concentration of octanoylated ghrelin in mice. The serum concentration of des-acyl ghrelin (without acyl modification) was also decreased, but the decrease was smaller than that of octanoylated ghrelin. Decreased octanoylated ghrelin production likely resulted from post-translational ghrelin processing, as there were no significant differences in gene expression in the stomach between oleic acid-treated mice and controls. These results suggest that oleic acid is a potential inhibitor of octanoylated ghrelin production and that our assay system is a valuable tool for screening compounds with suppressive effects on octanoylated ghrelin production.

  20. Subjective sleep duration and quality influence diet composition and circulating adipocytokines and ghrelin levels in teen-age girls.

    PubMed

    Al-Disi, Dara; Al-Daghri, Nasser; Khanam, Latifa; Al-Othman, Abdulaziz; Al-Saif, Mohammad; Sabico, Shaun; Chrousos, George

    2010-01-01

    Understanding the interplay between sleep duration and quality, diet and hormones of obesity may help design effective lifestyle intervention strategies. Here we studied such associations in lean and obese teen-aged Saudi girls. In this cross-sectional observational study, 126 girls (62 lean and 64 obese) aged 14 -18 years (16.5 ± 1.5) were evaluated. A general questionnaire, which included sleep and diet questions, was obtained and anthropometric measurements and overnight fasting blood samples for determination of glucose, lipid profile and serum levels of leptin, adiponectin, resistin and ghrelin were collected. Subjects that slept < 5 hours/day had a higher percent of carbohydrate intake (p = 0.04) than those who slept > 7 hours/day. Adiponectin levels were higher in the lean than the obese group and increased in proportion to hours of sleep. Ghrelin had an inverse association with subjective sleep duration (p = 0.04), while resistin levels were directly proportional to it. Thus, the duration and quality of sleep influenced diet composition and the circulating levels of adipocytokines and ghrelin in adolescent girls. Long and uninterrupted sleep was associated with a better diet and a more favorable hormonal profile.

  1. Effects of miglitol, vildagliptin, or their combination on serum insulin and peptide YY levels and plasma glucose, cholecystokinin, ghrelin, and obestatin levels.

    PubMed

    Aoki, Kazutaka; Kamiyama, Hiroshi; Masuda, Kiyomi; Kamiko, Kazunari; Noguchi, Yoshihiko; Tajima, Kazuki; Terauchi, Yasuo

    2014-01-01

    We previously reported that combination therapy with an α-glucosidase inhibitor (αGI) and a dipeptidyl peptidase-4 (DPP-4) inhibitor increased active glucagon-like peptide-1 (GLP-1) levels and decreased total glucose-dependent insulinotropic polypeptide (GIP) levels, compared with monotherapy, in non-diabetic men. However, the peptide YY (PYY), cholecystokinin (CCK), ghrelin, and obestatin levels in patients receiving a combination of αGIs and DPP-4 inhibitors have not been previously reported. We evaluated the effect of miglitol, vildagliptin, or their combination on these parameters. Miglitol and/or vildagliptin were administered according to four different intake schedules in eleven non-diabetic men (C: no drug, M: miglitol; V: vildagliptin, M+V: miglitol+vildagliptin). Blood samples were collected at 0, 30, 60, and 120 min after the start of breakfast. The plasma glucose, serum insulin, serum total PYY (PYY1-36 and PYY3-36), plasma CCK, plasma active ghrelin, and plasma obestatin levels were measured. The area under the curve (AUC) of the serum total PYY level in the M group was significantly greater than that in the C group, and the AUC of the serum total PYY level in the M+V group was significantly lower than that in the M group. The combination therapy did not change the AUC of the plasma CCK, plasma active ghrelin, plasma obestatin, and ghrelin/obestatin levels, compared with the control. The results of our study suggested that combination therapy with miglitol and vildagliptin had no effect on appetite regulation hormones, such as total PYY, CCK, active ghrelin, and obestatin, compared with the levels in the control group.

  2. Ghrelin: a multifunctional hormone in non-mammalian vertebrates.

    PubMed

    Kaiya, Hiroyuki; Miyazato, Mikiya; Kangawa, Kenji; Peter, Richard E; Unniappan, Suraj

    2008-02-01

    In mammals, ghrelin is a non-amidated peptide hormone, existing in both acylated and non-acylated forms, produced mainly from the X/A or ghrelin cells present in the mucosal layer of the stomach. Ghrelin is a natural ligand of the growth hormone (GH) secretagogue-receptor (GHS-R), and functions primarily as a GH-releasing hormone and an orexigen, as well as having several other biological actions. Among non-mammalian vertebrates, amino acid sequence of ghrelin has been reported in two species of cartilaginous fish, seven species of teleosts, two species of amphibians, one species of reptile and six species of birds. The structure and functions of ghrelin are highly conserved among vertebrates. This review presents a concise overview of ghrelin biology in non-mammalian vertebrates.

  3. Ghrelin and PYY levels in adolescents with severe obesity: effects of weight loss induced by long-term exercise training and modified food habits.

    PubMed

    Gueugnon, Carine; Mougin, Fabienne; Nguyen, Nhu Uyen; Bouhaddi, Malika; Nicolet-Guénat, Marie; Dumoulin, Gilles

    2012-05-01

    This study investigated (a) changes in ghrelin and peptide YY (PYY) concentrations during a weight reduction programme and (b) baseline ghrelin and PYY levels as predictors of weight loss in 32 severely obese adolescents (BMI z score = 4.1). Subjects spent an academic year in an institution for childhood obesity. Fasting ghrelin and PYY, leptin, insulin levels and insulin resistance were measured at baseline (month 0) and during the programme (months 3, 6, 9). In addition, 15 normal-weight teenagers served as reference for the baseline assessments. At baseline, obese teenagers had lower ghrelin and PYY concentrations than normal-weight adolescents (P < 0.05). Moreover, they showed significantly higher leptin, insulin levels and homeostasis model assessment (HOMA) (P < 0.0001). During the lifestyle modification, there was a significant decrease in body weight among obese teenagers, associated with an increase in ghrelin (apparent from month 6; P < 0.05), a decrease in leptin (from month 3; P < 0.05) and a decrease in insulin and HOMA (from month 3; P < 0.0001), without any significant change in PYY. Anthropometrical changes were correlated neither with baseline ghrelin levels nor with changes in ghrelin and PYY after the lifestyle modification. However, higher baseline PYY tended to correlate with greater anthropometrical changes (P < 0.1). In adolescents with severe obesity, a long-term combination of supervised aerobic exercises and a balanced diet led to weight reduction and increased ghrelin concentrations, without any change in PYY concentrations. Moreover, baseline PYY concentrations might be considered as predictors of weight loss.

  4. Ghrelin Exerts Analgesic Effects through Modulation of IL-10 and TGF-β Levels in a Rat Model of Inflammatory Pain

    PubMed Central

    Azizzadeh, Faranak; Mahmoodi, Javad; Sadigh-Eteghad, Saeed; Farajdokht, Fereshteh; Mohaddes, Gisou

    2017-01-01

    Background: Ghrelin is a peptide with attenuating effect on inflammatory pain. Both anti- and pro-inflammatory mediators have a role in the nociception and development of pain and hyperalgesia. IL-10 and TGF-β are anti-inflammatory cytokines and inhibit the expression of pro-inflammatory cytokines related to peripheral and central inflammatory pain. In this study, the effects of i.p. injection of ghrelin on the early and the late phases of pain, as well as serum levels of IL-10 and TGF-β, as anti-inflammatory cytokines, were investigated in formalin-induced pain in male rats. Methods: Adult male Wistar rats (n=48) were randomly divided into six groups: control, formalin+saline, ghrelin (40, 80, and 160 μg/kg), and morphine. Ghrelin was administered i.p. 30 min before inducing pain by formalin. Pain induced by intraplantar (i.pl.) injection of 50 µl formalin 5%, and pain behavior was studied for 60 min. Serum IL-10 and TGF-β levels were assessed by ELISA method. Results: The findings of the present study showed that ghrelin with high doses (80 and 160 μg/kg) significantly reduced pain intensity in both the early and the late phases of pain. The serum levels of cytokines, IL-10, and TGF-β1 showed a significant elevation with ghrelin at the dose of 160 μg/kg. Conclusion: Ghrelin is effective in reducing the intensity of both the early and the late phases of inflammatory pain. It seems that ghrelin exerts its analgesic effects in part by increasing the serum levels of anti-inflammatory cytokines. PMID:27703278

  5. Reciprocal relationship between plasma ghrelin level and arterial stiffness in hypertensive subjects.

    PubMed

    Zhao, Yin-Tao; Yang, Hai-Bo; Li, Ling; Gao, Ke; Li, Peng-Fei; Xie, Wei-Wei

    2013-11-01

    Arterial stiffness, considered an independent predictor of cardiovascular morbidity and mortality, is closely associated with hypertension. Futhermore, the role of ghrelin in the development of hypertension has been widely recognized. The purpose of the present study was to explore the potential relationship between circulating ghrelin and arterial stiffness in hypertensive subjects. A total of 192 patients with primary hypertension and 107 normotensive (NT) control subjects were enrolled in the present cross-sectional study. Plasma ghrelin was determined by ELISA. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV) and the augmentation index (AIx). Both baPWV and AIx values were markedly higher in the hypertensive compared with NT group (P < 0.01). In contrast, plasma ghrelin concentrations were significantly lower in hypertensive patients compared with NT subjects (P < 0.01). Plasma ghrelin concentrations were negatively correlated with age (odds ratio (OR) -1.836; P < 0.001), smoking (OR -1.347; P = 0.042), baPWV (OR -1.762; P < 0.001) and AIx (OR -1.516; P = 0.005), but positively associated with fasting plasma glucose (OR 1.293; P = 0.047) and HbA1c (OR 1.413; P = 0.025). The inverse correlation between circulating ghrelin and the extent of arterial stiffness suggests that ghrelin is an independent determinant of arterial stiffness, even after adjustment for confounding cardiovascular risk factors, and it actively participates in the pathophysiology of arterial stiffness in hypertensive subjects.

  6. Serum Levels of Acyl-Carnitines along the Continuum from Normal to Alzheimer's Dementia.

    PubMed

    Cristofano, Adriana; Sapere, Nadia; La Marca, Giancarlo; Angiolillo, Antonella; Vitale, Michela; Corbi, Graziamaria; Scapagnini, Giovanni; Intrieri, Mariano; Russo, Claudio; Corso, Gaetano; Di Costanzo, Alfonso

    2016-01-01

    This study aimed to determine the serum levels of free L-carnitine, acetyl-L-carnitine and 34 acyl-L-carnitine in healthy subjects and in patients with or at risk of Alzheimer's disease. Twenty-nine patients with probable Alzheimer's disease, 18 with mild cognitive impairment of the amnestic type, 24 with subjective memory complaint and 46 healthy subjects were enrolled in the study, and the levels of carnitine and acyl-carnitines were measured by tandem mass spectrometry. The concentrations of acetyl-L-carnitine progressively decreased passing from healthy subjects group (mean±SD, 5.6±1.3 μmol/L) to subjective memory complaint (4.3±0.9 μmol/L), mild cognitive impairment (4.0±0.53 μmol/L), up to Alzheimer's disease (3.5±0.6 μmol/L) group (p<0.001). The differences were significant for the comparisons: healthy subjects vs. subjective memory complaint, mild cognitive impairment or Alzheimer's disease group; and subjective memory complaint vs. Alzheimer's disease group. Other acyl-carnitines, such as malonyl-, 3-hydroxyisovaleryl-, hexenoyl-, decanoyl-, dodecanoyl-, dodecenoyl-, myristoyl-, tetradecenoyl-, hexadecenoyl-, stearoyl-, oleyl- and linoleyl-L-carnitine, showed a similar decreasing trend, passing from healthy subjects to patients at risk of or with Alzheimer's disease. These results suggest that serum acetyl-L-carnitine and other acyl-L-carnitine levels decrease along the continuum from healthy subjects to subjective memory complaint and mild cognitive impairment subjects, up to patients with Alzheimer's disease, and that the metabolism of some acyl-carnitines is finely connected among them. These findings also suggest that the serum levels of acetyl-L-carnitine and other acyl-L-carnitines could help to identify the patients before the phenotype conversion to Alzheimer's disease and the patients who would benefit from the treatment with acetyl-L-carnitine. However, further validation on a larger number of samples in a longitudinal study is needed

  7. Serum Levels of Acyl-Carnitines along the Continuum from Normal to Alzheimer's Dementia

    PubMed Central

    Sapere, Nadia; La Marca, Giancarlo; Angiolillo, Antonella; Vitale, Michela; Corbi, Graziamaria; Scapagnini, Giovanni; Intrieri, Mariano; Russo, Claudio

    2016-01-01

    This study aimed to determine the serum levels of free L-carnitine, acetyl-L-carnitine and 34 acyl-L-carnitine in healthy subjects and in patients with or at risk of Alzheimer’s disease. Twenty-nine patients with probable Alzheimer’s disease, 18 with mild cognitive impairment of the amnestic type, 24 with subjective memory complaint and 46 healthy subjects were enrolled in the study, and the levels of carnitine and acyl-carnitines were measured by tandem mass spectrometry. The concentrations of acetyl-L-carnitine progressively decreased passing from healthy subjects group (mean±SD, 5.6±1.3 μmol/L) to subjective memory complaint (4.3±0.9 μmol/L), mild cognitive impairment (4.0±0.53 μmol/L), up to Alzheimer’s disease (3.5±0.6 μmol/L) group (p<0.001). The differences were significant for the comparisons: healthy subjects vs. subjective memory complaint, mild cognitive impairment or Alzheimer’s disease group; and subjective memory complaint vs. Alzheimer’s disease group. Other acyl-carnitines, such as malonyl-, 3-hydroxyisovaleryl-, hexenoyl-, decanoyl-, dodecanoyl-, dodecenoyl-, myristoyl-, tetradecenoyl-, hexadecenoyl-, stearoyl-, oleyl- and linoleyl-L-carnitine, showed a similar decreasing trend, passing from healthy subjects to patients at risk of or with Alzheimer’s disease. These results suggest that serum acetyl-L-carnitine and other acyl-L-carnitine levels decrease along the continuum from healthy subjects to subjective memory complaint and mild cognitive impairment subjects, up to patients with Alzheimer’s disease, and that the metabolism of some acyl-carnitines is finely connected among them. These findings also suggest that the serum levels of acetyl-L-carnitine and other acyl-L-carnitines could help to identify the patients before the phenotype conversion to Alzheimer’s disease and the patients who would benefit from the treatment with acetyl-L-carnitine. However, further validation on a larger number of samples in a longitudinal

  8. Ghrelin and motilin in the gastrointestinal system.

    PubMed

    Chen, Chih-Yen; Tsai, Chang-Youh

    2012-01-01

    Human ghrelin and human motilin, belonging to the ghrelin/motilin-related peptide family, share 36% amino acid sequence identity, while the human ghrelin receptor exhibits a remarkable 50% overall identity with the human motilin receptor. In addition to their structural resemblance, ghrelin and motilin are the only two mammalian hormones known to decrease in the postprandial period. Ghrelin and motilin participate in initiating the migrating motor complex in the stomach, and stimulate gastrointestinal motility, accelerate gastric emptying, and induce "gastric hunger". In addition to modulating the release of growth hormone and gut motility, ghrelin plays a crucial role in the secretion and protection of the stomach and colon. Ghrelin mimetics and motilin agonists are currently being developed to reverse gastrointestinal hypomotility disorders. With additional appetite-enhancing, adiposity-promoting, and anti-inflammatory effects, ghrelin and rikkunshito (a traditional Japanese herb enhancing acyl ghrelin signaling) are superior to motilin in the treatment of cancer-related anorexia and cachexia, post-chemotherapy symptoms, rheumatological diseases, age-related frailty, as well as post-operative, septic, and post-burn gut ileus.

  9. Ghrelin receptor agonist, GHRP-2, produces antinociceptive effects at the supraspinal level via the opioid receptor in mice.

    PubMed

    Zeng, Ping; Li, Shu; Zheng, Yue-hui; Liu, Fu-Yan; Wang, Jing-lei; Zhang, Da-lei; Wei, Jie

    2014-05-01

    GHRP-2 is a synthetic agonist of ghrelin receptor. GHRP-2 has similar physiological functions with ghrelin. In our previous study, ghrelin (i.c.v.) could induce analgesic effect through an interaction with GHS-R1α and with the central opioid system in the acute pain in mice. To date, the function of GHRP-2 in pain processing was not understood. Therefore the aim of this study was to investigate the effects of GHRP-2 on pain modulation at supraspinal level in mice using the tail immersion test. Intracerebroventricular (i.c.v.) administration of GHRP-2 (0.1, 0.3, 1, 3 and 10 nmol/L) produced a concentration- and time-related antinociceptive effect. This effect could be fully antagonized by GHS-R1α antagonist [d-Lys(3)]-GHRP-6, indicating that the analgesic effect induced by GHRP-2 is mediated through the activation of GHS-R1α. Interestingly, naloxone, naltrindole and nor-binaltorphimine, but not β-funaltrexamine, could also block the analgesic effect markedly, suggesting that δ- and κ-opioid receptor is involved in the analgesic response evoked by GHRP-2. Moreover, i.c.v. administration of GHRP-2 potentiated the analgesic effect induced by morphine (i.c.v., 1 nmol/L) and this potentiated effect could not be reversed by [d-Lys(3)]-GHRP-6. Thus these findings may be a new strategy on investigating the interaction between ghrelin system and opioids on pain modulation. Furthermore, GHRP-2 may be a promising peptide for developing new analgesic drugs.

  10. Neutralizing circulating ghrelin by expressing a growth hormone secretagogue receptor-based protein protects against high-fat diet-induced obesity in mice.

    PubMed

    Gagnon, J; Zhu, L; Anini, Y; Wang, Q

    2015-09-01

    Ghrelin is a stomach-derived peptide hormone that stimulates appetite and promotes adiposity through binding to the growth hormone secretagogue receptor (GHS-R1a). Administration of ghrelin in rodents increases weight gain due to stimulating food intake and reducing fat utilization. Therefore, reducing circulating ghrelin levels holds the potential to reduce weight gain. We developed a GHS-R1a-fusion constructs of a decoy protein containing the ligand-binding domains of the ghrelin receptor. Intramuscular injection of the GHSR/Fc plasmid decreased circulating levels of acylated-ghrelin. When challenged with the high fat diet, treated mice displayed reduced weight gain compared with controls, which was associated with reduced fat accumulation in the peritoneum but not lean mass. Quantitative PCR with reverse transcription showed increased PPARγ and hormone sensitive lipase transcripts levels in adipose tissue of treated animals, illustrating a preference for increased fat utilization. Intra-peritoneal glucose tolerance and insulin tolerance tests showed improved glucose clearance and insulin sensitivity in GHSR/Fc treated animals. We suggest that in vivo expression of the GHSR-based fusion protein prevents diet-induced weight gain, altering adipose gene expression and improving glucose tolerance. These findings, while confirming the role of ghrelin in peripheral energy metabolism, suggest that a strategy involving neutralization of the circulation ghrelin by intramuscular injection of the GHSR1/Fc fusion construct may find clinical application in the treatment of obesity.

  11. Hindbrain ghrelin receptor signaling is sufficient to maintain fasting glucose.

    PubMed

    Scott, Michael M; Perello, Mario; Chuang, Jen-Chieh; Sakata, Ichiro; Gautron, Laurent; Lee, Charlotte E; Lauzon, Danielle; Elmquist, Joel K; Zigman, Jeffrey M

    2012-01-01

    The neuronal coordination of metabolic homeostasis requires the integration of hormonal signals with multiple interrelated central neuronal circuits to produce appropriate levels of food intake, energy expenditure and fuel availability. Ghrelin, a peripherally produced peptide hormone, circulates at high concentrations during nutrient scarcity. Ghrelin promotes food intake, an action lost in ghrelin receptor null mice and also helps maintain fasting blood glucose levels, ensuring an adequate supply of nutrients to the central nervous system. To better understand mechanisms of ghrelin action, we have examined the roles of ghrelin receptor (GHSR) expression in the mouse hindbrain. Notably, selective hindbrain ghrelin receptor expression was not sufficient to restore ghrelin-stimulated food intake. In contrast, the lowered fasting blood glucose levels observed in ghrelin receptor-deficient mice were returned to wild-type levels by selective re-expression of the ghrelin receptor in the hindbrain. Our results demonstrate the distributed nature of the neurons mediating ghrelin action.

  12. Potentiation of ghrelin signaling attenuates cancer anorexia-cachexia and prolongs survival.

    PubMed

    Fujitsuka, N; Asakawa, A; Uezono, Y; Minami, K; Yamaguchi, T; Niijima, A; Yada, T; Maejima, Y; Sedbazar, U; Sakai, T; Hattori, T; Kase, Y; Inui, A

    2011-07-26

    Cancer anorexia-cachexia syndrome is characterized by decreased food intake, weight loss, muscle tissue wasting and psychological distress, and this syndrome is a major source of increased morbidity and mortality in cancer patients. This study aimed to clarify the gut-brain peptides involved in the pathogenesis of the syndrome and determine effective treatment for cancer anorexia-cachexia. We show that both ghrelin insufficiency and resistance were observed in tumor-bearing rats. Corticotropin-releasing factor (CRF) decreased the plasma level of acyl ghrelin, and its receptor antagonist, α-helical CRF, increased food intake of these rats. The serotonin 2c receptor (5-HT2cR) antagonist SB242084 decreased hypothalamic CRF level and improved anorexia, gastrointestinal (GI) dysmotility and body weight loss. The ghrelin receptor antagonist (D-Lys3)-GHRP-6 worsened anorexia and hastened death in tumor-bearing rats. Ghrelin attenuated anorexia-cachexia in the short term, but failed to prolong survival, as did SB242084 administration. In addition, the herbal medicine rikkunshito improved anorexia, GI dysmotility, muscle wasting, and anxiety-related behavior and prolonged survival in animals and patients with cancer. The appetite-stimulating effect of rikkunshito was blocked by (D-Lys3)-GHRP-6. Active components of rikkunshito, hesperidin and atractylodin, potentiated ghrelin secretion and receptor signaling, respectively, and atractylodin prolonged survival in tumor-bearing rats. Our study demonstrates that the integrated mechanism underlying cancer anorexia-cachexia involves lowered ghrelin signaling due to excessive hypothalamic interactions of 5-HT with CRF through the 5-HT2cR. Potentiation of ghrelin receptor signaling may be an attractive treatment for anorexia, muscle wasting and prolong survival in patients with cancer anorexia-cachexia.

  13. Is there an effect of ghrelin/ghrelin analogs on cancer? A systematic review

    PubMed Central

    Sever, Sakine; White, Donna L

    2016-01-01

    Ghrelin is a hormone with multiple physiologic functions, including promotion of growth hormone release, stimulation of appetite and regulation of energy homeostasis. Treatment with ghrelin/ghrelin-receptor agonists is a prospective therapy for disease-related cachexia and malnutrition. In vitro studies have shown high expression of ghrelin in cancer tissue, although its role including its impact in cancer risk and progression has not been established. We performed a systematic literature review to identify peer-reviewed human or animal in vivo original research studies of ghrelin, ghrelin-receptor agonists, or ghrelin genetic variants and the risk, presence, or growth of cancer using structured searches in PubMed database as well as secondary searches of article reference lists, additional reviews and meta-analyses. Overall, 45 (73.8%) of the 61 studies reviewed, including all 11 involving exogenous ghrelin/ghrelin-receptor agonist treatment, reported either a null (no statistically significant difference) or inverse association of ghrelin/ghrelin-receptor agonists or ghrelin genetic variants with cancer risk, presence or growth; 10 (16.7%) studies reported positive associations; and 6 (10.0%) reported both negative or null and positive associations. Differences in serum ghrelin levels in cancer cases vs controls (typically lower) were reported for some but not all cancers. The majority of in vivo studies showed a null or inverse association of ghrelin with risk and progression of most cancers, suggesting that ghrelin/ghrelin-receptor agonist treatment may have a favorable safety profile to use for cancer cachexia. Additional large-scale prospective clinical trials as well as basic bioscientific research are warranted to further evaluate the safety and benefits of ghrelin treatment in patients with cancer. PMID:27552970

  14. Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels.

    PubMed

    Stanley, C A; Hale, D E; Coates, P M; Hall, C L; Corkey, B E; Yang, W; Kelley, R I; Gonzales, E L; Williamson, J R; Baker, L

    1983-11-01

    Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye's syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate less than 0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 mmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 mumole/liter), liver (200-500 nmole/g), and muscle (500-800 nmole/g); however, treatment with L-carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium-chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA-acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase.

  15. Leptin and ghrelin levels in colostrum, milk and blood plasma of sows and pig neonates during the first week of lactation.

    PubMed

    Woliński, Jarosław; Słupecka, Monika; Romanowicz, Katarzyna

    2014-02-01

    Radioimmunology was used to determine leptin and ghrelin levels in sow colostrum and milk in relation to those in sow and neonatal pig blood plasma and to the body weight of piglets during the first week of lactation. The highest concentration of leptin was found in colostrum on the second day of lactation (69.3 ± 6.3 ng/mL). Leptin concentrations in sow plasma were significantly lower than in colostrum/milk (2.19 ± 0.9 ng/mL, P = 0.7692) and were stable in the first 7 days of lactation. Total and active ghrelin concentrations in colostrum/milk were stable in the measured time points (6734 ± 261 pg/mL, P = 0.3397; 831 ± 242 pg/mL, P = 0.3988, respectively). Total ghrelin concentrations in sow plasma were lower than in colostrum/milk. These results indicate that pigs follow a unique species-specific pattern of leptin and ghrelin synthesis, release and existence, and that the mammary gland is an important source of leptin and ghrelin contained in colostrum/milk.

  16. Daily supplementation with ghrelin improves in vitro bovine blastocysts formation rate and alters gene expression related to embryo quality.

    PubMed

    Dovolou, Eleni; Periquesta, Eva; Messinis, Ioannis E; Tsiligianni, Theodora; Dafopoulos, Konstantinos; Gutierrez-Adan, Alfonso; Amiridis, Georgios S

    2014-03-01

    Ghrelin is a gastric peptide having regulatory role in the reproductive system functionality, acting mainly at central level. Because the expression of ghrelin system (ghrelin and its receptor) has been detected in the bovine ovary, the objectives of the present study were to investigate whether ghrelin can affect the developmental potential of in vitro-produced embryos, and to test their quality in terms of relative abundance of various genes related to metabolism, apoptosis and oxidation. In the first experiment, in vitro-produced zygotes were cultured in the absence (control [C]) and in the presence of three concentrations of acylated ghrelin (200 pg/mL [Ghr200], 800 pg/mL [Ghr800]; and 2000 pg/mL [Ghr2000]); blastocyst formation rates were examined on Days 7, 8, and 9. In the second experiment, only the 800 pg/mL dose of ghrelin was used. Zygotes were produced as in experiment 1 and 24 hours post insemination they were divided into 4 groups; in two groups (C; without ghrelin; Ghr800 with ghrelin), embryos were cultured without medium replacement; in the remaining two groups (Control N and GhrN), the culture medium was daily renewed. A pool of Day-7 blastocysts were snap frozen for relative mRNA abundance of various genes related to metabolism, oxidation, implantation, and apoptosis. In experiment 3, embryos were produced as in experiment 2, but in the absence of serum (semi-defined culture medium). In experiment 1, no differences were detected between C, Ghr200, and Ghr2000, although fewer blastocysts were produced in group Ghr800 compared with C. In experiment 2, the lowest blastocysts yield was found in Ghr800, whereas daily renewal of ghrelin (Ghr800N) resulted to increased blastocysts formation rate, which on Day 7 was the highest among groups (P < 0.05). In experiment 3, ghrelin significantly suppressed blastocysts yield. Significant differences were detected in various relative mRNA abundance, giving an overall final notion that embryos produced in the

  17. What is the real relevance of endogenous ghrelin?

    PubMed

    Al Massadi, Omar; López, Miguel; Fernø, Johan; Diéguez, Carlos; Nogueiras, Rubén

    2015-08-01

    Ghrelin is a pleiotropic and ubiquitous gastric hormone implicated in body physiology. Ghrelin exhibits potent orexigenic actions and increases body weight and adiposity. Ghrelin is also involved in other metabolic functions among which we can highlight the GH releasing activity and the regulation of glucose homeostasis. Ghrelin needs the enzyme GOAT to be acylated, a step essential for binding to the GHSR1a receptor to exert its functions. Genetic animal models emerge as important tools to delineate the physiological relevance of ghrelin on energy balance. Despite the numerous reports using different genetically engineered mouse models targeting the ghrelin system, its endogenous relevance in metabolism seems to be less important than its pharmaceutical options.

  18. Tissue distribution and effects of fasting and obesity on the ghrelin axis in mice.

    PubMed

    Morash, Michael G; Gagnon, Jeffrey; Nelson, Stephanie; Anini, Younes

    2010-08-09

    Ghrelin is a 28 amino acid peptide hormone derived from the 117 amino acid proghrelin, following cleavage by proprotein convertase 1 (PC1). In this study, we comprehensively assessed the tissue distribution and the effect of fasting and obesity on preproghrelin, Exon-4D, PC1 and GOAT expression and proghrelin-derived peptide (PGDP) secretion. The stomach was the major source of preproghrelin expression and PDGPs, followed by the small intestine. The remaining peripheral tissues (including the brain and pancreas) contained negligible expression levels. We detected obestatin in all stomach proghrelin cells, however, 22% of proghrelin cells in the small intestine did not express obestatin. There were strain differences in ghrelin secretion in response to fasting between CD1 and C57BL/6 mice. After a 24 hour-fast, CD1 mice had increased plasma levels of total ghrelin and obestatin with no change in preproghrelin mRNA or PGDP tissues levels. C57BL/6 mice showed a different response to a 24 hour-fast having increased proghrelin mRNA expression, stomach acylated ghrelin peptide and no change in plasma obestatin in C57BL/6 mice. In obese mice (ob/ob and diet-induced obesity (DIO)) there was a significant increase in preproghrelin mRNA levels while tissue and plasma PGDP levels were significantly reduced. Fasting did not affect PGDP in obese mice. Obese models displayed differences in GOAT expression, which was elevated in DIO mice, but reduced in ob/ob mice. We did not find co-localization of the leptin receptor in ghrelin expressing stomach cells, ruling out a direct effect of leptin on stomach ghrelin synthesis and secretion.

  19. Effect of ruminal fill on foraging behavior, intake rate, and plasma ghrelin, serum insulin and glucose levels of cattle grazing a vegetative micro-sward

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The impact of ruminal fill (RF) on foraging behavior, intake rate and levels of circulating ghrelin, insulin and glucose was measured with four rumen-cannulated lactating dairy cows foraging micro-swards of vegetative orchardgrass. The treatments compared were removal of 1.00 (RF0), 0.66 (RF33), 0....

  20. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults

    PubMed Central

    Rigamonti, Antonello E.; Piscitelli, Fabiana; Aveta, Teresa; Agosti, Fiorenza; De Col, Alessandra; Bini, Silvia; Cella, Silvano G.; Di Marzo, Vincenzo; Sartorio, Alessandro

    2015-01-01

    Background Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. Methods To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. Results The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. Conclusions When motivation to eat is generated by exposure to, and consumption of, chocolate a peripheral activation of specific endogenous rewarding chemical signals, including ghrelin, AEA, and 2-AG, is observed in obese subjects. Although preliminary, these findings predict the effectiveness of ghrelin and endocannabinoid antagonists in the treatment of obesity. PMID:26546790

  1. Plasma kisspeptin and ghrelin levels are independently correlated with physical activity in patients with anorexia nervosa.

    PubMed

    Hofmann, Tobias; Elbelt, Ulf; Haas, Verena; Ahnis, Anne; Klapp, Burghard F; Rose, Matthias; Stengel, Andreas

    2017-01-01

    While physical hyperactivity represents a frequent symptom of anorexia nervosa and may have a deleterious impact on the course of the disease, the underlying mechanisms are poorly understood. Since several food intake-regulatory hormones affect physical activity, the aim of the study was to investigate the association of physical activity with novel candidate hormones (kisspeptin, ghrelin, oxyntomodulin, orexin-A, FGF-21, R-spondin-1) possibly involved in patients with anorexia nervosa. Associations with psychometric parameters and body composition were also assessed. We included 38 female anorexia nervosa inpatients (body mass index, BMI, mean ± SD: 14.8 ± 1.7 kg/m(2)). Physical activity was evaluated using portable armband devices, body composition by bioelectrical impedance analysis. Blood withdrawal (hormones measured by ELISA) and psychometric assessment of depressiveness (PHQ-9), anxiety (GAD-7), perceived stress (PSQ-20) and disordered eating (EDI-2) were performed at the same time. Patients displayed a broad spectrum of physical activity (2479-26,047 steps/day) which showed a negative correlation with kisspeptin (r = -0.41, p = 0.01) and a positive association with ghrelin (r = 0.42, p = 0.01). The negative correlation with oxyntomodulin (r = -0.37, p = 0.03) was lost after consideration of potential confounders by regression analysis. No correlations were observed between physical activity and orexin-A, FGF-21 and R-spondin-1 (p > 0.05). Kisspeptin was positively correlated with BMI and body fat mass and negatively associated with the interpersonal distrust subscale of the EDI-2 (p < 0.01). Depressiveness, anxiety, and perceived stress did not correlate with kisspeptin or any other of the investigated hormones (p > 0.05). In conclusion, kisspeptin is inversely and ghrelin positively associated with physical activity as measured by daily step counts in anorexia nervosa patients suggesting an implication of these peptide hormones in

  2. Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons.

    PubMed

    Briggs, Dana I; Enriori, Pablo J; Lemus, Moyra B; Cowley, Michael A; Andrews, Zane B

    2010-10-01

    Circulating ghrelin is decreased in obesity, and peripheral ghrelin does not induce food intake in obese mice. We investigated whether ghrelin resistance was a centrally mediated phenomenon involving dysregulated neuropeptide Y (NPY) and agouti-related peptide (AgRP) circuits. We show that diet-induced obesity (DIO) (12 wk) suppresses the neuroendocrine ghrelin system by decreasing acylated and total plasma ghrelin, decreasing ghrelin and Goat mRNA in the stomach, and decreasing expression of hypothalamic GHSR. Peripheral (ip) or central (intracerebroventricular) ghrelin injection was able to induce food intake and arcuate nucleus Fos immunoreactivity in chow-fed but not high-fat diet-fed mice. DIO decreased expression of Npy and Agrp mRNA, and central ghrelin was unable to promote expression of these genes. Ghrelin did not induce AgRP or NPY secretion in hypothalamic explants from DIO mice. Injection of NPY intracerebroventricularly increased food intake in both chow-fed and high-fat diet-fed mice, indicating that downstream NPY/AgRP neural targets are intact and that defective NPY/AgRP function is a primary cause of ghrelin resistance. Ghrelin resistance in DIO is not confined to the NPY/AgRP neurons, because ghrelin did not stimulate growth hormone secretion in DIO mice. Collectively, our data suggests that DIO causes ghrelin resistance by reducing NPY/AgRP responsiveness to plasma ghrelin and suppressing the neuroendocrine ghrelin axis to limit further food intake. Ghrelin has a number of functions in the brain aside from appetite control, including cognitive function, mood regulation, and protecting against neurodegenerative diseases. Thus, central ghrelin resistance may potentiate obesity-related cognitive decline, and restoring ghrelin sensitivity may provide therapeutic outcomes for maintaining healthy aging.

  3. Adipokines, ghrelin and obesity-associated insulin resistance in nondiabetic patients with acute coronary syndrome.

    PubMed

    Barazzoni, Rocco; Aleksova, Aneta; Armellini, Ilaria; Cattin, Maria Rosa; Zanetti, Michela; Carriere, Cosimo; Giacca, Mauro; Dore, Franca; Guarnieri, Gianfranco; Sinagra, Gianfranco

    2012-12-01

    Altered glucose metabolism negatively modulates outcome in acute coronary syndromes (ACS). Insulin resistance is commonly associated with increasing BMI in the general population and these associations may involve obesity-related changes in circulating ghrelin and adipokines. We aimed at investigating interactions between BMI, insulin resistance and ACS and their associations with plasma ghrelin and adipokine concentrations. Homeostasis model assessment of insulin resistance (HOMA(IR))-insulin resistance index, plasma adiponectin, leptin, total (T-Ghrelin), acylated (Acyl-Ghrelin), and desacylated ghrelin (Desacyl-Ghrelin) were measured in 60 nondiabetic ACS patients and 44 subjects without ACS matched for age, sex, and BMI. Compared with non-ACS, ACS patients had similar HOMA(IR) and plasma adipokines, but lower T- and Desacyl-Ghrelin and higher Acyl-Ghrelin. Obesity (BMI > 30) was associated with higher HOMA(IR), lower adiponectin, and higher leptin (P < 0.05) similarly in ACS and non-ACS subjects. In ACS (n = 60) HOMA(IR) remained associated negatively with adiponectin and positively with leptin independently of BMI and c-reactive protein (CRP) (P < 0.05). On the other hand, low T- and Desacyl-Ghrelin with high Acyl-Ghrelin characterized both obese and non-obese ACS patients and were not associated with HOMA(IR). In conclusion, in ACS patients, obesity and obesity-related changes in plasma leptin and adiponectin are associated with and likely contribute to negatively modulate insulin resistance. ACS per se does not however enhance the negative impact of obesity on insulin sensitivity. High acylated and low desacylated ghrelin characterize ACS patients independently of obesity, but are not associated with insulin sensitivity.

  4. Ghrelin and the cardiovascular system.

    PubMed

    Isgaard, Jörgen

    2013-01-01

    Although ghrelin was initially associated with regulation of appetite, the cardiovascular system has also been recognized as a potentially important target for its effects. Moreover, experimental and a limited number of clinical studies suggest a potential role for ghrelin in the treatment of congestive heart failure. So far, reported cardiovascular effects of growth hormone secretagogues and/or ghrelin include lowering of peripheral resistance, either direct at the vascular level and/or by modulating sympathetic nervous activity. Other observed effects indicate possible improvement of contractility and cardioprotective and anti-inflammatory effects both in vivo and in vitro. Taken together, these results offer an interesting perspective on the future where further studies aiming at evaluating a role of growth hormone secretagogues and ghrelin in the treatment of cardiovascular disease are warranted.

  5. Sulfated gastrin stimulates ghrelin and growth hormone release but inhibits insulin secretion in cattle.

    PubMed

    Zhao, Hongqiong; Yannaing, Swe; Thanthan, Sint; Kuwayama, Hideto

    2011-11-01

    This study was designed to determine the effects of gastrin on the circulating levels of ghrelin, growth hormone (GH), insulin, glucagon and glucose in ruminants. Two experiments were done in eight Holstein steers. Animals were randomly assigned to receive intravenous bolus injections: (1) 0.1% bovine serum albumin in saline as vehicle, 0.8, 4.0 and 20.0 μg/kg body weight (BW) of bovine sulfated gastrin-34; (2) vehicle, 0.53 μg/kg BW of bovine sulfated gastrin-17 alone or combined with 20.0 μg/kg BW of [D-Lys(3)]-GHRP-6, the selective antagonist of GHS-R1a. Blood samples were collected from -10 to 150 min relative to injection time. Concentrations of acyl and total ghrelin in response to gastrin-34 injection were significantly increased in a dose-dependent manner. Concentrations of GH were also markedly elevated by gastrin-34 injection; however, the effect of 20.0 μg/kg was weaker than that of 4.0 μg/kg. The three doses of gastrin-34 equally decreased insulin levels within 15 min and maintained the level until the time of last sampling. Gastrin-34 had no effect (P > 0.05) on the levels of glucagon and glucose. Levels of acyl ghrelin increased after administration of gastrin-17 alone or combined with [D-Lys(3)]-GHRP-6; however, [D-Lys(3)]-GHRP-6 did not block the elevation of GH by gastrin-17. The present results indicate that sulfated gastrin stimulates both ghrelin and GH release, but the GHS-R1a may not contribute to the release of GH by gastrin. Moreover, sulfated gastrin seems to indirectly maintain the homeostasis of blood glucose through the down-regulation of insulin in ruminants.

  6. Expression of Cyanobacterial Acyl-ACP Reductase Elevates the Triacylglycerol Level in the Red Alga Cyanidioschyzon merolae.

    PubMed

    Sumiya, Nobuko; Kawase, Yasuko; Hayakawa, Jumpei; Matsuda, Mami; Nakamura, Mami; Era, Atsuko; Tanaka, Kan; Kondo, Akihiko; Hasunuma, Tomohisa; Imamura, Sousuke; Miyagishima, Shin-ya

    2015-10-01

    Nitrogen starvation is known to induce the accumulation of triacylglycerol (TAG) in many microalgae, and potential use of microalgae as a source of biofuel has been explored. However, nitrogen starvation also stops cellular growth. The expression of cyanobacterial acyl-acyl carrier protein (ACP) reductase in the unicellular red alga Cyanidioschyzon merolae chloroplasts resulted in an accumulation of TAG, which led to an increase in the number and size of lipid droplets while maintaining cellular growth. Transcriptome and metabolome analyses showed that the expression of acyl-ACP reductase altered the activities of several metabolic pathways. The activities of enzymes involved in fatty acid synthesis in chloroplasts, such as acetyl-CoA carboxylase and pyruvate dehydrogenase, were up-regulated, while pyruvate decarboxylation in mitochondria and the subsequent consumption of acetyl-CoA by the tricarboxylic acid (TCA) cycle were down-regulated. Aldehyde dehydrogenase, which oxidizes fatty aldehydes to fatty acids, was also up-regulated in the acyl-ACP reductase expresser. This activation was required for the lipid droplet accumulation and metabolic changes observed in the acyl-ACP reductase expresser. Nitrogen starvation also resulted in lipid droplet accumulation in C. merolae, while cell growth ceased as in the case of other algal species. The metabolic changes that occur upon the expression of acyl-ACP reductase are quite different from those caused by nitrogen starvation. Therefore, there should be a method for further increasing the storage lipid level while still maintaining cell growth that is different from the metabolic response to nitrogen starvation.

  7. The expression of ghrelin O-acyltransferase (GOAT) in human tissues.

    PubMed

    Lim, Chung Thong; Kola, Blerina; Grossman, Ashley; Korbonits, Márta

    2011-01-01

    Ghrelin is a circulating growth hormone-releasing and appetite-inducing brain-gut peptide. It needs to be acylated on its serine-3 with octanoate for its endocrine actions. The acyl-transferase that catalyses ghrelin octanoylation has recently been identified and named as GOAT (ghrelin O-acyltransferase); GOAT enzyme is coded by the MBOAT4 gene. This study aimed to investigate GOAT expression in the human. The distribution of GOAT mRNA expression was studied in various human tissues using classical and real-time reverse transcription and polymerase chain reaction. GOAT expression was found in all tissues studied (stomach, adrenal cortex, breast, right and left colon, duodenum, jejunum, ileum, fat, Fallopian tube, gallbladder, lymph node, lymphocyte cell line, kidney, liver, lung, muscle, myocardium, pituitary, oesophagus, pancreas, ovary, placenta, prostate, testis, spleen and thyroid). The widespread expression of GOAT corresponds to the widespread distribution of ghrelin expression. GOAT expression was high in stomach and gut, the major ghrelin-secreting tissues, and in the pituitary, in which ghrelin is known to show autocrine and paracrine effects. Identification of GOAT expression in various tissues support the concept that in addition to the important endocrine effect of acylated ghrelin, the paracrine effects of locally synthetised and acylated ghrelin may be important.

  8. Ghrelin: a metabolic signal affecting the reproductive system.

    PubMed

    Lorenzi, Teresa; Meli, Rosaria; Marzioni, Daniela; Morroni, Manrico; Baragli, Alessandra; Castellucci, Mario; Gualillo, Oreste; Muccioli, Giampiero

    2009-04-01

    Ghrelin, an acylated 28 amino acid gastric peptide, was isolated from the stomach as an endogenous ligand for growth hormone (GH) secretagogue receptor in 1999. Circulating ghrelin is mainly produced by specific cells in the stomach's oxyntic glands. Ghrelin potently stimulates GH release and food intake and exhibits diverse effects, including ones on glucose metabolism and on secretion and motility of the gastrointestinal tract. Besides these effects on food intake and energy homeostasis, ghrelin is also involved in controlling reproductive functions, and a role for it as a novel regulator of the hypothalamic-pituitary gonadal axis is clearly emerging. We review recent ghrelin research with emphasis on its roles in the reproductive axis.

  9. Exercise and ghrelin. A narrative overview of research.

    PubMed

    King, James A; Wasse, Lucy K; Stensel, David J; Nimmo, Myra A

    2013-09-01

    Since its discovery in 1999, ghrelin has been implicated in a multiplicity of physiological activities. Most notably, ghrelin has an important influence on energy metabolism and after the identification of its potent appetite stimulating effects ghrelin has been termed the 'hunger hormone'. Exercise is a stimulus which has a significant impact on energy homeostasis and consequently a substantial body of research has investigated the interaction between exercise and ghrelin. This narrative review provides an overview of research relating to the acute and chronic effects of exercise on circulating ghrelin (acylated, unacylated and total). To enhance study comparability, the scope of this review is limited to research undertaken in adult humans and consequently studies involving children and animals are not discussed. Although there is significant ambiguity within much of the early research, our review suggests that acute exercise transiently interferes with the production of acylated ghrelin. Furthermore, the consensus of evidence indicates that exercise training does not influence circulating ghrelin independent of weight loss. Additional research is needed to verify and extend the available literature, particularly by uncovering the mechanisms governing acute exercise-related changes and characterising responses in other populations such as females, older adults, and the obese.

  10. Ghrelin and leptin pathophysiology in chronic kidney disease.

    PubMed

    Gunta, Sujana S; Mak, Robert H

    2013-04-01

    Ghrelin is an orexigenic hormone with additional effects on the regulation of inflammation and the cardiovascular system. It may play an important role in the pathogenesis of cachexia/protein-energy wasting (PEW), inflammation and cardiovascular complications in chronic kidney disease (CKD). There are three circulating gene products of ghrelin, namely, acyl ghrelin, des-acyl ghrelin and obestatin, each with individual distinct functions. Perturbations of these circulating ghrelin proteins impact the overall milieu of CKD. Leptin is an anorexigenic hormone which is secreted from the adipocytes and interacts with ghrelin and other appetite-regulating hormones. Leptin also plays a role in regulating inflammation and the cardiovascular system. Indeed, ghrelin and leptin may play yin-and-yang roles in CKD pathophysiology. Clinical trials involving the use of the mimetics or antagonists of these hormones are limited to short-term phase I/II studies. Further understanding of their interactions in CKD pathophysiology is needed for potential large-scale clinical trials, which may impact the quality of life and survival of patients with CKD.

  11. Ablation of Ghrelin O-Acyltransferase Does Not Improve Glucose Intolerance or Body Adiposity in Mice on a Leptin-Deficient ob/ob Background

    PubMed Central

    Kirchner, Henriette; Heppner, Kristy M.; Holland, Jenna; Kabra, Dhiraj; Tschöp, Matthias H.; Pfluger, Paul T.

    2013-01-01

    Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two ghrelin isoforms acyl- and desacyl ghrelin in regulating glucose homeostasis. Therefore ghrelin activating enzyme Ghrelin-O-acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl ghrelin deficiency or desacyl ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl ghrelin nor the increased ratio of desacyl/acyl ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency. PMID:23630616

  12. Enhanced Ghrelin Levels and Hypothalamic Orexigenic AgRP and NPY Neuropeptide Expression in Models of Jejuno-Colonic Short Bowel Syndrome

    PubMed Central

    Gillard, Laura; Billiauws, Lore; Stan-Iuga, Bogdan; Ribeiro-Parenti, Lara; Jarry, Anne-Charlotte; Cavin, Jean-Baptiste; Cluzeaud, Françoise; Mayeur, Camille; Thomas, Muriel; Freund, Jean-Noël; Lacorte, Jean-Marc; Le Gall, Maude; Bado, André; Joly, Francisca; Le Beyec, Johanne

    2016-01-01

    Short bowel syndrome (SBS) patients developing hyperphagia have a better outcome. Gastrointestinal endocrine adaptations help to improve intestinal functions and food behaviour. We investigated neuroendocrine adaptations in SBS patients and rat models with jejuno-ileal (IR-JI) or jejuno-colonic (IR-JC) anastomosis with and without parenteral nutrition. Circulating levels of ghrelin, PYY, GLP-1, and GLP-2 were determined in SBS rat models and patients. Levels of mRNA for proglucagon, PYY and for hypothalamic neuropeptides were quantified by qRT-PCR in SBS rat models. Histology and immunostaining for Ki67, GLP-1 and PYY were performed in SBS rats. IR-JC rats, but not IR-JI, exhibited significantly higher crypt depths and number of Ki67-positive cells than sham. Fasting and/or postprandial plasma ghrelin and PYY concentrations were higher, or tend to be higher, in IR-JC rats and SBS-JC patients than in controls. Proglucagon and Pyy mRNA levels were significantly enhanced in IR-JC rats. Levels of mRNA coding hypothalamic orexigenic NPY and AgRP peptides were significantly higher in IR-JC than in sham rats. We demonstrate an increase of plasma ghrelin concentrations, major changes in hypothalamic neuropeptides levels and greater induction of PYY in SBS-JC rats and patients suggesting that jejuno-colonic continuity creates a peculiar environment promoting further gut-brain adaptations. PMID:27323884

  13. [Possible connection between ghrelin, resistin and TNF-alpha levels and the metabolic syndrome caused by atypical antipsychotics].

    PubMed

    Birkás Kováts, Dezso; Palik, Eva; Faludi, Gábor; Cseh, Károly

    2005-09-01

    Second generation antipsychotics (SGA) are obesitogenic and diabetogenic. Role of ghrelin (RIA), resistin and TNF-alpha (ELISA) in weight gain and insulin resistance (fasting plasma insulin, HOMA, ELISA) was studied in Hungarian psychiatryic patients (n=60) treated with SGA (clozapine, olanzapine, risperidone, quetiapine, 15 each). After 1 year, 80% of patients became overweight/obese (BMI > 27/30) and 35% (n= 21/60) presented impaired glucose tolerance (13/60) or diabetes (8/60). Ghrelin (1.3 +/- 0.6 ng/ml), resistin (9.8 +/- 3.7 ng/ml), TNF-alpha (5.8 +/- 1.7 pg/ml), insulin (10.4 +/- 7.6 U/ml, HOMA A: 2.5 +/- 1.8, HOMA B: 133 +/- 62.5) were significantly higher in patients than in healthy matched controls. Resistin and TNF-alpha positively correlated with each other, insulin, HOMA, and negatively with ghrelin. Ghrelin contributes to weight gain, resistin and TNF-alpha to insulin resistance. A negative feedback regulation may exist between adipocytokines and ghrelin production. SGA drugs enhance ghrelin production despite the suppressive effect of adipocytokines. All four SGA drugs are equally obesitogenic and diabetogenic.

  14. Progress in Small Molecule and Biologic Therapeutics Targeting Ghrelin Signaling.

    PubMed

    McGovern, Kayleigh R; Darling, Joseph E; Hougland, James L

    2016-01-01

    Ghrelin is a circulating peptide hormone involved in regulation of a wide array of physiological processes. As an endogenous ligand for growth hormone secretagogue receptor (GHSR1a), ghrelin is responsible for signaling involved in energy homeostasis, including appetite stimulation, glucose metabolism, insulin signaling, and adiposity. Ghrelin has also been implicated in modulation of several neurological processes. Dysregulation of ghrelin signaling is implicated in diseases related to these pathways, including obesity, type II diabetes, and regulation of appetite and body weight in patients with Prader-Willi syndrome. Multiple steps in the ghrelin signaling pathway are available for targeting in the development of therapeutics for these diseases. Agonists and antagonists of GHS-R1a have been widely studied and have shown varying levels of effectiveness within ghrelin-related physiological pathways. Agents targeting ghrelin directly, either through depletion of ghrelin levels in circulation or inhibitors of ghrelin O-acyltransferase whose action is required for ghrelin to become biologically active, are receiving increasing attention as potential therapeutic options. We discuss the approaches utilized to target ghrelin signaling and highlight the current challenges toward developing small-molecule agents as potential therapeutics for ghrelin-related diseases.

  15. Catalytic antibody degradation of ghrelin increases whole-body metabolic rate and reduces refeeding in fasting mice.

    PubMed

    Mayorov, Alexander V; Amara, Neri; Chang, Jason Y; Moss, Jason A; Hixon, Mark S; Ruiz, Diana I; Meijler, Michael M; Zorrilla, Eric P; Janda, Kim D

    2008-11-11

    Obesity is a chronic, costly, and globally prevalent condition, with excess caloric intake a suspected etiologic factor. Nonsurgical treatments are modestly efficacious, and weight loss maintenance is hampered by anti-famine homeostatic mechanisms. Ghrelin, a gastric hormone linked to meal initiation, energy expenditure, and fuel partitioning, is hypothesized to facilitate weight gain and impede weight loss. Unique among known animal peptides, the serine-3 residue of ghrelin is posttranslationally acylated with an n-octanoic acid, a modification important for the peptide's active blood-brain transport and growth hormone secretagogue receptor-1 agonist activity. Pharmacological degradation of ghrelin would be hypothesized to reduce ghrelin's biological effects. To study endogenous ghrelin's role in appetite and energy expenditure, we generated antibodies that hydrolyze the octanoyl moiety of ghrelin to form des-acyl ghrelin. The most proficient antibody catalyst, GHR-11E11, was found to display a second-order rate constant of 18 M(-1) x s(-1) for the hydrolysis of ghrelin to des-acyl ghrelin. I.v. administration of GHR-11E11 (50 mg/kg) maintained a greater metabolic rate in fasting C57BL/6J mice as compared with mice receiving a control antibody and suppressed 6-h refeeding after 24 h of food deprivation. Indirect respiratory measures of metabolism after refeeding and relative fuel substrate utilization were unaffected. The results support the hypothesis that acylated ghrelin stimulates appetite and curbs energy expenditure during deficient energy intake, whereas des-acyl ghrelin does not potently share these functions. Catalytic anti-ghrelin antibodies might thereby adjunctively aid consolidation of caloric restriction-induced weight loss and might also be therapeutically relevant to Prader-Willi syndrome, characterized after infancy by hyperghrelinemia, hyperphagia, and obesity.

  16. Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention.

    PubMed

    Davies, Jeffrey S; Kotokorpi, Pia; Eccles, Sinan R; Barnes, Sarah K; Tokarczuk, Pawel F; Allen, Sophie K; Whitworth, Hilary S; Guschina, Irina A; Evans, Bronwen A J; Mode, Agneta; Zigman, Jeffrey M; Wells, Timothy

    2009-06-01

    Circulating ghrelin elevates abdominal adiposity by a mechanism independent of its central orexigenic activity. In this study we tested the hypothesis that peripheral ghrelin induces a depot-specific increase in white adipose tissue (WAT) mass in vivo by GH secretagogue receptor (GHS-R(1a))-mediated lipolysis. Chronic iv infusion of acylated ghrelin increased retroperitoneal and inguinal WAT volume in rats without elevating superficial sc fat, food intake, or circulating lipids and glucose. Increased retroperitoneal WAT mass resulted from adipocyte enlargement probably due to reduced lipid export (ATP-binding cassette transporter G1 mRNA expression and circulating free fatty acids were halved by ghrelin infusion). In contrast, ghrelin treatment did not up-regulate biomarkers of adipogenesis (peroxisome proliferator-activated receptor-gamma2 or CCAAT/enhancer binding protein-alpha) or substrate uptake (glucose transporter 4, lipoprotein lipase, or CD36) and although ghrelin elevated sterol-regulatory element-binding protein 1c expression, WAT-specific mediators of lipogenesis (liver X receptor-alpha and fatty acid synthase) were unchanged. Adiposity was unaffected by infusion of unacylated ghrelin, and the effects of acylated ghrelin were abolished by transcriptional blockade of GHS-R(1a), but GHS-R(1a) mRNA expression was similar in responsive and unresponsive WAT. Microarray analysis suggested that depot-specific sensitivity to ghrelin may arise from differential fine tuning of signal transduction and/or lipid-handling mechanisms. Acylated ghrelin also induced hepatic steatosis, increasing lipid droplet number and triacylglycerol content by a GHS-R(1a)-dependent mechanism. Our data imply that, during periods of energy insufficiency, exposure to acylated ghrelin may limit energy utilization in specific WAT depots by GHS-R(1a)-dependent lipid retention.

  17. Ghrelin in obesity and endocrine diseases.

    PubMed

    Scerif, Miski; Goldstone, Anthony P; Korbonits, Márta

    2011-06-20

    Ghrelin shows orexigenic effect through its action on the hypothalamic appetite-regulating pathways, while in the periphery ghrelin increases adipose tissue accumulation and has a diabetogenic effect on the liver and pancreas. Adenosine monophosphate-activated protein kinase (AMPK) has been suggested as one of the mediators of ghrelin's effects. Plasma ghrelin levels are dependent on body mass index as well as food intake patterns. Ghrelin levels are in general reduced in obese individuals and in subjects with insulin resistance. In contrast to other forms of obesity, patients with Prader-Willi syndrome (PWS) display high levels of ghrelin, reduced visceral adiposity and relative hypoinsulinemia. Relationships between obesity and common genomic variants of GHRL and GHS-R genes have been studied. Ghrelin may have a role in the weight-reducing effect of bariatric surgery; however, this is a much debated issue. Altered ghrelin levels have also been observed in Cushing's syndrome and thyroid disease probably due to the secondary insulin resistance in these subjects.

  18. Characterization of Ghrelin O-Acyltransferase (GOAT) in goldfish (Carassius auratus)

    PubMed Central

    Blanco, Ayelén Melisa; Gómez-Boronat, Miguel; Alonso-Gómez, Ángel Luis; Yufa, Roman; Unniappan, Suraj; Delgado, María Jesús; Valenciano, Ana Isabel

    2017-01-01

    Ghrelin is the only known hormone posttranslationally modified with an acylation. This modification is crucial for most of ghrelin’s physiological effects and is catalyzed by the polytopic enzyme ghrelin O-acyltransferase (GOAT). The aim of this study was to characterize GOAT in a teleost model, goldfish (Carassius auratus). First, the full-length cDNA sequence was obtained by RT-PCR and rapid amplification of cDNA ends methods. Two highly homologous cDNAs of 1491 and 1413 bp, respectively, named goat-V1 and goat-V2 were identified. Deduced protein sequences (393 and 367 amino acids, respectively) are predicted to present 11 and 9 transmembrane regions, respectively, and both contain two conserved key residues proposed to be involved in catalysis: asparagine 273 and histidine 304. RT-qPCR revealed that both forms of goat mRNAs show a similar widespread tissue distribution, with the highest expression in the gastrointestinal tract and gonads and less but considerable expression in brain, pituitary, liver and adipose tissue. Immunostaining of intestinal sections showed the presence of GOAT immunoreactive cells in the intestinal mucosa, some of which colocalize with ghrelin. Using an in vitro approach, we observed that acylated ghrelin downregulates GOAT gene and protein levels in cultured intestine in a time-dependent manner. Finally, we found a rhythmic oscillation of goat mRNA expression in the hypothalamus, pituitary and intestinal bulb of goldfish fed at midday, but not at midnight. Together, these findings report novel data characterizing GOAT, and offer new information about the ghrelinergic system in fish. PMID:28178327

  19. Actions of Agonists and Antagonists of the ghrelin/GHS-R Pathway on GH Secretion, Appetite, and cFos Activity

    PubMed Central

    Hassouna, Rim; Labarthe, Alexandra; Zizzari, Philippe; Videau, Catherine; Culler, Michael; Epelbaum, Jacques; Tolle, Virginie

    2012-01-01

    The stimulatory effects of ghrelin, a 28-AA acylated peptide originally isolated from stomach, on growth hormone (GH) secretion and feeding are exclusively mediated through the growth hormone secretagogue 1a receptor (GHS-R1a), the only ghrelin receptor described so far. Several GHS-R1a agonists and antagonists have been developed to treat metabolic or nutritional disorders but their mechanisms of action in the central nervous system remain poorly understood. In the present study, we compared the activity of BIM-28163, a GHS-R1a antagonist, and of several agonists, including native ghrelin and the potent synthetic agonist, BIM-28131, to modulate food intake, GH secretion, and cFos activity in arcuate nucleus (ArcN), nucleus tractus solitarius (NTS), and area postrema (AP) in wild-type and NPY-GFP mice. BIM-28131 was as effective as ghrelin in stimulating GH secretion, but more active than ghrelin in inducing feeding. It stimulated cFos activity similarly to ghrelin in the NTS and AP but was more powerful in the ArcN, suggesting that the super-agonist activity of BIM-28131 is mostly mediated in the ArcN. BIM-28163 antagonized ghrelin-induced GH secretion but not ghrelin-induced food consumption and cFos activation, rather it stimulated food intake and cFos activity without affecting GH secretion. The level of cFos activation was dependent on the region considered: BIM-28163 was as active as ghrelin in the NTS, but less active in the ArcN and AP. All compounds also induced cFos immunoreactivity in ArcN NPY neurons but BIM-28131 was the most active. In conclusion, these data demonstrate that two peptide analogs of ghrelin, BIM-28163, and BIM-28131, are powerful stimulators of appetite in mice, acting through pathways and key brain regions involved in the control of appetite that are only partially superimposable from those activated by ghrelin. A better understanding of the molecular pathways activated by these compounds could be useful in devising future therapeutic

  20. Fat mass and obesity-associated gene (FTO) is linked to higher plasma levels of the hunger hormone ghrelin and lower serum levels of the satiety hormone leptin in older adults.

    PubMed

    Benedict, Christian; Axelsson, Tomas; Söderberg, Stefan; Larsson, Anders; Ingelsson, Erik; Lind, Lars; Schiöth, Helgi B

    2014-11-01

    The mechanisms through which common polymorphisms in the fat mass and obesity-associated gene (FTO) drive the development of obesity in humans are poorly understood. Using cross-sectional data from 985 older people (50% females) who participated at age 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), circulating levels of ghrelin and leptin were measured after an overnight fast. In addition, subjects were genotyped for FTO rs17817449 (AA, n = 345 [35%]; AC/CA, n = 481 [48.8%]; CC, n = 159 [16.1%]). Linear regression analyses controlling for sex, self-reported physical activity level, fasting plasma glucose, and BMI were used. A positive relationship between the number of FTO C risk alleles and plasma ghrelin levels was found (P = 0.005; relative plasma ghrelin difference between CC and AA carriers = ∼ 9%). In contrast, serum levels of the satiety-enhancing hormone leptin were inversely linked to the number of FTO C risk alleles (P = 0.001; relative serum leptin difference between CC and AA carriers = ∼ 11%). These associations were also found when controlling for waist circumference. The present findings suggest that FTO may facilitate weight gain in humans by shifting the endocrine balance from the satiety hormone leptin toward the hunger-promoting hormone ghrelin.

  1. Impact of bariatric surgery on ghrelin and obestatin levels in obesity or type 2 diabetes mellitus rat model.

    PubMed

    Zhou, Donglei; Jiang, Xun; Ding, Weixing; Zhang, Dingyu; Yang, Lei; Zhen, Chengzhu; Lu, Liesheng

    2014-01-01

    We aimed to evaluate the therapeutic efficacy on weight control by different bariatric surgeries and investigate the ghrelin and obestatin changes after these surgeries in obesity and nonobese type 2 diabetes mellitus (T2DM) rats. Obese rats were randomly assigned to receive sleeve gastrectomy (SG, n = 8), minigastric bypass (MGBP, n = 8), roux-en-Y gastric bypass (RYGBP, n = 8), and sham operation (SO, n = 4). Another 4 rats served as control. Besides, Goto-Kakisaki (GK) rats were also randomly divided into similar groups except for total gastrectomy (TG, n = 8) group. The results showed that in obese rats, weigh loss in RYGBP group was similar to that in MGBP group but larger than that in SG group. Ghrelin significantly increased in RYGB group, but obestatin increased in MGBP group. Ghrelin/obestatin ratio significantly decreased in SG group. In GK rats, weight loss was most obvious in TG group. Postoperatively, ghrelin was significantly increased in MGBP and RYGB groups but decreased in TG group. Obestatin also showed an increase in MGBP and RYGB groups. Ghrelin/obestatin in TG group decreased significantly. In conclusion, RYGB and MGBP may be more suitable for obese rats, but TG may be the best strategy for T2DM rats to control weight with different mechanisms.

  2. Impact of Bariatric Surgery on Ghrelin and Obestatin Levels in Obesity or Type 2 Diabetes Mellitus Rat Model

    PubMed Central

    Zhou, Donglei; Jiang, Xun; Ding, Weixing; Zhang, Dingyu; Yang, Lei; Zhen, Chengzhu; Lu, Liesheng

    2014-01-01

    We aimed to evaluate the therapeutic efficacy on weight control by different bariatric surgeries and investigate the ghrelin and obestatin changes after these surgeries in obesity and nonobese type 2 diabetes mellitus (T2DM) rats. Obese rats were randomly assigned to receive sleeve gastrectomy (SG, n = 8), minigastric bypass (MGBP, n = 8), roux-en-Y gastric bypass (RYGBP, n = 8), and sham operation (SO, n = 4). Another 4 rats served as control. Besides, Goto-Kakisaki (GK) rats were also randomly divided into similar groups except for total gastrectomy (TG, n = 8) group. The results showed that in obese rats, weigh loss in RYGBP group was similar to that in MGBP group but larger than that in SG group. Ghrelin significantly increased in RYGB group, but obestatin increased in MGBP group. Ghrelin/obestatin ratio significantly decreased in SG group. In GK rats, weight loss was most obvious in TG group. Postoperatively, ghrelin was significantly increased in MGBP and RYGB groups but decreased in TG group. Obestatin also showed an increase in MGBP and RYGB groups. Ghrelin/obestatin in TG group decreased significantly. In conclusion, RYGB and MGBP may be more suitable for obese rats, but TG may be the best strategy for T2DM rats to control weight with different mechanisms. PMID:24672803

  3. Genome-level and biochemical diversity of the acyl-activating enzyme superfamily in plants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In higher plants, the superfamily of carboxyl-CoA ligases and related proteins, collectively called acyl activating enzymes (AAEs), has evolved to provide enzymes for many pathways of primary and secondary metabolism and for the conjugation of hormones to amino acids. Across the superfamily there is...

  4. Plasma ghrelin is positively associated with body fat, liver fat and milk fat content but not with feed intake of dairy cows after parturition.

    PubMed

    Börner, Sabina; Derno, Michael; Hacke, Sandra; Kautzsch, Ulrike; Schäff, Christine; Thanthan, Sint; Kuwayama, Hideto; Hammon, Harald M; Röntgen, Monika; Weikard, Rosemarie; Kühn, Christa; Tuchscherer, Armin; Kuhla, Björn

    2013-02-01

    Ghrelin is a gastrointestinal peptide hormone that is present in blood mostly in a non-posttranslationally modified form, with a minor proportion acylated at Ser(3). Both ghrelin forms were initially assigned a role in the control of food intake but there is accumulating evidence for their involvement in fat allocation and utilization. We investigated changes in the ghrelin system in dairy cows, exhibiting differences in body fat mobilization and fatty liver, from late pregnancy to early lactation. Sixteen dairy cows underwent liver biopsy and were retrospectively grouped based on high (H) or low (L) liver fat content post-partum. Both groups had a comparable feed intake in week -6 (before parturition) and week 2 (after parturition). Only before parturition was preprandial total ghrelin concentration higher in L than in H cows and only after parturition was the basal plasma concentration of non-esterified fatty acids higher in H than in L cows. Both before and after parturition, H cows had higher preprandial plasma concentrations of acyl ghrelin, a higher acyl:total ghrelin ratio, lower plasma triacylglyceride concentrations and a lower respiratory quotient compared with L cows. These group differences could not be attributed to an allelic variant of the acyl ghrelin receptor. Rather, the ratio of acyl:total ghrelin correlated with several aspects of fat metabolism and with respiratory quotient but not with feed intake. These results show that endogenous ghrelin forms are associated with fat allocation, fatty liver, and utilization of fat during the periparturient period.

  5. The Antidepressant-like Effects of Estrogen-mediated Ghrelin

    PubMed Central

    Wang, Pu; Liu, Changhong; Liu, Lei; Zhang, Xingyi; Ren, Bingzhong; Li, Bingjin

    2015-01-01

    Ghrelin, one of the brain-gut peptides, stimulates food-intake. Recently, ghrelin has also shown to play an important role in depression treatment. However, the mechanism of ghrelin’s antidepressant-like actions is unknown. On the other hand, sex differences in depression, and the fluctuation of estrogens secretion have been proved to play a key role in depression. It has been reported that women have higher level of ghrelin expression, and ghrelin can stimulate estrogen secretion while estrogen acts as a positive feedback mechanism to up-regulate ghrelin level. Ghrelin may be a potential regulator of reproductive function, and estrogen may have additional effect in ghrelin’s antidepressantlike actions. In this review, we summarize antidepressant-like effects of ghrelin and estrogen in basic and clinical studies, and provide new insight on ghrelin’s effect in depression. PMID:26412072

  6. Novel analogs of ghrelin: physiological and clinical implications.

    PubMed

    Halem, Heather A; Taylor, John E; Dong, Jesse Z; Shen, Yeelana; Datta, Rakesh; Abizaid, Alfonso; Diano, Sabrina; Horvath, Tamas; Zizzari, Philippe; Bluet-Pajot, Marie-Thèrèse; Epelbaum, Jacques; Culler, Michael D

    2004-08-01

    Ghrelin, the 28 amino acid peptide recently identified as the natural ligand for the growth hormone (GH) secretagogue (GHS) receptor, has multiple activities in addition to stimulation of GH secretion, including stimulation of feeding and weight gain. To utilize these actions for potential therapeutic benefit, we have produced analogs of human ghrelin with enhanced metabolic stability, affinity for the GHS receptor, and efficacy in stimulating weight gain. We have also discovered an analog of ghrelin, BIM-28163, that is an antagonist at the GHS receptor and that fully inhibits GHS receptor activation induced by native ghrelin. In vivo, BIM-28163 does not increase GH secretion but fully blocks ghrelin-induced GH secretion. In contrast, BIM-28163 acts as a full agonist with regard to the ghrelin actions of stimulating weight gain and food intake. These results suggest that a receptor other than the GHS receptor mediates the actions of ghrelin on feeding and weight gain. This concept is strengthened by our observation that at certain hypothalamic sites, BIM-28163 acts as an antagonist of ghrelin-induced neuronal activation, while at other sites, both ghrelin and BIM-28163 induce neuronal activation via the same receptor. Collectively, these results indicate the existence of a novel ghrelin receptor that may regulate the feeding activity of ghrelin. Using BIM-28163 as a tool to define the endogenous role of ghrelin in normal GH secretion, we have demonstrated that antagonism of the GHS receptor in normal rats does not impair the pulsatility of GH secretion but lowers the pulse amplitude and mean GH level. These results demonstrate that endogenous ghrelin acts to amplify the basic pattern of GH secretion established by the interplay of hypothalamic GH-releasing hormone and somatostatin. These studies demonstrate the feasibility of creating ghrelin analogs that are selective for specific activities, as well as their utility in dissecting the role of ghrelin in both

  7. In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features.

    PubMed

    Ibáñez-Costa, Alejandro; Gahete, Manuel D; Rivero-Cortés, Esther; Rincón-Fernández, David; Nelson, Richard; Beltrán, Manuel; de la Riva, Andrés; Japón, Miguel A; Venegas-Moreno, Eva; Gálvez, Ma Ángeles; García-Arnés, Juan A; Soto-Moreno, Alfonso; Morgan, Jennifer; Tsomaia, Natia; Culler, Michael D; Dieguez, Carlos; Castaño, Justo P; Luque, Raúl M

    2015-03-04

    Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas compared with normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24-72 h) increased GH and ACTH secretion, Ca(2+) and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors.

  8. In1-ghrelin splicing variant is overexpressed in pituitary adenomas and increases their aggressive features

    PubMed Central

    Ibáñez-Costa, Alejandro; Gahete, Manuel D.; Rivero-Cortés, Esther; Rincón-Fernández, David; Nelson, Richard; Beltrán, Manuel; de la Riva, Andrés; Japón, Miguel A.; Venegas-Moreno, Eva; Gálvez, Ma Ángeles; García-Arnés, Juan A.; Soto-Moreno, Alfonso; Morgan, Jennifer; Tsomaia, Natia; Culler, Michael D.; Dieguez, Carlos; Castaño, Justo P.; Luque, Raúl M.

    2015-01-01

    Pituitary adenomas comprise a heterogeneous subset of pathologies causing serious comorbidities, which would benefit from identification of novel, common molecular/cellular biomarkers and therapeutic targets. The ghrelin system has been linked to development of certain endocrine-related cancers. Systematic analysis of the presence and functional implications of some components of the ghrelin system, including native ghrelin, receptors and the recently discovered splicing variant In1-ghrelin, in human normal pituitaries (n = 11) and pituitary adenomas (n = 169) revealed that expression pattern of ghrelin system suffers a clear alteration in pituitary adenomasas comparedwith normal pituitary, where In1-ghrelin is markedly overexpressed. Interestingly, in cultured pituitary adenoma cells In1-ghrelin treatment (acylated peptides at 100 nM; 24–72 h) increased GH and ACTH secretion, Ca2+ and ERK1/2 signaling and cell viability, whereas In1-ghrelin silencing (using a specific siRNA; 100 nM) reduced cell viability. These results indicate that an alteration of the ghrelin system, specially its In1-ghrelin variant, could contribute to pathogenesis of different pituitary adenomas types, and suggest that this variant and its related ghrelin system could provide new tools to identify novel, more general diagnostic, prognostic and potential therapeutic targets in pituitary tumors. PMID:25737012

  9. The role of ghrelin in weight-regulation disorders: implications in clinical practice.

    PubMed

    Solomou, Solomis; Korbonits, Márta

    2014-01-01

    Ghrelin, an orexigenic protein with a unique lipid chain modification, is considered to be an important gut-brain signal for appetite control and energy balance. The ghrelin receptor, growth-hormone secretagogue receptor type 1a, is able to bind acylated ghrelin. The first recognised effect of ghrelin was the induction of growth hormone release from the somatotroph cells of the anterior pituitary. Moreover, by acting on vagal afferents or centrally, ghrelin can activate hypothalamic arcuate neurons that secrete the orexigenic peptides neuropeptide Y and agouti-related peptide, and inhibit the anorexigenic neurons secreting pro-opiomelanocortin and α-melanocyte-stimulating hormone. The orexigenic signalling pathway of ghrelin involves adenosine monophosphate-activated protein kinase. It has been proposed that ghrelin can also increase dopaminergic transmission from the ventral tegmental area to the nucleus accumbens, leading to augmentation of afferent reward signals. Present evidence suggests that ghrelin plays an important role in obesity, eating disorders, and cachexia, as well as in regulating appetite and energy balance in healthy individuals. In pathological states, ghrelin can be lower than normal as is seen in obese individuals, or can be higher than normal as has been reported for Prader-Willi syndrome, anorexia nervosa, bulimia nervosa, and certain types of cachexia. In the future, the application of compounds targeting the ghrelin pathway could involve the use of pharmacotherapies of ghrelin agonists, antagonists or inverse agonists, neutralisation of ghrelin by vaccines and spiegelmers, desacyl ghrelin analogues, as well as inhibitors of the GOAT enzyme which attaches the lipid modification to desacyl ghrelin to synthetise ghrelin.

  10. Is Ghrelin Synthesized in the Central Nervous System?

    PubMed Central

    Cabral, Agustina; López Soto, Eduardo J.; Epelbaum, Jacques; Perelló, Mario

    2017-01-01

    Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals. PMID:28294994

  11. Is Ghrelin Synthesized in the Central Nervous System?

    PubMed

    Cabral, Agustina; López Soto, Eduardo J; Epelbaum, Jacques; Perelló, Mario

    2017-03-15

    Ghrelin is an octanoylated peptide that acts via its specific receptor, the growth hormone secretagogue receptor type 1a (GHSR-1a), and regulates a vast variety of physiological functions. It is well established that ghrelin is predominantly synthesized by a distinct population of endocrine cells located within the gastric oxyntic mucosa. In addition, some studies have reported that ghrelin could also be synthesized in some brain regions, such as the hypothalamus. However, evidences of neuronal production of ghrelin have been inconsistent and, as a consequence, it is still as a matter of debate if ghrelin can be centrally produced. Here, we provide a comprehensive review and discussion of the data supporting, or not, the notion that the mammalian central nervous system can synthetize ghrelin. We conclude that no irrefutable and reproducible evidence exists supporting the notion that ghrelin is synthetized, at physiologically relevant levels, in the central nervous system of adult mammals.

  12. Correlation between colonic secretion and colonic motility in rats: Role of ghrelin

    PubMed Central

    Huang, Hsien-Hao; Ting, Ching-Heng; Syu, Yu-Fong; Chang, Shi-Chuan; Chen, Chih-Yen

    2016-01-01

    AIM To explore the relationship between colonic secretory function and colonic motility. METHODS Using a rat model chronically implanted with intracerebroventricular (ICV) and cecal catheters, we validated the correlation between colonic secretion and colonic motor functions, as well as the role of ICV injection volume. RESULTS Compared to saline controls (5 μL/rat), ICV acyl ghrelin at 1 nmol/5 μL enhanced the total fecal weight, accelerated the colonic transit time, and increased the fecal pellet output during the first hour post-injection, while ICV des-acyl ghrelin at 1 nmol/5 μL only accelerated the colonic transit time. These stimulatory effects on colonic motility and/or secretion from acyl ghrelin and des-acyl ghrelin disappeared when the ICV injection volume increased to 10 μL compared with saline controls (10 μL/rat). Additionally, the ICV injection of 10 μL of saline significantly shortened the colonic transit time compared with the ICV injection of 5 μL of saline. The total fecal weight during the first hour post-injection correlated with the colonic transit time and fecal pellet output after the ICV injection of acyl ghrelin (1 nmol/5 μL), whereas the total fecal weight during the first hour post-injection correlated with the fecal pellet output but not the colonic transit time after the ICV injection of des-acyl ghrelin (1 nmol/5 μL). CONCLUSION Colonic secretion does not always correlate with colonic motility in response to different colonic stimulations. Acyl ghrelin stimulates colonic secretion. PMID:28028362

  13. Lean mean fat reducing "ghrelin" machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity.

    PubMed

    Schellekens, Harriët; Dinan, Timothy G; Cryan, John F

    2010-01-01

    Obesity has reached epidemic proportions not only in Western societies but also in the developing world. Current pharmacological treatments for obesity are either lacking in efficacy and/or are burdened with adverse side effects. Thus, novel strategies are required. A better understanding of the intricate molecular pathways controlling energy homeostasis may lead to novel therapeutic intervention. The circulating hormone, ghrelin represents a major target in the molecular signalling regulating food intake, appetite and energy expenditure and its circulating levels often display aberrant signalling in obesity. Ghrelin exerts its central orexigenic action mainly in the hypothalamus and in particular in the arcuate nucleus via activation of specific G-protein coupled receptors (GHS-R). In this review we describe current pharmacological models of how ghrelin regulates food intake and how manipulating ghrelin signalling may give novel insight into developing better and more selective anti-obesity drugs. Accumulating data suggests multiple ghrelin variants and additional receptors exist to play a role in energy metabolism and these may well play an important role in obesity. In addition, the recent findings of hypothalamic GHS-R crosstalk and heterodimerization may add to the understanding of the complexity of bodyweight regulation.

  14. Ghrelin in obesity, physiological and pharmacological considerations.

    PubMed

    Álvarez-Castro, Paula; Pena, Lara; Cordido, Fernando

    2013-04-01

    The aim of this review is to summarize the physiological and pharmacological aspects of ghrelin. Obesity can be defined as an excess of body fat and is associated with significant disturbances in metabolic and endocrine function. Obesity has become a worldwide epidemic. In obesity there is a decreased growth hormone (GH) secretion, and the altered somatotroph secretion in obesity is functional. Ghrelin is a peptide that has a unique structure with 28 amino-acids and an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. The pathophysiological mechanism responsible for GH hyposecretion in obesity is probably multifactorial, and there is probably a defect in ghrelin secretion. Ghrelin is the only known circulating orexigenic factor, and has been found to be reduced in obese humans. Ghrelin levels in blood decrease during periods of feeding. Due to its orexigenic and metabolic effects, ghrelin has a potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal and cardiac disease, and age-related frailty. Theoretically ghrelin receptor antagonists could be employed as anti-obesity drugs, blocking the orexigenic signal. By blocking the constitutive receptor activity, inverse agonists of the ghrelin receptor may lower the set-point for hunger, and could be used for the treatment of obesity. In summary, ghrelin secretion is reduced in obesity, and could be partly responsible for GH hyposecretion in obesity, ghrelin antagonist or partial inverse agonists should be considered for the treatment of obesity.

  15. A novel human ghrelin variant (In1-ghrelin) and ghrelin-O-acyltransferase are overexpressed in breast cancer: potential pathophysiological relevance.

    PubMed

    Gahete, Manuel D; Córdoba-Chacón, José; Hergueta-Redondo, Marta; Martínez-Fuentes, Antonio J; Kineman, Rhonda D; Moreno-Bueno, Gema; Luque, Raúl M; Castaño, Justo P

    2011-01-01

    The human ghrelin gene, which encodes the ghrelin and obestatin peptides, contains 5 exons (Ex), with Ex1-Ex4 encoding a 117 amino-acid (aa) preproprotein that is known to be processed to yield a 28-aa (ghrelin) and/or a 23-aa (obestatin) mature peptides, which possess biological activities in multiple tissues. However, the ghrelin gene also encodes additional peptides through alternative splicing or post-translational modifications. Indeed, we previously identified a spliced mRNA ghrelin variant in mouse (In2-ghrelin-variant), which is regulated in a tissue-dependent manner by metabolic status and may thus be of biological relevance. Here, we have characterized a new human ghrelin variant that contains Ex0-1, intron (In) 1, and Ex2 and lacks Ex3-4. This human In1-ghrelin variant would encode a new prepropeptide that conserves the first 12aa of native-ghrelin (including the Ser3-potential octanoylation site) but has a different C-terminal tail. Expression of In1-variant was detected in 22 human tissues and its levels were positively correlated with those of ghrelin-O-acyltransferase (GOAT; p = 0.0001) but not with native-ghrelin expression, suggesting that In1-ghrelin could be a primary substrate for GOAT in human tissues. Interestingly, levels of In1-ghrelin variant expression in breast cancer samples were 8-times higher than those of normal mammary tissue, and showed a strong correlation in breast tumors with GOAT (p = 0.0001), ghrelin receptor-type 1b (GHSR1b; p = 0.049) and cyclin-D3 (a cell-cycle inducer/proliferation marker; p = 0.009), but not with native-ghrelin or GHSR1a expression. Interestingly, In1-ghrelin variant overexpression increased basal proliferation of MDA-MB-231 breast cancer cells. Taken together, our results provide evidence that In1-ghrelin is a novel element of the ghrelin family with a potential pathophysiological role in breast cancer.

  16. Ghrelin O-acyltransferase (GOAT) enzyme is overexpressed in prostate cancer, and its levels are associated with patient's metabolic status: Potential value as a non-invasive biomarker.

    PubMed

    Hormaechea-Agulla, Daniel; Gómez-Gómez, Enrique; Ibáñez-Costa, Alejandro; Carrasco-Valiente, Julia; Rivero-Cortés, Esther; L-López, Fernando; Pedraza-Arevalo, Sergio; Valero-Rosa, José; Sánchez-Sánchez, Rafael; Ortega-Salas, Rosa; Moreno, María M; Gahete, Manuel D; López-Miranda, José; Requena, María J; Castaño, Justo P; Luque, Raúl M

    2016-12-01

    Ghrelin-O-acyltransferase (GOAT) is the key enzyme regulating ghrelin activity, and has been proposed as a potential therapeutic target for obesity/diabetes and as a biomarker in some endocrine-related cancers. However, GOAT presence and putative role in prostate-cancer (PCa) is largely unknown. Here, we demonstrate, for the first time, that GOAT is overexpressed (mRNA/protein-level) in prostatic tissues (n = 52) and plasma/urine-samples (n = 85) of PCa-patients, compared with matched controls [healthy prostate tissues (n = 12) and plasma/urine-samples from BMI-matched controls (n = 28), respectively]. Interestingly, GOAT levels in PCa-patients correlated with aggressiveness and metabolic conditions (i.e. diabetes). Actually, GOAT expression was regulated by metabolic inputs (i.e. In1-ghrelin, insulin/IGF-I) in cultured normal prostate cells and PCa-cell lines. Importantly, ROC-curve analysis unveiled a valuable diagnostic potential for GOAT to discriminate PCa at the tissue/plasma/urine-level with high sensitivity/specificity, particularly in non-diabetic individuals. Moreover, we discovered that GOAT is secreted by PCa-cells, and that its levels are higher in urine samples from a stimulated post-massage vs. pre-massage prostate-test. In conclusion, plasmatic GOAT levels exhibit high specificity/sensitivity to predict PCa-presence compared with other PCa-biomarkers, especially in non-diabetic individuals, suggesting that GOAT holds potential as a novel non-invasive PCa-biomarker.

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

    PubMed

    Rogers, Nicole H; Walsh, Heidi; Alvarez-Garcia, Oscar; Park, Seongjoon; Gaylinn, Bruce; Thorner, Michael O; Smith, Roy G

    2016-04-01

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

  18. A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice.

    PubMed

    Engel, Jörgen A; Nylander, Ingrid; Jerlhag, Elisabet

    2015-12-01

    Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Met-enkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leu-enkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959׳s ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GHS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction.

  19. Association of circulating active and total ghrelin concentrations with dry matter intake, growth, and carcass characteristics of finishing beef cattle.

    PubMed

    Foote, A P; Hales, K E; Lents, C A; Freetly, H C

    2014-12-01

    Ghrelin is a gut peptide that when acylated is thought to stimulate appetite. Circulating ghrelin concentrations could potentially be used as a predictor of DMI in cattle. The objective of this experiment was to determine the association of circulating ghrelin concentrations with DMI and other production traits. Steers and heifers were fed a finishing diet, and individual intake was recorded for 84 d. Blood samples were collected via jugular venipuncture following the DMI and ADG measurement period. Plasma active ghrelin and total ghrelin were quantified using commercial RIA. Active ghrelin was not correlated to DMI (P=0.36), but when DMI was modeled using a multivariate analysis including plasma metabolites and sex, active ghrelin was shown to be positively associated with DMI (P<0.01) and accounted for 6.2% of the variation accounted for by the regression model (R2=0.33). Total ghrelin was negatively correlated to DMI (P<0.01), but was not significant in a multivariate regression analysis (P=0.13). The ratio of active:total ghrelin was positively associated with DMI (P<0.01) and accounted for 10.2% of the variation in the model (R2=0.35). Active ghrelin was positively associated with ADG (P<0.05), while total ghrelin was negatively associated with ADG (P<0.01), and the ratio of active:total ghrelin was positively associated with ADG (P<0.01). Active ghrelin was not associated with G:F (P=0.88), but total ghrelin concentrations were negatively associated with G:F (P<0.01) and accounted for 10.24% of the variation (R2=0.25). Heifers consumed less feed than steers (P<0.01), tended to have greater active ghrelin concentrations (P=0.06), and had greater total ghrelin concentrations than steers (P=0.04). Total ghrelin concentrations were not different between sire breeds (P=0.80), but active ghrelin concentrations and the ratio of active:total ghrelin differed between breeds (P<0.01), indicating that genetics have an effect on the amount and form of circulating ghrelin

  20. The Stomach-Derived Hormone Ghrelin Increases Impulsive Behavior.

    PubMed

    Anderberg, Rozita H; Hansson, Caroline; Fenander, Maya; Richard, Jennifer E; Dickson, Suzanne L; Nissbrandt, Hans; Bergquist, Filip; Skibicka, Karolina P

    2016-04-01

    Impulsivity, defined as impaired decision making, is associated with many psychiatric and behavioral disorders, such as attention-deficit/hyperactivity disorder as well as eating disorders. Recent data indicate that there is a strong positive correlation between food reward behavior and impulsivity, but the mechanisms behind this relationship remain unknown. Here we hypothesize that ghrelin, an orexigenic hormone produced by the stomach and known to increase food reward behavior, also increases impulsivity. In order to assess the impact of ghrelin on impulsivity, rats were trained in three complementary tests of impulsive behavior and choice: differential reinforcement of low rate (DRL), go/no-go, and delay discounting. Ghrelin injection into the lateral ventricle increased impulsive behavior, as indicated by reduced efficiency of performance in the DRL test, and increased lever pressing during the no-go periods of the go/no-go test. Central ghrelin stimulation also increased impulsive choice, as evidenced by the reduced choice for large rewards when delivered with a delay in the delay discounting test. In order to determine whether signaling at the central ghrelin receptors is necessary for maintenance of normal levels of impulsive behavior, DRL performance was assessed following ghrelin receptor blockade with central infusion of a ghrelin receptor antagonist. Central ghrelin receptor blockade reduced impulsive behavior, as reflected by increased efficiency of performance in the DRL task. To further investigate the neurobiological substrate underlying the impulsivity effect of ghrelin, we microinjected ghrelin into the ventral tegmental area, an area harboring dopaminergic cell bodies. Ghrelin receptor stimulation within the VTA was sufficient to increase impulsive behavior. We further evaluated the impact of ghrelin on dopamine-related gene expression and dopamine turnover in brain areas key in impulsive behavior control. This study provides the first

  1. Mediation of oxidative stress in hypothalamic ghrelin-associated appetite control in rats treated with phenylpropanolamine.

    PubMed

    Yu, C-H; Chu, S-C; Chen, P-N; Hsieh, Y-S; Kuo, D-Y

    2017-04-01

    Phenylpropanolamine (PPA)-induced appetite control is associated with oxidative stress in the hypothalamus. This study explored whether hypothalamic antioxidants participated in hypothalamic ghrelin system-associated appetite control in PPA-treated rats. Rats were given PPA daily for 4 days, and changes in food intake and the expression of neuropeptide Y (NPY), the cocaine- and amphetamine-regulated transcript (CART), superoxide dismutase, catalase, ghrelin, acyl ghrelin (AG), ghrelin O-acyltransferase (GOAT) and the ghrelin receptor (GHSR1a) were examined and compared. Results showed that both food intake and the expression of NPY and ghrelin/AG/GOAT/GHSR1a decreased in response to PPA treatment with maximum decrease on Day 2 of the treatment. In contrast, the expression of antioxidants and CART increased, with the maximum increase on Day 2, with the expression opposite to that of NPY and ghrelin. A cerebral infusion of either a GHSR1a antagonist or reactive oxygen species scavenger modulated feeding behavior and NPY, CART, antioxidants and ghrelin system expression, showing the involvement of ghrelin signaling and oxidative stress in regulating PPA-mediated appetite control. We suggest that hypothalamic ghrelin signaling system, with the help of antioxidants, may participate in NPY/CART-mediated appetite control in PPA-treated rats.

  2. Ghrelin Attenuates Intestinal Barrier Dysfunction Following Intracerebral Hemorrhage in Mice

    PubMed Central

    Cheng, Yijun; Wei, Yongxu; Yang, Wenlei; Cai, Yu; Chen, Bin; Yang, Guoyuan; Shang, Hanbing; Zhao, Weiguo

    2016-01-01

    Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier dysfunction post-ICH and its possible underlying mechanisms are still unknown. This study was designed to investigate whether ghrelin administration attenuates intestinal barrier dysfunction in experimental ICH using an intrastriatal autologous blood infusion mouse model. Our data showed that treatment with ghrelin markedly attenuated intestinal mucosal injury at both histomorphometric and ultrastructural levels post-ICH. Ghrelin reduced ICH-induced intestinal permeability according to fluorescein isothiocyanate conjugated-dextran (FITC-D) and Evans blue extravasation assays. Concomitantly, the intestinal tight junction-related protein markers, Zonula occludens-1 (ZO-1) and claudin-5 were upregulated by ghrelin post-ICH. Additionally, ghrelin reduced intestinal intercellular adhesion molecule-1 (ICAM-1) expression at the mRNA and protein levels following ICH. Furthermore, ghrelin suppressed the translocation of intestinal endotoxin post-ICH. These changes were accompanied by improved survival rates and an attenuation of body weight loss post-ICH. In conclusion, our results suggest that ghrelin reduced intestinal barrier dysfunction, thereby reducing mortality and weight loss, indicating that ghrelin is a potential therapeutic agent in ICH-induced intestinal barrier dysfunction therapy. PMID:27929421

  3. Novel molecular aspects of ghrelin and leptin in the control of adipobiology and the cardiovascular system.

    PubMed

    Rodríguez, Amaia

    2014-01-01

    Ghrelin and leptin show opposite effects on energy balance. Ghrelin constitutes a gut hormone that is secreted to the bloodstream in two major forms, acylated and desacyl ghrelin. The isoforms of ghrelin not only promote adiposity by the activation of hypothalamic orexigenic neurons but also directly stimulate the expression of several fat storage-related proteins in adipocytes, including ACC, FAS, LPL and perilipin, thereby stimulating intracytoplasmic lipid accumulation. Moreover, both acylated and desacyl ghrelin reduce TNF-α-induced apoptosis and autophagy in adipocytes, suggesting an anti-inflammatory role of ghrelin in human adipose tissue. On the other hand, leptin is an adipokine with lipolytic effects. In this sense, leptin modulates via PI3K/Akt/mTOR the expression of aquaglyceroporins such as AQP3 and AQP7 that facilitate glycerol efflux from adipocytes in response to the lipolytic stimuli via its translocation from the cytosolic fraction (AQP3) or lipid droplets (AQP7) to the plasma membrane. Ghrelin and leptin also participate in the homeostasis of the cardiovascular system. Ghrelin operates as a cardioprotective factor with increased circulating acylated ghrelin concentrations in patients with left ventricular hypertrophy (LVH) causally related to LV remodeling during the progression to LVH. Additionally, leptin induces vasodilation by inducible NO synthase expression (iNOS) in the vascular wall. In this sense, leptin inhibits the angiotensin II-induced Ca(2+) increase, contraction and proliferation of VSMC through NO-dependent mechanisms. Together, dysregulation of circulating ghrelin isoforms and leptin resistance associated to obesity, type 2 diabetes, or the metabolic syndrome contribute to cardiometabolic derangements observed in these pathologies.

  4. Ghrelin in Central Neurons

    PubMed Central

    Ferrini, F; Salio, C; Lossi, L; Merighi, A

    2009-01-01

    Ghrelin, an orexigenic peptide synthesized by endocrine cells of the gastric mucosa, is released in the bloodstream in response to a negative energetic status. Since discovery, the hypothalamus was identified as the main source of ghrelin in the CNS, and effects of the peptide have been mainly observed in this area of the brain. In recent years, an increasing number of studies have reported ghrelin synthesis and effects in specific populations of neurons also outside the hypothalamus. Thus, ghrelin activity has been described in midbrain, hindbrain, hippocampus, and spinal cord. The spectrum of functions and biological effects produced by the peptide on central neurons is remarkably wide and complex. It ranges from modulation of membrane excitability, to control of neurotransmitter release, neuronal gene expression, and neuronal survival and proliferation. There is not at present a general consensus concerning the source of ghrelin acting on central neurons. Whereas it is widely accepted that the hypothalamus represents the most important endogenous source of the hormone in CNS, the existence of extra-hypothalamic ghrelin-synthesizing neurons is still controversial. In addition, circulating ghrelin can theoretically be another natural ligand for central ghrelin receptors. This paper gives an overview on the distribution of ghrelin and its receptor across the CNS and critically analyses the data available so far as regarding the effects of ghrelin on central neurotransmission. PMID:19721816

  5. Ghrelin in central neurons.

    PubMed

    Ferrini, F; Salio, C; Lossi, L; Merighi, A

    2009-03-01

    Ghrelin, an orexigenic peptide synthesized by endocrine cells of the gastric mucosa, is released in the bloodstream in response to a negative energetic status. Since discovery, the hypothalamus was identified as the main source of ghrelin in the CNS, and effects of the peptide have been mainly observed in this area of the brain. In recent years, an increasing number of studies have reported ghrelin synthesis and effects in specific populations of neurons also outside the hypothalamus. Thus, ghrelin activity has been described in midbrain, hindbrain, hippocampus, and spinal cord. The spectrum of functions and biological effects produced by the peptide on central neurons is remarkably wide and complex. It ranges from modulation of membrane excitability, to control of neurotransmitter release, neuronal gene expression, and neuronal survival and proliferation. There is not at present a general consensus concerning the source of ghrelin acting on central neurons. Whereas it is widely accepted that the hypothalamus represents the most important endogenous source of the hormone in CNS, the existence of extra-hypothalamic ghrelin-synthesizing neurons is still controversial. In addition, circulating ghrelin can theoretically be another natural ligand for central ghrelin receptors. This paper gives an overview on the distribution of ghrelin and its receptor across the CNS and critically analyses the data available so far as regarding the effects of ghrelin on central neurotransmission.

  6. Effects of intracerebroventricular infusions of ghrelin on secretion of follicle-stimulating hormone in peripubertal female sheep.

    PubMed

    Wójcik-Gładysz, Anna; Wańkowska, Marta; Gajewska, Alina; Misztal, Tomasz; Zielińska-Górska, Marlena; Szlis, Michał; Polkowska, Jolanta

    2016-06-16

    Reproduction depends on mechanisms responsible for the regulation of energy homeostasis and puberty is a developmental period when reproductive and somatic maturity are achieved. Ghrelin affects the activity of the hypothalamo-pituitary-gonadal axis under conditions of energy insufficiency. An in vivo model based on intracerebroventricular (i.c.v.) infusions was used to determine whether centrally administered acyl ghrelin affects transcriptional and translational activity of FSH in peripubertal lambs and whether ghrelin administration mimics the effects of short-term fasting. Standard-fed lambs received either Ringer-Lock (R-L) solution (120 µL h-1) or ghrelin (120 µL h-1, 100 µg day-1). Animals experiencing a short-term (72 h) fast were treated only with R-L solution. In each experimental group, i.c.v. infusions occurred for 3 consecutive days. Immunohistochemistry, in situ hybridisation and real-time reverse transcription quantitative polymerase chain reaction analyses revealed that short-term fasting, as well as exogenous acyl ghrelin administration to standard-fed peripubertal lambs, augmented FSHβ mRNA expression and immunoreactive FSH accumulation. In addition to the effects of ghrelin on FSH synthesis in standard-fed animals, effects on gonadotrophin release were also observed. Acyl ghrelin increased the pulse amplitude for gonadotrophin release, which resulted in an elevation in mean serum FSH concentrations. In conclusion, the present data suggest that ghrelin participates in an endocrine network that modulates gonadotrophic activity in peripubertal female sheep.

  7. Estradiol modulates Kiss1 neuronal response to ghrelin

    PubMed Central

    Frazao, Renata; Lemko, Heather M. Dungan; da Silva, Regina P.; Ratra, Dhirender V.; Lee, Charlotte E.; Williams, Kevin W.; Zigman, Jeffrey M.

    2014-01-01

    Ghrelin is a metabolic signal regulating energy homeostasis. Circulating ghrelin levels rise during starvation and fall after a meal, and therefore, ghrelin may function as a signal of negative energy balance. Ghrelin may also act as a modulator of reproductive physiology, as acute ghrelin administration suppresses gonadotropin secretion and inhibits the neuroendocrine reproductive axis. Interestingly, ghrelin's effect in female metabolism varies according to the estrogen milieu predicting an interaction between ghrelin and estrogens, likely at the hypothalamic level. Here, we show that ghrelin receptor (GHSR) and estrogen receptor-α (ERα) are coexpressed in several hypothalamic sites. Higher levels of circulating estradiol increased the expression of GHSR mRNA and the co-xpression of GHSR mRNA and ERα selectively in the arcuate nucleus (ARC). Subsets of preoptic and ARC Kiss1 neurons coexpressed GHSR. Increased colocalization was observed in ARC Kiss1 neurons of ovariectomized estradiol-treated (OVX + E2; 80%) compared with ovariectomized oil-treated (OVX; 25%) mice. Acute actions of ghrelin on ARC Kiss1 neurons were also modulated by estradiol; 75 and 22% of Kiss1 neurons of OVX + E2 and OVX mice, respectively, depolarized in response to ghrelin. Our findings indicate that ghrelin and estradiol may interact in several hypothalamic sites. In the ARC, high levels of E2 increase GHSR mRNA expression, modifying the colocalization rate with ERα and Kiss1 and the proportion of Kiss1 neurons acutely responding to ghrelin. Our findings indicate that E2 alters the responsiveness of kisspeptin neurons to metabolic signals, potentially acting as a critical player in the metabolic control of the reproductive physiology. PMID:24473434

  8. Regulatory neuropeptides (ghrelin, obestatin and nesfatin-1) levels in serum and reproductive tissues of female and male rats with fructose-induced metabolic syndrome.

    PubMed

    Catak, Zekiye; Aydin, Suleyman; Sahin, Ibrahim; Kuloglu, Tuncay; Aksoy, Aziz; Dagli, Adile Ferda

    2014-06-01

    Although, the exact mechanisms underlying the development of the metabolic syndrome (MetS) are not still completely understood, obesity, circulated peptide hormone levels and their interaction with genetic factors are considered largely responsible. The purpose of this study is to explore how the levels of ghrelin, obestatin (OBS) and NUCB2/nesfatin-1 (NES)/NUCB2 change in serum and the reproductive tissues of female and male rats with fructose-induced metabolic syndrome, and whether the levels of each hormone is correlated with the hormones involved with fertility. Experiments were conducted on 5-week-old Sprague-Dawley male and female rats assigned to either a control group or a MetS group. Controls were fed standard rat food and water ad libitum, while the MetS group was fed standard food with 10% (v/v) fructose solution added to their drinking water for 12 weeks with a 12/12h photoperiod circle. Then, all animals were sacrificed after a one night fast. Peptides levels in the serum and reproductive tissues of rats were studied using the ELISA method while the immunoreactivity of reproductive system peptide hormones were shown by immunohistochemical staining method. Furthermore, the other biochemical parameters were measured using Konelab-60 equipment and infertility hormones were measured with Immulite2000. Fasting serum insulin, glucose, triglyceride, alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) levels were statistically significantly higher, and the amount of high density lipoprotein cholesterol (HDL-C) was significantly lower, in the MetS groups. Serum and tissue supernatant NES levels were significantly higher in the rats with MetS than the control group. Ghrelin, OBS and NES were expressed in the cytoplasm, concentrated around the apical parts of the epithelial cells in the reproductive tissues of the rats. The amounts of ghrelin were lower in the reproductive

  9. Disturbance of circulating ghrelin and obestatin in chronic heart failure patients especially in those with cachexia.

    PubMed

    Xin, Xing; Ren, An-Jing; Zheng, Xing; Qin, Yong-Wen; Zhao, Xian-Xian; Yuan, Wen-Jun; Guo, Zhi-Fu

    2009-12-01

    Plasma ghrelin was elevated in chronic heart failure (CHF) patients with cachexia. Obestatin, a sibling of ghrelin, opposes several actions of ghrelin. We, therefore, investigated plasma obestatin and ghrelin levels in patients with CHF. Total plasma ghrelin and obestatin levels were measured in 65 patients with CHF (22 with cardiac cachexia) and 15 controls. Ghrelin levels were significantly higher in patients with cachexia (1237.8+/-47.9 pg/ml) than those without cachexia (P=0.041) and controls (P<0.01). Obestatin levels correlated positively with ghrelin levels, and obestatin levels were significantly increased in patients with cachexia (282.3+/-13.0 pg/ml) than patients without cachexia and controls (both P<0.01). However, the ghrelin to obestatin ratios (4.5+/-0.2) were significantly lower in CHF patients with cachexia than controls (P<0.01). Ghrelin and ratio of ghrelin to obestatin were independent predictors of the development of cardiac cachexia. No association was found between ghrelin, obestatin and New York Heart Association functional class, brain natriuretic peptide. There was disturbance of circulating ghrelin and obestatin in the CHF patients especially those with cachexia, which may have a role in the pathogenesis of cardiac cachexia in CHF.

  10. Long-term treatment of ghrelin stimulates feeding, fat deposition, and alters the GH/IGF-I axis in the tilapia, Oreochromis mossambicus.

    PubMed

    Riley, Larry G; Fox, Bradley K; Kaiya, Hiroyuki; Hirano, Tetsuya; Grau, E Gordon

    2005-05-15

    Recently, a new peptide, ghrelin, which specifically stimulates growth hormone (GH) release from the pituitary, was identified in the rat and human stomach. Ghrelin has been shown to stimulate GH release by acting through a growth hormone secretagogue receptor. We have identified two ghrelins (ghrelin-C8 and -C10) in the stomach of tilapia, a euryhaline fish. The current study was aimed at investigating the in vivo effect of the two tilapia ghrelins on feeding, fat deposition, and on the GH/IGF-I axis. Tilapia were implanted with micro-osmotic pumps containing either ghrelin-C8, ghrelin-C10 or saline (control). Ghrelin was delivered at a continuous rate of 10 ng/h for 21 days. Food consumption increased significantly in those animals that received ghrelin-C10 but not ghrelin-C8. Treatment with ghrelin-C10 increased body weight significantly without altering body length. Hence, the condition factor was significantly higher in the ghrelin-C10 group compared with the control. Liver weight and total fat content in the liver were also elevated significantly in the fish treated with ghrelin-C10. There was no effect of either ghrelin on plasma GH levels, whereas plasma IGF-I levels were reduced significantly in the ghrelin-C10 group. These findings demonstrate that ghrelin plays a role in feeding and fat metabolism in the tilapia, and suggest that the two forms of ghrelin may be acting through different receptors.

  11. The Sweetener-Sensing Mechanisms of the Ghrelin Cell

    PubMed Central

    Steensels, Sandra; Vancleef, Laurien; Depoortere, Inge

    2016-01-01

    Carbohydrate administration decreases plasma levels of the ‘hunger hormone’ ghrelin. The ghrelin cell is co-localized with the sweet taste receptor subunit, TAS1R3, and the gustatory G-protein, gustducin, both involved in the sensing of sweeteners by entero-endocrine cells. This study investigated the role of gustducin-mediated sweet taste receptor signaling on ghrelin secretion in a gastric ghrelinoma cell line, tissue segments and mice. The monosaccharide d-glucose and low-intensity sweetener oligofructose (OFS) decreased (p < 0.001) ghrelin secretion while the high-intensity sweetener sucralose increased (p < 0.001) ghrelin secretion in vitro. These effects were not mediated via the sweet taste receptor or glucose transporters (the sodium-dependent glucose cotransporter SGLT-1 and GLUT2). The effect of these compounds was mimicked ex vivo in gastric and jejunal segments from both wild type (WT) and α-gustducin knockout (α-gust−/−) mice. In vivo, the sensing of d-glucose was polarized since intragastric but not intravenous administration of d-glucose decreased (p < 0.05) ghrelin levels in an α-gustducin independent manner which involved inhibition of duodenal ghrelin release. In contrast, neither OFS nor sucralose affected ghrelin secretion in vivo. In conclusion, α-gustducin-mediated sweet taste receptor signaling does not play a functional role in the sensing of carbohydrates, or low- or high-intensity sweeteners by the ghrelin cell. PMID:27941594

  12. Early onset of ghrelin production in a marsupial.

    PubMed

    Menzies, Brandon R; Shaw, Geoff; Fletcher, Terry P; Renfree, Marilyn B

    2009-02-27

    Ghrelin regulates appetite in mammals and can stimulate growth hormone (GH) release from the pituitary. In rats and humans, ghrelin cells appear in the stomach during late fetal life. Nevertheless, the role of ghrelin in early mammalian development is not well understood. Marsupials deliver highly altricial young that weigh less than 1g so they must feed and digest milk at a comparatively immature stage of development. Since they complete their growth and differentiation while in the pouch, they are accessible models in which to determine the time course of ghrelin production during development. We examined the distribution of gastric ghrelin cells, plasma ghrelin concentrations and pituitary expression of the ghrelin receptor (ghsr-1alpha) and GH in the tammar wallaby, Macropus eugenii. There were ghrelin immunopositive cells in the developing mesenchyme of the stomach from day 10 post partum (pp) to day 150pp. Subsequently ghrelin protein in the fore-stomach declined and was absent by day 250pp but remained in the gastric cells of the hind-stomach. Ghrelin was detected in the developing pancreas from day 10pp but was absent by day 150pp and in the adult. Pituitary ghsr-1alpha expression and plasma concentrations of ghrelin increased significantly up to day 70-120pp while GH expression was also elevated, declining with GH to reach adult levels by day 180pp. These results demonstrate an early onset of gastric ghrelin expression in the tammar in concert with a functional stomach at a relatively earlier stage than that of developmentally more mature eutherian young.

  13. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance.

    PubMed

    Sun, Yuxiang; Butte, Nancy F; Garcia, Jose M; Smith, Roy G

    2008-02-01

    Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R), are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and negative (caloric restriction) energy balance. In contrast to results from young N2 mutant mice, changes in body weight and energy expenditure are not clearly distinguishable across genotypes. Although respiratory quotient was lower in mice fed a high-fat diet, no differences were evident between littermate wild-type and null genotypes. With normal chow, a modest decrease trend in respiratory quotient was detected in ghrelin(-/-) mice but not in Ghsr(-/-) mice. Under caloric restriction, the weight loss of ghrelin(-/-) and Ghsr(-/-) mice was identical to wild-type littermates, but blood glucose levels were significantly lower. We conclude that adult congenic ghrelin(-/-) and Ghsr(-/-) mice are not resistant to diet-induced obesity but under conditions of negative energy balance show impairment in maintaining glucose homeostasis. These results support our hypothesis that the primary metabolic function of ghrelin in adult mice is to modulate glucose sensing and insulin sensitivity, rather than directly regulate energy intake and energy expenditure.

  14. Clinical application of ghrelin.

    PubMed

    Strasser, Florian

    2012-01-01

    Ghrelin as a human natural hormone is involved in fundamental regulatory processes of eating and energy balance. Ghrelin signals the nutrient availability from the gastrointestinal tract to the central nervous system, up-regulates food intake and lowers energy expenditure mainly through hypothalamic mediators acting both centrally and peripherally including the gastrointestinal tract (motility, epithelium), promotes both neuro-endocrine and inflammatory signals to increase skeletal muscle growth and decrease protein breakdown, and increases lipolysis while body fat utilization is reduced. Ghrelin does more to exert its probably sentinel role around "human energy": it influences through mainly extra-hypothalamic actions the hedonic and incentive value of food, mood and anxiety, sleep-wake regulation, learning and memory, and neurogenesis. Recently numerous ghrelin gene-derived peptides were discovered, demonstrating the complexity within the ghrelin/ghrelin receptor axis. For clinical applications, not only the natural ghrelin and its slice variants, but also several modified or artificial molecules acting at ghrelin-associated receptors were and are developed. Current clinical applications are limited to clinical studies, focusing mainly on cachexia in chronic heart failure, COPD, cancer, endstage- renal-disease or cystic fibrosis, but also on frailty in elderly, gastrointestinal motility (e.g., gastroparesis, functional dyspepsia, postoperative ileus), after curative gastrectomy, anorexia nervosa, growth hormone deficient patients, alcohol craving, sleep-wake regulation (e.g. major depression), or sympathetic nervous activity in obesity. The results of completed, preliminary studies support the clinical potential of ghrelin, ghrelin gene-derived peptides, and artificial analogues, suggesting that larger clinical trials are demanded to move ghrelin towards an available and reimbursed pharmaceutical intervention.

  15. Ghrelin and appetite control in humans--potential application in the treatment of obesity.

    PubMed

    Patterson, Michael; Bloom, Stephen R; Gardiner, James V

    2011-11-01

    Ghrelin is a peptide hormone secreted into circulation from the stomach. It has been postulated to act as a signal of hunger. Ghrelin administration acutely increases energy intake in lean and obese humans and chronically induces weight gain and adiposity in rodents. Circulating ghrelin levels are elevated by fasting and suppressed following a meal. Inhibiting ghrelin signaling therefore appears an attractive target for anti-obesity therapies. A number of different approaches to inhibiting the ghrelin system to treat obesity have been explored. Despite this, over a decade after its discovery, no ghrelin based anti-obesity therapies are close to reaching the market. This article discusses the role of ghrelin in appetite control in humans, examines different approaches to inhibiting the ghrelin system and assesses their potential as anti-obesity therapies.

  16. Associations of ghrelin with eating behaviors, stress, metabolic factors, and telomere length among overweight and obese women: preliminary evidence of attenuated ghrelin effects in obesity?

    PubMed

    Buss, Julia; Havel, Peter J; Epel, Elissa; Lin, Jue; Blackburn, Elizabeth; Daubenmier, Jennifer

    2014-05-01

    Ghrelin regulates homeostatic food intake, hedonic eating, and is a mediator in the stress response. In addition, ghrelin has metabolic, cardiovascular, and anti-aging effects. This cross-sectional study examined associations between total plasma ghrelin, caloric intake based on 3day diet diaries, hedonic eating attitudes, stress-related and metabolic factors, and leukocyte telomere length in overweight (n=25) and obese women (n=22). We hypothesized associations between total plasma ghrelin and eating behaviors, stress, metabolic, cardiovascular, and cell aging factors among overweight women, but not among obese women due to lower circulating ghrelin levels and/or central resistance to ghrelin. Confirming previous studies demonstrating lowered plasma ghrelin in obesity, ghrelin levels were lower in the obese compared with overweight women. Among the overweight, ghrelin was positively correlated with caloric intake, giving in to cravings for highly palatable foods, and a flatter diurnal cortisol slope across 3days. These relationships were non-significant among the obese group. Among overweight women, ghrelin was negatively correlated with insulin resistance, systolic blood pressure, and heart rate, and positively correlated with telomere length. Among the obese subjects, plasma ghrelin concentrations were negatively correlated with insulin resistance, but were not significantly correlated with blood pressure, heart rate or telomere length. Total plasma ghrelin and its associations with food intake, hedonic eating, and stress are decreased in obesity, providing evidence consistent with the theory that central resistance to ghrelin develops in obesity and ghrelin's function in appetite regulation may have evolved to prevent starvation in food scarcity rather than cope with modern food excess. Furthermore, ghrelin is associated with metabolic and cardiovascular health, and may have anti-aging effects, but these effects may be attenuated in obesity.

  17. Reduction in circulating ghrelin concentration after maturation does not affect food intake.

    PubMed

    Ariyasu, Hiroyuki; Yamada, Go; Iwakura, Hiroshi; Matsumura, Sigenobu; Inoue, Kazuo; Kangawa, Kenji; Nakao, Kazuwa; Akamizu, Takashi

    2014-01-01

    Ghrelin has a potent orexigenic effect and induces adiposity when administered exogenously. Since plasma ghrelin levels rise before meals, ghrelin was thought to play a crucial role in the regulation of appetite. In contrast, mice deficient in the production of ghrelin or the corresponding receptor, GHS-R, do not eat less, throwing the role of ghrelin in the regulation of energy homeostasis into question. Since these mice lack ghrelin or GHS-R from the time of conception, the possibility that compensatory mechanisms may have arisen during development cannot be ruled out. In this study, we used a transgenic mouse model that expresses human diphtheria toxin (DT) receptor cDNA under the control of the ghrelin promoter (GPDTR-Tg mice). As previously reported, an injection of DT into this mouse model ablates ghrelin-secreting cells in the stomach but not in the hypothalamus, resulting in a reduction in circulating ghrelin levels. We used this model system to evaluate the physiological roles of circulating ghrelin in the regulation of food intake. Meal patterns, diurnal and nocturnal meal sizes, and cumulative food intake of DT-treated GPDTR-Tg mice were not affected, although circulating ghrelin levels markedly decreased even after fasting. These mice also displayed normal responses to starvation; however, the use of fat increased and slower weight gain when maintained on a high fat diet was observed. Together, these data suggest that circulating ghrelin does not play a crucial role in feeding behavior, but rather is involved in maintaining body weight.

  18. An Integrative Review on Role and Mechanisms of Ghrelin in Stress, Anxiety and Depression.

    PubMed

    Bali, Anjana; Jaggi, Amteshwar Singh

    2016-01-01

    Ghrelin is orexigenic hormone primarily synthesized by endocrine X/A-like cells of gastric oxyntic mucosa to stimulate appetite and food intake along with regulation of growth hormone and insulin secretion; glucose and lipid metabolism; gastrointestinal motility; blood pressure, heart rate and neurogenesis. Furthermore, peripherally (after crossing the blood brain barrier) as well as centrally synthesized ghrelin (in the hypothalamus) regulates diverse functions of central nervous system including stress-associated behavioral functions. Exposure to stress alters the ghrelin levels and alteration in ghrelin levels significantly affects neuro-endocrinological parameters; metabolism-related physiology, behavior and mood. Studies have shown both anxiolytic and anxiogenic role of ghrelin suggesting its dual role in modulating anxiety-related behavior. However, it is proposed that increase in ghrelin levels during stress condition is an endogenous stress coping behavior and increased ghrelin levels may be required to prevent excessive anxiety. In preclinical and clinical studies, an elevation in ghrelin levels during depression has been correlated with their antidepressant activities. Ghrelin-induced modulation of stress and associated conditions has been linked to alteration in hypothalamic-pituitary-adrenal (HPA) axis; autonomic nervous system (mainly sympathetic nervous system and serotonergic neurotransmission. A reciprocal relationship has been reported between corticotropin-releasing hormone (CRH) and ghrelin as ghrelin increases the release of CRH, ACTH and corticosteroids; while CRH decreases the expression of ghrelin. Similarly, ghrelin increases the serotonin turnover and in turn, serotonin controls ghrelin signaling to modulate anxiety-related behavior. The present review discusses the dual role of ghrelin in stress and related behavioral disorders along with possible mechanisms.

  19. Effect of Deletion of Ghrelin-O-Acyltransferase on the Pulsatile Release of Growth Hormone in Mice.

    PubMed

    Xie, T Y; Ngo, S T; Veldhuis, J D; Jeffery, P L; Chopin, L K; Tschöp, M; Waters, M J; Tolle, V; Epelbaum, J; Chen, C; Steyn, F J

    2015-12-01

    Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of

  20. Continuous antagonism of the ghrelin receptor results in early induction of salt-sensitive hypertension.

    PubMed

    Sato, Takahiro; Nakashima, Yoshiki; Nakamura, Yuki; Ida, Takanori; Kojima, Masayasu

    2011-02-01

    Ghrelin is a hormone that mediates a variety of physiological roles, such as stimulating appetite, initiating food intake, and modulating energy metabolism. Although it has been reported that a bolus injection of ghrelin decreases blood pressure, the effect of continuous ghrelin administration on vasoregulation has yet to be determined. We examined the longitudinal effect of ghrelin on vasoregulation using Dahl-Iwai salt-sensitive rats. In this model, a high-salt diet induced high blood pressure and increased ghrelin levels but reduced food intake. In salt-sensitive hypertension, cumulative food intake decreased, while both ghrelin messenger RNA levels and plasma ghrelin content increased. Continuous administration of a ghrelin receptor agonist, growth hormone releasing peptide-6 (GHRP-6), for 2 weeks by mini-osmotic pump did not change blood pressure values although the cumulative food intake recovered. In contrast, continuous administration of a ghrelin receptor antagonist, [D-Lys³]-GHRP-6, induced early elevations in blood pressure without changes in heart rate. Quantitative RT-PCR revealed high expression levels of genes involved in the catecholamine biosynthetic pathway, tyrosine hydroxylase and dopamine-β-hydroxylase, after continuous [D-Lys³]-GHRP-6 administration. These results indicate that continuous antagonism of the ghrelin receptor results in early induction of salt-sensitive hypertension in this animal model and suggests that increases in autonomic nervous activity induced by ghrelin receptor antagonism are responsible, as indicated by the high expression levels of genes in the catecholamine biosynthetic pathway.

  1. Sunflower (Helianthus annuus) long-chain acyl-coenzyme A synthetases expressed at high levels in developing seeds.

    PubMed

    Aznar-Moreno, Jose A; Venegas Calerón, Mónica; Martínez-Force, Enrique; Garcés, Rafael; Mullen, Robert; Gidda, Satinder K; Salas, Joaquín J

    2014-03-01

    Long chain fatty acid synthetases (LACSs) activate the fatty acid chains produced by plastidial de novo biosynthesis to generate acyl-CoA derivatives, important intermediates in lipid metabolism. Oilseeds, like sunflower, accumulate high levels of triacylglycerols (TAGs) in their seeds to nourish the embryo during germination. This requires that sunflower seed endosperm supports very active glycerolipid synthesis during development. Sunflower seed plastids produce large amounts of fatty acids, which must be activated through the action of LACSs, in order to be incorporated into TAGs. We cloned two different LACS genes from developing sunflower endosperm, HaLACS1 and HaLACS2, which displayed sequence homology with Arabidopsis LACS9 and LACS8 genes, respectively. These genes were expressed at high levels in developing seeds and exhibited distinct subcellular distributions. We generated constructs in which these proteins were fused to green fluorescent protein and performed transient expression experiments in tobacco cells. The HaLACS1 protein associated with the external envelope of tobacco chloroplasts, whereas HaLACS2 was strongly bound to the endoplasmic reticulum. Finally, both proteins were overexpressed in Escherichia coli and recovered as active enzymes in the bacterial membranes. Both enzymes displayed similar substrate specificities, with a very high preference for oleic acid and weaker activity toward stearic acid. On the basis of our findings, we discuss the role of these enzymes in sunflower oil synthesis.

  2. Ghrelin and cancer.

    PubMed

    Chopin, Lisa; Walpole, Carina; Seim, Inge; Cunningham, Peter; Murray, Rachael; Whiteside, Eliza; Josh, Peter; Herington, Adrian

    2011-06-20

    Ghrelin is a peptide hormone that was originally isolated from the stomach as the endogenous ligand for the growth hormone secretagogue receptor (GHSR). Ghrelin has many functions, including the regulation of appetite and gut motility, growth hormone release from the anterior pituitary and roles in the cardiovascular and immune systems. Ghrelin and its receptor are expressed in a number of cancers and cancer cell lines and may play a role in processes associated with cancer progression, including cell proliferation, apoptosis, and cell invasion and migration.

  3. Circulating ghrelin and ghrelin to obestatin ratio are low in patients with untreated mild-to-moderate hypertension.

    PubMed

    Li, Zhao-Feng; Guo, Zhi-Fu; Yang, Shu-Guang; Zheng, Xing; Cao, Jiang; Qin, Yong-Wen

    2010-12-10

    Obestatin, encoded by the same gene as ghrelin, was first described as a physiological opponent of ghrelin. We investigated fasting plasma ghrelin and obestatin levels and ratio of ghrelin to obestatin in humans with untreated mild-to-moderate hypertension and humans with normal blood pressure. We found that the plasma concentration of ghrelin and the ratio of ghrelin to obestatin were significantly lower in hypertension group compared with control group (236.3±12.3 pg/ml vs 381.4±25.6 pg/ml, P<0.01; 0.89±0.06 vs 1.2±0.06, P<0.01). The plasma concentration of obestatin was lower in hypertension group compared with control group, but the difference between the two groups was not significant (276.2±15.1 pg/ml vs 325.4±25.8 pg/ml, P>0.05). In a multiple regression model, systolic blood pressure, triglyceride and obestatin were independent predictors of ghrelin (standardized coefficient=-0.332; P=0.019; standardized coefficient=-0.302; P=0.030; standardized coefficient=0.630; P<0.0005, respectively). In another multiple regression model, only ghrelin was an independent predictor of obestatin (standardized coefficient=0.861; P<0.0005). Both systolic blood pressure and triglyceride were independent predictors of ratio of ghrelin to obestatin (standardized coefficient=-0.385; P=0.033; standardized coefficient=-0.430; P=0.018, respectively). Our data suggests that there are disturbances of ghrelin and obestatin in the circulating plasma of humans and the ghrelin/obestatin system might play a role in blood pressure regulation.

  4. Effects of ghrelin on anorexia in tumor-bearing mice with eicosanoid-related cachexia.

    PubMed

    Wang, Wenhua; Andersson, Marianne; Iresjö, Britt-Marie; Lönnroth, Christina; Lundholm, Kent

    2006-06-01

    Ghrelin is a novel brain-gut peptide that stimulates food intake and may secondarily increase body weight via a growth hormone secretagogue receptor (GHS-R). Tumor-bearing mice (MCG101), characterized by anorexia, fat loss and muscle wasting due to increased concentration of PGE2 and proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha), were provided ghrelin i.p. at a low (20 microg/day) and high dose (40 microg/day) to examine the ability of ghrelin to counteract tumor-induced anorexia. Immunohistochemical staining and Western blot analyses were used to identify GHS-R expression in the brain as well as its relationship to NPY expression in hypothalamic neurons. GHS-R mRNA in hypothalamus and ghrelin mRNA in gastric fundus were quantified by RT-PCR. Body composition was determined by carcass extractions. GHS-R expression in hypothalamus and plasma ghrelin levels were significantly increased in freely-fed tumor-bearing mice, while gastric fundus expression of ghrelin was unaltered compared to non-tumor-bearing mice (controls). Ghrelin treatment increased food intake, body weight and whole body fat at both low and high doses of ghrelin in normal controls, while tumor-bearing mice showed improved intake and body composition at the high dose of ghrelin only. Exogenous ghrelin normalized the GHS-R expression in hypothalamus from tumor-bearing mice without alterations in the gastric fundus expression of ghrelin. Tumor growth was not altered by exogenous ghrelin. Our results indicate that MCG 101-bearing mice became ghrelin resistant despite upregulation of hypothalamic GHS-R expression, which confirms similar indirect observations in cancer patients. Thus, other factors downstream of the ghrelin-GHS-R system appear to be more important than ghrelin to explain cancer-induced anorexia.

  5. Altered lipid and salt taste responsivity in ghrelin and GOAT null mice.

    PubMed

    Cai, Huan; Cong, Wei-Na; Daimon, Caitlin M; Wang, Rui; Tschöp, Matthias H; Sévigny, Jean; Martin, Bronwen; Maudsley, Stuart

    2013-01-01

    Taste perception plays an important role in regulating food preference, eating behavior and energy homeostasis. Taste perception is modulated by a variety of factors, including gastric hormones such as ghrelin. Ghrelin can regulate growth hormone release, food intake, adiposity, and energy metabolism. Octanoylation of ghrelin by ghrelin O-acyltransferase (GOAT) is a specific post-translational modification which is essential for many biological activities of ghrelin. Ghrelin and GOAT are both widely expressed in many organs including the gustatory system. In the current study, overall metabolic profiles were assessed in wild-type (WT), ghrelin knockout (ghrelin(-/-)), and GOAT knockout (GOAT(-/-)) mice. Ghrelin(-/-) mice exhibited decreased food intake, increased plasma triglycerides and increased ketone bodies compared to WT mice while demonstrating WT-like body weight, fat composition and glucose control. In contrast GOAT(-/-) mice exhibited reduced body weight, adiposity, resting glucose and insulin levels compared to WT mice. Brief access taste behavioral tests were performed to determine taste responsivity in WT, ghrelin(-/-) and GOAT(-/-) mice. Ghrelin and GOAT null mice possessed reduced lipid taste responsivity. Furthermore, we found that salty taste responsivity was attenuated in ghrelin(-/-) mice, yet potentiated in GOAT(-/-) mice compared to WT mice. Expression of the potential lipid taste regulators Cd36 and Gpr120 were reduced in the taste buds of ghrelin and GOAT null mice, while the salt-sensitive ENaC subunit was increased in GOAT(-/-) mice compared with WT mice. The altered expression of Cd36, Gpr120 and ENaC may be responsible for the altered lipid and salt taste perception in ghrelin(-/-) and GOAT(-/-) mice. The data presented in the current study potentially implicates ghrelin signaling activity in the modulation of both lipid and salt taste modalities.

  6. A RAPID Method for Blood Processing to Increase the Yield of Plasma Peptide Levels in Human Blood.

    PubMed

    Teuffel, Pauline; Goebel-Stengel, Miriam; Hofmann, Tobias; Prinz, Philip; Scharner, Sophie; Körner, Jan L; Grötzinger, Carsten; Rose, Matthias; Klapp, Burghard F; Stengel, Andreas

    2016-04-28

    Research in the field of food intake regulation is gaining importance. This often includes the measurement of peptides regulating food intake. For the correct determination of a peptide's concentration, it should be stable during blood processing. However, this is not the case for several peptides which are quickly degraded by endogenous peptidases. Recently, we developed a blood processing method employing Reduced temperatures, Acidification, Protease inhibition, Isotopic exogenous controls and Dilution (RAPID) for the use in rats. Here, we have established this technique for the use in humans and investigated recovery, molecular form and circulating concentration of food intake regulatory hormones. The RAPID method significantly improved the recovery for (125)I-labeled somatostatin-28 (+39%), glucagon-like peptide-1 (+35%), acyl ghrelin and glucagon (+32%), insulin and kisspeptin (+29%), nesfatin-1 (+28%), leptin (+21%) and peptide YY3-36 (+19%) compared to standard processing (EDTA blood on ice, p <0.001). High performance liquid chromatography showed the elution of endogenous acyl ghrelin at the expected position after RAPID processing, while after standard processing 62% of acyl ghrelin were degraded resulting in an earlier peak likely representing desacyl ghrelin. After RAPID processing the acyl/desacyl ghrelin ratio in blood of normal weight subjects was 1:3 compared to 1:23 following standard processing (p = 0.03). Also endogenous kisspeptin levels were higher after RAPID compared to standard processing (+99%, p = 0.02). The RAPID blood processing method can be used in humans, yields higher peptide levels and allows for assessment of the correct molecular form.

  7. [Ghrelin: beyond hunger regulation].

    PubMed

    Milke García, Maria del Pilar

    2005-01-01

    Man ingests food to mitigate hunger (mediated by physiological and biochemical signals), satisfy appetite (subjective sensation) and because of psychosocial reasons. Satiation biomarkers (stop feeding) are gastric distention and hormones (CCK, GLP-1) and satiety biomarkers (induce feeding) are food-induced thermogenesis, body temperature, glycaemia and also hormones (insulin, leptin and ghrelin). Oxidative metabolism/body composition, tryptophan/serotonin and proinflammatory cytokines are also implicated on hunger physiology. At the present time, ghrelin is the only known circulating orexigenic with potential on hunger/body weight regulation. It is a neuropeptide (endogenous ligand for the GH secretagogue) recently isolated from the oxyntic mucosa and synthesized mainly in the stomach. Its blood concentration depends on diet, hyperglucemia and adiposity/leptin. It is secreted 1-2 hours preprandially and its concentration decreases drastically during the postprandium. Ghrelin acts on the lateral hypothalamus and theoretically inhibits proinflammatory cytokine secretion and antagonizes leptin. Ghrelin physiologically increases food intake and stimulates adipogenesis, gastrointestinal motility and gastric acid secretion, and has other hormonal and cardiovascular functions. Ghrelin blood concentration is reduced in massive obesity, non-alcoholic steatohepatitis, polycystic ovary syndrome, acromegaly, hypogonadism, ageing, short bowel syndrome and rheumatoid arthritis; and increased in primary or secondary anorexia, starvation, chronic liver disease and celiac disease. Cerebral and peritoneal ghrelin administration (rats) and systemic administration (rats and healthy volunteers, cancer patients or patients on peritoneal dialysis) promotes food consumption and increases adiposity, of utmost importance in the treatment of patients with anorexia.

  8. Effect of Cheonggukjang supplementation upon hepatic acyl-CoA synthase, carnitine palmitoyltransferase I, acyl-CoA oxidase and uncoupling protein 2 mRNA levels in C57BL/6J mice fed with high fat diet

    PubMed Central

    Soh, Ju-Ryoun; Shin, Dong-Hwa; Kwon, Dae Young

    2007-01-01

    This study investigated the effect of Cheonggukjang on mRNA levels of hepatic acyl-CoA synthase (ACS), carnitine palmitoyltransferase I (CPT-I), acyl-CoA oxidase (ACO) and uncoupling protein 2 (UCP2), and on serum lipid profiles in C57BL/6J mice. Thirty male C57BL/6J mice were divided into three groups; normal diet (ND), high fat diet (HD) and high fat diet with 40% Cheonggukjang (HDC). Energy intake was significantly higher in the HDC group than in the ND and HD groups. The HDC group normalized in weight gain, epididymal and back fat (g/100 g) accumulation which are increased by high fat diet. Serum concentrations of triglyceride and total cholesterol in the HDC were significantly lower than those in the HD group. These results were confirmed by hepatic mRNA expression of enzymes and protein (ACS, CPT-1, ACO, UCP2) which is related with lipid metabolism by RT-PCR. Hepatic CPT-I, ACO and UCP2 mRNA expression was increased by Cheonggukjang supplementation. We demonstrated that Cheonggukjang supplement leads to increased mRNA expressions of enzymes and protein involved in fatty acid oxidation in liver, reduced accumulation of body fat and improvement of serum lipids in high fat diet fed mice. PMID:18850232

  9. Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling.

    PubMed

    Huang, Chiung-Chun; Chou, Dylan; Yeh, Che-Ming; Hsu, Kuei-Sen

    2016-02-01

    Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training. Here, we explored this hypothesis by implementing food deprivation (FD) stress in mice to determine its effects on fear extinction and LTD induction at T-LA synapses. We found that FD increased plasma acylated ghrelin levels and enhanced fear extinction and its retention. Augmentation of fear extinction by FD was blocked by pretreatment with growth hormone secretagogue receptor type-1a antagonist D-Lys(3)-GHRP-6, suggesting an involvement of ghrelin signaling. Confirming previous findings, two distinct forms of LTD coexist at thalamic inputs to LA pyramidal neurons that can be induced by low-frequency stimulation (LFS) or paired-pulse LFS (PP-LFS) paired with postsynaptic depolarization, respectively. Unexpectedly, we found that FD impaired the induction of PP-LFS- and group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, but not LFS-induced LTD. Ghrelin mimicked the effects of FD to impair the induction of PP-LFS- and DHPG-induced LTD at T-LA synapses, which were blocked by co-application of D-Lys(3)-GHRP-6. The sensitivity of synaptic transmission to 1-naphthyl acetyl spermine was not altered by either FD or ghrelin treatment. These results highlight distinct features of fear extinction and LTD at T-LA synapses.

  10. Abnormal ghrelin secretion contributes to gastrointestinal symptoms in multiple system atrophy patients.

    PubMed

    Ozawa, Tetsutaro; Tokunaga, Jun; Arakawa, Musashi; Ishikawa, Atsushi; Takeuchi, Ryoko; Mezaki, Naomi; Miura, Takeshi; Sakai, Naoko; Hokari, Mariko; Takeshima, Akari; Utsumi, Kota; Kondo, Takashi; Yokoseki, Akio; Nishizawa, Masatoyo

    2013-08-01

    Patients with multiple system atrophy (MSA) often have evidence of compromised gastrointestinal motility. Ghrelin is a gut hormone that influences gastrointestinal motility in humans. The aim of this study was to determine whether ghrelin secretion is affected in MSA patients, and to investigate the relation between ghrelin secretion and gastrointestinal symptoms. Plasma levels of active ghrelin and unacylated ghrelin were measured in patients with MSA (n = 30), other atypical parkinsonian disorders including progressive supranuclear palsy-Richardson syndrome and corticobasal syndrome (n = 24), and control subjects (n = 24) using enzyme-linked immunosorbent assays. Gastrointestinal symptoms were quantified in all subjects using a self-report questionnaire. The ratio of active ghrelin to total ghrelin in the plasma (active ghrelin ratio) was lower in patients with MSA (mean: 8.0 %) than in patients with other atypical parkinsonian disorders (mean: 13.7 %, P = 0.001) and control subjects (mean: 13.9 %, P = 0.001). The active ghrelin ratio was correlated with the severity of gastrointestinal symptoms in MSA (r = -0.5, P = 0.004). Our observations indicate that ghrelin secretion is affected in patients with MSA. The low active ghrelin ratio may contribute to gastrointestinal symptoms in MSA.

  11. Ghrelin and the growth hormone secretagogue receptor in growth and development.

    PubMed

    Chanoine, J-P; De Waele, K; Walia, P

    2009-04-01

    The pancreas is a major source of ghrelin in the perinatal period, whereas gastric production progressively increases after birth. Loss of function of the genes for ghrelin or for the constitutively activated growth hormone secretagogue receptor (GHSR) does not affect birth weight and early postnatal growth. However, ghrl(-/-) or ghsr(-/-) mice fed a high fat diet starting soon after weaning are resistant to diet-induced obesity, suggesting that ghrelin affects the maturation of the metabolic axes involved in energy balance. In addition, animal and human studies suggest that GHSR plays a physiological role in linear growth. In mice, absence of the GHSR gene is associated with lower insulin-like growth factor 1 concentrations and lower body mass in adult animals, independently of food intake. In humans, a mutation of the GHSR gene that impairs the constitutive activity of the receptor was found in two families with short stature. Administration of acylated ghrelin to rat pups directly does not affect weight gain. In contrast, administration of ghrelin to pregnant or lactating rats results in greater fetal weight and postnatal weight gain, respectively, suggesting that maternal ghrelin may stimulate perinatal growth. These data point toward a physiological role for ghrelin and GHSR in growth and/or in the maturation of hormonal systems involved in the regulation of energy balance.

  12. Correlation of ghrelin concentration and ghrelin, ghrelin-O-acetyltransferase (GOAT) and growth hormone secretagogue receptor 1a mRNAs expression in the proventriculus and brain of the growing chicken.

    PubMed

    Kitazawa, Takio; Hiraga, Takeo; Teraoka, Hiroki; Yaosaka, Noriko; Kaiya, Hiroyuki

    2015-01-01

    To determine mechanisms for age-related decrease of GHS-R1a expression in the chicken proventriculus, changes in mRNA expression of ghrelin and ghrelin-O-acetyltransferase (GOAT) as well as ghrelin concentrations in the proventriculus and plasma were examined in growing chickens. Changes in expression levels of ghrelin, GOAT and GHS-R1a mRNAs were also examined in different brain regions (pituitary, hypothalamus, thalamus, cerebellum, cerebral cortex, olfactory bulb, midbrain and medulla oblongata). Ghrelin concentrations in the proventriculus and plasma increased with aging and reached plateaus at 30-50 days after hatching. High level of ghrelin mRNA decreased at 3 days after hatching, and it became stable at half of the initial level. Expression levels of GHS-R1a and GOAT decreased 3 or 5 days after hatching and became stable at low levels. Significant negative correlations were found between plasma ghrelin and mRNA levels of GOAT and GHS-R1a. Expression levels of ghrelin mRNA were different in the brain regions, but a significant change was not seen with aging. GHS-R1a expression was detected in all brain regions, and age-dependent changes were observed in the pituitary and cerebellum. Different from the proventriculus, the expression of GOAT in the brain increased or did not change with aging. These results suggest that decreased GHS-R1a and GOAT mRNA expression in the proventriculus is due to endogenous ghrelin-induced down-regulation. Expression levels of ghrelin, GOAT and GHS-R1a in the brain were independently regulated from that in the proventriculus, and age-related and region-dependent regulation pattern suggests a local effect of ghrelin system in chicken brain.

  13. Is really endogenous ghrelin a hunger signal in chickens? Association of GHSR SNPs with increase appetite, growth traits, expression and serum level of GHRL, and GH.

    PubMed

    El-Magd, Mohammed Abu; Saleh, Ayman A; Abdel-Hamid, Tamer M; Saleh, Rasha M; Afifi, Mohammed A

    2016-10-01

    Chicken growth hormone secretagogue receptor (GHSR) is a receptor for ghrelin (GHRL), a peptide hormone produced by chicken proventriculus, which stimulates growth hormone (GH) release and food intake. The purpose of this study was to search for single nucleotide polymorphisms (SNPs) in exon 2 of GHSR gene and to analyze their effect on the appetite, growth traits and expression levels of GHSR, GHRL, and GH genes as well as serum levels of GH and GHRL in Mandara chicken. Two adjacent SNPs, A239G and G244A, were detected in exon 2 of GHSR gene. G244A SNP was non-synonymous mutation and led to replacement of lysine amino acid (aa) by arginine aa, while A239G SNP was synonymous mutation. The combined genotypes of A239G and G244A SNPs produced three haplotypes; GG/GG, GG/AG, AG/AG, which associated significantly (P<0.05) with growth traits (body weight, average daily gain, shank length, keel length, chest circumference) at age from >4 to 16w. Chickens with the homozygous GG/GG haplotype showed higher growth performance than other chickens. The two SNPs were also correlated with mRNA levels of GHSR and GH (in pituitary gland), and GHRL (in proventriculus and hypothalamus) as well as with serum level of GH and GHRL. Also, chickens with GG/GG haplotype showed higher mRNA and serum levels. This is the first study to demonstrate that SNPs in GHSR can increase appetite, growth traits, expression and level of GHRL, suggesting a hunger signal role for endogenous GHRL.

  14. Association studies on ghrelin and ghrelin receptor gene polymorphisms with obesity.

    PubMed

    Gueorguiev, Maria; Lecoeur, Cécile; Meyre, David; Benzinou, Michael; Mein, Charles A; Hinney, Anke; Vatin, Vincent; Weill, Jacques; Heude, Barbara; Hebebrand, Johannes; Grossman, Ashley B; Korbonits, Márta; Froguel, Philippe

    2009-04-01

    Ghrelin exerts a stimulatory effect on appetite and regulates energy homeostasis. Ghrelin gene variants have been shown to be associated with metabolic traits, although there is evidence suggesting linkage and association with obesity and the ghrelin receptor (GHSR). We hypothesized that these genes are good candidates for susceptibility to obesity. Direct sequencing identified 12 ghrelin single-nucleotide polymorphisms (SNPs) and 8 GHSR SNPs. The 10 common SNPs were genotyped in 1,275 obese subjects and in 1,059 subjects from a general population cohort of European origin. In the obesity case-control study, the GHSR SNP rs572169 was found to be associated with obesity (P = 0.007 in additive model, P = 0.001 in dominant model, odds ratio (OR) 1.73, 95% confidence interval (1.23-2.44)). The ghrelin variant, g.A265T (rs4684677), showed an association with obesity (P = 0.009, BMI adjusted for age and sex) in obese families. The ghrelin variant, g.A-604G (rs27647), showed an association with insulin levels at 2-h post-oral glucose tolerance test (OGTT) (P = 0.009) in obese families. We found an association between the eating behavior "overeating" and the GHSR SNP rs2232169 (P = 0.02) in obese subjects. However, none of these associations remained significant when corrected for multiple comparisons. Replication of the nominal associations with obesity could not be confirmed in a German genome-wide association (GWA) study for rs4684677 and rs572169 polymorphisms. Our data suggest that common polymorphisms in ghrelin and its receptor genes are not major contributors to the development of polygenic obesity, although common variants may alter body weight and eating behavior and contribute to insulin resistance, in particular in the context of early-onset obesity.

  15. Ghrelin secretion is not reduced by increased fat mass during diet-induced obesity.

    PubMed

    Qi, Xiang; Reed, Jason T; Wang, Guiyun; Han, Song; Englander, Ella W; Greeley, George H

    2008-08-01

    Ghrelin is a stomach hormone that stimulates growth hormone (GH) secretion, adiposity, and food intake. Gastric ghrelin production and secretion are regulated by caloric intake; ghrelin secretion increases during fasting, decreases with refeeding, and is reduced by diet-induced obesity. The aim of the present study was to test the hypotheses that 1) an increase in body adiposity will play an inhibitory role in the reduction of gastric ghrelin synthesis and secretion during chronic ingestion of a high-fat (HF) diet and 2) chronic ingestion of an HF diet will suppress the rise in circulating ghrelin levels in response to acute fasting. Adult male Sprague-Dawley rats were fed a standard AIN-76A (approximately 5-12% of calories from fat) or an HF (approximately 45% of calories from fat) diet. The effect of increased adiposity on gastric ghrelin homeostasis was assessed by comparison of stomach ghrelin production and plasma ghrelin levels in obese and nonobese rats fed the HF diet. HF diet-fed, nonobese rats were generated by administration of triiodothyronine to lower body fat accumulation. Our findings indicate that an increased fat mass per se does not exert an inhibitory effect on ghrelin homeostasis during ingestion of the HF diet. Additionally, the magnitude of change in plasma ghrelin in response to fasting was not blunted, indicating that a presumed, endogenous signal for activation of ingestive behavior remains intact, despite excess stored calories in HF-fed rats.

  16. Ghrelin-Reactive Immunoglobulins in Conditions of Altered Appetite and Energy Balance

    PubMed Central

    Fetissov, Sergueï O.; Lucas, Nicolas; Legrand, Romain

    2017-01-01

    Part of circulating ghrelin is bound to immunoglobulins (Ig) protecting it from degradation and preserving its functional activity. This review summarizes the data on ghrelin- and desacyl-ghrelin-reactive IgG in conditions of altered appetite and energy balance. Plasma levels and affinity kinetics of such IgG were compared in patients with obesity and anorexia nervosa (AN) and in animal models of obesity including ob/ob mice, high-fat diet-induced obese mice, and obese Zucker rats as well as in mice after chronic food restriction and activity-based anorexia and in rats with methotrexate-induced anorexia. We show that plasmatic IgG in both obese humans and animals are characterized by increased affinity for ghrelin. In contrast, patients with AN and anorectic rodents all show lower affinity of ghrelin- and desacyl-ghrelin-reactive IgG, respectively, the changes which were not observed in non-anorectic, chronically starved mice. We also show that affinity of ghrelin-reactive IgG correlate with plasma levels of ghrelin. These data point to common mechanisms underlying modifications of affinity kinetics properties of ghrelin-reactive IgG during chronic alterations of energy balance in humans and rodents and support a functional role of such autoantibodies in ghrelin-mediated regulation of appetite. PMID:28191004

  17. Ghrelin, food intake, and botanical extracts: A Review

    PubMed Central

    Rezaie, Peyman; Mazidi, Mohsen; Nematy, Mohsen

    2015-01-01

    A kind of growth hormone secretagogue (GHS), ghrelin, was first isolated from the rat stomach and plays a major role in the activation of the growth hormone secretagogue receptor 1a (GHS-R1a) resulting the release of growth hormone (GH). The preproghrelin gene is placed on chromosome 3, at locus 3p25 –2 in humans and constitutes five exons and three introns. Ghrelin is most plentifully expressed in particular cells in the oxyntic glands of the gastric epithelium, initially named X/A-like cells. Almost 60-70% of circulating ghrelin is secreted by the stomach. Plasma ghrelin concentration alters throughout the day. Ghrelin has been suggested to act as a meal initiator because of its appetite-stimulating influences in free feeding rats in short period. In addition to ghrelin’s function as a meal motivator, it seems to contribute in long-term energy balance and nutritional status. In addition, many studies have been carried out in order to investigate the effects of natural and medicinal plants and botanical extracts on appetite, food intake, energy hemostasis, and the level of related hormones including ghrelin. Due to the importance of ghrelin in nutritional and medical sciences, this review was performed to understand new aspects of this hormone’s function. PMID:26445708

  18. Intracerebroventricular injection of ghrelin decreases wheel running activity in rats.

    PubMed

    Miyatake, Yumiko; Shiuchi, Tetsuya; Mawatari, Kazuaki; Toda, Satomi; Taniguchi, Yasuko; Futami, Akari; Sato, Fukiko; Kuroda, Masashi; Sebe, Mayu; Tsutsumi, Rie; Harada, Nagakatsu; Minokoshi, Yasuhiko; Kitamura, Tadahiro; Gotoh, Koro; Ueno, Masaki; Nakaya, Yutaka; Sakaue, Hiroshi

    2017-01-01

    There is an increasing interest in elucidating the molecular mechanisms by which voluntary exercise is regulated. In this study, we examined how the central nervous system regulates exercise. We used SPORTS rats, which were established in our laboratory as a highly voluntary murine exercise model. SPORTS rats showed lower levels of serum ghrelin compared with those of the parental line of Wistar rats. Intracerebroventricular and intraperitoneal injection of ghrelin decreased wheel-running activity in SPORTS rats. In addition, daily injection of the ghrelin inhibitor JMV3002 into the lateral ventricles of Wistar rats increased wheel-running activity. Co-administration of obestatin inhibited ghrelin-induced increases in food intake but did not inhibit ghrelin-induced suppression of voluntary exercise in rats. Growth hormone secretagogue receptor (GHSR) in the hypothalamus and hippocampus of SPORTS rats was not difference that in control rats. We created an arcuate nucleus destruction model by administering monosodium glutamate (MSG) to neonatal SPORTS rats. Injection of ghrelin into MSG-treated rats decreased voluntary exercise but did not increase food intake, suggesting that wheel-running activity is not controlled by the arcuate nucleus neurons that regulate feeding. These results provide new insights into the mechanism by which ghrelin regulates voluntary activity independent of arcuate nucleus neurons.

  19. Prevention of diet-induced obesity by safflower oil: insights at the levels of PPARalpha, orexin, and ghrelin gene expression of adipocytes in mice.

    PubMed

    Zhang, Zhong; Li, Qiang; Liu, Fengchen; Sun, Yuqian; Zhang, Jinchao

    2010-03-15

    The aim of this study was to investigate the prevention of diet-induced obesity by a high safflower oil diet and adipocytic gene expression in mice. Forty 3-week-old C57BL/6 mice were randomly divided into three groups: control group (CON, 5% lard + 5% safflower oil), high lard group (LAR, 45% lard + 5% safflower oil), and high safflower oil group (SAF, 45% safflower oil + 5% lard). After 10 weeks, 10 mice of the LAR group were switched to high safflower oil diet (LAR-SAF). Ten weeks later, glucose tolerance tests were performed by intraperitoneal injection of glucose. Circulating levels of lipid and insulin were measured and white adipose tissues were taken for gene chip and reverse transcriptase-polymerase chain reaction analysis. The LAR group showed higher body weight, adiposity index, insulin, and lipids than the CON group (P<0.05). The body weight in the LAR-SAF group decreased after dietary reversal. The plasma biochemical profiles decreased in the LAR-SAF and SAF groups (P<0.05) compared with those of the LAR group. The blood glucose level of the LAR-SAF group was reduced during intraperitoneal glucose tolerance test compared with that of the LAR group. The LAR-SAF group had lower levels of Orexin and Ghrelin gene expression, whereas the level of PPARalpha gene expression was significantly enhanced compared with that of the LAR group. So, the SAF diet can alter adipocytic adiposity-related gene expression and result in effective amelioration of diet-induced obesity.

  20. Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease.

    PubMed

    Nahata, Miwa; Muto, Shuichi; Oridate, Nobuhiko; Ohnishi, Shunsuke; Nakagawa, Koji; Sadakane, Chiharu; Saegusa, Yayoi; Hattori, Tomohisa; Asaka, Masahiro; Takeda, Hiroshi

    2012-07-01

    Gastroesophageal reflux disease (GERD) is often associated with decreased upper gastrointestinal motility, and ghrelin is an appetite-stimulating hormone known to increase gastrointestinal motility. We investigated whether ghrelin signaling is impaired in rats with GERD and studied its involvement in upper gastrointestinal motility. GERD was induced surgically in Wistar rats. Rats were injected intravenously with ghrelin (3 nmol/rat), after which gastric emptying, food intake, gastroduodenal motility, and growth hormone (GH) release were investigated. Furthermore, plasma ghrelin levels and the expression of ghrelin-related genes in the stomach and hypothalamus were examined. In addition, we administered ghrelin to GERD rats treated with rikkunshito, a Kampo medicine, and examined its effects on gastroduodenal motility. GERD rats showed a considerable decrease in gastric emptying, food intake, and antral motility. Ghrelin administration significantly increased gastric emptying, food intake, and antral and duodenal motility in sham-operated rats, but not in GERD rats. The effect of ghrelin on GH release was also attenuated in GERD rats, which had significantly increased plasma ghrelin levels and expression of orexigenic neuropeptide Y/agouti-related peptide mRNA in the hypothalamus. The number of ghrelin-positive cells in the gastric body decreased in GERD rats, but the expression of gastric preproghrelin and GH secretagogue receptor mRNA was not affected. However, when ghrelin was exogenously administered to GERD rats treated with rikkunshito, a significant increase in antral motility was observed. These results suggest that gastrointestinal dysmotility is associated with impaired ghrelin signaling in GERD rats and that rikkunshito restores gastrointestinal motility by improving the ghrelin response.

  1. Inhibition of pancreatic protein secretion by ghrelin in the rat

    PubMed Central

    Zhang, Weizhen; Chen, Min; Chen, Xuequn; Segura, Bradley J; Mulholland, Michael W

    2001-01-01

    The role of ghrelin in the regulation of pancreatic protein secretion was investigated in vivo using anaesthetized rats with pancreatic ductal cannulas, and in isolated pancreatic acinar cells and pancreatic lobules in vitro. In vivo, pancreatic protein output stimulated by CCK-8 (400 pmol kg−1 h−1) was dose-dependently inhibited by continuous ghrelin infusion (1.2 and 12 nmol kg−1 h−1) by 45 ± 8 and 84 ± 7 %, respectively. In rats with acute subdiaphragmatic vagotomy, ghrelin (12 nmol kg−1 h−1) significantly inhibited CCK-stimulated pancreatic protein secretion by 75 ± 18 %. Infusion of ghrelin (12 nmol kg−1 h−1) abolished pancreatic protein secretion caused by the central vagal stimulant 2-deoxy-d-glucose (75 mg kg−1), whereas bethanechol-stimulated pancreatic protein output was inhibited by only 59 ± 7 %. In vitro, ghrelin (10−11–10−7m) produced no change in basal amylase release from dispersed, purified acinar cells. Co-incubation of ghrelin (10−11−10−7m) with CCK−8 (10−10m) demonstrated no inhibition of CCK-stimulated amylase release from dispersed acini. In contrast, ghrelin (10−9−10−7m) dose-dependently inhibited amylase release from pancreatic lobules exposed to 75 mm potassium. Our results show that (1) ghrelin is a potent inhibitor of pancreatic exocrine secretion in anaesthetized rats in vivo and in pancreatic lobules in vitro; and (2) the actions of ghrelin are indirect and may be exerted at the level of intrapancreatic neurons. PMID:11711576

  2. Expression and Possible Immune-regulatory Function of Ghrelin in Oral Epithelium

    PubMed Central

    Ohta, K.; Laborde, N.J.; Kajiya, M.; Shin, J.; Zhu, T.; Thondukolam, A.K.; Min, C.; Kamata, N.; Karimbux, N.Y.; Stashenko, P.; Kawai, T.

    2011-01-01

    Originally found in stomach mucosa, ghrelin is a peptide appetite hormone that has been implicated as an immuno-modulatory factor. Ghrelin has also been found in salivary glands and saliva; however, its expression patterns and biological properties in the oral cavity remain unclear. Therefore, we investigated the expression patterns of ghrelin in saliva, gingival crevicular fluid (GCF), and gingival tissue, as well as its in vitro effects on IL-8 production by TNF-α or LPS-stimulated oral epithelial cells. In the clinical samples obtained from 12 healthy volunteers, the concentration of ghrelin in GCF remarkably exceeded that detected in saliva. The expression of ghrelin mRNAs and growth hormone secretagogue (GHS) receptors could be detected in human oral epithelial cells. Immunohistochemical analysis revealed the expression of ghrelin in gingival epithelium, as well as in fibroblasts in the lamina propria. Ghrelin increased intracellular calcium mobilization and cAMP levels in oral epithelial cells, suggesting that ghrelin acts on epithelial cells to induce cell signaling. Furthermore, synthetic ghrelin inhibited the production of IL-8 from TNF-α or LPS-stimulated oral epithelial cells. These results indicate that ghrelin produced in the oral cavity appears to play a regulatory role in innate immune responses to inflammatory infection. PMID:21865591

  3. CRF Type 2 Receptors Mediate the Metabolic Effects of Ghrelin in C2C12 cells

    PubMed Central

    Gershon, Eran; Vale, Wylie W

    2014-01-01

    Objective Ghrelin is known to regulate appetite control and cellular metabolism. The Corticotropin-Releasing Factor (CRF) family is also known to regulate energy balance. In this study, we investigated the links between ghrelin and the CRF family in C2C12 cells, a mouse myoblast cell line. Design and methods C2C12 cells were treated with ghrelin in the presence or absence of CRF receptor antagonists and then subjected to different metabolic analyses. Results Ghrelin enhanced glucose uptake by C2C12 cells, induced GLUT4 translocation to the cell surface and decreased RBP4 expression. A CRF-R2 selective antagonist, anti-sauvagine-30, blocked ghrelin-induced glucose uptake, Ghrelin upregulated CRF-R2 but not CRF-R1 levels. Moreover, ghrelin-treated C2C12 cells displayed a cAMP and pERK activation in response to Ucn3, a CRF-R2 specific ligand, but not in response to CRF or stressin, CRF-R1 specific ligands. Ghrelin also induced UCP2 and UCP3 expression, which were blocked by anti-sauvagine-30. Ghrelin did not induce fatty acids uptake by C2C12 cells or ACC expression. Even though C2C12 cells clearly exhibited responses to ghrelin, the known ghrelin receptor, GHSR1a, was not detectable in C2C12 cells. Conclusion Our results suggest that, ghrelin plays a role in regulating muscle glucose and, raise the possibility that suppression of the CRF-R2 pathway might provide benefits in high ghrelin states. PMID:23804489

  4. Are hungry sheep more pessimistic? The effects of food restriction on cognitive bias and the involvement of ghrelin in its regulation.

    PubMed

    Verbeek, Else; Ferguson, Drewe; Lee, Caroline

    2014-01-17

    Food restriction is considered to be a welfare issue in extensively reared animals. However, the effects of food restriction on the affective state, and its physiological regulation, are unknown. In Experiment 1, we aimed to assess the effects of increased plasma concentrations of acyl-ghrelin on judgement bias (an indicator of affective states) by fasting sheep for 24h or by ghrelin administration. In Experiment 2, we aimed to assess the effects of chronic food restriction on judgement bias and attention bias towards a food-related cue. For the judgement bias test, sheep were trained in an arena to approach a positive location cue associated with conspecifics and not approach a negative location cue associated with a dog. Three non-trained, non-reinforced ambiguous location cues were situated between the positive and negative locations. Attention bias towards a food-related cue was assessed by placing an empty food bucket against the wall of the arena halfway between the entry point and the positive location. In Experiment 1, sheep were divided into three treatments; 24h fast, ghrelin administration or control. Judgement bias, locomotor activity and plasma cortisol concentrations were assessed. The ghrelin treated group tended to express a more pessimistic bias compared to the control group (P<0.1), and plasma cortisol concentrations tended to be increased (P<0.1). In Experiment 2, sheep were subjected to a high feeding level (HF) or low feeding level (LF) for 7days. The LF group tended to show a more optimistic judgement bias (P<0.1). When the food-related cue was presented, LF ewes took longer to reach the positive location (P<0.001), spent longer with their head inside the bucket (P<0.001) and more time interacting with the bucket (P<0.01). This study provides preliminary evidence that food restriction alters judgement bias and attention bias towards a food-related cue which may indicate altered affective states of sheep.

  5. Ghrelin O-acyltransferase knockout mice show resistance to obesity when fed high-sucrose diet.

    PubMed

    Kouno, Tetsuya; Akiyama, Nobuteru; Ito, Takahito; Okuda, Tomohiko; Nanchi, Isamu; Notoya, Mitsuru; Oka, Shogo; Yukioka, Hideo

    2016-02-01

    Ghrelin is an appetite-stimulating hormone secreted from stomach. Since the discovery that acylation of the serine-3 residue by ghrelin O-acyltransferase (GOAT) is essential for exerting its functions, GOAT has been regarded as an therapeutic target for attenuating appetite, and thus for the treatment of obesity and diabetes. However, contrary to the expectations, GOAT-knockout (KO) mice have not shown meaningful body weight reduction, under high-fat diet. Here, in this study, we sought to determine whether GOAT has a role in body weight regulation and glucose metabolism with a focus on dietary sucrose, because macronutrient composition of diet is important for appetite regulation. We found that peripherally administered acylated-ghrelin, but not unacylated one, stimulated sucrose consumption in a two-bottle-drinking test. The role of acylated-ghrelin in sucrose preference was further supported by the finding that GOAT KO mice consumed less sucrose solution compared with WT littermates. Then, we investigated the effect of dietary composition of sucrose on food intake and body weight in GOAT KO and WT mice. As a result, when fed on high-fat diet, food intake and body weight were similar between GOAT KO and WT mice. However, when fed on high-fat, high-sucrose diet, GOAT KO mice showed significantly reduced food intake and marked resistance to obesity, leading to amelioration of glucose metabolism. These results suggest that blockade of acylated-ghrelin production offers therapeutic potential for obesity and metabolic disorders caused by overeating of palatable food.

  6. Expression of obestatin and ghrelin in papillary thyroid carcinoma.

    PubMed

    Karaoglu, Aziz; Aydin, Suleyman; Dagli, Adile F; Cummings, David E; Ozercan, Ibrahim H; Canatan, Halit; Ozkan, Yusuf

    2009-03-01

    Ghrelin and obestatin are two peptide hormones with opposing roles in the control of appetite: orexigenic and anorexigenic, respectively. Loss of appetite is a common, serious complication of many forms of malignancy. The goals of this study were to investigate: (i) whether there are differences in ghrelin and obestatin peptide expression in thyroid tissues from a series of papillary carcinoma cases and normal controls, and (ii) whether there are correlations between tissue ghrelin and obestatin levels in series of papillary carcinoma cases and normal controls. Immunohistochemical analysis showed that in sections of benign human thyroid tissue, anti-ghrelin antibody reacted with intense staining in colloid-filled follicles. In benign thyroid tissues, colloids displayed plentiful dispersion in comparison with papillary microcarcinomas, whereas colloids in malignant thyroid tissues were uncommon. We found markedly lower tissue ghrelin levels in thyroid tissue of patients with papillary carcinomas, compared with normal thyroid tissues (P = 0.001). Immunohistochemical analysis also showed that obestatin in papillary carcinoma stained positively to various degrees. Obestatin tissue levels in papillary carcinomas tended to be slightly higher than those in normal thyroid tissue, but this was not statistically significant (P = 0.29). We also report that thyroid tissue of patients with Hashimoto's thyroiditis produced ghrelin and obestatin at similar levels as in normal thyroid tissue, even though colloid in Hashimoto's disease is scarce. We conclude that depressed expression of ghrelin, but not obestatin, is specific to papillary carcinoma, and this difference might constitute a diagnostic tool to differentiate papillary carcinoma from normal thyroid tissue. We currently do not know how these peptides are regulated and what factors are involved in papillary carcinoma, which inhibit the expression of ghrelin but not obestatin. This issue warrants further studies.

  7. Ghrelin receptor in Japanese fire belly newt, Cynops pyrrhogaster.

    PubMed

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2015-11-01

    We identified cDNA encoding a functional ghrelin receptor (growth hormone secretagogue-receptor 1a (GHS-R1a)) in a urodele amphibian, the Japanese fire belly newt (Cynops pyrrhogaster). Two functional receptor proteins, composed of 378- and 362-amino acids, were deduced from the identified cDNA because two candidate initiation methionine sites were found. The long-chain receptor protein shared 80%, 69%, and 59% identities with the bullfrog GHS-R1a, human GHS-R1a and tilapia GHS-R1a-like receptor, respectively. Phylogenetic analysis suggested that the newt receptor is grouped to the clade of the tetrapod homologs, and very closed to anuran amphibians. In functional analyses, homologous newt ghrelin, heterologous bullfrog and rat ghrelin, and a GHS-R1a agonist, GHRP-6 increased intracellular Ca(2+) concentration in human embryonic kidney (HEK) 293 cells stably expressed newt GHS-R1a. The responsiveness was much greater in the short-chain receptor than in the long-chain receptor. Both receptors preferred to bind Ser(3)-ghrelin including newt and rat ghrelin than Thr(3)-ghrelin with bullfrog ghrelin. GHRP-6 has a similar affinity to bullfrog ghrelin. GHS-R1a mRNA was expressed in the brain, pituitary, intestine, pancreas, testis and fat body with high level, and eyes, heart, stomach, liver, gall bladder, kidney and dorsal skin with low level. In a fasting experiment, gene expression of GHS-R1a in the brain and pituitary increased 4days after fasting, and the increased level decreased to the initial level 2weeks after fasting. These changes are consistent with the change in ghrelin mRNA. In contrast, expression of ghrelin and GHS-R1a mRNA in the stomach decreased on day 4 after fasting, and increased 2weeks after fasting. These results indicate that ghrelin and its receptor system are present and altered by energy states in this newt.

  8. The Hormone Ghrelin Prevents Traumatic Brain Injury Induced Intestinal Dysfunction

    PubMed Central

    Bansal, Vishal; Ryu, Seok Yong; Blow, Chelsea; Costantini, Todd; Loomis, William; Eliceiri, Brian; Baird, Andrew; Wolf, Paul

    2010-01-01

    Abstract Intestinal barrier breakdown following traumatic brain injury (TBI) is characterized by increased intestinal permeability, leading to bacterial translocation, and inflammation. The hormone ghrelin may prevent intestinal injury and have anti-inflammatory properties. We hypothesized that exogenous ghrelin prevents intestinal injury following TBI. A weight-drop model created severe TBI in three groups of anesthetized Balb/c mice. Group TBI: animals underwent TBI only; Group TBI/ghrelin: animals were given 10 μg of ghrelin intraperitoneally prior and 1 h following TBI; Group sham: no TBI or ghrelin injection. Intestinal permeability was measured 6 h following TBI by detecting serum levels of FITC-Dextran after injection into the intact ileum. The terminal ileum was harvested for histology, expression of the tight junction protein MLCK and inflammatory cytokine TNF-α. Permeability increased in the TBI group compared to the sham group (109.7 ± 21.8 μg/mL vs. 32.2 ± 10.1 μg/mL; p < 0.002). Ghrelin prevented TBI-induced permeability (28.3 ± 4.2 μg/mL vs. 109.7 ± 21.8 μg/mL; p < 0.001). The intestines of the TBI group showed blunting and necrosis of villi compared to the sham group, while ghrelin injection preserved intestinal architecture. Intestinal MLCK increased 73% compared to the sham group (p < 0.03). Ghrelin prevented TBI-induced MLCK expression to sham levels. Intestinal TNF-α increased following TBI compared to the sham group (46.2 ± 7.1 pg/mL vs. 24.4 ± 2.2 pg/mL p < 0.001). Ghrelin reduced TNF-α to sham levels (29.2 ± 5.0 pg/mL; p = NS). We therefore conclude that ghrelin prevents TBI-induced injury, as determined by intestinal permeability, histology, and intestinal levels of TNF-α. The mechanism for ghrelin mediating intestinal protection is likely multifactorial, and further studies are needed to delineate these possibilities. PMID:20858122

  9. Ghrelin-Induced Enhancement of Vasopressin and Oxytocin Secretion in Rat Neurohypophyseal Cell Cultures.

    PubMed

    Gálfi, M; Radács, M; Molnár, Zs; Budai, I; Tóth, G; Pósa, A; Kupai, K; Szalai, Z; Szabó, R; Molnár, H A; Gardi, J; László, Ferenc A; Varga, Cs

    2016-12-01

    The effects of ghrelin on vasopressin and oxytocin secretion were studied in 13-14-day cell cultures of isolated rat neurohypophyseal tissue. The vasopressin and oxytocin contents of the supernatant were determined by radioimmunoassay after a 1- or 2-h incubation. Significantly increased levels of vasopressin and oxytocin production were detected in the cell culture media following ghrelin administration, depending on the ghrelin doses. The oxytocin level proved to be more elevated than that of vasopressin. The increase of vasopressin and oxytocin secretion could be totally blocked by previous administration of the ghrelin receptor antagonist ([D-Lys(3)]-growth hormone-releasing peptide-6). Application of the ghrelin receptor antagonist after ghrelin administration proved ineffective. The results indicate that vasopressin and oxytocin release is influenced directly by the ghrelin system, and the effects of ghrelin on vasopressin and oxytocin secretion from the neurohypophyseal tissue in rats can occur at the level of the posterior pituitary. Our observations lend support to the view that neurohypophysis contains ghrelin receptors.

  10. Diet-induced obesity suppresses ghrelin in rat gastrointestinal tract and serum.

    PubMed

    Sahin, Ibrahim; Aydin, Suleyman; Ozkan, Yusuf; Dagli, Adile Ferda; Akin, Kadir Okhan; Guzel, Saadet Pilten; Catak, Zekiye; Ozercan, Mehmet Resat

    2011-09-01

    The aims of the present study were to examine ghrelin expression in serum and gastrointestinal tract (GIT) tissues, and to measure tissue ghrelin levels and obesity-related alterations in some serum biochemical variables in rats with diet-induced obesity (DIO). The study included 12 male rats, 60 days old. The rats were randomly allocated to two groups (n = 6). Rats in the DIO group were fed a cafeteria-style diet to induce obesity, while those in the control group were fed on standard rat pellets. After a 12 week diet program including an adaptation period all rats were decapitated, tissues were individually fixed, ghrelin expression was examined by immunohistochemistry , and tissue and serum ghrelin levels were measured by radioimmunoassay. Serum biochemical variables were measured using an autoanalyzer. When the baseline and week 12 body mass index and GIT ghrelin expression were compared between DIO and control rats, BMI had increased and ghrelin expression decreased due to obesity. The RIA results were consistent with these findings. Serum glucose, LDL cholesterol, and total cholesterol levels were elevated and HDL cholesterol significantly decreased in the DIO group. A comparison of GIT tissues between the control and obese groups demonstrated that ghrelin was decreased in all tissues of the latter. This decrease was brought about a decline in the circulating ghrelin pool. This suggests that rather than being associated with a change in a single tissue, obesity is a pathological condition in which ghrelin expression is changed in all tissues.

  11. Mouse ghrelin-O-acyltransferase (GOAT) plays a critical role in bile acid reabsorption.

    PubMed

    Kang, Kihwa; Schmahl, Jennifer; Lee, Jong-Min; Garcia, Karen; Patil, Ketan; Chen, Amelia; Keene, Michelle; Murphy, Andrew; Sleeman, Mark W

    2012-01-01

    Ghrelin is a unique peptide gut hormone that requires post-translational modification to stimulate both feeding and growth hormone release. Ghrelin O-acyltransferase (GOAT) was identified as a specific acyl-transferase for ghrelin, and recent genetic deletion studies of the Goat gene (Goat(-/-)) uncovered the role of ghrelin in the regulation of glucose homeostasis. To further understand the physiological functions of the GOAT/ghrelin system, we have conducted a metabolomic and microarray profile of Goat-null mice, as well as determined Goat expression in different tissues using the lacZ reporter gene. Serum metabolite profile analysis revealed that Goat(-/-) mice exhibited increased secondary bile acids >2.5-fold. This was attributed to increased mRNA and protein expression of the ileal sodium-dependent bile acid transporter (ISBT) in the intestinal and biliary tract. Increased expression of additional solute carrier proteins, including Slc5a12 (>10-fold) were also detected in the small intestine and bile duct. Goat staining was consistently observed in the pituitary glands, stomach, and intestines, and to a lesser extent in the gallbladder and pancreatic duct. This is the first report that the GOAT/ghrelin system regulates bile acid metabolism, and these findings suggest a novel function of GOAT in the regulation of intestinal bile acid reabsorption..

  12. Reduced autophagy in livers of fasted, fat-depleted, ghrelin-deficient mice: Reversal by growth hormone

    PubMed Central

    Zhang, Yuanyuan; Fang, Fei; Goldstein, Joseph L.; Brown, Michael S.; Zhao, Tong-Jin

    2015-01-01

    Plasma growth hormone (GH) and hepatic autophagy each have been reported to protect against hypoglycemia in the fasted state, but previous data have not linked the two. Here we demonstrate a connection using a mouse model of fasting in a fat-depleted state. Mice were subjected to 1 wk of 60% calorie restriction, causing them to lose nearly all body fat. They were then fasted for 23 h. During fasting, WT mice developed massive increases in plasma GH and a concomitant increase in hepatic autophagy, allowing them to maintain viable levels of blood glucose. In contrast, lethal hypoglycemia occurred in mice deficient in the GH secretagogue ghrelin as a result of knockout of the gene encoding ghrelin O-acyltransferase (GOAT), which catalyzes a required acylation of the peptide. Fasting fat-depleted Goat−/− mice showed a blunted increase in GH and a marked decrease in hepatic autophagy. Restoration of GH by infusion during the week of calorie restriction maintained autophagy in the Goat−/− mice and prevented lethal hypoglycemia. Acute injections of GH after 7 d of calorie restriction also restored hepatic autophagy, but failed to increase blood glucose, perhaps owing to ATP deficiency in the liver. These data indicate that GH stimulation of autophagy is necessary over the long term, but not sufficient over the short term to maintain blood glucose levels in fasted, fat-depleted mice. PMID:25583513

  13. Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3T3-L1 adipocytes.

    PubMed

    Miegueu, Pierre; St Pierre, David; Broglio, Fabio; Cianflone, Katherine

    2011-02-01

    Acyl-ghrelin (AG), desacyl-ghrelin (DAG) and obestatin are all derived from the same gene transcript; however their plasma levels do not necessarily change in parallel. The influence of these peptides towards the development of obesity and their direct effects on adipocyte physiology has not been thoroughly investigated. This study was designed to evaluate the direct effects of peptides of the ghrelin family on preadipocyte proliferation, differentiation and adipocyte lipid and glucose metabolism in 3T3-L1 cells. 3T3 cells were treated with physiological peptide concentrations for 1 h to 9 days, and the relevant assays measured. In preadipocytes, AG, GHRP-6 and DAG stimulated proliferation, measured as (3)H-thymidine incorporation (up to 200%, P < 0.05), while all peptides stimulated differentiation (up to 300%, P < 0.01) as compared to standard differentiation conditions. In adipocytes, FA uptake was increased in a concentration-dependent manner especially with obestatin (three- to fourfold, P < 0.001) and DAG (three- to fivefold, P < 0.001). By contrast, glucose transport was unchanged. DAG and obestatin significantly decreased lipolysis measured as non-esterified fatty acid and glycerol release by 50%, P < 0.05-0.01 and 51%, P < 0.01, respectively. Interestingly, DAG stimulation of FA uptake was blocked with GHSR1 antagonist (D-lys(3))-GHRP-6 (P < 0.05), phospholipase C inhibitor U73122 and phosphatidylinositol-3-kinase inhibitor wortmannin (P < 0.001). Finally, in omental but not subcutaneous human adipose tissue, GHSR1 correlated with BMI (r = 0.549, P < 0.05) and insulin (r = 0.681, P < 0.01). Taken together, these results suggest that ghrelin-related peptides may directly affect adipose tissue metabolism.

  14. Ghrelin Modulates Physiologic and Pathologic Retinal Angiogenesis through GHSR-1a

    PubMed Central

    Zaniolo, Karine; Sapieha, Przemyslaw; Shao, Zhuo; Stahl, Andreas; Zhu, Tang; Tremblay, Sophie; Picard, Emilie; Madaan, Ankush; Blais, Martine; Lachapelle, Pierre; Mancini, Joseph; Hardy, Pierre; Smith, Lois E. H.; Ong, Huy

    2011-01-01

    Purpose. Vascular degeneration and the ensuing abnormal vascular proliferation are central to proliferative retinopathies. Given the metabolic discordance associated with these diseases, the authors explored the role of ghrelin and its growth hormone secretagogue receptor 1a (GHSR-1a) in proliferative retinopathy. Methods. In a rat model of oxygen-induced retinopathy (OIR), the contribution of ghrelin and GHSR-1a was investigated using the stable ghrelin analogs [Dap3]-ghrelin and GHRP6 and the GSHR-1a antagonists JMV-2959 and [D-Lys3]-GHRP-6. Plasma and retinal levels of ghrelin were analyzed by ELISA, whereas retinal expression and localization of GHSR-1a were examined by immunohistochemistry and Western blot analysis. The angiogenic and vasoprotective properties of ghrelin and its receptor were further confirmed in aortic explants and in models of vaso-obliteration. Results. Ghrelin is produced locally in the retina, whereas GHSR-1a is abundantly expressed in retinal endothelial cells. Ghrelin levels decrease during the vaso-obliterative phase and rise during the proliferative phase of OIR. Intravitreal delivery of [Dap3]-ghrelin during OIR significantly reduces retinal vessel loss when administered during the hyperoxic phase. Conversely, during the neovascular phase, ghrelin promotes pathologic angiogenesis through the activation of GHSR-1a. These angiogenic effects were confirmed ex vivo in aortic explants. Conclusions. New roles were disclosed for the ghrelin-GHSR-1a pathway in the preservation of retinal vasculature during the vaso-obliterative phase of OIR and during the angiogenic phase of OIR. These findings suggest that the ghrelin-GHSR-1a pathway can exert opposing effects on retinal vasculature, depending on the phase of retinopathy, and thus holds therapeutic potential for proliferative retinopathies. PMID:21642627

  15. Gastrin mediated down regulation of ghrelin and its pathophysiological role in atrophic gastritis.

    PubMed

    Rau, T T; Sonst, A; Rogler, A; Burnat, G; Neumann, H; Oeckl, K; Neuhuber, W; Dimmler, A; Faller, G; Brzozowski, T; Hartmann, A; Konturek, P C

    2013-12-01

    The gastric hormone ghrelin is known as an important factor for energy homeostasis, appetite regulation and control of body weight. So far, ghrelin has mainly been examined as a serological marker for gastrointestinal diseases, and only a few publications have highlighted its role in local effects like mucus secretion. Ghrelin can be regarded as a gastroprotective factor, but little is known about the distribution and activity of ghrelin cells in pathologically modified tissues. We aimed to examine the morphological changes in ghrelin expression under several inflammatory, metaplastic and carcinogenic conditions of the upper gastrointestinal tract. In particular, autoimmune gastritis showed interesting remodeling effects in terms of ghrelin expression within neuroendocrine cell hyperplasia by immunohistochemistry. Using confocal laser microscopy, the gastrin/cholecystokinin receptor (CCKB) could be detected on normal ghrelin cells as well as in autoimmune gastritis. Functionally, we found evidence for a physiological interaction between gastrin and ghrelin in a primary rodent cell culture model. Additionally, we gathered serological data from patients with different basic gastrin levels due to long-term autoimmune gastritis or short-term proton pump inhibitor treatment with slightly reactive plasma gastrin elevations. Total ghrelin plasma levels showed a significantly inverse correlation with gastrin under long-term conditions. Autoimmune gastritis as a relevant condition within gastric carcinogenesis therefore has two effects on ghrelin-positive cells due to hypergastrinemia. On the one hand, gastrin stimulates the proliferation of ghrelinpositive cells as integral part of neuroendocrine cell hyperplasia, while on the other hand, plasma ghrelin is reduced by gastrin and lost in pseudopyloric and intestinal metaplastic areas. Ghrelin is necessary for the maintenance of the mucosal barrier and might play a role in gastric carcinogenesis, if altered under these pre

  16. Psychiatric comorbidity and plasma levels of 2-acyl-glycerols in outpatient treatment alcohol users. Analysis of gender differences.

    PubMed

    García Marchena, Nuria; Araos, Pedro; Pavón, Francisco Javier; Ponce, Guillermo; Pedraz, María; Serrano, Antonia; Arias, Francisco; Romero-Sanchiz, Pablo; Suárez, Juan; Pastor, Antoni; De la Torre, Rafael; Torrens, Marta; Rubio, Gabriel; Rodríguez de Fonseca, Fernando

    2016-09-29

    Alcohol addiction is associated with high psychiatric comorbidity. Objective stratification of patients is necessary to optimize care and improve prognosis. The present study is designed to gain insights into this challenge by addressing the following objectives: a) to estimate the prevalence of psychiatric comorbidities in a sample of outpatients seeking treatment for alcohol use disorder, b) to describe the existence of gender differences and c) to validate 2-acyl-glycerols as biomarkers of alcohol use disorder and/or psychiatric comorbidity. One hundred and sixty-two patients were recruited and evaluated with the semi-structured interview PRISM. The presence of psychopathology was associated with a greater number of criteria for alcohol abuse and dependence according to DSM-IV-TR. We found gender differences in psychiatric comorbidity, e.g., mood disorder, as well as in comorbid substance use disorders. The prevalence of lifetime psychiatric comorbidity was 68.5%, with mood disorders the most frequent (37%), followed by attention deficit disorder (24.7%) and anxiety disorders (17.9%). Substance-induced disorders were more frequent in mood and psychotic disorders, whereas the primary disorders were more prevalent in patients with comorbid anxiety disorders. We found that 2-acyl-glycerols were significantly decreased in comorbid anxiety disorders in alcohol dependent patients in the last year, which makes them a potential biomarker for this psychopathological condition.

  17. Mice lacking ghrelin receptors resist the development of diet-induced obesity

    PubMed Central

    Zigman, Jeffrey M.; Nakano, Yoshihide; Coppari, Roberto; Balthasar, Nina; Marcus, Jacob N.; Lee, Charlotte E.; Jones, Juli E.; Deysher, Amy E.; Waxman, Amanda R.; White, Ryan D.; Williams, Todd D.; Lachey, Jennifer L.; Seeley, Randy J.; Lowell, Bradford B.; Elmquist, Joel K.

    2005-01-01

    Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity. PMID:16322794

  18. Possible involvement of ghrelin on pain threshold in obesity.

    PubMed

    Guneli, Ensari; Gumustekin, Mukaddes; Ates, Mehmet

    2010-03-01

    Pain threshold (or perception) can increase or decrease according to some factors like gender, depression or individual differences. Also, previous studies showed that pain threshold can change in obesity but, these studies on the effects of obesity on pain threshold have given controversial results. In the obese people who were exposed to pain stimulation to determined pain threshold, an increased pain threshold was observed. Contrarily, in the studies using electrophysiological test had lower pain threshold, which indicates a reverse correlation between degree of overweight and the threshold of the nociceptive reflex. These studies indicate possible interrelationships between the endogenous opioids, nociception and obesity or eating behavior. Nevertheless, its mechanism is still unclear. The endocrine changes that play an important role in obesity can lead an increase or decrease in pain threshold. There are a few researches about these hormonal factors which are related to pain pathways, that they are nociceptive (like leptin) or antinociceptive effect (like ghrelin, orexin A and B). Ghrelin is one of the hormones which is related to obesity. There are studies which prove the relationship between this hormone and the systems that play a role in pain modulation in the brain. However, there is no previous knowledge about the effects of ghrelin on pain threshold in obesity. But, many strong evidence are present to hypothesise that ghrelin may have effects on pain threshold. Obesity and fasting are the two main situations in which ghrelin secretion is mostly modified. Circulating ghrelin levels negatively correlate with BMI, meaning increased ghrelin secretion during fasting, malnutrition, cachexia, and in anorexia nervosa and reduced ghrelin secretion in obesity. Therefore, we have the opinion that ghrelin play an important role in obesity-pain relationship and/or regulate other systems that are related to pain pathway. Based on the above analyses, we propose a

  19. A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear

    PubMed Central

    Meyer, Retsina M.; Burgos-Robles, Anthony; Liu, Elizabeth; Correia, Susana S.; Goosens, Ki A.

    2014-01-01

    Hormones in the hypothalamus-pituitary-adrenal (HPA) axis mediate many of the bodily responses to stressors, yet there is not a clear relationship between the levels of these hormones and stress-associated mental illnesses such as post-traumatic stress disorder (PTSD). Therefore, other hormones are likely to be involved in this effect of stress. Here we used a rodent model of PTSD in which rats repeatedly exposed to a stressor display heightened fear learning following auditory Pavlovian fear conditioning. Our results show that stress-related increases in circulating ghrelin, a peptide hormone, are necessary and sufficient for stress-associated vulnerability to exacerbated fear learning and these actions of ghrelin occur in the amygdala. Importantly, these actions are also independent of the classic HPA stress axis. Repeated systemic administration of a ghrelin receptor agonist enhanced fear memory but did not increase either corticotropin releasing factor (CRF) or corticosterone. Repeated intra-amygdala infusion of a ghrelin receptor agonist produced a similar enhancement of fear memory. Ghrelin receptor antagonism during repeated stress abolished stress-related enhancement of fear memory without blunting stress-induced corticosterone release. We also examined links between ghrelin and growth hormone (GH), a major downstream effector of the ghrelin receptor. GH protein was upregulated in the amygdala following chronic stress, and its release from amygdala neurons was increased by ghrelin receptor stimulation. Virus-mediated overexpression of GH in the amygdala was also sufficient to increase fear. Finally, virus-mediated overexpression of a GH receptor antagonist was sufficient to block the fear enhancing effects of repeated ghrelin receptor stimulation. Thus, ghrelin requires GH in the amygdala to exert fear-enhancing effects. These results suggest that ghrelin mediates a novel branch of the stress response and highlight a previously unrecognized role for ghrelin

  20. Upregulation and nuclear translocation of testicular ghrelin protects differentiating spermatogonia from ionizing radiation injury

    PubMed Central

    Li, W; Zeng, Y; Zhao, J; Zhu, C-J; Hou, W-G; Zhang, S

    2014-01-01

    Proper control of apoptotic signaling is important for maintenance of testicular homeostasis after ionizing radiation (IR). Herein, we challenged the hypothesis that ghrelin, a pleiotropic modulator, is potentially involved in IR-induced germ cell injury. Lower body exposure to 2 Gy of IR induced a notable increase of ghrelin expression in the nuclear of differentiating spermatogonia at defined stages, with an impairment in the Leydig cells (LCs)-expressing ghrelin. Unexpectedly, inhibition of the ghrelin pathway by intraperitoneal injection of a specific GHS-R1α antagonist enhanced spermatogonia elimination by apoptosis during the early recovery following IR, and thereafter resulted in impaired male fertility, suggesting that the anti-apoptotic effects of evoked ghrelin, although transient along testicular IR injury, have a profound influence on the post-injury recovery. In addition, inhibition of ghrelin signaling resulted in a significant increase in the intratesticular testosterone (T) level at the end of 21 days after IR, which should stimulate the spermatogenic recovery from surviving spermatogonia to a certain extent during the late stage. We further demonstrated that the upregulation and nuclear trafficking of ghrelin, elaborately regulated by IR-elicited antioxidant system in spermatogonia, may act through a p53-dependent mechanism. The elicitation of ghrelin expression by IR stress, the regulation of ghrelin expression by IR-induced oxidative stress and the interaction between p53 and ghrelin signaling during IR injury were confirmed in cultured spermatogonia. Hence, our results represent the first evidence in support of a radioprotective role of ghrelin in the differentiating spermatogonia. The acutely, delicate regulation of local-produced ghrelin appears to be a fine-tune mechanism modulating the balance between testicular homeostasis and early IR injury. PMID:24853426

  1. Obestatin partially suppresses ghrelin stimulation of appetite in "high-responders" grass carp, Ctenopharyngodon idellus.

    PubMed

    Yuan, Xiaochen; Cai, Wenjing; Liang, Xu-Fang; Su, Hang; Yuan, Yongchao; Li, Aixuan; Tao, Ya-Xiong

    2015-06-01

    Ghrelin and obestatin are two gastrointestinal peptides obtained by post-translational processing of a common precursor, preproghrelin. The effect of obestatin on food intake is still controversial. The aim of the present study was to investigate the effects of ghrelin and obestatin on food intake in grass carp, Ctenopharyngodon idellus. Fish received intraperitoneal (IP) injection of saline, ghrelin (100 ng g(-1)BW), obestatin-like (25 ng g(-1)BW) and ghrelin in combination with obestatin-like. Ghrelin stimulation of food intake varied considerably among individual fish with 70.8% eliciting a robust response. In these high-responders, food intake was significantly increased by IP ghrelin within 2 h. Co-administration of ghrelin and obestatin-like resulted in a decrease in food intake, indicating that obestatin was able to antagonize the effect of ghrelin. However, IP obestatin-like alone could not regulate food intake in grass carp. RT-PCR analysis demonstrated that IP ghrelin peptide led to a significant increase in mRNA abundance of NPY, Y8a and Y8b genes compared to saline injected fish, while in combination with obestatin-like peptide decreased ghrelin-induced gene expressions of these three genes. IP sole obestatin-like peptide did not modify the expression levels of NPY, Y8a, Y8b, CART and POMC compared to the control group. Therefore, IP administration of obestatin-like peptide, partially blocking the ghrelin-induced appetite, investigated the possible involvement of obestatin as a mediator of the ghrelin stimulatory action on food intake, at least in "high-responders" grass carp.

  2. Upregulation and nuclear translocation of testicular ghrelin protects differentiating spermatogonia from ionizing radiation injury.

    PubMed

    Li, W; Zeng, Y; Zhao, J; Zhu, C-J; Hou, W-G; Zhang, S

    2014-05-22

    Proper control of apoptotic signaling is important for maintenance of testicular homeostasis after ionizing radiation (IR). Herein, we challenged the hypothesis that ghrelin, a pleiotropic modulator, is potentially involved in IR-induced germ cell injury. Lower body exposure to 2 Gy of IR induced a notable increase of ghrelin expression in the nuclear of differentiating spermatogonia at defined stages, with an impairment in the Leydig cells (LCs)-expressing ghrelin. Unexpectedly, inhibition of the ghrelin pathway by intraperitoneal injection of a specific GHS-R1α antagonist enhanced spermatogonia elimination by apoptosis during the early recovery following IR, and thereafter resulted in impaired male fertility, suggesting that the anti-apoptotic effects of evoked ghrelin, although transient along testicular IR injury, have a profound influence on the post-injury recovery. In addition, inhibition of ghrelin signaling resulted in a significant increase in the intratesticular testosterone (T) level at the end of 21 days after IR, which should stimulate the spermatogenic recovery from surviving spermatogonia to a certain extent during the late stage. We further demonstrated that the upregulation and nuclear trafficking of ghrelin, elaborately regulated by IR-elicited antioxidant system in spermatogonia, may act through a p53-dependent mechanism. The elicitation of ghrelin expression by IR stress, the regulation of ghrelin expression by IR-induced oxidative stress and the interaction between p53 and ghrelin signaling during IR injury were confirmed in cultured spermatogonia. Hence, our results represent the first evidence in support of a radioprotective role of ghrelin in the differentiating spermatogonia. The acutely, delicate regulation of local-produced ghrelin appears to be a fine-tune mechanism modulating the balance between testicular homeostasis and early IR injury.

  3. Physiological roles revealed by ghrelin and ghrelin receptor deficient mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is a hormone made in the stomach and known primarily for its growth hormone releasing and orexigenic properties. Nevertheless, ghrelin through its receptor, the GHS-R1a, has been shown to exert many roles including regulation of glucose homeostasis, memory & learning, food addiction and neur...

  4. Fasting plasma total ghrelin concentrations in monozygotic twins discordant for obesity.

    PubMed

    Leskelä, Piia; Ukkola, Olavi; Vartiainen, Johanna; Rönnemaa, Tapani; Kaprio, Jaakko; Bouchard, Claude; Kesäniemi, Y Antero

    2009-02-01

    Ghrelin is a hormone that is involved in the regulation of food intake. Neuronal, endocrine, and genetic factors have been shown to regulate plasma ghrelin levels; but the determinants of fasting ghrelin concentrations are not yet fully understood. The main aim was to explore the roles of adiposity and genetic differences in determining fasting plasma total ghrelin levels. We measured total ghrelin levels in a population of 23 monozygotic twin pairs discordant for obesity. In addition, 2 variants of ghrelin gene, namely, Arg51Gln and Leu72Met, were genotyped in 3 populations of monozygotic twin pairs: 23 obesity-discordant, 43 lean-concordant, and 46 obesity-concordant twin pairs. In discordant twins, lean co-twins had higher fasting plasma total ghrelin levels (950 pg/mL, SD = 328 pg/mL) than obese twins (720 pg/mL, SD = 143 pg/mL; P = .003). Arg51Gln-polymorphism of the ghrelin gene was equally distributed between the twin groups. However, there were significant differences in genotype frequencies at the Leu72Met polymorphism between the discordant and obese-concordant groups (P = .003) and between the discordant and lean-concordant groups (P = .011), but not between the 2 concordant groups. In the discordant group, there were fewer Met carriers (4%) than among the obese (17%) or the lean-concordant groups (15%). Plasma total ghrelin levels are affected by acquired obesity independent of genetic background. The Leu72 allele is particularly common among monozygotic twins discordant for obesity, suggesting that this ghrelin allele is more permissive in the regulation of energy balance. The ghrelin gene may thus play a role in the regulation of variability of body weight, such that Leu72 allele carriers are more prone to weight variability in response to environmental factors.

  5. Intracoronary ghrelin infusion decreases coronary blood flow in anesthetized pigs.

    PubMed

    Grossini, Elena; Molinari, Claudio; Mary, David A S G; Ghigo, Ezio; Bona, Gianni; Vacca, Giovanni

    2007-02-01

    The peptide ghrelin has been linked to the atherosclerotic process and coronary artery disease. We planned to study, for the first time, the primary effects of ghrelin on the intact coronary circulation and determine the mechanisms involved. In 24 sodium pentobarbitone-anesthetized pigs, changes in anterior descending coronary blood flow caused by intracoronary infusion of ghrelin at constant heart rate and arterial pressure were assessed using electromagnetic flowmeters. In 20 pigs, intracoronary infusion of ghrelin decreased coronary blood flow without affecting left ventricular maximum rate of change of left ventricular systolic pressure (dP/dt(max)), filling pressures of the heart or plasma levels of GH. In four pigs, this decrease was graded by step increments of infused dose of the hormone. The mechanisms of the above response were studied in the 20 pigs by repeating the experiment after coronary flow had returned to the control values observed before infusion. The ghrelin-induced coronary vasoconstriction was not affected by iv atropine (five pigs) or phentolamine (five pigs). This response was abolished by iv butoxamine (five pigs) and intracoronary N(omega)-nitro-l-arginine methyl ester (five pigs), even after reversing the increase in arterial pressure and coronary vascular resistance caused by the two blocking agents with iv infusion of papaverine. The present study showed that intracoronary infusion of ghrelin primarily caused coronary vasoconstriction. The mechanisms of this response were shown to involve the inhibition of a vasodilatory beta(2)-adrenergic receptor-mediated effect related to the release of nitric oxide.

  6. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cachexia is a wasting syndrome associated with cancer, AIDS, multiple sclerosis, and several other disease states. It is characterized by weight loss, fatigue, loss of appetite, and skeletal muscle atrophy and is associated with poor patient prognosis, making it an important treatment target. Ghreli...

  7. Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation.

    PubMed

    Naznin, Farhana; Toshinai, Koji; Waise, T M Zaved; NamKoong, Cherl; Md Moin, Abu Saleh; Sakoda, Hideyuki; Nakazato, Masamitsu

    2015-07-01

    Ghrelin, a stomach-derived orexigenic peptide, transmits starvation signals to the hypothalamus via the vagus afferent nerve. Peripheral administration of ghrelin does not induce food intake in high fat diet (HFD)-induced obese mice. We investigated whether this ghrelin resistance was caused by dysfunction of the vagus afferent pathway. Administration (s.c.) of ghrelin did not induce food intake, suppression of oxygen consumption, electrical activity of the vagal afferent nerve, phosphorylation of ERK2 and AMP-activated protein kinase alpha in the nodose ganglion, or Fos expression in hypothalamic arcuate nucleus of mice fed a HFD for 12 weeks. Administration of anti-ghrelin IgG did not induce suppression of food intake in HFD-fed mice. Expression levels of ghrelin receptor mRNA in the nodose ganglion and hypothalamus of HFD-fed mice were reduced. Inflammatory responses, including upregulation of macrophage/microglia markers and inflammatory cytokines, occurred in the nodose ganglion and hypothalamus of HFD-fed mice. A HFD blunted ghrelin signaling in the nodose ganglion via a mechanism involving in situ activation of inflammation. These results indicate that ghrelin resistance in the obese state may be caused by dysregulation of ghrelin signaling via the vagal afferent.

  8. DESACYL GHRELIN INHIBITS THE OREXIGENIC EFFECT OF PERIPHERALLY INJECTED GHRELIN IN RATS

    PubMed Central

    Inhoff, Tobias; Mönnikes, Hubert; Noetzel, Steffen; Stengel, Andreas; Goebel, Miriam; Dinh, Q. Thai; Riedl, Andrea; Bannert, Norbert; Wisser, Anna-Sophia; Wiedenmann, Bertram; Klapp, Burghard F.; Taché, Yvette

    2008-01-01

    Studies showed that the metabolic unlike the neuroendocrine effects of ghrelin could be abrogated by co-administered unacylated ghrelin. The aim was to investigate the interaction between ghrelin and desacyl ghrelin administered intraperitoneally on food intake and neuronal activity (c-Fos) in the arcuate nucleus in non-fasted rats. Ghrelin (13 μg/kg) significantly increased food intake within the first 30 min post injection. Desacyl ghrelin at 64 and 127 μg/kg injected simultaneously with ghrelin abolished the stimulatory effect of ghrelin on food intake. Desacyl ghrelin alone at both doses did not alter food intake. Both doses of desacyl ghrelin injected separately in the light phase had no effects on food intake when rats were fasted for 12 h. Ghrelin and desacyl ghrelin (64 μg/kg) injected alone increased the number of Fos positive neurons in the arcuate nucleus compared to vehicle. The effect on neuronal activity induced by ghrelin was significantly reduced when injected simultaneously with desacyl ghrelin. Double labeling revealed that nesfatin-1 immunoreactive neurons in the arcuate nucleus are activated by simultaneous injection of ghrelin and desacyl ghrelin. These results suggest that desacyl ghrelin suppresses ghrelin-induced food intake by curbing ghrelin-induced increased neuronal activity in the arcuate nucleus and recruiting nesfatin-1 immunopositive neurons. PMID:18938204

  9. Ghrelin Protects against Renal Damages Induced by Angiotensin-II via an Antioxidative Stress Mechanism in Mice

    PubMed Central

    Fujimura, Keiko; Wakino, Shu; Minakuchi, Hitoshi; Hasegawa, Kazuhiro; Hosoya, Koji; Komatsu, Motoaki; Kaneko, Yuka; Shinozuka, Keisuke; Washida, Naoki; Kanda, Takeshi; Tokuyama, Hirobumi; Hayashi, Koichi; Itoh, Hiroshi

    2014-01-01

    We explored the renal protective effects by a gut peptide, Ghrelin. Daily peritoneal injection with Ghrelin ameliorated renal damages in continuously angiotensin II (AngII)-infused C57BL/6 mice as assessed by urinary excretion of protein and renal tubular markers. AngII-induced increase in reactive oxygen species (ROS) levels and senescent changes were attenuated by Ghrelin. Ghrelin also inhibited AngII-induced upregulations of transforming growth factor-β (TGF-β) and plasminogen activator inhibitor-1 (PAI-1), ameliorating renal fibrotic changes. These effects were accompanied by concomitant increase in mitochondria uncoupling protein, UCP2 as well as in a key regulator of mitochondria biosynthesis, PGC1α. In renal proximal cell line, HK-2 cells, Ghrelin reduced mitochondria membrane potential and mitochondria-derived ROS. The transfection of UCP2 siRNA abolished the decrease in mitochondria-derived ROS by Ghrelin. Ghrelin ameliorated AngII-induced renal tubular cell senescent changes and AngII-induced TGF-β and PAI-1 expressions. Finally, Ghrelin receptor, growth hormone secretagogue receptor (GHSR)-null mice exhibited an increase in tubular damages, renal ROS levels, renal senescent changes and fibrosis complicated with renal dysfunction. GHSR-null mice harbored elongated mitochondria in the proximal tubules. In conclusion, Ghrelin suppressed AngII-induced renal damages through its UCP2 dependent anti-oxidative stress effect and mitochondria maintenance. Ghrelin/GHSR pathway played an important role in the maintenance of ROS levels in the kidney. PMID:24747517

  10. Reconstruction-Dependent Recovery from Anorexia and Time-Related Recovery of Regulatory Ghrelin System in Gastrectomized Rats

    PubMed Central

    Koizumi, Masaru; Dezaki, Katsuya; Hosoda, Hiroshi; Damdindorj, Boldbaatar; Sone, Hideyuki; Ming, Lu; Hosoya, Yoshinori; Sata, Naohiro; Kobayashi, Eiji; Kangawa, Kenji; Nagai, Hideo; Yasuda, Yoshikazu; Yada, Toshihiko

    2010-01-01

    Gastrectomy reduces food intake and body weight (BW) hampering recovery of physical conditions. It also reduces plasma levels of stomach-derived orexigenic ghrelin. This study explored changes in orexigenic ghrelin system in rats receiving total gastrectomy with Billroth II (B-II) or Roux-en-Y (R-Y) method. Feeding and BW were reduced by gastrectomy and subsequently recovered to a greater extent with R-Y than B-II while plasma ghrelin decreased similarly. At postoperative 12th week, ghrelin contents increased in the duodenum and pancreas, plasma ghrelin levels increased upon fasting, and ghrelin injection promoted feeding but not in earlier periods. In summary, gastrectomized rats partially recover feeding and BW, in a reconstruction-dependent manner. At 12th week, ghrelin is upregulated in extra-stomach tissues, plasma ghrelin levels are physiologically regulated, and orexigenic effect of exogenous ghrelin is restored. This time-related recovery of ghrelin system may provide a strategy for promoting feeding, BW, and thereby physical conditions in gastrectomized patients. PMID:20721337

  11. Importance of melanin-concentrating hormone receptor for the acute effects of ghrelin.

    PubMed

    Bjursell, Mikael; Egecioglu, Emil; Gerdin, Anna-Karin; Svensson, Lennart; Oscarsson, Jan; Morgan, David; Snaith, Michael; Törnell, Jan; Bohlooly-Y, Mohammad

    2005-01-28

    The hypothalamic peptide melanin-concentrating hormone (MCH) and the gastric hormone ghrelin take part in the regulation of energy homeostasis and stimulate food intake. In the present study, ghrelin was administered centrally to MCH-receptor knockout (MCHr KO) mice. MCHr KO mice and wild type (WT) controls both consumed more food when treated with ghrelin. After ghrelin administration, the serum levels of insulin increased only in WT mice whereas the serum levels of corticosterone increased both in WT and MCHr KO mice. The level of growth hormone (GH) mRNA in the pituitary gland was markedly increased in response to ghrelin injection in the WT mice but was unaffected in the MCHr KO mice. The different ghrelin responses could not be explained by a difference in growth hormone secretagogue receptor expression between MCHr KO and WT mice in the pituitary or hypothalamus. In summary, the MCHr is not required for ghrelin induced feeding. However, the MCHr does play a role for the effect of ghrelin on GH expression in the pituitary and serum insulin levels.

  12. Unexpected Reaction Pathway for butyrylcholinesterase-catalyzed inactivation of “hunger hormone” ghrelin

    PubMed Central

    Yao, Jianzhuang; Yuan, Yaxia; Zheng, Fang; Zhan, Chang-Guo

    2016-01-01

    Extensive computational modeling and simulations have been carried out, in the present study, to uncover the fundamental reaction pathway for butyrylcholinesterase (BChE)-catalyzed hydrolysis of ghrelin, demonstrating that the acylation process of BChE-catalyzed hydrolysis of ghrelin follows an unprecedented single-step reaction pathway and the single-step acylation process is rate-determining. The free energy barrier (18.8 kcal/mol) calculated for the rate-determining step is reasonably close to the experimentally-derived free energy barrier (~19.4 kcal/mol), suggesting that the obtained mechanistic insights are reasonable. The single-step reaction pathway for the acylation is remarkably different from the well-known two-step acylation reaction pathway for numerous ester hydrolysis reactions catalyzed by a serine esterase. This is the first time demonstrating that a single-step reaction pathway is possible for an ester hydrolysis reaction catalyzed by a serine esterase and, therefore, one no longer can simply assume that the acylation process must follow the well-known two-step reaction pathway. PMID:26922910

  13. Unexpected Reaction Pathway for butyrylcholinesterase-catalyzed inactivation of “hunger hormone” ghrelin

    NASA Astrophysics Data System (ADS)

    Yao, Jianzhuang; Yuan, Yaxia; Zheng, Fang; Zhan, Chang-Guo

    2016-02-01

    Extensive computational modeling and simulations have been carried out, in the present study, to uncover the fundamental reaction pathway for butyrylcholinesterase (BChE)-catalyzed hydrolysis of ghrelin, demonstrating that the acylation process of BChE-catalyzed hydrolysis of ghrelin follows an unprecedented single-step reaction pathway and the single-step acylation process is rate-determining. The free energy barrier (18.8 kcal/mol) calculated for the rate-determining step is reasonably close to the experimentally-derived free energy barrier (~19.4 kcal/mol), suggesting that the obtained mechanistic insights are reasonable. The single-step reaction pathway for the acylation is remarkably different from the well-known two-step acylation reaction pathway for numerous ester hydrolysis reactions catalyzed by a serine esterase. This is the first time demonstrating that a single-step reaction pathway is possible for an ester hydrolysis reaction catalyzed by a serine esterase and, therefore, one no longer can simply assume that the acylation process must follow the well-known two-step reaction pathway.

  14. Regulation of oxidative stress and somatostatin, cholecystokinin, apelin gene expressions by ghrelin in stomach of newborn diabetic rats.

    PubMed

    Coskun, Zeynep Mine; Sacan, Ozlem; Karatug, Ayse; Turk, Neslihan; Yanardag, Refiye; Bolkent, Sehnaz; Bolkent, Sema

    2013-09-01

    The aim of the study was to determine whether ghrelin treatment has a protective effect on gene expression and biochemical changes in the stomach of newborn streptozotocin (STZ) induced diabetic rats. In this study, four groups of Wistar rats were used: control, ghrelin control, diabetic and diabetic+ghrelin. The rats were sacrificed after four weeks of treatment for diabetes. The gene expressions of: somatostatin, cholecystokinin, apelin and the altered active caspase-3, active caspase-8, proliferating cell nuclear antigen, were investigated in the pyloric region of the stomach and antioxidant parameters were measured in all the stomach. Although ghrelin treatment to diabetic rats lowered the stomach lipid peroxidation levels, the stomach glutathione levels were increased. Exogenous ghrelin caused an increased activities of stomach catalase, superoxide dismutase, glutathione reductase and glutathione peroxidase in diabetic rats. Numbers of somatostatin, cholecystokinin and proliferating cell nuclear antigen immunoreactive cells decreased in the diabetic+ghrelin group compared to the diabetic group. Apelin mRNA expressions were remarkably less in the diabetic+ghrelin rats than in diabetic rats. The results may indicate that ghrelin treatment has a protective effect to some extent on the diabetic rats. This protection is possibly accomplished through the antioxidant activity of ghrelin observed in type 2 diabetes. Consequently exogenous ghrelin may be a candidate for therapeutic treatment of diabetes.

  15. Ghrelin inhibits LPS-induced release of IL-6 from mouse dopaminergic neurones

    PubMed Central

    2013-01-01

    Background Ghrelin is an orexigenic stomach hormone that acts centrally to increase mid-brain dopamine neurone activity, amplify dopamine signaling and protect against neurotoxin-induced dopamine cell death in the mouse substantia nigra pars compacta (SNpc). In addition, ghrelin inhibits the lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines from peripheral macrophages, T-cells and from LPS stimulated microglia. Here we sought to determine whether ghrelin attenuates pro-inflammatory cytokine release from dopaminergic neurones. Findings The dopaminergic SN4741 cell-line, which derives from the mouse substantia nigra (SN) and expresses the ghrelin-receptor (growth hormone secretagogue receptor (GHS-R)) and the ghrelin-O-acyl transferase (GOAT) enzyme, was used to determine the neuro-immunomodulatory action of ghrelin. We induced innate immune activation via LPS challenge (1 μg/ml) of SN4741 neurones that had been pre-cultured in the presence or absence of ghrelin (1, 10, 100 nM) for 4 h. After 24 h supernatants were collected for detection of IL-1 beta (IL-1β ), TNF alpha (TNF-α) and IL-6 cytokines via enzyme linked immunosorbent assay (ELISA) analysis. Nuclear translocation of the transcription factor nuclear factor kappa B (NF-κB) was analyzed by Western blotting, and to determine viability of treatments a cell viability assay and caspase-3 immunohistochemistry were performed. We provide evidence that while IL-1β and TNF-α were not detectable under any conditions, SN4741 neurones constitutively released IL-6 under basal conditions and treatment with LPS significantly increased IL-6 secretion. Pre-treatment of neurones with ghrelin attenuated LPS-mediated IL-6 release at 24 h, an affect that was inhibited by the GHS-R antagonist [D-Lys3]-GHRP-6. However, while ghrelin pre-treatment attenuated the LPS-mediated increase in NF-κB, there was no alteration in its nuclear translocation. Cell viability assay and caspase-3 immunocytochemistry

  16. Ghrelin and cachexia in chronic kidney disease.

    PubMed

    Suzuki, Hajime; Asakawa, Akihiro; Amitani, Haruka; Nakamura, Norifumi; Inui, Akio

    2013-04-01

    Ghrelin is a growth hormone (GH) secretagogue and a potent orexigenic factor that stimulates feeding by interacting with hypothalamic feeding-regulatory nuclei. Its multifaceted effects are potentially beneficial as a treatment in human disease states. In both adult and pediatric chronic kidney disease (CKD) patients, decreased appetite plays a major role in wasting, which in turn is linked to morbidity and mortality; wasting has also been linked to high levels of leptin and proinflammatory cytokines. The beneficial effects of ghrelin treatment in CKD are potentially mediated by multiple concurrent actions, including the stimulation of appetite-regulating centers, anti-inflammatory effects, and direct kidney effects. Further evaluation of this appetite-regulating hormone in CKD is needed to confirm previous findings and to determine the underlying mechanisms.

  17. Treatment of cachexia: melanocortin and ghrelin interventions.

    PubMed

    Steinman, Jeremy; DeBoer, Mark Daniel

    2013-01-01

    Cachexia is a condition typified by wasting of fat and LBM caused by anorexia and further endocrinological modulation of energy stores. Diseases known to cause cachectic symptoms include cancer, chronic kidney disease, and chronic heart failure; these conditions are associated with increased levels of proinflammatory cytokines and increased resting energy expenditure. Early studies have suggested the central melanocortin system as one of the main mediators of the symptoms of cachexia. Pharmacological and genetic antagonism of these pathways attenuates cachectic symptoms in laboratory models; effects have yet to be studied in humans. In addition, ghrelin, an endogenous orexigenic hormone with receptors on melanocortinergic neurons, has been shown to ameliorate symptoms of cachexia, at least in part, by an increase in appetite via melanocortin modulation, in addition to its anticatabolic and anti-inflammatory effects. These effects of ghrelin have been confirmed in multiple types of cachexia in both laboratory and human studies, suggesting a positive future for cachexia treatments.

  18. Plasma Levels of Acylation-Stimulating Protein Are Strongly Predicted by Waist/Hip Ratio and Correlate with Decreased LDL Size in Men

    PubMed Central

    Saleh, Jumana; Wahab, Rabab A.; Farhan, Hatem; Al-Amri, Issa; Cianflone, Katherine

    2013-01-01

    The association of abdominal obesity with cardiovascular risk is often linked to altered secretion of adipose-derived factors and an abnormal lipid profile including formation of atherogenic small dense low density lipoprotein particles (sdLDL). Acylation-stimulating protein (ASP) is an adipose-derived hormone that exhibits potent lipogenic effects. Plasma ASP levels increase in obesity; however, the association of ASP levels with body fat distribution is not yet established, and no study to date has investigated the association of ASP with LDL size. In this study, we examined the association of ASP levels with abdominal obesity measures and the lipid profile including LDL size in 83 men with a wide range of abdominal girths. Regression analysis showed that waist/hip ratio was the main predictor of ASP levels (β = 0.52, P < 0.0001), significantly followed by decreased LDL size. BMI and TG levels, although positively correlated with ASP levels, were excluded as significant predictors in regression analysis. No correlation was found with LDL-C or apoB levels. ASP levels were 62.5% higher in abdominally obese compared to nonobese men. Waist/hip ratio presenting as the main predictor of ASP levels, suggests increased ASP production by abdominal fat which, as proposed previously, may result from resistance to ASP function causing delayed TG clearance and subsequent formation of atherogenic sdLDL. PMID:24533222

  19. Ghrelin and gastrointestinal stromal tumors

    PubMed Central

    Zhu, Chang-Zhen; Liu, Dong; Kang, Wei-Ming; Yu, Jian-Chun; Ma, Zhi-Qiang; Ye, Xin; Li, Kang

    2017-01-01

    Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs. PMID:28348480

  20. Ghrelin and gastrointestinal stromal tumors.

    PubMed

    Zhu, Chang-Zhen; Liu, Dong; Kang, Wei-Ming; Yu, Jian-Chun; Ma, Zhi-Qiang; Ye, Xin; Li, Kang

    2017-03-14

    Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs.

  1. The effect of leptin, ghrelin, and neuropeptide-Y on serum Tnf-Α, Il-1β, Il-6, Fgf-2, galanin levels and oxidative stress in an experimental generalized convulsive seizure model.

    PubMed

    Oztas, Berrin; Sahin, Deniz; Kir, Hale; Eraldemir, Fatma Ceyla; Musul, Mert; Kuskay, Sevinç; Ates, Nurbay

    2017-02-01

    The objective of this study is to examine the effects of the endogenous ligands leptin, ghrelin, and neuropeptide Y (NPY) on seizure generation, the oxidant/antioxidant balance, and cytokine levels, which are a result of immune response in a convulsive seizure model. With this goal, Wistar rats were divided into 5 groups-Group 1: Saline, Group 2: Saline+PTZ (65mg/kg), Group 3: leptin (4mg/kg)+PTZ, Group 4: ghrelin (80μg/kg)+PTZ, and Group 5: NPY (60μg/kg)+PTZ. All injections were delivered intraperitoneally, and simultaneous electroencephalography (EEG) records were obtained. Seizure activity was scored by observing seizure behavior, and the onset time, latency, and seizure duration were determined according to the EEG records. At the end of the experiments, blood samples were obtained in all groups to assess the serum TNF-α, IL-1β, IL-6, FGF-2, galanin, nitric oxide (NOֹ), malondialdehyde (MDA), and glutathione (GSH) levels. The electrophysiological and biochemical findings (p<0.05) of this study show that all three peptides have anticonvulsant effects in the pentylenetetrazol (PTZ)-induced generalized tonic-clonic convulsive seizure model. The reduction of the levels of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 caused by leptin, ghrelin, and NPY shows that these peptides may have anti-inflammatory effects in epileptic seizures. Also, leptin significantly increases the serum levels of the endogenous anticonvulsive agent galanin. The fact that each one of these endogenous peptides reduces the levels of MDA and increases the serum levels of GSH leads to the belief that they may have protective effects against oxidative damage that is thought to play a role in the pathogenesis of epilepsy. Our study contributes to the clarification of the role of these peptides in the brain in seizure-induced oxidative stress and immune system physiology and also presents new approaches to the etiology and treatment of tendency to epileptic seizures.

  2. Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin.

    PubMed

    Wang, Qian; Liu, Chen; Uchida, Aki; Chuang, Jen-Chieh; Walker, Angela; Liu, Tiemin; Osborne-Lawrence, Sherri; Mason, Brittany L; Mosher, Christina; Berglund, Eric D; Elmquist, Joel K; Zigman, Jeffrey M

    2014-02-01

    The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreER(T2) transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia.

  3. Acute one-cigarette smoking decreases ghrelin hormone in saliva: a pilot study.

    PubMed

    Kaabi, Yahia A; Khalifa, Mohiealdeen A

    2014-01-01

    Cigarette smoking is commonly associated with weight loss and mechanisms for these weight changes are still elusive. Ghrelin is a peptide hormone that works in a neuroendocrine fashion to stimulate hunger and the desire for food intake. Ghrelin is also secreted in saliva, probably to enhance food taste. In the current study, we tested the direct impact of acute cigarette smoking on total ghrelin found in saliva. Methods. Blood and saliva samples were collected from 30 healthy nonsmoker male volunteers before and after one-cigarette smoke. Total ghrelin in serum and saliva was measured by ELISA based method. Results. Data showed a statistically significant reduction in salivary ghrelin after smoking (P < 0.0001). In serum, total ghrelin levels were not affected before and after smoking (P = 0.1362). Additionally, positive correlation was observed between serum and salivary ghrelin before smoking (r = 0.4143 and P = 0.0158); however, this correlation was lost after smoking (r = 0.1147 and P = 0.5461). Conclusion. Acute one-cigarette smoking can negatively affect ghrelin levels in saliva that might contribute to the dull food taste in smokers.

  4. Acute One-Cigarette Smoking Decreases Ghrelin Hormone in Saliva: A Pilot Study

    PubMed Central

    Kaabi, Yahia A.; Khalifa, Mohiealdeen A.

    2014-01-01

    Cigarette smoking is commonly associated with weight loss and mechanisms for these weight changes are still elusive. Ghrelin is a peptide hormone that works in a neuroendocrine fashion to stimulate hunger and the desire for food intake. Ghrelin is also secreted in saliva, probably to enhance food taste. In the current study, we tested the direct impact of acute cigarette smoking on total ghrelin found in saliva. Methods. Blood and saliva samples were collected from 30 healthy nonsmoker male volunteers before and after one-cigarette smoke. Total ghrelin in serum and saliva was measured by ELISA based method. Results. Data showed a statistically significant reduction in salivary ghrelin after smoking (P < 0.0001). In serum, total ghrelin levels were not affected before and after smoking (P = 0.1362). Additionally, positive correlation was observed between serum and salivary ghrelin before smoking (r = 0.4143 and P = 0.0158); however, this correlation was lost after smoking (r = 0.1147 and P = 0.5461). Conclusion. Acute one-cigarette smoking can negatively affect ghrelin levels in saliva that might contribute to the dull food taste in smokers. PMID:24808912

  5. Attenuation of systemic morphine-induced analgesia by central administration of ghrelin and related peptides in mice.

    PubMed

    Zeng, Ping; Chen, Jia-Xiang; Yang, Bei; Zhi, Xing; Guo, Fa-Xian; Sun, Meng-Li; Wang, Jing-Lei; Wei, Jie

    2013-12-01

    Ghrelin, an acylated 28-amino peptide secreted in the gastric endocrine cells, has been demonstrated to stimulate the release of growth hormone, increase food intake, and inhibit pro-inflammatory cascade, etc. Ghrelin mainly combines with its receptor (GHS-R1α) to play the role in physiological and pathological functions. It has been reported that ghrelin plays important roles in the control of pain through interaction with the opioid system in inflammatory pain and acute pain. However, very few studies show the effect of supraspinal ghrelin system on antinociception induced by intraperitoneal (i.p.) administration of morphine. In the present study, intracerebroventricular (i.c.v.) injection of ghrelin (0.1, 1, 10 and 100 nmol/L) produced inhibition of systemic morphine (6 mg/kg, i.p.) analgesia in the tail withdrawal test. Similarly, i.c.v. injection GHRP-6 and GHRP-2 which are the agonists of GHS-R1α, also decreased analgesia effect induced by morphine injected intraperitoneally in mice. Furthermore, these anti-opioid activities of ghrelin and related peptides were not blocked by pretreatment with the GHS-R1α selective antagonist [d-Lys(3)]-GHRP-6 (100 nmol/L, i.c.v.). These results demonstrated that central ghrelin and related peptides could inhibit the analgesia effect induced by intraperitoneal (i.p.) administration of morphine. The anti-opioid effects of ghrelin and related peptides do not interact with GHS-R1a. These findings may pave the way for a new strategy on investigating the interaction between ghrelin system and opioids on pain modulation.

  6. Interrelationship between feeding level and the metabolic hormones leptin, ghrelin and obestatin in control of chicken egg laying and release of ovarian hormones.

    PubMed

    Sirotkin, Alexander V; Grossmann, Roland

    2015-06-01

    The aim of the present experiment is to examine the role of nutritional status, metabolic hormones and their interrelationships in the control of chicken ovarian ovulatory and secretory activity. For this purpose, we identified the effect of food restriction, administration of leptin, ghrelin 1-18, obestatin and combinations of food restriction with these hormones for 3days on chicken ovulation (egg laying) rate and ovarian hormone release. The release of progesterone (P), testosterone (T), estradiol (E) and arginine-vasotocin (AVT) by isolated and cultured ovarian fragments was determined by EIA. It was observed that food restriction significantly reduced the egg-laying rate, T, E and AVT release and promoted P output by ovarian fragments. Leptin, administrated to ad libitum-fed chickens, did not change these parameters besides promoting E release. Nevertheless, administration of leptin was able to prevent the effect of food restriction on ovulation, T and E (but not P or AVT) release. Ghrelin 1-18 administration to ad libitum-fed birds did not affect the measured parameters besides a reduction in P release. Ghrelin 1-18 administration prevented the food restriction-induced decrease in ovarian T, E and AVT, but it did not change P output or egg laying. Obestatin administrated to control chicken promoted their ovarian P, E and inhibited ovarian AVT release but did not affect egg laying. It was able to promote the effect of food restriction on P, T and AVT, but not E release or egg laying. Our results (1) confirm an inhibitory effect of food restriction on chicken ovulation rate; (2) shows that food restriction-induced reduction in egg laying is associated with a decrease in ovarian T, E and AVT and an increase in ovarian P release; (3) confirm the involvement of metabolic hormones leptin, ghrelin and obestatin in the control of chicken ovarian hormones output; and (4) the ability of metabolic hormones to mimic/antagonize or prevent/promote the effects of food

  7. Ghrelin Induces Leptin Resistance by Activation of Suppressor of Cytokine Signaling 3 Expression in Male Rats: Implications in Satiety Regulation

    PubMed Central

    Heldsinger, Andrea; Grabauskas, Gintautas; Wu, Xiaoyin; Zhou, ShiYi; Lu, Yuanxu; Song, Il

    2014-01-01

    The anorexigenic adipocyte-derived hormone leptin and the orexigenic hormone ghrelin act in opposition to regulate feeding behavior via the vagal afferent pathways. The mechanisms by which ghrelin exerts its inhibitory effects on leptin are unknown. We hypothesized that ghrelin activates the exchange protein activated by cAMP (Epac), inducing increased SOCS3 expression, which negatively affects leptin signal transduction and neuronal firing in nodose ganglia (NG) neurons. We showed that 91 ± 3% of leptin receptor (LRb) –bearing neurons contained ghrelin receptors (GHS-R1a) and that ghrelin significantly inhibited leptin-stimulated STAT3 phosphorylation in rat NG neurons. Studies of the signaling cascades used by ghrelin showed that ghrelin caused a significant increase in Epac and suppressor of cytokine signaling 3 (SOCS3) expression in cultured rat NG neurons. Transient transfection of cultured NG neurons to silence SOCS3 and Epac genes reversed the inhibitory effects of ghrelin on leptin-stimulated STAT3 phosphorylation. Patch-clamp studies and recordings of single neuronal discharges of vagal primary afferent neurons showed that ghrelin markedly inhibited leptin-stimulated neuronal firing, an action abolished by silencing SOCS3 expression in NG. Plasma ghrelin levels increased significantly during fasting. This was accompanied by enhanced SOCS3 expression in the NG and prevented by treatment with a ghrelin antagonist. Feeding studies showed that silencing SOCS3 expression in the NG reduced food intake evoked by endogenous leptin. We conclude that ghrelin exerts its inhibitory effects on leptin-stimulated neuronal firing by increasing SOCS3 expression. The SOCS3 signaling pathway plays a pivotal role in ghrelin's inhibitory effect on STAT3 phosphorylation, neuronal firing, and feeding behavior. PMID:25060362

  8. Ghrelin induces leptin resistance by activation of suppressor of cytokine signaling 3 expression in male rats: implications in satiety regulation.

    PubMed

    Heldsinger, Andrea; Grabauskas, Gintautas; Wu, Xiaoyin; Zhou, ShiYi; Lu, Yuanxu; Song, Il; Owyang, Chung

    2014-10-01

    The anorexigenic adipocyte-derived hormone leptin and the orexigenic hormone ghrelin act in opposition to regulate feeding behavior via the vagal afferent pathways. The mechanisms by which ghrelin exerts its inhibitory effects on leptin are unknown. We hypothesized that ghrelin activates the exchange protein activated by cAMP (Epac), inducing increased SOCS3 expression, which negatively affects leptin signal transduction and neuronal firing in nodose ganglia (NG) neurons. We showed that 91 ± 3% of leptin receptor (LRb) -bearing neurons contained ghrelin receptors (GHS-R1a) and that ghrelin significantly inhibited leptin-stimulated STAT3 phosphorylation in rat NG neurons. Studies of the signaling cascades used by ghrelin showed that ghrelin caused a significant increase in Epac and suppressor of cytokine signaling 3 (SOCS3) expression in cultured rat NG neurons. Transient transfection of cultured NG neurons to silence SOCS3 and Epac genes reversed the inhibitory effects of ghrelin on leptin-stimulated STAT3 phosphorylation. Patch-clamp studies and recordings of single neuronal discharges of vagal primary afferent neurons showed that ghrelin markedly inhibited leptin-stimulated neuronal firing, an action abolished by silencing SOCS3 expression in NG. Plasma ghrelin levels increased significantly during fasting. This was accompanied by enhanced SOCS3 expression in the NG and prevented by treatment with a ghrelin antagonist. Feeding studies showed that silencing SOCS3 expression in the NG reduced food intake evoked by endogenous leptin. We conclude that ghrelin exerts its inhibitory effects on leptin-stimulated neuronal firing by increasing SOCS3 expression. The SOCS3 signaling pathway plays a pivotal role in ghrelin's inhibitory effect on STAT3 phosphorylation, neuronal firing, and feeding behavior.

  9. What is the general action of ghrelin for vertebrates? - comparisons of ghrelin's effects across vertebrates.

    PubMed

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2013-01-15

    Ten years and more passed since ghrelin was discovered. Various physiological actions of ghrelin have been documented in both mammalian and nonmammalian vertebrates. Do these actions have any commonality? In this review, we focused on several effects of ghrelin, and compared the effect across vertebrates. We would like to discuss possible general function of ghrelin in vertebrates.

  10. The Neurobiological Impact of Ghrelin Suppression after Oesophagectomy

    PubMed Central

    Murphy, Conor F.; le Roux, Carel W.

    2016-01-01

    Ghrelin, discovered in 1999, is a 28-amino-acid hormone, best recognized as a stimulator of growth hormone secretion, but with pleiotropic functions in the area of energy homeostasis, such as appetite stimulation and energy expenditure regulation. As the intrinsic ligand of the growth hormone secretagogue receptor (GHS-R), ghrelin appears to have a broad array of effects, but its primary role is still an area of debate. Produced mainly from oxyntic glands in the stomach, but with a multitude of extra-metabolic roles, ghrelin is implicated in complex neurobiological processes. Comprehensive studies within the areas of obesity and metabolic surgery have clarified the mechanism of these operations. As a stimulator of growth hormone (GH), and an apparent inducer of positive energy balance, other areas of interest include its impact on carcinogenesis and tumour proliferation and its role in the cancer cachexia syndrome. This has led several authors to study the hormone in the cancer setting. Ghrelin levels are acutely reduced following an oesophagectomy, a primary treatment modality for oesophageal cancer. We sought to investigate the nature of this postoperative ghrelin suppression, and its neurobiological implications. PMID:28035969

  11. Plasma ghrelin concentrations, food intake, and anorexia in liver failure.

    PubMed

    Marchesini, Giulio; Bianchi, Giampaolo; Lucidi, Paola; Villanova, Nicola; Zoli, Marco; De Feo, Pierpaolo

    2004-05-01

    Ghrelin is related to feeding behavior and nutrition in several physiological and pathological conditions. We tested the hypothesis that the anorexia and the decreased food intake of advanced liver failure might be associated with hyperghrelinemia. Fasting ghrelin was measured in 43 cirrhotic patients, food intake was self-assessed using the Corli score and a 3-d dietary record (n = 25), and anorexia/hunger was tested by a Likert scale. Fifty healthy subjects, matched for age and body mass index, served as controls. Ghrelin levels were not systematically increased in cirrhosis (414 +/- 164 vs. 398 +/- 142 pmol/liter in controls) but increased with decreasing Corli score (P = 0.014) and along the scale of anorexia/hunger (P = 0.0001), which were both related to the 3-d dietary record (P = 0.009 and P < 0.0001, respectively). Logistical regression confirmed that high ghrelin (>500 pmol/liter) was significantly associated with a low calorie intake [odds ratio (OR), 3.03 for any 100-calorie reduced intake; P = 0.015], a reduced Corli score (OR, 3.09; P = 0.031), and the anorexia score (OR, 3.37; P = 0.009), after adjustment for body mass index. The study confirms the previously observed relationship of fasting ghrelin with food intake in disease-associated malnutrition. In the presence of anorexia, hyperghrelinemia might indicate a compensatory mechanism trying to stimulate food intake, which is nonetheless ineffective in the physiological range.

  12. The Amygdala as a Neurobiological Target for Ghrelin in Rats: Neuroanatomical, Electrophysiological and Behavioral Evidence

    PubMed Central

    Alvarez-Crespo, Mayte; Skibicka, Karolina P.; Farkas, Imre; Molnár, Csilla S.; Egecioglu, Emil; Hrabovszky, Erik; Liposits, Zsolt; Dickson, Suzanne L.

    2012-01-01

    Here, we sought to demonstrate that the orexigenic circulating hormone, ghrelin, is able to exert neurobiological effects (including those linked to feeding control) at the level of the amygdala, involving neuroanatomical, electrophysiological and behavioural studies. We found that ghrelin receptors (GHS-R) are densely expressed in several subnuclei of the amygdala, notably in ventrolateral (LaVL) and ventromedial (LaVM) parts of the lateral amygdaloid nucleus. Using whole-cell patch clamp electrophysiology to record from cells in the lateral amygdaloid nucleus, we found that ghrelin reduced the frequency of mEPSCs recorded from large pyramidal-like neurons, an effect that could be blocked by co-application of a ghrelin receptor antagonist. In ad libitum fed rats, intra-amygdala administration of ghrelin produced a large orexigenic response that lasted throughout the 4 hr of testing. Conversely, in hungry, fasted rats ghrelin receptor blockade in the amygdala significantly reduced food intake. Finally, we investigated a possible interaction between ghrelin's effects on feeding control and emotional reactivity exerted at the level of the amygdala. In rats allowed to feed during a 1-hour period between ghrelin injection and anxiety testing (elevated plus maze and open field), intra-amygdala ghrelin had no effect on anxiety-like behavior. By contrast, if the rats were not given access to food during this 1-hour period, a decrease in anxiety-like behavior was observed in both tests. Collectively, these data indicate that the amygdala is a valid target brain area for ghrelin where its neurobiological effects are important for food intake and for the suppression of emotional (anxiety-like) behaviors if food is not available. PMID:23071554

  13. Protective effects of ghrelin on cisplatin-induced nephrotoxicity in mice.

    PubMed

    Nojiri, Takashi; Hosoda, Hiroshi; Kimura, Toru; Tokudome, Takeshi; Miura, Koichi; Takabatake, Hiroyuki; Miyazato, Mikiya; Okumura, Meinoshin; Kangawa, Kenji

    2016-08-01

    Cisplatin is a potent chemotherapeutic agent that has activity against malignant tumors. However, cisplatin causes various adverse effects, such as nephrotoxicity, which are associated with high morbidity and mortality. Recent studies have revealed that the mechanism of cisplatin nephrotoxicity includes a robust inflammatory response. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin might have protective effects against cisplatin nephrotoxicity. Mice were randomly divided into three groups: control, cisplatin with vehicle, and cisplatin with ghrelin. Ghrelin (0.8μg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started one day before cisplatin injection. At 72h after cisplatin administration (20mg/kg, intraperitoneally), we measured serum blood urea nitrogen and creatinine, urine albumin/creatinine, renal mRNA levels of monocyte chemoattractant protein-1, interleukin-6, tumor necrosis factor-α, interleukin-1β, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin by real-time polymerase chain reaction, and histological changes. Ghrelin significantly attenuated the increase in serum blood urea nitrogen and creatinine induced by cisplatin. Ghrelin tended to attenuate the increase in urine albumin/creatinine, although not significantly. Cisplatin-induced renal tubular injury and apoptosis were significantly attenuated by ghrelin pretreatment. Consequently, ghrelin significantly attenuated renal mRNA levels of monocyte chemoattractant protein-1, interleukin-6, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin. In conclusion, ghrelin produces protective effects in cisplatin-induced nephrotoxicity through inhibition of inflammatory reactions. Pretreatment with ghrelin may become a new prophylactic candidate for cisplatin-induced nephrotoxicity.

  14. Ghrelin does not affect gastrointestinal contractility in rainbow trout and goldfish in vitro.

    PubMed

    Kitazawa, Takio; Itoh, Kentaro; Yaosaka, Noriko; Maruyama, Keisuke; Matsuda, Kouhei; Teraoka, Hiroki; Kaiya, Hiroyuki

    2012-09-15

    Ghrelin has been identified in rainbow trout and goldfish, and it has been shown to regulate growth hormone release and food intake in these species as seen in mammals. The aim of this study was to investigate the functional role of ghrelin in regulation of gastrointestinal contractility in both fishes. Neither rainbow trout ghrelin nor rat ghrelin affected the contractility of gastrointestinal strips of rainbow trout. Similarly, goldfish ghrelin-17 and rat ghrelin did not cause marked contraction in the goldfish intestinal bulb. Detail examinations using the goldfish intestine revealed that human neurotensin, substance-P, goldfish neuromedine-U and carbachol showed apparent contractile activities in the intestinal strips. Electrical field stimulation (EFS, 1-20 Hz) caused a frequency-dependent contraction of the intestinal bulb. Atropine partially inhibited and tetrodotoxin abolished the EFS-induced contraction. Pretreatments with goldfish ghrelin-17 and rat ghrelin did not modify the EFS-induced contraction. The mRNAs of two types of growth hormone secretagogue receptor (GHS-R), GHS-R1a-1 and GHS-R1a-2, were detected in the goldfish intestine, and the expression level of GHS-R1a-2 was 4-times higher than that of GHS-R1a-1. The expression levels of GHS-R1a-1 and GHS-R1a-2 in four regions of the goldfish intestine (intestinal bulb, intestine-1, intestine-2 and intestine-3) were almost the same. In conclusion, ghrelin does not affect gastrointestinal contractility of the rainbow trout and goldfish, although GHSR-like receptor/GHS-R1a is expressed entire intestine. These results suggest diversity of ghrelin function in vertebrates.

  15. Sequencing analysis of ghrelin gene 5' flanking region: relations between the sequence variants, fasting plasma total ghrelin concentrations, and body mass index.

    PubMed

    Vartiainen, Johanna; Kesäniemi, Y Antero; Ukkola, Olavi

    2006-10-01

    Ghrelin is a 28-amino-acid peptide with several functions linked to energy metabolism. Low ghrelin plasma concentrations are associated with obesity, hypertension, and type 2 diabetes mellitus, whereas high concentrations reflect states of negative energy balance. Several studies addressing the hormonal and neural regulation of ghrelin gene expression have been carried out, but the role of genetic factors in the regulation of ghrelin plasma levels remains unclear. To elucidate the role of genetic factors in the regulation of ghrelin expression, we screened 1657 nucleotides of the ghrelin gene 5' flanking region (promoter and possible regulatory sites) for new sequential variations from patient samples with low (n = 50) and high (n = 50) fasting plasma total ghrelin concentrations (low- and high-ghrelin groups). Eleven single nucleotide polymorphisms (SNPs), 3 of which were rare variants (allelic frequency less than 1%) were found in our population. The genotype distribution patterns of the SNPs did not differ between the study groups, except for SNP-501A>C (P = .039). In addition, the SNP-01A>C was associated with body mass index (BMI) (P = .018). This variant was studied further in our large and well-defined Oulu Project Elucidating Risk for Atherosclerosis (OPERA) cohort (n = 1045) by the restriction fragment length polymorphism (RFLP) technique. No significant association of SNP-501A>C genotypes with fasting ghrelin plasma concentrations was found in the whole OPERA population. However, the association of this SNP with BMI and with waist circumference reached statistical significance in OPERA (P = .047 and .049, respectively), remaining of borderline significance for BMI after adjustments (P = .055). The results indicate that factors other than the 11 SNPs found in this study in the 5' flanking region of ghrelin gene are the main determinants of ghrelin plasma levels. However, SNP-501 A>C genotype distribution seems to be different in subjects having the highest

  16. Oxidative acylation using thioacids

    NASA Technical Reports Server (NTRS)

    Liu, R.; Orgel, L. E.

    1997-01-01

    Several important prebiotic reactions, including the coupling of amino acids into polypeptides by the formation of amide linkages, involve acylation. Theae reactions present a challenge to the understanding of prebiotic synthesis. Condensation reactions relying on dehydrating agents are either inefficient in aqueous solution or require strongly acidic conditions and high temperatures. Activated amino acids such as thioester derivatives have therefore been suggested as likely substrates for prebiotic peptide synthesis. Here we propose a closely related route to amide bond formation involving oxidative acylation by thioacids. We find that phenylalanine, leucine and phenylphosphate are acylated efficiently in aqueous solution by thioacetic acid and an oxidizing agent. From a prebiotic point of view, oxidative acylation has the advantage of proceeding efficiently in solution and under mild conditions. We anticipate that oxidative acylation should prove to be a general method for activating carboxylic acids, including amino acids.

  17. Obestatin and Ghrelin May Have a Complementary Function During Acute and Chronic Period in Mice.

    PubMed

    Udum, Duygu; Belenli, Deniz; Ilhan, Tuncay; Gunes, Nazmiye; Sonat, Fusun; Yalcin, Murat

    2016-01-01

    Obestatin is described as an anorexigenic peptide, and has adverse effects of ghrelin. It has no inhibitory effects on acute/chronic food intake, and it has been reported by several researchers. The role of obestatin in metabolism is still not clear. In the present study, the purpose is to determine the effects of chronically administrated obestatin. For this purpose, (1 µmol/kg; i.p.) or ghrelin (1 µmol/kg; i.p.) and food restriction (24h fast:24h fed) on plasma obestatin, ghrelin, leptin, insulin, cholecystokinin (CCK) and glucose levels, and body weight gain were investigated for 14 days in mice. Additionally, mice were treated with acute ip (100 nmol/kg) injections of obestatin or ghrelin to investigate the food consumptions, plasma obestatin and ghrelin levels to determine unknown acute effects of obestatin. Plasma ghrelin levels increased significantly in obestatin administered mice when compared with the control group for chronic treatment. This increase is consistent with immunohistochemical findings which claim that the number of ghrelin and obestatin immunopositive cells in fundus tissue of stomach are considerably high in obestatin treated animals. Plasma obestatin and ghrelin levels has shown an increase endogenously in food restricted mice, but plasma leptin and insulin levels have been found to be lower compared to the control group. Acute administration of obestatin caused a decrease in plasma obestatin level at 60 min after injection and had no effect on the reduction of food intake in each treatment time. These results imply that obestatin may not itself be involved in the metabolism regulation; however, obestatin accompanied by ghrelin may play a role in the long-term regulation of metabolism.

  18. Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease

    PubMed Central

    Bayliss, Jacqueline A.; Lemus, Moyra B.; Stark, Romana; Santos, Vanessa V.; Thompson, Aiysha; Rees, Daniel J.; Galic, Sandra; Elsworth, John D.; Kemp, Bruce E.; Davies, Jeffrey S.

    2016-01-01

    Calorie restriction (CR) is neuroprotective in Parkinson's disease (PD) although the mechanisms are unknown. In this study we hypothesized that elevated ghrelin, a gut hormone with neuroprotective properties, during CR prevents neurodegeneration in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. CR attenuated the MPTP-induced loss of substantia nigra (SN) dopamine neurons and striatal dopamine turnover in ghrelin WT but not KO mice, demonstrating that ghrelin mediates CR's neuroprotective effect. CR elevated phosphorylated AMPK and ACC levels in the striatum of WT but not KO mice suggesting that AMPK is a target for ghrelin-induced neuroprotection. Indeed, exogenous ghrelin significantly increased pAMPK in the SN. Genetic deletion of AMPKβ1 and 2 subunits only in dopamine neurons prevented ghrelin-induced AMPK phosphorylation and neuroprotection. Hence, ghrelin signaling through AMPK in SN dopamine neurons mediates CR's neuroprotective effects. We consider targeting AMPK in dopamine neurons may recapitulate neuroprotective effects of CR without requiring dietary intervention. SIGNIFICANCE STATEMENT The neuroprotective mechanisms of calorie restriction (CR) in Parkinson's disease are unknown. Indeed, the difficulty to adhere to CR necessitates an alternative method to recapitulate the neuroprotective benefits of CR while bypassing dietary constraints. Here we show that CR increases plasma ghrelin, which targets substantia nigra dopamine to maintain neuronal survival. Selective deletion on AMPK beta1 and beta2 subunits only in DAT cre-expressing neurons shows that the ghrelin-induced neuroprotection requires activation of AMPK in substantia nigra dopamine neurons. We have discovered ghrelin as a key metabolic signal, and AMPK in dopamine neurons as its target, which links calorie restriction with neuroprotection in Parkinson's disease. Thus, targeting AMPK in dopamine neurons may provide novel neuroprotective benefits in Parkinson's disease. PMID

  19. Altered Lipid and Salt Taste Responsivity in Ghrelin and GOAT Null Mice

    PubMed Central

    Daimon, Caitlin M.; Wang, Rui; Tschöp, Matthias H.; Sévigny, Jean; Martin, Bronwen; Maudsley, Stuart

    2013-01-01

    Taste perception plays an important role in regulating food preference, eating behavior and energy homeostasis. Taste perception is modulated by a variety of factors, including gastric hormones such as ghrelin. Ghrelin can regulate growth hormone release, food intake, adiposity, and energy metabolism. Octanoylation of ghrelin by ghrelin O-acyltransferase (GOAT) is a specific post-translational modification which is essential for many biological activities of ghrelin. Ghrelin and GOAT are both widely expressed in many organs including the gustatory system. In the current study, overall metabolic profiles were assessed in wild-type (WT), ghrelin knockout (ghrelin−/−), and GOAT knockout (GOAT−/−) mice. Ghrelin−/− mice exhibited decreased food intake, increased plasma triglycerides and increased ketone bodies compared to WT mice while demonstrating WT-like body weight, fat composition and glucose control. In contrast GOAT−/− mice exhibited reduced body weight, adiposity, resting glucose and insulin levels compared to WT mice. Brief access taste behavioral tests were performed to determine taste responsivity in WT, ghrelin−/− and GOAT−/− mice. Ghrelin and GOAT null mice possessed reduced lipid taste responsivity. Furthermore, we found that salty taste responsivity was attenuated in ghrelin−/− mice, yet potentiated in GOAT−/− mice compared to WT mice. Expression of the potential lipid taste regulators Cd36 and Gpr120 were reduced in the taste buds of ghrelin and GOAT null mice, while the salt-sensitive ENaC subunit was increased in GOAT−/− mice compared with WT mice. The altered expression of Cd36, Gpr120 and ENaC may be responsible for the altered lipid and salt taste perception in ghrelin−/− and GOAT−/− mice. The data presented in the current study potentially implicates ghrelin signaling activity in the modulation of both lipid and salt taste modalities. PMID:24124572

  20. Therapeutic effect of ghrelin in the course of cerulein-induced acute pancreatitis in rats.

    PubMed

    Warzecha, Z; Ceranowicz, P; Dembinski, A; Cieszkowski, J; Kusnierz-Cabala, B; Tomaszewska, R; Kuwahara, A; Kato, I

    2010-08-01

    Recent studies have shown that pretreatment with ghrelin exhibits protective effect in the gut. Administration of ghrelin reduces gastric mucosal damage, as well as inhibits the development of experimental pancreatitis. However, this protective effect requires administration of ghrelin before gastric or pancreatic damage and thus has a limited clinical value. The aim of present study was to assess the influence of ghrelin administered after development of acute pancreatitis on the course of this disease. Acute pancreatitis was induced by cerulein. Ghrelin was administered twice a day for 1, 2, 4, 6 or 9 days at the dose of 4, 8 or 16 nmol/kg/dose. The first dose of ghrelin was given 24 hours after last injection of cerulein. The severity of acute pancreatitis was assessed between 0 h and 10 days after cessation of cerulein administration. Administration of caerulein led to the development of acute edematous pancreatitis and maximal severity of this disease was observed 24 hours after induction of pancreatitis. Treatment with ghrelin reduced morphological signs of pancreatic damage such as pancreatic edema, leukocyte infiltration and vacuolization of acinar cells, and led to earlier regeneration of the pancreas. Also biochemical indexes of the severity of acute pancreatitis, serum activity of lipase and amylase were significantly reduced in animals treated with ghrelin. These effects were accompanied by an increase in the pancreatic DNA synthesis and a decrease in serum level of pro-inflammatory interleukin-1b. Administration of ghrelin improved pancreatic blood flow in rats with acute pancreatitis. We conclude that: (1) treatment with ghrelin exhibits therapeutic effect in caerulein-induced experimental acute pancreatitis; (2) this effect is related, at least in part, to the improvement of pancreatic blood flow, reduction in proinflammatory interleukin-1beta and stimulation of pancreatic cell proliferation.

  1. Ghrelin and obestatin modulate growth hormone-releasing hormone release and synaptic inputs onto growth hormone-releasing hormone neurons.

    PubMed

    Feng, Dan D; Yang, Seung-Kwon; Loudes, Catherine; Simon, Axelle; Al-Sarraf, Tamara; Culler, Michael; Alvear-Perez, Rodrigo; Llorens-Cortes, Catherine; Chen, Chen; Epelbaum, Jacques; Gardette, Robert

    2011-09-01

    Ghrelin, a natural ligand of the growth hormone secretagogue receptor (GHS-R), is synthesized in the stomach but may also be expressed in lesser quantity in the hypothalamus where the GHS-R is located on growth hormone-releasing hormone (GHRH) neurons. Obestatin, a peptide derived from the same precursor as ghrelin, is able to antagonize the ghrelin-induced increase of growth hormone (GH) secretion in vivo but not from pituitary explants in vitro. Thus, the blockade of ghrelin-induced GH release by obestatin could be mediated at the hypothalamic level by the neuronal network that controls pituitary GH secretion. Ghrelin increased GHRH and decreased somatostatin (somatotropin-releasing inhibitory factor) release from hypothalamic explants, whereas obestatin only reduced the ghrelin-induced increase of GHRH release, thus indicating that the effect of ghrelin and obestatin is targeted to GHRH neurons. Patch-clamp recordings on mouse GHRH-enhanced green fluorescent protein neurons indicated that ghrelin and obestatin had no significant effects on glutamatergic synaptic transmission. Ghrelin decreased GABAergic synaptic transmission in 44% of the recorded neurons, an effect blocked in the presence of the GHS-R antagonist BIM28163, and stimulated the firing rate of 78% of GHRH neurons. Obestatin blocked the effects of ghrelin by acting on a receptor different from the GHS-R. These data suggest that: (i) ghrelin increases GHRH neuron excitability by increasing their action potential firing rate and decreasing the strength of GABA inhibitory inputs, thereby leading to an enhanced GHRH release; and (ii) obestatin counteracts ghrelin actions. Such interactions on GHRH neurons probably participate in the control of GH secretion.

  2. Ghrelin: much more than a hunger hormone

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is a multifaceted gut hormone that activates its receptor, growth hormone secretagogue receptor (GHS-R). Ghrelin's hallmark functions are its stimulatory effects on growth hormone release, food intake and fat deposition. Ghrelin is famously known as the 'hunger hormone'. However, ample recen...

  3. Thermogenic characterization of ghrelin receptor null mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin is the only known circulating orexigenic hormone that increases food intake and promotes adiposity, and these physiological functions of ghrelin are mediated through its receptor growth hormone secretagogue receptor (GHS-R). Ghrelin/GHS-R signaling plays a crucial role in energy homeostasis....

  4. Characteristics associated with fasting appetite hormones (obestatin, ghrelin, and leptin).

    PubMed

    Beasley, Jeannette M; Ange, Brett A; Anderson, Cheryl A M; Miller Iii, Edgar R; Holbrook, Janet T; Appel, Lawrence J

    2009-02-01

    Obestatin, derived from the same gene as the hunger hormone ghrelin, may reduce food intake in animals. The role of obestatin in human physiology is unclear. We evaluated cross-sectional associations between participant characteristics and fasting levels of obestatin as well two other hormones associated with energy balance, ghrelin and leptin. Data are from the baseline visit of the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OMNI-Heart) Trial that enrolled adults with elevated blood pressure (systolic 120-159 mm Hg or a diastolic of 80-99 mm Hg) but who were otherwise healthy. Partial Spearman's correlations and linear regression models estimated the association between age, gender, BMI, physical activity, and smoking with fasting hormones. Obestatin was directly associated with ghrelin (r = 0.45, P < 0.05). On average, overweight (BMI 25-30) and obese (BMI > 30) individuals had obestatin concentrations that were 12.6 (s.d. 8.8) and 25.4 (s.d. 8.4) pg/ml lower compared to normal weight (BMI < 25) individuals, respectively (P for trend = 0.002). Overweight (BMI 25-30) and obese (BMI > 30) individuals had ghrelin concentrations that were 161.7 (s.d. 69.6) and 284.7 (s.d. 66.5) pg/ml lower compared to normal weight (BMI < 25) individuals, respectively (P for trend <0.0001). A 5 unit increase in BMI was associated with 41.3% (s.d. 4.3%) (P < 0.0001) higher leptin. Obestatin and ghrelin are directly correlated and share the same patterns of association with participant characteristics. Modifiable risk factors for chronic diseases, such as BMI, are associated with fasting levels of leptin, obestatin, and ghrelin.

  5. Ghrelin Facilitates GLUT2-, SGLT1- and SGLT2-mediated Intestinal Glucose Transport in Goldfish (Carassius auratus)

    PubMed Central

    Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Ramesh, Naresh; Delgado, María Jesús; Valenciano, Ana Isabel; Unniappan, Suraj

    2017-01-01

    Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co-transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells. Some cells containing GLUT2, SGLT1 and SGLT2 coexpressed the ghrelin/growth hormone secretagogue receptor 1a (GHS-R1a). Intraperitoneal glucose administration led to a significant increase in serum ghrelin levels, as well as an upregulation of intestinal preproghrelin, ghrelin O-acyltransferase and ghs-r1 expression. In vivo and in vitro ghrelin treatment caused a concentration- and time-dependent modulation (mainly stimulatory) of GLUT2, SGLT1 and SGLT2. These effects were abolished by the GHS-R1a antagonist [D-Lys3]-GHRP-6 and the phospholipase C inhibitor U73122, suggesting that ghrelin actions on glucose transporters are mediated by GHS-R1a via the PLC/PKC signaling pathway. Finally, ghrelin stimulated the translocation of GLUT2 into the plasma membrane of goldfish primary intestinal cells. Overall, data reported here indicate an important role for ghrelin in the modulation of glucoregulatory machinery and glucose homeostasis in fish. PMID:28338019

  6. Ghrelin Facilitates GLUT2-, SGLT1- and SGLT2-mediated Intestinal Glucose Transport in Goldfish (Carassius auratus).

    PubMed

    Blanco, Ayelén Melisa; Bertucci, Juan Ignacio; Ramesh, Naresh; Delgado, María Jesús; Valenciano, Ana Isabel; Unniappan, Suraj

    2017-03-24

    Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co-transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells. Some cells containing GLUT2, SGLT1 and SGLT2 coexpressed the ghrelin/growth hormone secretagogue receptor 1a (GHS-R1a). Intraperitoneal glucose administration led to a significant increase in serum ghrelin levels, as well as an upregulation of intestinal preproghrelin, ghrelin O-acyltransferase and ghs-r1 expression. In vivo and in vitro ghrelin treatment caused a concentration- and time-dependent modulation (mainly stimulatory) of GLUT2, SGLT1 and SGLT2. These effects were abolished by the GHS-R1a antagonist [D-Lys3]-GHRP-6 and the phospholipase C inhibitor U73122, suggesting that ghrelin actions on glucose transporters are mediated by GHS-R1a via the PLC/PKC signaling pathway. Finally, ghrelin stimulated the translocation of GLUT2 into the plasma membrane of goldfish primary intestinal cells. Overall, data reported here indicate an important role for ghrelin in the modulation of glucoregulatory machinery and glucose homeostasis in fish.

  7. Immunization against active ghrelin using virus-like particles for obesity treatment.

    PubMed

    Andrade, Sara; Pinho, Filipa; Ribeiro, Andreia M; Carreira, Marcos; Casanueva, Felipe F; Roy, Polly; Monteiro, Mariana P

    2013-01-01

    Ghrelin is a gut hormone that stimulates food intake. In physiological conditions, ghrelin plasma levels rise with fasting and decrease after meals. Obese individuals have low fasting ghrelin levels that rise after food restriction, which is pointed out as a reason for the difficulty in maintaining weight loss. Some bariatric surgery procedures prevent rise in ghrelin levels with weight loss and this has been hypothesised to contribute to the long-term success of the treatment. The main goal of this study was to develop a safe and effective anti-ghrelin vaccine for obesity, through the chemical conjugation of ghrelin with a virus like particle, namely NS1 protein tubules from the Bluetongue Virus (BTV) using a hetero-bifunctional cross linker. Male adult C57BL/6 mice, with a normal weight and with diet-induced obesity (DIO), were randomized into six weight matched groups (n=6/group) and each group of mice received three intra-peritoneal injections with two weeks intervals, containing either 75 μg of ghrelin- NS1 immunoconjugate, 75 μg of NS1 or PBS. Our data show that immunized animals present increasing titres of anti-ghrelin antibodies, while their cumulative food intake significantly decreased and energy expenditure was significantly enhanced, although there were no significative changes in body weight.Vaccinated DIO mice also displayed significant decrease of NPY gene expression in the basal hypothalamus reflecting a decrease in central orexigenic signals. This study suggests that this anti-ghrelin vaccine has a positive impact on energy homeostasis and may be an additional therapeutical tool to be used with diet and exercise for obesity treatment.

  8. Cloning and tissue distribution of a fatty acyl Δ6-desaturase-like gene and effects of dietary lipid levels on its expression in the hepatopancreas of Chinese mitten crab (Eriocheir sinensis).

    PubMed

    Yang, Zhigang; Guo, Zihao; Ji, Lianyuan; Zeng, Qitao; Wang, Yao; Yang, Xiaozhen; Cheng, Yongxu

    2013-06-01

    Fatty acyl Δ6-desaturase is the rate-limiting enzyme in the biosynthetic pathway of highly unsaturated fatty acids (HUFAs) in vertebrates. In this report, a fatty acyl Δ6-desaturase-like cDNA was cloned from the hepatopancreas of Eriocheir sinensis (Chinese mitten crab) and characterized by performing rapid-amplification of cDNA ends. The 2278-bp long full-length cDNA encodes a polypeptide with 442 amino acids. Gene expression analysis via real-time quantitative polymerase chain reaction revealed that the fatty acyl Δ6-desaturase-like transcripts are widely distributed in various tissues, with high expression levels in the hepatopancreas and cranial ganglia. This study focuses on the nutritional regulation of genes involved in the HUFA biosynthetic pathway in Chinese mitten crab. A feeding trial was performed whereby crablets were fed for 238 d with four different diets: control diet without oil lipids (added with 3% basic lipid of the fundamental diets); fish oil diet (FO; added with 3% of the fundamental diets); soybean oil diet (SO; added with 3% of the fundamental diets); and FO/SO diet (1:1; added with 3% of the fundamental diets). The hepatopancreas of crabs sampled at 168 d and 238 d to determine the effects on fatty acyl Δ6-desaturase-like mRNA expression. The results show that the expression of fatty acyl Δ6-desaturase-like is higher in the hepatopancreas of crabs fed with SO diet than those fed with FO diet. Furthermore, gene expression increased by 2.45-fold in the hepatopancreas of crabs fed with SO after 238 d than those fed after 168 d but remained steady for those fed with FO after 238 d.

  9. Blunted hypothalamic ghrelin signaling reduces diet intake in rats fed a low-protein diet in late pregnancy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diet intake in pregnant rats fed a low-protein (LP) diet was significantly reduced during late pregnancy despite elevated plasma levels of ghrelin. In this study, we hypothesized that ghrelin signaling in the hypothalamus is blunted under a low-protein diet condition and therefore, it does not stimu...

  10. Lack of effect of ghrelin treatment on melatonin production in rat pineal and Harderian glands.

    PubMed

    Djeridane, Yasmina; Touitou, Yvan

    2005-04-01

    The effects of ghrelin, a peptide hormone secreted from the stomach, on melatonin remain unknown. The aim of the study was to investigate possible ghrelin-melatonin interactions by studying the effect of ghrelin treatment on melatonin production in rat pineal and Harderian glands. Young (9 weeks) and old (20 months) male Wistar rats, maintained under a light:dark cycle regimen of 12:12, were assigned randomly to either a single subcutaneous (s.c.) injection of saline or ghrelin (1 microg/rat or 15 microg/rat) 1 h before sacrifice in the middle of the dark phase, or repeated s.c. saline or ghrelin injections (15 microg/rat), 3, 2 and 1 h before sacrificed in the middle of the dark phase. Neither ghrelin doses (1 microg/rat or 15 microg/rat) nor type of treatment (acute or repeated) influenced melatonin levels or the melatonin synthesizing enzymes N-acetyltransferase and hydroxyindole-O-methyltransferase activities, either in pineal gland or in Harderian glands. At the concentrations used, ghrelin does not influence melatonin production in rat pineal and Harderian glands, and therefore is not involved in the regulation of melatonin secretion, at least under our experimental conditions.

  11. Exogenous Ghrelin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats.

    PubMed

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Ceranowicz, Dagmara; Gałązka, Krystyna; Bonior, Joanna; Jaworek, Jolanta; Bartuś, Krzysztof; Gil, Krzysztof; Olszanecki, Rafał; Dembiński, Artur

    2016-09-01

    Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% acetic acid solution led to induction of colitis in all animals. Damage of the colonic wall was accompanied by an increase in mucosal concentration of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well mucosal activity of myeloperoxidase. Moreover, induction of colitis led to a reduction in colonic blood flow and DNA synthesis. Administration of ghrelin after induction of colitis led to faster regeneration of the colonic wall and reduction in colonic levels of IL-1β, TNF-α, and myeloperoxidase. In addition, treatment with ghrelin improved mucosal DNA synthesis and blood flow. Our study disclosed that ghrelin exhibits a strong anti-inflammatory and healing effect in acetic acid-induced colitis. Our current observation in association with previous findings that ghrelin exhibits curative effect in trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis suggest that therapeutic effect of ghrelin in the colon is universal and independent of the primary cause of colitis.

  12. Augmenting Effect of DA-9601 on Ghrelin in an Acute Gastric Injury Model

    PubMed Central

    Baek, Yoo Hum; Lee, Kang Nyeong; Jun, Dae Won; Yoon, Byung Chul; Kim, Ju Mi; Oh, Tae Young

    2011-01-01

    Background/Aims Acute gastric injury by alcohol or indomethacin has been reported to be prevented by DA-9601, an extract of the herb Artemisia asiatica. Ghrelin, an endogenously produced gastrointestinal peptide hormone, has also been demonstrated to play a role in gastric mucosal defense. The aim of this study was to investigate the effects of DA-9601 on ghrelin in an acute gastric injury model induced by alcohol or indomethacin. Methods A total of 140 Sprague-Dawley rats were divided into two groups, a placebo group and a DA-9601-pretreated group. Thirty minutes later, half of the rats in each group received ethanol injury and the other half received indomethacin injury. Levels of serum ghrelin and gastric mucosal ghrelin mRNA were measured by ELISA and RT-PCR, respectively. Results Immediately after ethanol administration, ghrelin increased in both groups pretreated with DA-9601 and placebo. However, the increase occurred more rapidly and was higher in the DA-9601-pretreated rats than in the controls that did not receive DA-9601-pretreatment. Similarly, from 30 minutes to 2 hours after indomethacin administration, the DA-9601-pretreated rats showed a significant increase in serum and gastric mucosal ghrelin concentrations, whereas placebo-pretreated rats showed only a mild increase. Conclusions DA-9601 potentiates the endogenous production and secretion of ghrelin in acute gastric injury models induced by ethanol or indomethacin. PMID:21461072

  13. Exogenous Ghrelin Accelerates the Healing of Acetic Acid-Induced Colitis in Rats

    PubMed Central

    Matuszyk, Aleksandra; Ceranowicz, Piotr; Warzecha, Zygmunt; Cieszkowski, Jakub; Ceranowicz, Dagmara; Gałązka, Krystyna; Bonior, Joanna; Jaworek, Jolanta; Bartuś, Krzysztof; Gil, Krzysztof; Olszanecki, Rafał; Dembiński, Artur

    2016-01-01

    Previous studies have shown that ghrelin reduces colonic inflammation induced by trinitrobenzene sulfonic acid and dextran sodium sulfate. In the present study we determined the effect of treatment with ghrelin on the course of acetic acid-induced colitis in rats. Rectal administration of 3% acetic acid solution led to induction of colitis in all animals. Damage of the colonic wall was accompanied by an increase in mucosal concentration of pro-inflammatory interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), as well mucosal activity of myeloperoxidase. Moreover, induction of colitis led to a reduction in colonic blood flow and DNA synthesis. Administration of ghrelin after induction of colitis led to faster regeneration of the colonic wall and reduction in colonic levels of IL-1β, TNF-α, and myeloperoxidase. In addition, treatment with ghrelin improved mucosal DNA synthesis and blood flow. Our study disclosed that ghrelin exhibits a strong anti-inflammatory and healing effect in acetic acid-induced colitis. Our current observation in association with previous findings that ghrelin exhibits curative effect in trinitrobenzene sulfonic acid- and dextran sodium sulfate-induced colitis suggest that therapeutic effect of ghrelin in the colon is universal and independent of the primary cause of colitis. PMID:27598133

  14. Acyl homoserine lactone changes the abundance of proteins and the levels of organic acids associated with stationary phase in Salmonella Enteritidis.

    PubMed

    de Almeida, Felipe Alves; Pimentel-Filho, Natan de Jesus; Carrijo, Lanna Clícia; Bento, Cláudia Braga Pereira; Baracat-Pereira, Maria Cristina; Pinto, Uelinton Manoel; de Oliveira, Leandro Licursi; Vanetti, Maria Cristina Dantas

    2017-01-01

    Quorum sensing (QS) is cell-cell communication mechanism mediated by signaling molecules known as autoinducers (AIs) that lead to differential gene expression. Salmonella is unable to synthesize the AI-1 acyl homoserine lactone (AHL), but is able to recognize AHLs produced by other microorganisms through SdiA protein. Our study aimed to evaluate the influence of AI-1 on the abundance of proteins and the levels of organic acids of Salmonella Enteritidis. The presence of N-dodecyl-homoserine lactone (C12-HSL) did not interfere on the growth or the total amount of extracted proteins of Salmonella. However, the abundance of the proteins PheT, HtpG, PtsI, Adi, TalB, PmgI (or GpmI), Eno, and PykF enhanced while the abundance of the proteins RplB, RplE, RpsB, Tsf, OmpA, OmpC, OmpD, and GapA decreased when Salmonella Enteritidis was anaerobically cultivated in the presence of C12-HSL. Additionally, the bacterium produced less succinic, lactic, and acetic acids in the presence of C12-HSL. However, the concentration of extracellular formic acid reached 20.46 mM after 24 h and was not detected when the growth was in the absence of AI-1. Considering the cultivation period for protein extraction, their abundance, process and function, as well as the levels of organic acids, we observed in cells cultivated in presence of C12-HSL a correlation with what is described in the literature as entry into the stationary phase of growth, mainly related to nitrogen and amino acid starvation and acid stress. Further studies are needed in order to determine the specific role of the differentially abundant proteins and extracellular organic acids secreted by Salmonella in the presence of quorum sensing signaling molecules.

  15. Ghrelin increases the motivation to eat, but does not alter food palatability.

    PubMed

    Overduin, Joost; Figlewicz, Dianne P; Bennett-Jay, Jennifer; Kittleson, Sepideh; Cummings, David E

    2012-08-01

    Homeostatic eating cannot explain overconsumption of food and pathological weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., "liking") and the motivation to self-administer (i.e., "wanting") food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devalued with quinine supplementation, ghrelin failed to reverse the quinine-associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using lever pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 h of food deprivation. Pretreatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in lever pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability.

  16. Ghrelin modulates sympathetic nervous system activity and stress response in lean and overweight men.

    PubMed

    Lambert, Elisabeth; Lambert, Gavin; Ika-Sari, Carolina; Dawood, Tye; Lee, Katie; Chopra, Reena; Straznicky, Nora; Eikelis, Nina; Drew, Sara; Tilbrook, Alan; Dixon, John; Esler, Murray; Schlaich, Markus P

    2011-07-01

    Ghrelin is a growth hormone-releasing peptide secreted by the stomach with potent effects on appetite. Experimental and clinical studies indicate that ghrelin also influences cardiovascular regulation and metabolic function and mediates behavioral responses to stress. We investigated the effects of ghrelin on blood pressure (BP), sympathetic nervous system activity, and mental stress responses in lean (n=13) and overweight or obese (n=13) individuals. Subjects received an intravenous infusion of human ghrelin (5 pmol/kg per minute for 1 hour) and saline in a randomized fashion. Ghrelin decreased systolic (-6 and -11 mm Hg) and diastolic BP (-8 mm Hg for both), increased muscle sympathetic nervous system activity (18±2 to 28±3 bursts per min, P<0.05 and from 21±2 to 32±3 bursts per min, P<0.001) in lean and overweight or obese subjects, respectively, without a significant change in heart rate, calf blood flow, or vascular resistance. Ghrelin induced a rise in plasma glucose concentration in lean individuals (P<0.05) and increased cortisol levels in both groups (P<0.05). Stress induced a significant change in mean BP (+22 and +27 mm Hg), heart rate (+36 and +29 bpm), and muscle sympathetic nervous system activity (+6.1±1.6 and +6.8±2.7 bursts per min) during saline infusion in lean and overweight or obese subjects, respectively. During ghrelin infusion, the changes in BP and muscle sympathetic nerve activity in response to stress were significantly reduced in both groups (P<0.05). In conclusion, ghrelin exerts unique effects in that it reduces BP and increases muscle sympathetic nervous system activity and blunts cardiovascular responses to mental stress. These responses may represent a combination of peripheral (baroreflex-mediated) and central effects of ghrelin.

  17. Polymorphism of rs1044925 in the acyl-CoA:cholesterol acyltransferase-1 gene and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

    PubMed Central

    2010-01-01

    Background The association of rs1044925 polymorphism in the acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) gene and serum lipid profiles is not well known in different ethnic groups. Bai Ku Yao is a special subgroup of the Yao minority in China. The present study was carried out to clarify the association of rs1044925 polymorphism in the ACAT-1 gene and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 626 subjects of Bai Ku Yao and 624 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of rs1044925 polymorphism in the ACAT-1 gene was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.01 for all). The frequency of A and C alleles was 79.0% and 21.0% in Bai Ku Yao, and 87.3% and 12.7% in Han (P < 0.001); respectively. The frequency of AA, AC and CC genotypes was 63.2%, 31.4% and 5.2% in Bai Ku Yao, and 75.6%, 23.2% and 1.1% in Han (P < 0.001); respectively. The levels of TC, LDL-C and ApoB in Bai Ku Yao but not in Han were different between the AA and AC/CC genotypes in females but not in males (P < 0.05 for all). The C allele carriers had lower serum TC, LDL-C and ApoB levels as compared with the C allele noncarriers. The levels of TC, LDL-C and ApoB in Bai Ku Yao but not in Han were correlated with genotypes in females but not in males (P < 0.05 for all). Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, and blood pressure in both ethnic groups (P < 0.05-0.001). Conclusions These results suggest that the polymorphism of rs1044925 in the ACAT-1 gene is mainly associated with female serum TC, LDL-C and

  18. Ghrelin counteracts salt-induced hypertension via promoting diuresis and renal nitric oxide production in Dahl rats.

    PubMed

    Aoki, Hirotaka; Nakata, Masanori; Dezaki, Katsuya; Lu, Ming; Gantulga, Darambazar; Yamamoto, Keiji; Shimada, Kazuyuki; Kario, Kazuomi; Yada, Toshihiko

    2013-01-01

    Ghrelin is the endogenous ligand for the growth hormone-secretagogue receptor expressed in various tissues including the heart, blood vessels and kidney. This study sought to determine the effects of long-term treatment with ghrelin (10 nmol/kg, twice a day, intraperitoneally) on the hypertension induced by high salt (8.0% NaCl) diet in Dahl salt-sensitive hypertensive (DS) rats. Systolic blood pressure (SBP) was measured by a tail cuff method. During the treatment period for 3 weeks, high salt diet increased blood pressure compared to normal salt (0.3% NaCl) diet, and this hypertension was partly but significantly (P<0.01) attenuated by simultaneous treatment with ghrelin. Ghrelin significantly increased urine volume and tended to increase urine Na⁺ excretion. Furthermore, ghrelin increased urine nitric oxide (NO) excretion and tended to increase renal neuronal nitric oxide synthase (nNOS) mRNA expression. Ghrelin did not alter the plasma angiotensin II level and renin activity, nor urine catecholamine levels. Furthermore, ghrelin prevented the high salt-induced increases in heart thickness and plasma ANP mRNA expression. These results demonstrate that long-term ghrelin treatment counteracts salt-induced hypertension in DS rats primarily through diuretic action associated with increased renal NO production, thereby exerting cardio-protective effects.

  19. Ghrelin: new insights into female reproductive system-associated disorders and pregnancy.

    PubMed

    Angelidis, George; Dafopoulos, Konstantinos; Messini, Christina I; Valotassiou, Varvara; Georgoulias, Panagiotis; Messinis, Ioannis E

    2012-09-01

    Ghrelin is considered the endogenous ligand of growth hormone secretagogue receptor type 1a, and its modulatory actions have been demonstrated in a large array of endocrine and nonendocrine functions. According to recent studies, ghrelin seems to act at different levels of the reproductive system, exerting predominantly inhibitory effects on mammalian reproduction. It has been shown to influence the reproductive system by regulating hormone secretion from the brain and by acting directly on the gonads to affect tissue development and steroidogenesis. Thus, the endocrine network, which integrates energy balance and fertility, might involve ghrelin. Furthermore, ghrelin levels and actions have been assessed in various female reproductive system disorders. The findings could lead to a better understanding of the pathogenesis of these disorders and, possibly, to more beneficial therapeutic strategies.

  20. Ghrelin Attenuates Liver Fibrosis through Regulation of TGF-β1 Expression and Autophagy.

    PubMed

    Mao, Yuqing; Zhang, Shaoren; Yu, Fujun; Li, Huanqing; Guo, Chuanyong; Fan, Xiaoming

    2015-09-10

    Ghrelin is a stomach-derived growth hormone secretagogue that promotes various physiological effects, including energy metabolism and amelioration of inflammation. The purpose of this study was to investigate the protective mechanism of ghrelin against liver fibrosis. Liver fibrosis was induced in C57BL/6 mice by intraperitoneal injection of CCl₄ (2.0 mL/kg of 10% CCl₄ v/v solution in peanut oil) two times per week for eight weeks. Ghrelin (10 μg/kg) was intraperitoneally injected two times per week for eight weeks. A second murine liver fibrosis model was induced by bile duct ligation (BDL) and concurrent ghrelin administration for four weeks. Hematoxylin eosin (H&E), and Masson's trichrome were used to detect pathological changes to liver tissue. Western blotting was used to detect protein levels of transforming growth factor (TGF)-β1, phosphorylated Smad3 (p-Smad3), I-collage, α-smooth muscle actin (α-SMA), matrix metalloproteinases (MMPs) 2, tissue inhibitor of matrix metalloproteinases (TIMPs) 1, phosphorylated NF-κB (p-NF-κB), and microtubule-associated protein light chain 3 (LC3). In addition, qRT-PCR was used to detect mRNA levels of TGF-β1, I-collage, α-SMA, MMP2, TIMP1 and LC3, while levels of TGF-β1, p-Smad3, I-collage, α-SMA, and LC3 were detected immunohistochemically. Levels of aspartate aminotransferase and alanine aminotransferase were significantly decreased by ghrelin treatment. Ghrelin administration also significantly reduced the extent of pathological changes in both murine liver fibrosis models. Expression levels of I-collage and α-SMA in both models were clearly reduced by ghrelin administration. Furthermore, ghrelin treatment decreased protein expression of TGF-β1 and p-Smad3. The protein levels of NF-κB and LC3 were increased in the CCl₄- and BDL-treatment groups but were significantly reduced following ghrelin treatment. In addition, ghrelin inhibited extracellular matrix formation by decreasing NF-κB expression and

  1. Genetic selection for body weight in chickens has altered responses of the brain's AMPK system to food intake regulation effect of ghrelin, but not obestatin.

    PubMed

    Xu, Pingwen; Siegel, Paul B; Denbow, D Michael

    2011-08-01

    The effects of ghrelin and obestatin regulation of food intake are different in mammals and chickens. We investigated central effects of ghrelin and obestatin in lines of chickens selected 50 generations for high (HWS) or low (LWS) body weight. We hypothesized that the effect of ghrelin and obestatin on food intake in 5-day-old chicks is mediated by the AMP-activated protein kinase (AMPK) system and selection for body weight alters the brain's response to ghrelin and obestatin by changing the neuronal AMPK system. Although intracerebroventricular (ICV) ghrelin injection decreased food intake in both lines, the threshold for the anorexigenic effect of central ghrelin was lower in LWS than HWS chicks. Obestatin caused a linear dose-dependent increase in food intake in HWS but not LWS chicks. ICV injection of 0.4 nmol ghrelin inhibited hypothalamic AMPK related gene expression and phosphorylation of AMPK α and acetyl-CoA carboxylase (ACC) with the magnitude of inhibition different in the two lines. In contrast, ICV injection of 4 nmol obestatin did not affect mRNA expression of AMPK system or phosphorylation of AMPK and ACC in either line. These data support the premise of a lower threshold for anorexigenic effect of central ghrelin in LWS than HWS chicks, and this difference may be associated with differential hypothalamic AMPK signaling. Additionally, the hypothalamic mRNA level of ghrelin was significantly higher in LWS than HWS, which may have also contributed to the different threshold response to ghrelin in these two lines. The expression of the ghrelin receptor was also higher in the LWS line, but not until 56 days of age. In summary, selection for body weight has resulted in differences in the central ghrelin and obestatin system, and an altered brain AMPK system may contribute to the different neuronal response to ghrelin, but not obestatin.

  2. Hepatic changes in metabolic gene expression in old ghrelin and ghrelin receptor knockout mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ghrelin knockout (GKO) and ghrelin receptor (growth hormone secretagogue receptor) knockout (GHSRKO) mice exhibit enhanced insulin sensitivity, but the mechanism is unclear. Insulin sensitivity declines with age and is inversely associated with accumulation of lipid in liver, a key glucoregulatory ...

  3. Association of ghrelin with cardiometabolic risk factors in Iranian adolescents: the CASPIAN-III study

    PubMed Central

    Heshmat, Ramin; Shafiee, Gita; Qorbani, Mostafa; Azizi-Soleiman, Fatemeh; Djalalinia, Shirin; Esmaeil Motlagh, Mohammad; Ardalan, Gelayol; Ahadi, Zeinab; Safari, Omid; Safiri, Saeid; Kelishadi, Roya

    2016-01-01

    Introduction: Current evidence suggests that ghrelin could contribute to the development of metabolic syndrome (MetS) in adults, but limited experience exists in adolescents. This study aims to explore the association of ghrelin levels with the MetS components among Iranian adolescents. Methods: In this case-control study, 32 adolescents with MetS and 148 healthy controls were selected randomly from the childhood and Adolescence Surveillance and Prevention of Adult Non communicable disease (CASPIAN-III) study. MetS was defined according to the Adult Treatment Panel III (ATP III) criteria modified for children and adolescents. Anthropometric measures (including body mass index [BMI], waist circumference [WC] and waist to height ratio [WHtR]), blood pressure (BP) and biochemical data (including fasting blood sugar [FBS], triglyceride [TG], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC] and gerlin) were measured. Results: Total ghrelin level was significantly higher in students without MetS compared to those with MetS (748.89 ± 85.04 vs. 728.72 ± 90.36 [pg/mL]; P < 0.001). Significant negative correlations were seen between ghrelin levels and BMI, WC, WHtR, TG, and TC. Ghrelin had also relatively strong inverse correlations with FBS (r = −0.59, P< 0.001), LDL-C (r = −0.56, P < 0.001), and positive correlation with HDL-C (r = 0.60, P < 0.001). Compared with the children with MetS, in those without MetS, ghrelin was significantly associated with HDL-C and LDL-C. A decreasing trend was observed in the mean ghrelin level across increasing number of MetS components (P for trend <0.001). Conclusion: We observed a relationship between ghrelin concentration and MetS components in adolescents. PMID:27777695

  4. Bicuculline, a GABAA-receptor antagonist, blocked HPA axis activation induced by ghrelin under an acute stress.

    PubMed

    Gastón, M S; Cid, M P; Salvatierra, N A

    2017-03-01

    Ghrelin is a peptide of 28 amino acids with a homology between species, which acts on the central nervous system to regulate different actions, including the control of growth hormone secretion and metabolic regulation. It has been suggested that central ghrelin is a mediator of behavior linked to stress responses and induces anxiety in rodents and birds. Previously, we observed that the anxiogenic-like behavior induced by ghrelin injected into the intermediate medial mesopallium (IMM) of the forebrain was blocked by bicuculline (a GABAA receptor competitive antagonist) but not by diazepam (a GABAA receptor allosteric agonist) in neonatal meat-type chicks (Cobb). Numerous studies have indicated that hypothalamic-pituitary-adrenal (HPA) axis activation mediates the response to stress in mammals and birds. However, it is still unclear whether this effect of ghrelin is associated with HPA activation. Therefore, we investigated whether anxiety behavior induced by intra-IMM ghrelin and mediated through GABAA receptors could be associated with HPA axis activation in the neonatal chick. In the present study, in an Open Field test, intraperitoneal bicuculline methiodide blocked anxiogenic-like behavior as well as the increase in plasma ACTH and corticosterone levels induced by ghrelin (30pmol) in neonatal chicks. Moreover, we showed for the first time that a competitive antagonist of GABAA receptor suppressed the HPA axis activation induced by an anxiogenic dose of ghrelin. These results show that the anxiogenic ghrelin action involves the activation of the HPA axis, with a complex functional interaction with the GABAA receptor.

  5. Ghrelin in small intestine, its contribution to regulation of food intake and body weight in cross-intestinal parabiotic rats.

    PubMed

    Noguchi, Hitoshi; Masaki, Takayuki; Kakuma, Tetsuya; Nakazato, Masamitsu; Yoshimatsu, Hironobu

    2011-01-01

    Ghrelin has been shown to be associated with feeding behavior in humans and rodents. It has been suggested that ghrelin may play a role behind the effect of bariatric surgery. Inbred rats were made into parabiotic pairs so that they shared a single abdominal cavity. A further operation is performed later in which the small intestines are transected and re-connected so that one rat continually lost nutrition to its partner. Changes in food intake and body weight were recorded. Seven weeks later, content of ghrelin in the plasma, stomach and upper intestines were measured in the paired rats. Rats which lost nutrients to its counterpart (Loss rats) ingested significantly more food than sham control rats (p<0.001). Rats which gained nutrient (Gain rats) ingested less than controls (p<0.001). There was no significant difference in body weight, blood glucose, insulin, free fatty acids and triglycerides between the paired rats. There was significantly higher levels of ghrelin in the plasma (p<0.008) and the intestine of the Loss rats (p<0.02). There were no difference in ghrelin in the stomach between parabiotic rats and sham operated controls. The ghrelin content of the plasma and intestines were significantly higher in the Loss rats, which ate more, and normal in the Gain rats, which ate less than controls. Because no remarkable changes in the ghrelin content were observed in the stomach, difference in the quality of the chime may affect the local synthesis and release of ghrelin.

  6. A radioimmunoassay for rat ghrelin: evaluation of method and effects of nonylphenol on ghrelin secretion in force-fed young rats.

    PubMed

    Chang, Yen-Jui; Huang, Wei-Ju; Lin, Han-Wei; Chang, Ling-Ling; Chang, Full-Young; Wang, Paulus S

    2011-10-31

    Antiserum YJC 13-31 against the rat ghrelin conjugated to bovine serum albumin (BSA) was produced in the rabbit and a double antibody radioimmunoassay (RIA) for ghrelin has been developed. Characterization results of this antiserum revealed no cross-reaction with human growth hormone and somatostatin. Weak cross-reactions with insulin (0.1%), rat growth hormone (0.1%) and glucagon (0.3%) were observed, which scarcely interfered the assay system. The sensitivity of this RIA was 5 pg per assay tube. With the rat serum samples, the within-assay precision was 7.1% and the between-assay precision was 12.3%. The RIA was also available to detect the ghrelin in rat tissue extracts with good parallelism to the rat ghrelin standard. In application, the serum ghrelin and corticosterone levels in weaned rats were measured by RIA. Gavage of saline was sufficient to raise serum ghrelin from 2.6 +/- 0.18 to 6.7 +/- 0.7 ng/ml (P < 0.01). Gavage with nonylphenol (NP) suppressed the elevation of serum ghrelin levels in a dose-dependent manner. Besides, gavages of saline elevated the serum levels of corticosterone from 108.8 +/- 13.5 to 188.7 +/- 23.5 ng/ml (P < 0.01) but the elevation effects of corticosterone from gavages were overcome by NP in the low dose of 50 mg/kg. It can be speculated that ingestion of NP is harmful to young animals during growth and environmental adaptation.

  7. The Human Experience With Ghrelin Administration

    PubMed Central

    Garin, Margaret C.; Burns, Carrie M.; Kaul, Shailja

    2013-01-01

    Context: Ghrelin is an endogenous stimulator of GH and is implicated in a number of physiological processes. Clinical trials have been performed in a variety of patient populations, but there is no comprehensive review of the beneficial and adverse consequences of ghrelin administration to humans. Evidence Acquisition: PubMed was utilized, and the reference list of each article was screened. We included 121 published articles in which ghrelin was administered to humans. Evidence Synthesis: Ghrelin has been administered as an infusion or a bolus in a variety of doses to 1850 study participants, including healthy participants and patients with obesity, prior gastrectomy, cancer, pituitary disease, diabetes mellitus, eating disorders, and other conditions. There is strong evidence that ghrelin stimulates appetite and increases circulating GH, ACTH, cortisol, prolactin, and glucose across varied patient populations. There is a paucity of evidence regarding the effects of ghrelin on LH, FSH, TSH, insulin, lipolysis, body composition, cardiac function, pulmonary function, the vasculature, and sleep. Adverse effects occurred in 20% of participants, with a predominance of flushing and gastric rumbles and a mild degree of severity. The few serious adverse events occurred in patients with advanced illness and were not clearly attributable to ghrelin. Route of administration may affect the pattern of adverse effects. Conclusions: Existing literature supports the short-term safety of ghrelin administration and its efficacy as an appetite stimulant in diverse patient populations. There is some evidence to suggest that ghrelin has wider ranging therapeutic effects, although these areas require further investigation. PMID:23533240

  8. Ghrelin Receptors in Non-Mammalian Vertebrates

    PubMed Central

    Kaiya, Hiroyuki; Kangawa, Kenji; Miyazato, Mikiya

    2012-01-01

    The growth hormone secretagogue-receptor (GHS-R) was discovered in humans and pigs in 1996. The endogenous ligand, ghrelin, was discovered 3 years later, in 1999, and our understanding of the physiological significance of the ghrelin system in vertebrates has grown steadily since then. Although the ghrelin system in non-mammalian vertebrates is a subject of great interest, protein sequence data for the receptor in non-mammalian vertebrates has been limited until recently, and related biological information has not been well organized. In this review, we summarize current information related to the ghrelin receptor in non-mammalian vertebrates. PMID:23882259

  9. Ghrelin increases food intake, swimming activity and growth in juvenile brown trout (Salmo trutta).

    PubMed

    Tinoco, Ana B; Näslund, Joacim; Delgado, María J; de Pedro, Nuria; Johnsson, Jörgen I; Jönsson, Elisabeth

    2014-01-30

    Several key functions of ghrelin are well conserved through vertebrate phylogeny. However, some of ghrelin's effects are contradictory and among teleosts only a limited number of species have been used in functional studies on food intake and foraging-related behaviors. Here we investigated the long-term effects of ghrelin on food intake, growth, swimming activity and aggressive contest behavior in one year old wild brown trout (Salmo trutta) using intraperitoneal implants. Food intake and swimming activity were individually recorded starting from day 1, and aggressive behavior was tested at day 11, after ghrelin implantation. Body weight and growth rate were measured from the beginning to the end of the experiment. Triglycerides and lipase activity in muscle and liver; monoaminergic activity in the telencephalon and brainstem; and neuropeptide Y (NPY) mRNA levels in the hypothalamus were analyzed. Ghrelin treatment was found to increase food intake and growth without modifying lipid deposition or lipid metabolism in liver and muscle. Ghrelin treatment led to an increased foraging activity and a trend towards a higher swimming activity. Moreover, ghrelin-treated fish showed a tendency to initiate more conflicts, but this motivation was not reflected in a higher ability to win the conflicts. No changes were observed in monoaminergic activity and NPY mRNA levels in the brain. Ghrelin is therefore suggested to act as an orexigenic hormone regulating behavior in juvenile wild brown trout. These actions are accompanied with an increased growth without the alteration of liver and muscle lipid metabolism and they do not seem to be mediated by changes in brain monoaminergic activity or hypothalamic expression of NPY.

  10. Elevated blood plasma concentrations of active ghrelin and obestatin in benign ovarian neoplasms and ovarian cancers.

    PubMed

    Markowska, A; Ziółkowska, A; Jaszczyńska-Nowinka, K; Madry, R; Malendowicz, L K

    2009-01-01

    Both ghrelin and obestatin are derived from preproghrelin by post-translational processing. The two peptides are secreted into the blood but circulating levels of these peptides have not been assessed in women with ovarian tumours. Therefore, the purpose of this study was to evaluate peripheral blood concentrations of active and total ghrelin and obestatin in patients with benign ovarian tumours and those with ovarian cancer. The studies were conducted on 22 patients operated due to benign ovarian tumours, and 31 patients operated due to ovarian cancer. A control group consisted of 32 women, 24 to 65 years of age. Both in women with benign ovarian tumours and those with ovarian cancer blood concentrations of active ghrelin and obestatin were higher than in the control group (active ghrelin: 90 +/- 4, 84 +/- 4 and 56 +/- 9 pg/ml, respectively, obestatin: 660 +/- 36; 630 +/- 30 and 538 +/- 31 ng/ml (x +/- SE), respectively). In contrast, total ghrelin concentrations in blood were similar in the studied groups. The alterations resulted in increased values of active to total ghrelin concentration ratio in the peripheral blood of patients with benign ovarian tumours or with ovarian cancer (0.79 +/- 0.02 and 0.93 +/- 0.05, respectively vs 0.58 +/- 0.02 in the control group). Due to the absence of any convincing proof for the presence of a functional GHS-R-1a receptor for ghrelin in human ovaries it did not seem probable that the observed elevated levels of active ghrelin and obestatin were directly linked to development of ovarian tumours.

  11. Ghrelin and obestatin expression in oral squamous cell carcinoma: an immunohistochemical and biochemical study.

    PubMed

    Alnema, Manar M; Aydin, Suleyman; Ozkan, Yusuf; Dagli, Adile F; Ozercan, Hanifi I; Yildirim, Nezahat; Sahin, Ibrahim; Karaoglu, Aziz; Kilic, Nermin; Yilmaz, Mustafa; Ozercan, Mehmet R; Donder, Emir

    2010-06-01

    The underlying molecular mechanism of carcinogenesis in oral squamous cell carcinoma (OSCC) is poorly understood and appears to be controlled on many genetic, environmental, and hormonal factors. Obestatin and ghrelin, two recently discovered hormones, are co-expressed in endocrine cells. The purpose of this investigation was to examine the immunohistochemical features of OSCCs in relation to the tissue concentration of ghrelin and obestatin. The association between OSCC and Epstein Barr Virus (EBV) status was also explored. The expression of ghrelin and obestatin was examined by immunohistochemistry and immunoassay in oral biopsy specimens: 10 benign squamous epithelial cell samples, 10 microinvasive squamous cell carcinomas, and seven well-differentiated and seven poorly differentiated OSCCs. The presence of EBV was evaluated in these samples using immunohistochemistry. The concentrations of ghrelin and obestatin in tissue homogenates were measured by RIA and ELISA, respectively. Squamous cell carcinomas and benign tissue samples were positive for anti-EBV antibody, and obestatin and ghrelin were shown to be co-expressed in all stratified squamous epithelium samples. Expression of ghrelin and obestatin was decreased or absent in OSCCs in relation to the invasiveness of the carcinoma; ghrelin and obestatin levels in cancerous tissue homogenates were lower than in benign tissue homogenates. These results indicate that the concentrations and distribution of immunoreactive obestatin and ghrelin might be helpful in distinguishing OSCC from benign tumors. Maintaining normal levels of these hormones might be required for regulation of normal cell division. However, detailed studies will be required for better understanding of the complex mechanism of carcinogenesis relating to OSCCs.

  12. Ghrelin at the interface of obesity and reward.

    PubMed

    Schellekens, Harriët; Dinan, Timothy G; Cryan, John F

    2013-01-01

    The prevalence of obesity continues to increase and has reached epidemic proportions. Accumulating data over the past few decades have given us key insights and broadened our understanding of the peripheral and central regulation of energy homeostasis. Despite this, the currently available pharmacological treatments, reducing body weight, remain limited due to poor efficacy and side effects. The gastric peptide ghrelin has been identified as the only orexigenic hormone from the periphery to act in the hypothalamus to stimulate food intake. Recently, a role for ghrelin and its receptor at the interface between homeostatic control of appetite and reward circuitries modulating the hedonic aspects of food has also emerged. Nonhomeostatic factors such as the rewarding and motivational value of food, which increase with food palatability and caloric content, can override homeostatic control of food intake. This nonhomeostatic decision to eat leads to overconsumption beyond nutritional needs and is being recognized as a key component in the underlying causes for the increase in obesity incidence worldwide. In addition, the hedonic feeding behavior has been linked to food addiction and an important role for ghrelin in the development of addiction has been suggested. Moreover, plasma ghrelin levels are responsive to conditions of stress, and recent evidence has implicated ghrelin in stress-induced food-reward behavior. The prominent role of the ghrelinergic system in the regulation of feeding gives rise to it as an effective target for the development of successful antiobesity pharmacotherapies that not only affect satiety but also selectively modulate the rewarding properties of food and reduce the desire to eat.

  13. A postweaning reduction in circulating ghrelin temporarily alters growth hormone (GH) responsiveness to GH-releasing hormone in male mice but does not affect somatic growth.

    PubMed

    Ariyasu, Hiroyuki; Iwakura, Hiroshi; Yamada, Go; Kanamoto, Naotetsu; Bando, Mika; Kohno, Kenji; Sato, Takahiro; Kojima, Masayasu; Nakao, Kazuwa; Kangawa, Kenji; Akamizu, Takashi

    2010-04-01

    Ghrelin was initially identified as an endogenous ligand for the GH secretagogue receptor. When administrated exogenously, ghrelin stimulates GH release and food intake. Previous reports in ghrelin-null mice, which do not exhibit impaired growth nor appetite, question the physiologic role of ghrelin in the regulation of the GH/IGF-I axis. In this study, we generated a transgenic mouse that expresses human diphtheria toxin (DT) receptor (DTR) cDNA in ghrelin-secretion cells [ghrelin-promoter DTR-transgenic (GPDTR-Tg) mice]. Administration of DT to this mouse ablates ghrelin-secretion cells in a controlled manner. After injection of DT into GPDTR-Tg mice, ghrelin-secreting cells were ablated, and plasma levels of ghrelin were markedly decreased [nontransgenic littermates, 70.6 +/- 10.2 fmol/ml vs. GPDTR-Tg, 5.3 +/- 2.3 fmol/ml]. To elucidate the physiological roles of circulating ghrelin on GH secretion and somatic growth, 3-wk-old GPDTR-Tg mice were treated with DT twice a week for 5 wk. The GH responses to GHRH in male GPDTR-Tg mice were significantly lower than those in wild-type mice at 5 wk of age. However, those were normalized at 8 wk of age. In contrast, in female mice, there was no difference in GH response to GHRH between GPDTR-Tg mice and controls at 5 or 8 wk of age. The gender-dependent differences in response to GHRH were observed in ghrelin-ablated mice. However, GPDTR-Tg mice did not display any decreases in IGF-I levels or any growth retardation. Our results strongly suggest that circulating ghrelin does not play a crucial role in somatic growth.

  14. Obese adolescents show impaired meal responses of the appetite-regulating hormones ghrelin and PYY.

    PubMed

    Mittelman, Steven D; Klier, Katie; Braun, Sharon; Azen, Colleen; Geffner, Mitchell E; Buchanan, Thomas A

    2010-05-01

    Ghrelin and peptide YY (PYY) stimulate hunger and satiety, respectively. The physiology of these hormones during normal meal intake remains unclear. This study was designed to compare the responses of these two hormones to meal intake between lean and obese Hispanic adolescents. A total of 10 obese and 7 lean Hispanic youth, aged 11-14 years, consumed two mixed meals, one small and one large, during which plasma measurements of active and total ghrelin and total PYY were obtained. Obese subjects tended to consume more calories during the small meal than lean subjects, although this did not reach statistical significance. Intake of the small meal significantly suppressed active ghrelin and stimulated PYY levels in the lean subjects, and these changes were further accentuated by the large meals. In obese subjects, the suppression of active ghrelin and stimulation of PYY by caloric intake were blunted. Interestingly, a paradoxical stimulation of active ghrelin levels was noted during the small meals in both lean and obese subjects. This stimulation was not seen during the larger meals in lean subjects, but remained present in the obese subjects. Thus, meal-related changes in active ghrelin and PYY are blunted in obese as compared to lean Hispanic subjects. This blunting could contribute to the development or worsening of obesity.

  15. Ontogeny expression of ghrelin, neuropeptide Y and cholecystokinin in blunt snout bream, Megalobrama amblycephala.

    PubMed

    Ping, H-C; Feng, K; Zhang, G-R; Wei, K-J; Zou, G-W; Wang, W-M

    2014-04-01

    Ghrelin, neuropeptide Y (NPY) and cholecystokinin (CCK) all have important roles in the regulation of feeding in fish and mammals. To better understand the role of the three peptides in appetite regulation in the early developmental stages of blunt snout bream (Megalobrama amblycephala), partial cDNA sequences of ghrelin, NPY and CCK genes were cloned. And then, real-time quantitative PCR and RT-PCR were used to detect and quantify the mRNA expressions of these genes from zygotes to larvae of 50 days after hatching (DAH). Ghrelin, NPY and CCK were all expressed throughout the embryonic and larval development stages, and the expression levels were higher in larval stages than in embryonic stages. Ghrelin and NPY mRNA expressions were upregulated at 1, 3, 5 DAH, while CCK mRNA expression was reduced significantly at 3 DAH. The mRNA expression levels of three genes in larvae varied significantly until 30 DAH. In adult fish, all three peptides were detected to be expressed in brain and several peripheral tissues. Ghrelin mRNA was mainly expressed in the intestine, whereas NPY and CCK mRNAs were mainly expressed in the brain. Taken together, these results indicate that ghrelin, NPY and CCK may have roles in early development and participate in the regulation of feeding of larvae in blunt snout bream and will be helpful for further investigation into feed intake regulation in adults of this species.

  16. Ghrelin modulates testicular germ cells apoptosis and proliferation in adult normal rats

    SciTech Connect

    Kheradmand, Arash; Dezfoulian, Omid; Alirezaei, Masoud; Rasoulian, Bahram

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer Spermatogenesis is closely associated with the balance between germ cells proliferation and apoptosis. Black-Right-Pointing-Pointer Numerous studies have documented the direct action of ghrelin in the modulation of apoptosis in different cell types. Black-Right-Pointing-Pointer Ghrelin may be considered as a modulator of spermatogenesis in normal adult rats. Black-Right-Pointing-Pointer Ghrelin may be potentially implicated for abnormal spermatogenesis in some testicular germ cell tumors. -- Abstract: Under normal condition in the most mammals, spermatogenesis is closely associated with the balance between germ cells proliferation and apoptosis. The present study was designed to determine the effects of ghrelin treatment on in vivo quality and quantity expression of apoptosis and proliferation specific indices in rat testicular germ cells. Twenty eight adult normal rats were subdivided into equal control and treatment groups. Treatment group received 3 nmol of ghrelin as subcutaneous injection for 30 consecutive days or vehicle to the control animals. The rats from each group (n = 7) were killed on days 10 and 30 and their testes were taken for immunocytochemical evaluation and caspase-3 assay. Immunohistochemical analysis indicated that the accumulations of Bax and PCNA peptides are generally more prominent in spermatocytes and spermatogonia of both groups. Likewise, the mean percentage of immunoreactive spermatocytes against Bax increased (P < 0.01) in the ghrelin-treated group on day 10, while despite of 30% increment in the Bax level of spermatocytes in the treated rats on day 30, however, it was not statistically significant. During the experimental period, only a few spermatogonia represented Bax expression and the changes of Bax immunolabling cells were negligible upon ghrelin treatment. Likewise, there were immunostaining cells against Bcl-2 in each germ cell neither in the control nor in the treated animals. In fact

  17. Decreased ghrelin-induced GH release in thyrotoxicosis: comparison with GH-releasing peptide-6 (GHRP-6) and GHRH.

    PubMed

    Nascif, Sergio Oliva; Correa-Silva, Silvia Regina; Silva, Marcos Roberto; Lengyel, Ana-Maria Judith

    2007-01-01

    In thyrotoxicosis GH response to several stimuli is impaired, but there is no data on ghrelin-induced GH release in these patients. Ghrelin is a potent GH secretagogue and it also increases glucose levels in men. The aim of this study was to evaluate the effects of ghrelin (1 microg/kg), GHRP-6 (1 mug/kg) and GHRH (100 microg), i.v., on GH levels in 10 hyperthyroid patients and in 8 controls. Glucose levels were also measured during ghrelin and GHRP-6 administration. In control subjects and hyperthyroid patients peak GH (microg/l; mean +/- SE) values after ghrelin injection (controls: 66.7 +/- 13.6; hyper: 19.3 +/- 2.4) were significantly higher than those obtained after GHRP-6 (controls: 26.7 +/- 5.1; hyper: 12.6 +/- 1.3) and GHRH (controls: 13.5 +/- 4.3; hyper: 5.3 +/- 1.3). There was a significant decrease in GH responsiveness to ghrelin, GHRP-6 and GHRH in the hyperthyroid group compared to controls. In control subjects and hyperthyroid patients basal glucose (mmol/l) values were 4.5 +/- 0.1 and 4.7 +/- 0.2, respectively. There was a significant increase in glucose levels 30 min after ghrelin injection (controls: 4.9 +/- 0.1; hyper: 5.2 +/- 0.2), which remained elevated up to 120 min. When the two groups were compared no differences in glucose values were observed. GHRP-6 administration was not able to increase glucose levels in both groups. Our data shows that GH release after ghrelin, GHRP-6 and GHRH administration is decreased in thyrotoxicosis. This suggests that thyroid hormone excess interferes with GH-releasing pathways activated by these peptides. Our results also suggest that ghrelin's ability to increase glucose levels is not altered in thyrotoxicosis.

  18. The influence of pretreatment with ghrelin on the development of acetic-acid-induced colitis in rats.

    PubMed

    Maduzia, D; Matuszyk, A; Ceranowicz, D; Warzecha, Z; Ceranowicz, P; Fyderek, K; Galazka, K; Dembinski, A

    2015-12-01

    Ghrelin has been primarily shown to exhibit protective and therapeutic effect in the gut. Pretreatment with ghrelin inhibits the development of acute pancreatitis and accelerates pancreatic recovery in the course of this disease. In the stomach, ghrelin reduces gastric mucosal damage induced by ethanol, stress or alendronate, as well as accelerates the healing of acetic acid-induced gastric and duodenal ulcer. The aim of present studies was to investigate the effect of pretreatment with ghrelin on the development of acetic acid-induced colitis. Studies have been performed on male Wistar rats. Animals were treated intraperitoneally with saline (control) or ghrelin (4, 8 or 16 nmol/kg/dose). Saline or ghrelin was given twice: 8 and 1 h before induction of colitis. Colitis was induced by a rectal enema with 1 ml of 4% solution of acetic acid and the severity of colitis was assessed 1 or 24 hours after induction of inflammation. Rectal administration of acetic acid induced colitis in all animals. Damage of colonic wall was seen at the macroscopic and microscopic level. This effect was accompanied by a reduction in colonic blood flow and mucosal DNA synthesis. Moreover, induction of colitis significantly increased mucosal concentration of pro-inflammatory interleukin-1β (IL-1β), activity of myeloperoxidase and concentration of malondialdehyde (MDA). Mucosal activity of superoxide dismutase (SOD) was reduced. Pretreatment with ghrelin reduced the area and grade of mucosal damage. This effect was accompanied by an improvement of blood flow, DNA synthesis and SOD activity in colonic mucosa. Moreover, ghrelin administration reduced mucosal concentration of IL-1β and MDA, as well as decreased mucosal activity of myeloperoxidase. Administration of ghrelin protects the large bowel against the development of the acetic acid-induced colitis and this effect seems to be related to the ghrelin-evoked anti-inflammatory and anti-oxidative effects.

  19. Acyl-Lipid Metabolism

    PubMed Central

    Li-Beisson, Yonghua; Shorrosh, Basil; Beisson, Fred; Andersson, Mats X.; Arondel, Vincent; Bates, Philip D.; Baud, Sébastien; Bird, David; DeBono, Allan; Durrett, Timothy P.; Franke, Rochus B.; Graham, Ian A.; Katayama, Kenta; Kelly, Amélie A.; Larson, Tony; Markham, Jonathan E.; Miquel, Martine; Molina, Isabel; Nishida, Ikuo; Rowland, Owen; Samuels, Lacey; Schmid, Katherine M.; Wada, Hajime; Welti, Ruth; Xu, Changcheng; Zallot, Rémi; Ohlrogge, John

    2010-01-01

    Acyl lipids in Arabidopsis and all other plants have a myriad of diverse functions. These include providing the core diffusion barrier of the membranes that separates cells and subcellular organelles. This function alone involves more than 10 membrane lipid classes, including the phospholipids, galactolipids, and sphingolipids, and within each class the variations in acyl chain composition expand the number of structures to several hundred possible molecular species. Acyl lipids in the form of triacylglycerol account for 35% of the weight of Arabidopsis seeds and represent their major form of carbon and energy storage. A layer of cutin and cuticular waxes that restricts the loss of water and provides protection from invasions by pathogens and other stresses covers the entire aerial surface of Arabidopsis. Similar functions are provided by suberin and its associated waxes that are localized in roots, seed coats, and abscission zones and are produced in response to wounding. This chapter focuses on the metabolic pathways that are associated with the biosynthesis and degradation of the acyl lipids mentioned above. These pathways, enzymes, and genes are also presented in detail in an associated website (ARALIP: http://aralip.plantbiology.msu.edu/). Protocols and methods used for analysis of Arabidopsis lipids are provided. Finally, a detailed summary of the composition of Arabidopsis lipids is provided in three figures and 15 tables. PMID:22303259

  20. Acyl-Lipid Metabolism

    PubMed Central

    Li-Beisson, Yonghua; Shorrosh, Basil; Beisson, Fred; Andersson, Mats X.; Arondel, Vincent; Bates, Philip D.; Baud, Sébastien; Bird, David; DeBono, Allan; Durrett, Timothy P.; Franke, Rochus B.; Graham, Ian A.; Katayama, Kenta; Kelly, Amélie A.; Larson, Tony; Markham, Jonathan E.; Miquel, Martine; Molina, Isabel; Nishida, Ikuo; Rowland, Owen; Samuels, Lacey; Schmid, Katherine M.; Wada, Hajime; Welti, Ruth; Xu, Changcheng; Zallot, Rémi; Ohlrogge, John

    2013-01-01

    Acyl lipids in Arabidopsis and all other plants have a myriad of diverse functions. These include providing the core diffusion barrier of the membranes that separates cells and subcellular organelles. This function alone involves more than 10 membrane lipid classes, including the phospholipids, galactolipids, and sphingolipids, and within each class the variations in acyl chain composition expand the number of structures to several hundred possible molecular species. Acyl lipids in the form of triacylglycerol account for 35% of the weight of Arabidopsis seeds and represent their major form of carbon and energy storage. A layer of cutin and cuticular waxes that restricts the loss of water and provides protection from invasions by pathogens and other stresses covers the entire aerial surface of Arabidopsis. Similar functions are provided by suberin and its associated waxes that are localized in roots, seed coats, and abscission zones and are produced in response to wounding. This chapter focuses on the metabolic pathways that are associated with the biosynthesis and degradation of the acyl lipids mentioned above. These pathways, enzymes, and genes are also presented in detail in an associated website (ARALIP: http://aralip.plantbiology.msu.edu/). Protocols and methods used for analysis of Arabidopsis lipids are provided. Finally, a detailed summary of the composition of Arabidopsis lipids is provided in three figures and 15 tables. PMID:23505340

  1. Ghrelin in the gastrointestinal tract and blood circulation of perinatal low and normal weight piglets.

    PubMed

    Willemen, S A; De Vos, M; Huygelen, V; Fransen, E; Tambuyzer, B R; Casteleyn, C; Van Cruchten, S; Van Ginneken, C

    2013-12-01

    Ghrelin, the 'hunger' hormone, is an endogenous growth hormone secretagogue that exerts a wide range of physiological functions. Its perinatal presence suggests that ghrelin might be involved in growth and metabolism processes during intrauterine and postnatal life. Intrauterine growth-restricted (IUGR) neonates have altered endocrine and metabolic pathways because of malnutrition during foetal development. These changes might include an altered gastrointestinal presence of ghrelin cells (GCs). As ghrelin is mainly secreted by the stomach, this altered presence might be reflected in its serum concentrations. Small-for-gestational age (SGA) pigs appear to be a natural occurring model for IUGR children. Therefore, the first aim of this study was to investigate the presence of gastrointestinal GCs expressing active ghrelin in normal weight (NW) foetal and postnatal piglets compared with their SGA littermates using immunohistochemical analysis in combination with stereological methods. Second, total ghrelin serum concentrations of these piglets were analysed with a porcine radioactive immunoassay. In addition, the growth of the gastric pars fundica in the NW and SGA piglets was analysed stereologically. Corresponding with humans and rats, it was shown that opened- and closed-type immunoreactive GCs are distributed along the entire gastrointestinal tract of the perinatal NW and SGA piglets. However, in contrast to the rat's stomach, the porcine GCs do not disperse from the glandular base to the glandular neck during perinatal development. Furthermore, stereological analysis demonstrated that the NW neonates have a higher amount of gastric cells expressing active ghrelin compared with the SGA piglets that could result in higher milk consumption during the neonatal period. This finding is, however, not reflected in total serum ghrelin levels, which showed no difference between the NW and SGA piglets. Moreover, the stereological volume densities of the fundic layers

  2. The effects of fever on hormone ghrelins, immunoglobulins, and heat shock protein 70 expression after swine flu vaccinations.

    PubMed

    Aydin, Suleyman; Guven, Tumer; Sahin, İbrahim; Aksoy, Aziz; Kendir, Yalçın; İlhan, Mustafa N; Citil, Cihan; Catak, Zekiye; Ustun, Cemal

    2012-10-01

    For analyzing the changes in immunoglobulins, HSP70, ghrelin levels in blood samples were collected from volunteers vaccinated against swine flu before the vaccinations and on days 3, and 15, and 1 and 2 months after the vaccination in the presence or absence of fever associated with the it. The study included 11 subjects having developed a fever, and 13 subjects not having a fever, and 20 control subjects. Immunoglobulins were measured by nephelometry, and HSP70 and ghrelins by appropriate ELISA tests. The level of ghrelin was reduced, while the level of HSP70 was significantly increased in subjects who developed fevers. When temperatures were normalized, both levels were found similar to the control group. These results indicate that the increase in serum immunoglobulins levels associated with vaccinations, along with, elevations in HSP70 and reduced ghrelin levels associated with fever, may be the important parameters in the clinical evaluation and follow-up of treatments with vaccines.

  3. Ghrelin in plants: what is the function of an appetite hormone in plants?

    PubMed

    Aydin, Suleyman; Geckil, Hikmet; Zengin, Fikriye; Ibrahim Ozercan, H; Karatas, Fikret; Aydin, Suna; Turgut-Balik, Dilek; Ozkan, Yusuf; Dagli, Ferda; Celik, Venhar

    2006-07-01

    In the present work, we provide compelling evidence for the expression of a ghrelin-like peptide hormone that has only been associated with animals, in various plant tissues. Ghrelin, the appetite stimulating hormone, has been identified from a number of different species including humans, rat, pig, mouse, gerbil, eel, goldfish, bullfrog and chicken. The study here was conducted using an immunohistochemistry assay to screen whether plants have any ghrelin immunoreactivity. In this respect, Prunus x domestica L. and Marus alba were examined. Immunohistochemistry results showed that there is a strong human ghrelin immunoreactivity substance in the parenchyma cells of these plants. This was entirely unexpected since this hormone was considered to be present solely in animals. Thus, this study is the first to report the presence of a peptide with ghrelin-like activity in plants, a finding that has only been observed in the animal kingdom. RIA analysis confirmed that these plants contain significant amounts of this substance. Furthermore, reverse-phase HPLC analyses of plant extracts showed an elution characteristic of the peptide identical to that of human ghrelin. In general, fruit from both plants had higher levels of the peptide than the vegetative parts.

  4. Is there a role for ghrelin in central dopaminergic systems? Focus on nigrostriatal and mesocorticolimbic pathways.

    PubMed

    Stievenard, Alicia; Méquinion, Mathieu; Andrews, Zane B; Destée, Alain; Chartier-Harlin, Marie-Christine; Viltart, Odile; Vanbesien-Mailliot, Christel C

    2017-02-01

    The gastro-intestinal peptide ghrelin has been assigned many functions. These include appetite regulation, energy metabolism, glucose homeostasis, intestinal motility, anxiety, memory or neuroprotection. In the last decade, this pleiotropic peptide has been proposed as a therapeutic agent in gastroparesis for diabetes and in cachexia for cancer. Ghrelin and its receptor, which is expressed throughout the brain, play an important role in motivation and reward. Ghrelin finely modulates the mesencephalic dopaminergic signaling and is thus currently studied in pathological conditions including dopamine-related disorders. Dopamine regulates motivated behaviors, modulating reward processes, emotions and motor functions to enable the survival of individuals and species. Numerous dopamine-related disorders including Parkinson's disease or eating disorders like anorexia nervosa involve altered ghrelin levels. However, despite the growing interest for ghrelin in these pathological conditions, global integrative studies investigating its role in brain dopaminergic structures are still lacking. In this review, we discuss the role of ghrelin on dopaminergic neurons and its relevance in the search for new therapeutics for Parkinson's disease- and anorexia nervosa-related dopamine deficits.

  5. Synthesis and pharmacological evaluation of indolinone derivatives as novel ghrelin receptor antagonists.

    PubMed

    Puleo, Letizia; Marini, Pietro; Avallone, Roberta; Zanchet, Marco; Bandiera, Silvio; Baroni, Marco; Croci, Tiziano

    2012-09-15

    The ghrelin receptor is a G-protein-coupled receptor (GPCR) widely expressed in the brain, stomach and the intestine. It was firstly identified during studies aimed to find synthetic modulators of growth hormone (GH) secretion. GHSR and its endogenous ligand ghrelin were found to be involved in hunger response. Through food intake regulation, they could affect body weight and adiposity. Thus GHSR antagonists rapidly became an attractive target to treat obesity and feeding disorders. In this study we describe the biological properties of new indolinone derivatives identified as a new, chiral class of ghrelin antagonists. Their synthesis as well as the structure-activity relationship will be discussed herein. The in vitro identified compound 14f was a potent GHSR1a antagonist (IC(50) = 7 nM). When tested in vivo, on gastric emptying model, 14f showed an inhibitory intrinsic effect when given alone and it dose dependently inhibited ghrelin stimulation. Compound 14f also reduced food intake stimulated both by fasting condition (high level of endogenous ghrelin) and by icv ghrelin. Moreover this compound improved glucose tolerance in ipGTT test.

  6. Effects of ghrelin and motilin on smooth muscle contractility of the isolated gastrointestinal tract from the bullfrog and Japanese fire belly newt.

    PubMed

    Kitazawa, Takio; Shimazaki, Misato; Kikuta, Ayumi; Yaosaka, Noriko; Teraoka, Hiroki; Kaiya, Hiroyuki

    2016-06-01

    Ghrelin has been identified in some amphibians and is known to stimulate growth hormone release and food intake as seen in mammals. Ghrelin regulates gastrointestinal motility in mammals and birds. The aim of this study was to determine whether ghrelin affects gastrointestinal smooth muscle contractility in bullfrogs (anuran) and Japanese fire belly newts (urodelian) in vitro. Neither bullfrog ghrelin nor rat ghrelin affected longitudinal smooth muscle contractility of gastrointestinal strips from the bullfrog. Expression of growth hormone secretagogue receptor 1a (GHS-R1a) mRNA was confirmed in the bullfrog gastrointestinal tract, and the expression level in the gastric mucosa was lower than that in the intestinal mucosa. In contrast, some gastrointestinal peptides, including substance P, neurotensin and motilin, and the muscarinic receptor agonist carbachol showed marked contraction, indicating normality of the smooth muscle preparations. Similar results were obtained in another amphibian, the Japanese fire belly newt. Newt ghrelin and rat ghrelin did not cause any contraction in gastrointestinal longitudinal muscle, whereas substance P and carbachol were effective causing contraction. In conclusion, ghrelin does not affect contractility of the gastrointestinal smooth muscle in anuran and urodelian amphibians, similar to results for rainbow trout and goldfish (fish) but different from results for rats and chickens. The results suggest diversity of ghrelin actions on the gastrointestinal tract across animals. This study also showed for the first time that motilin induces gastrointestinal contraction in amphibians.

  7. Ghrelin decreases food intake in juvenile rainbow trout (Oncorhynchus mykiss) through the central anorexigenic corticotropin-releasing factor system.

    PubMed

    Jönsson, Elisabeth; Kaiya, Hiroyuki; Björnsson, Björn Thrandur

    2010-03-01

    Ghrelin stimulates pituitary growth hormone (GH) release, and has a key role in the regulation of food intake and adiposity in vertebrates. To investigate the central effect of native rainbow trout ghrelin (rtghrelin) on food intake in rainbow trout, as well as its possible mode of action, four groups of fish received a single injection into the third brain ventricle (i.c.v. injection): (1) control group (physiological saline) (2) ghrelin-treated group (2.0 ng rtghrelin g bwt(-1)), (3) group given the corticotropin-releasing hormone receptor antagonist alpha-helical CRF 9-41 (ahCRF) (4.0 ng g bwt(-1)) and (4) group receiving the same dose of both ghrelin and ahCRF. Food intake was assessed 1h after treatment. In addition, the presence of the GHS-R (the ghrelin receptor) in the rainbow trout CNS was examined with Western blot. To investigate peripheral effects of ghrelin, rainbow trout received an intraperitoneal cholesterol-based implant with or without rtghrelin, and daily food intake was measured during 14 days. Weight and length were measured at the start and termination of the experiment and specific growth rates were calculated. Mesenteric fat stores, muscle and liver lipid content were analysed after the treatment period. Central ghrelin injections decreased food intake compared with controls, and treatment with ahCRF abolished the ghrelin-effect. Western blot analysis of the GHS-R revealed a single band at around 60 kDa in pituitary, hypothalamus, brain and stomach. Long-term peripheral ghrelin treatment decreased daily food intake compared with controls. This was reflected in a ghrelin-induced decrease in weight growth rate (p<0.06). There was no effect of ghrelin on plasma GH levels or tissue fat stores. The conclusion from this study is that the GHS-R is indicated in the CNS in rainbow trout and that ghrelin may act there as an anorexigenic hormone, through a CRF-mediated pathway. Elevated peripheral ghrelin levels also seem to lead to decreased feed

  8. Anticipation of a psychosocial stressor differentially influences ghrelin, cortisol and food intake among emotional and non-emotional eaters.

    PubMed

    Raspopow, Kate; Abizaid, Alfonso; Matheson, Kimberly; Anisman, Hymie

    2014-03-01

    Negative emotions trigger eating in some individuals (emotional eaters) possibly by influencing stress hormones that contribute to eating regulation (e.g., cortisol), or eating-related peptides (e.g., ghrelin) signaling food initiation. The present study assessed whether stressor-elicited cortisol and ghrelin changes would differ between emotional and non-emotional eaters, and whether eating would influence these neuroendocrine responses. Undergraduate women (N=103) who completed measures of emotional eating, were assigned to anticipate either a stressful (public speaking) or non-stressful event. During this period, participants were or were not offered food. Blood samples were taken continuously over a 40-min period to assess changes of cortisol and ghrelin levels, and mood was assessed after the anticipation period. Baseline ghrelin levels were lower in emotional than non-emotional eaters, and this relation was mediated by percent body fat. Ghrelin levels were elevated among women anticipating a stressor, compared to those in the control condition. Additionally, the normal decline of ghrelin following food consumption was not apparent among emotional eaters. Although food intake was not tied to hormone responses, reported hunger was associated with greater food intake for women in the stressor condition. It was suggested that emotional eating coupled with subjective feelings of hunger, might contribute to eating in response to an acute stressor. Additionally, feedback mechanisms controlling the normalization of ghrelin levels might be disturbed in emotional eaters. The similarity of the ghrelin profile of emotional eaters to that of binge eaters and obese individuals, raises the possibility that disturbed ghrelin response might be a risk factor for such conditions.

  9. Decreased GH secretion and enhanced ACTH and cortisol release after ghrelin administration in Cushing's disease: comparison with GH-releasing peptide-6 (GHRP-6) and GHRH.

    PubMed

    Correa-Silva, Silvia Regina; Nascif, Sérgio Oliva; Lengyel, Ana-Maria Judith

    2006-01-01

    GH responsiveness to GH secretagogues (GHS) is blunted in Cushing's disease (CD), while ACTH/cortisol responses are enhanced, by mechanisms still unclear. Ghrelin, the endogenous ligand for GHS-receptors (GHS-R), increases GH, ACTH, cortisol and glucose levels in humans. This study evaluated the GH, ACTH, cortisol and glucose-releasing effects of ghrelin in CD in comparison with GHRP-6. GHRH-induced GH release was also studied. Ten patients with CD (BMI 26.9+/-1.0 kg/m(2)) and ten controls (BMI 24.4+/-1.1 kg/m(2)) received ghrelin (1 microg/kg), GHRP-6 (1 microg/kg) and GHRH (100 microg) separately. GH, ACTH, cortisol and glucose levels were measured. In CD ghrelin-induced GH (microg/L; mean +/- SE) release (peak: 7.2+/-3.0) was higher than seen with GHRP-6 (2.7+/-1.0) and GHRH (0.7+/-0.2), but lower than in controls (ghrelin: 58.3+/-12.1; GHRP-6: 22.9+/-4.8; GHRH: 11.3+/-3.7). In controls ACTH (pg/mL) release after ghrelin (79.2+/-26.8) was higher than after GHRP-6 (23.6+/-5.7). In CD these responses (ghrelin: 192+/-43; GHRP-6: 185+/-56) were similar, and enhanced compared to controls. The same was observed with cortisol. Glucose levels failed to increase after ghrelin in CD, differently than in controls. Our data suggests that hypothalamic and pituitary pathways of GH release activated by ghrelin, GHRP-6 and GHRH are deranged in chronic hypercortisolism. The increased ACTH/cortisol responses to ghrelin and GHRP-6 in CD could be mediated by overexpression of GHS-R in ACTH-secreting adenomas. Hypercortisolism apparently impairs the ability of ghrelin to increase glucose levels.

  10. Ghrelin receptor controls obesity by fat burning

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Emerging evidence show that brown fat in the body produces heat to burn energy, thus prompting weight loss. Ghrelin is the only known hormone which increases appetite and promotes weight gain. We have reported that mice that lack the receptor which mediates the functions of ghrelin are lean. Our fu...

  11. The acute ghrelin response to a psychological stress challenge does not predict the post-stress urge to eat.

    PubMed

    Rouach, V; Bloch, M; Rosenberg, N; Gilad, S; Limor, R; Stern, N; Greenman, Y

    2007-07-01

    Ghrelin is a growth hormone and cortisol secretagogue that plays an important role in appetite and weight regulation. It is not known whether ghrelin is involved in the eating response to stress in humans. In the present study we examined the effects of psychologically induced stress on plasma ghrelin levels in patients with binge-eating disorder (BED) (n=8) and in healthy subjects of normal (n=8) or increased (n=8) body mass index (BMI). Volunteers were subjected to the standardized trier social stress test (TSST). Heart rate, blood pressure, serum cortisol, serum prolactin, and plasma ghrelin levels were measured throughout the test. In addition, subjects were requested to rate their feelings of anxiety, tension, urge to eat uncontrollably and desire to eat sweets by means of a visual analog scale both before and after the TSST. There was a significant rise in the systolic blood pressure (p=0.003) in the study population, reflecting induction of physiological changes by the psychological challenge. Basal ghrelin levels were higher in healthy normal weight (385.4+/-79 pg/ml) than in obese (170.4+/-15.7 pg/ml) subjects (p<0.033). Basal ghrelin levels in patients with BED (240+/-40.8 pg/ml) were at an intermediate level between thin and healthy obese subjects, but this difference did not attain statistical significance. There were no differences in ghrelin levels throughout the test among the groups after correction for BMI, age and gender. A significant difference in the trend time of ghrelin was revealed when the three groups were analyzed according to their cortisol response to stress. Ghrelin levels increased in cortisol responders whereas no change or a decrease in ghrelin levels occurred in cortisol non-responders (p=0.038). Furthermore, a positive correlation was found between the change in ghrelin and the change in cortisol during TSST (r=0.444, p=0.029) but not between the change in ghrelin and the change in systolic blood pressure. The combined score of

  12. Neurogenic Effects of Ghrelin on the Hippocampus

    PubMed Central

    Kim, Chanyang; Kim, Sehee; Park, Seungjoon

    2017-01-01

    Mammalian neurogenesis continues throughout adulthood in the subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus in the hippocampus. It is well known that hippocampal neurogenesis is essential in mediating hippocampus-dependent learning and memory. Ghrelin, a peptide hormone mainly synthesized in the stomach, has been shown to play a major role in the regulation of energy metabolism. A plethora of evidence indicates that ghrelin can also exert important effects on neurogenesis in the hippocampus of the adult brain. The aim of this review is to discuss the current role of ghrelin on the in vivo and in vitro regulation of neurogenesis in the adult hippocampus. We will also discuss the possible role of ghrelin in dietary restriction-induced hippocampal neurogenesis and the link between ghrelin-induced hippocampal neurogenesis and cognitive functions. PMID:28282857

  13. Genetic variants of ghrelin in metabolic disorders.

    PubMed

    Ukkola, Olavi

    2011-11-01

    An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity-related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity.

  14. Neurogenic Effects of Ghrelin on the Hippocampus.

    PubMed

    Kim, Chanyang; Kim, Sehee; Park, Seungjoon

    2017-03-08

    Mammalian neurogenesis continues throughout adulthood in the subventricular zone of the lateral ventricle and in the subgranular zone of the dentate gyrus in the hippocampus. It is well known that hippocampal neurogenesis is essential in mediating hippocampus-dependent learning and memory. Ghrelin, a peptide hormone mainly synthesized in the stomach, has been shown to play a major role in the regulation of energy metabolism. A plethora of evidence indicates that ghrelin can also exert important effects on neurogenesis in the hippocampus of the adult brain. The aim of this review is to discuss the current role of ghrelin on the in vivo and in vitro regulation of neurogenesis in the adult hippocampus. We will also discuss the possible role of ghrelin in dietary restriction-induced hippocampal neurogenesis and the link between ghrelin-induced hippocampal neurogenesis and cognitive functions.

  15. Elevated blood active ghrelin and normal total ghrelin and obestatin concentrations in uterine leiomyoma.

    PubMed

    Markowska, A; Ziolkowska, A; Nowinka, K; Malendowicz, L K

    2009-01-01

    Ghrelin and obestatin originate from the same peptide precursor, preproghrelin. Both peptides are secreted in the blood. We investigated serum active and total ghrelin and obestatin concentrations in women with uterine myomatosis. Serum concentrations of active ghrelin in uterine leiomyoma were significantly higher compared to women in the control group (86 +/- 3 vs 56 +/- 9 pg/ml, respectively; p < 0.02). On the other hand, serum concentrations of total ghrelin and obestatin in uterine leiomyoma did not differ from those in the control group. In the control group the ratio of active to total ghrelin concentrations amounted to 0.62, while in women with uterine myoma it was 0.95, pointing to a prevalence of the active form of ghrelin in women with uterine myoma. Also the ratio of active ghrelin concentration to obestatin concentration was higher in the latter group while the ratio of total circulating ghrelin to obestatin concentrations was similar in the two groups. The data may suggest a role of active ghrelin in the development of a myoma. Moreover, the results indicate that increased blood ratios of active to total ghrelin and to obestatin concentrations are not specific for cachexia.

  16. GENOME-WIDE SCAN FOR SERUM GHRELIN DETECTS LINKAGE ON CHROMOSOME 1P36 IN HISPANIC CHILDREN: RESULTS FROM THE VIVA LA FAMILIA STUDY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was conducted to investigate genetic influence on serum ghrelin and its relationship with adiposity-related phenotypes in Hispanic children (n = 1030) from the Viva La Familia study (VFS). Anthropometric measurements and levels of serum ghrelin were estimated and genetic analyses conducte...

  17. Effect of weight reduction on leptin, total ghrelin and obestatin concentrations in prepubertal children.

    PubMed

    Arrigo, T; Gitto, E; Ferraù, V; Munafò, C; Alibrandi, A; Marseglia, G L; Salpietro, A; Miraglia Del Giudice, M; Leonardi, S; Ciprandi, G; Salpietro, C

    2012-01-01

    The aim of the study was to evaluate fasting levels of glucose, insulin, leptin, total ghrelin, and obestatin in a group of prepubescent obese children before and after weight loss. We enrolled 64 prepubescent obese children, but only 35 completed the study (mean age 7.6 +- 0.9 years, 19 females) and 20 normal-weight prepubescent children as controls. Fasting plasma concentration of glucose, insulin, Homeostasis Model assessment for insulin resistance (HOMA-IR), and leptin, total ghrelin, and obestatin levels were measured at baseline and after a 6-month lifestyle intervention (i.e. improved nutrition and increased physical activity). At baseline, obese children showed significantly (p less than 0.001) higher leptin and obestatin levels, and lower total ghrelin concentrations than control subjects. Weight loss significantly (p less than 0.001) diminished plasma leptin and insulin levels and increased ghrelin and obestatin concentrations. Weight loss in prepubescent children is associated with a significant change in leptin, ghrelin and obestatin concentrations. These results confirm the hypothesis that levels of these hormones are closely associated with obesity in childhood and might take part, as consequence but not as a cause, in glucose, fat, and energy metabolism.

  18. Obestatin and insulin in pancreas of newborn diabetic rats treated with exogenous ghrelin.

    PubMed

    Turk, Neslihan; Dağistanli, Fatma Kaya; Sacan, Ozlem; Yanardag, Refiye; Bolkent, Sema

    2012-07-01

    The aim of the study was to evaluate the effect of ghrelin treatment on obestatin, insulin gene expression and biochemical parameters in the pancreas of newborn-streptozocin (STZ) diabetic rats. Rats were divided into 4 groups. Group I: control rats treated with physiological saline; group II: control rats treated with 100 μg/kg/day ghrelin; group III: two days after birth rats that received 100mg/kg STZ injected as a single dose to induce neonatal diabetes; group IV: neonatal-STZ-diabetic rats treated with ghrelin for four weeks. Sections of the pancreas were examined with immunohistochemistry for the expression of obestatin and insulin and in situ hybridization for the expression of insulin mRNA. The blood glucose levels were measured. Tissue homogenates were used for protein, glutathione, lipid peroxidation and non-enzymatic glycosylation levels and antioxidant enzyme analysis. There was a significant difference in blood glucose levels in newborn-STZ-diabetic rats compared to ghrelin treated diabetic rats at weeks 1, 2 and 4. In group IV, pancreatic non-enzymatic glycosylation and lipid peroxidation levels were decreased, however, glutathione levels and enzymatic activities were increased. Insulin peptide and mRNA (+) signals in islets of Langerhans and obestatin immunopositive cell numbers showed an increase in group IV compared to group III. These results suggest that administration of ghrelin to newborn rats may prevent effects of diabetes.

  19. Peripheral injections of cholecystokinin, apelin, ghrelin and orexin in cavefish (Astyanax fasciatus mexicanus): effects on feeding and on the brain expression levels of tyrosine hydroxylase, mechanistic target of rapamycin and appetite-related hormones.

    PubMed

    Penney, Carla C; Volkoff, Hélène

    2014-01-15

    The effects of intraperitoneal injections of cholecystokinin (CCK), apelin, ghrelin, and orexin on food intake were examined in the blind cavefish Astyanax fasciatus mexicanus. CCK (50ng/g) induced a decrease in food intake whereas apelin (100ng/g), orexin (100ng/g), and ghrelin (100ng/g) induced an increase in food intake as compared to saline-injected control fish. In order to better understand the central mechanism by which these hormones act, we examined the effects of injections on the brain mRNA expression of two metabolic enzymes, tyrosine hydroxylase (TH), and mechanistic target of rapamycin (mTOR), and of appetite-regulating peptides, CCK, orexin, apelin and cocaine and amphetamine regulated transcript (CART). CCK injections induced a decrease in brain apelin injections, apelin injections induced an increase in TH, mTOR, and orexin brain expressions, orexin treatment increased brain TH expression and ghrelin injections induced an increase in mTOR and orexin brain expressions. CART expression was not affected by any of the injection treatments. Our results suggest that the enzymes TH and mTOR and the hormones CCK, apelin, orexin, and ghrelin all regulate food intake in cavefish through a complex network of interactions.

  20. Acyl-CoA binding proteins: multiplicity and function.

    PubMed

    Gossett, R E; Frolov, A A; Roths, J B; Behnke, W D; Kier, A B; Schroeder, F

    1996-09-01

    The physiological role of long-chain fatty acyl-CoA is thought to be primarily in intermediary metabolism of fatty acids. However, recent data show that nM to microM levels of these lipophilic molecules are potent regulators of cell functions in vitro. Although long-chain fatty acyl-CoA are present at several hundred microM concentration in the cell, very little long-chain fatty acyl-CoA actually exists as free or unbound molecules, but rather is bound with high affinity to membrane lipids and/or proteins. Recently, there is growing awareness that cytosol contains nonenzymatic proteins also capable of binding long-chain fatty acyl-CoA with high affinity. Although the identity of the cytosolic long-chain fatty acyl-CoA binding protein(s) has been the subject of some controversy, there is growing evidence that several diverse nonenzymatic cytosolic proteins will bind long-chain fatty acyl-CoA. Not only does acyl-CoA binding protein specifically bind medium and long-chain fatty acyl-CoA (LCFA-CoA), but ubiquitous proteins with multiple ligand specificities such as the fatty acid binding proteins and sterol carrier protein-2 also bind LCFA-CoA with high affinity. The potential of these acyl-CoA binding proteins to influence the level of free LCFA-CoA and thereby the amount of LCFA-CoA bound to regulatory sites in proteins and enzymes is only now being examined in detail. The purpose of this article is to explore the identity, nature, function, and pathobiology of these fascinating newly discovered long-chain fatty acyl-CoA binding proteins. The relative contributions of these three different protein families to LCFA-CoA utilization and/or regulation of cellular activities are the focus of new directions in this field.

  1. Presence of adropin, nesfatin-1, apelin-12, ghrelins and salusins peptides in the milk, cheese whey and plasma of dairy cows.

    PubMed

    Aydin, Suleyman

    2013-05-01

    Biological fluids (milk and serum/plasma) and cheese whey milk-derived fluid contain numerous molecules, especially amino acids and proteins. Therefore, the purpose of this study was to find out whether cheese whey (n:6), cow milk (n:6) and its blood (n=6) have adropin, nesfatin-1, apelin-12, ghrelins and salusin peptides. Adropin, nesfatin-1, apelin-12 concentrations were measured by ELISA, whereas ghrelin and salusin concentrations were measured by EIA methods. It was found that adropin, nesfatin-1, apelin-12, des-acylated ghrelin and salusins in cheese whey were higher than in the corresponding milk peptides and plasma of dairy cows, with the exception of salusin alpha and acylated ghrelin in milk being the same than that of the corresponding cheese whey concentration and plasma of dairy cows. A correlation was also found between milk peptides and cheese whey, as also with plasma of dairy cows. The data suggest that peptides in cow milk might be an important and nutritious food for (neonatal) calves and human diet due to their biological and physiological properties.

  2. B-type natriuretic peptide modulates ghrelin, hunger, and satiety in healthy men.

    PubMed

    Vila, Greisa; Grimm, Gabriele; Resl, Michael; Heinisch, Birgit; Einwallner, Elisa; Esterbauer, Harald; Dieplinger, Benjamin; Mueller, Thomas; Luger, Anton; Clodi, Martin

    2012-10-01

    Chronic heart failure is accompanied by anorexia and increased release of B-type natriuretic peptide (BNP) from ventricular cardiomyocytes. The pathophysiological mechanisms linking heart failure and appetite regulation remain unknown. In this study, we investigated the impact of intravenous BNP administration on appetite-regulating hormones and subjective ratings of hunger and satiety in 10 healthy volunteers. Participants received in a randomized, placebo-controlled, crossover, single-blinded study (subject) placebo once and 3.0 pmol/kg/min human BNP-32 once administered as a continuous infusion during 4 h. Circulating concentrations of appetite-regulating peptides were measured hourly. Subjective ratings of hunger and satiety were evaluated by visual analog scales. BNP inhibited the fasting-induced increase in total and acylated ghrelin concentrations over time (P = 0.043 and P = 0.038, respectively). In addition, BNP decreased the subjective rating of hunger (P = 0.009) and increased the feeling of satiety (P = 0.012) when compared with placebo. There were no significant changes in circulating peptide YY, glucagon-like peptide 1, oxyntomodulin, pancreatic polypeptide, leptin, and adiponectin concentrations. In summary, our results demonstrate that BNP exerts anorectic effects and reduces ghrelin concentrations in men. These data, taken together with the known cardiovascular properties of ghrelin, support the existence of a heart-gut-brain axis, which could be therapeutically targeted in patients with heart failure and obesity.

  3. Voluntary exercise attenuates obesity-associated inflammation through ghrelin expressed in macrophages.

    PubMed

    Kizaki, Takako; Maegawa, Taketeru; Sakurai, Takuya; Ogasawara, Jun-etsu; Ookawara, Tomomi; Oh-ishi, Shuji; Izawa, Tetsuya; Haga, Shukoh; Ohno, Hideki

    2011-09-30

    Chronic low-level inflammation is associated with obesity and a sedentary lifestyle, causing metabolic disturbances such as insulin resistance. Exercise training has been shown to decrease chronic low-level systemic inflammation in high-fat diet (HFD)-induced obesity. However, the molecular mechanisms mediating its beneficial effects are not fully understood. Ghrelin is a peptide hormone predominantly produced in the stomach that stimulates appetite and induces growth hormone release. In addition to these well-known functions, recent studies suggest that ghrelin localizes to immune cells and exerts an anti-inflammatory effect. The purpose of the current study was to investigate the role of ghrelin expressed in macrophages in the anti-inflammatory effects of voluntary exercise training. Expression of tumor necrosis factor-α (TNF-α), monocyte chemotactic protein (MCP)-1 and F4/80 was increased in adipose tissue from mice fed a HFD (HFD mice) compared with mice fed a standard diet (SD mice), whereas the expression of these inflammatory cytokines was markedly decreased in mice performing voluntary wheel running during the feeding of a HFD (HFEx mice). The expression of TNF-α was also increased in peritoneal macrophages by a HFD and exercise training inhibited the increase of TNF-α expression. Interestingly, expression of ghrelin in peritoneal macrophages was decreased by a HFD and recovered by exercise training. Suppression of ghrelin expression by siRNA increased TNF-α expression and LPS-stimulated NF-κB activation in RAW264 cells, which is a macrophage cell line. TNF-α expression by stimulation with LPS was significantly suppressed in RAW264 cells cultured in the presence of ghrelin. These results suggest that ghrelin exerts potent anti-inflammatory effects in macrophages and functions as a mediator of the beneficial effects of exercise training.

  4. Ghrelin: Central and Peripheral Implications in Anorexia Nervosa

    PubMed Central

    Méquinion, Mathieu; Langlet, Fanny; Zgheib, Sara; Dickson, Suzanne; Dehouck, Bénédicte; Chauveau, Christophe; Viltart, Odile

    2012-01-01

    Increasing clinical and therapeutic interest in the neurobiology of eating disorders reflects their dramatic impact on health. Chronic food restriction resulting in severe weight loss is a major symptom described in restrictive anorexia nervosa (AN) patients, and they also suffer from metabolic disturbances, infertility, osteopenia, and osteoporosis. Restrictive AN, mostly observed in young women, is the third largest cause of chronic illness in teenagers of industrialized countries. From a neurobiological perspective, AN-linked behaviors can be considered an adaptation that permits the endurance of reduced energy supply, involving central and/or peripheral reprograming. The severe weight loss observed in AN patients is accompanied by significant changes in hormones involved in energy balance, feeding behavior, and bone formation, all of which can be replicated in animals models. Increasing evidence suggests that AN could be an addictive behavior disorder, potentially linking defects in the reward mechanism with suppressed food intake, heightened physical activity, and mood disorder. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone that drives food-motivated behavior, are increased. This increase in plasma ghrelin levels seems paradoxical in light of the restrained eating adopted by AN patients, and may rather result from an adaptation to the disease. The aim of this review is to describe the role played by ghrelin in AN focusing on its central vs. peripheral actions. In AN patients and in rodent AN models, chronic food restriction induces profound alterations in the « ghrelin » signaling that leads to the development of inappropriate behaviors like hyperactivity or addiction to food starvation and therefore a greater depletion in energy reserves. The question of a transient insensitivity to ghrelin and/or a potential metabolic reprograming is discussed in regard of new clinical treatments currently investigated. PMID:23549309

  5. Ghrelin Modulates Lateral Amygdala Neuronal Firing and Blocks Acquisition for Conditioned Taste Aversion

    PubMed Central

    Liu, Tianwei; Yu, Ming; Xiao, Kewei; Kong, Qingnuan; Zhao, Renliang; Li, Guo-Dong; Zhou, Yu

    2013-01-01

    Ghrelin is an orexigenic brain-gut hormone promoting feeding and regulating energy metabolism in human and rodents. An increasing number of studies have reported that ghrelin and its identified receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), produces remarkably wide and complex functions and biological effects on specific populations of neurons in central nervous system. In this study, we sought to explore the in vivo effects of acute ghrelin exposure on lateral amygdala (LA) neurons at the physiological and behavioral levels. In vivo extracellular single-unit recordings showed that ghrelin with the concentration of several nanomolars (nM) stimulated spontaneous firing of the LA neurons, an effect that was dose-dependent and could be blocked by co-application of a GHS-R1a antagonist D-Lys3-GHRP-6. We also found that D-Lys3-GHRP-6 inhibited spontaneous firing of the LA neurons in a dose-dependent manner, revealing that tonic GHS-R1a activity contributes to orchestrate the basal activity of the LA neurons. Behaviorally, we found that microinfusion of ghrelin (12 ng) into LA before training interfered with the acquisition of conditioned taste aversion (CTA) as tested at 24 h after conditioning. Pre-treatment with either purified IgG against GHS-R1a or GHS-R1a antagonist blocked ghrelin’s effect on CTA memory acquisition. Ghrelin (12 ng) had no effect on CTA memory consolidation or the expression of acquired CTA memory; neither did it affect the total liquid consumption of tested rats. Altogether, our data indicated that ghrelin locally infused into LA blocks acquisition of CTA and its modulation effects on neuronal firing may be involved in this process. PMID:23762368

  6. Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacotherapy

    PubMed Central

    Altabas, Velimir; Zjačić-Rotkvić, Vanja

    2015-01-01

    Obesity is a medical condition caused by accumulated excess body fat with negative impact on patients’ health, including decreased life expectancy. It has become a major health problem in most developed and developing countries, since the worldwide prevalence of obesity nearly doubled during the last 30 years. Consequently, novel treatments focusing on obesity are being investigated. Potential targets include several pathophysiological mechanisms involved in appetite control affecting multiple organ systems, like adipose tissue; some cell types in the stomach and gut; pancreas; thyroid gland; several hypothalamic areas; and centers located in the brainstem. One of the most important orexigenic neuropeptides is ghrelin, which is produced and secreted primarily by ghrelin cells located in the stomach and duodenum. In humans, plasma ghrelin levels rise when the stomach is empty and fall shortly after meal ingestion. In fat tissue, ghrelin increases fat storage. In the brain, it exerts its orexigenic action through activation of NPY/AgRP neurons in the arcuate nucleus. From the pharmacological point of view, it seems that opposing ghrelin activity could be used as a therapeutic principle in treating obesity. The principal idea of antiobesity drugs is to augment anorexigenic and lipolytic signaling, or to block orexigenic and lipogenic mediators. Recent studies have shown that therapeutic vaccines could be a new approach in the development of antiobesity medications. A vaccine should provoke an immune response to a specific causal factor for a particular disease. Several types of anti-ghrelin vaccines have been developed so far, with significant immune response in terms of rising anti-ghrelin antibodies. However, in the only clinical trial performed yet, the results were disappointing, showing no additional weight loss in the study group. Until now, several studies have demonstrated the “proof of concept”, but more studies are required to develop prophylactic and

  7. Ghrelin signaling in heart remodeling of adult obese mice.

    PubMed

    Lacerda-Miranda, Glauciane; Soares, Vivian M; Vieira, Anatalia K G; Lessa, Juliana G; Rodrigues-Cunha, Alessandra C S; Cortez, Erika; Garcia-Souza, Erica P; Moura, Anibal S

    2012-05-01

    Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology, content and phosphorilation of cardiac proteins: ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK) and actin were achieved by Western blotting. GHSR-1a gene expression was analyzed by Real Time-PCR. We observed hyperglycemia and higher liver and visceral fat weight in obese when compared to control group. Obese mice presented a marked increase in heart weight/tibia length, indicating an enlarged heart size or a remodeling process. Obese mice had increased GHSR-1a content and expression in the heart associated to PI3K content and increased AKT content and phosphorylation. In contrast, AMPK content and phosphorylation in heart was not different between experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. Our data suggest that remodeled myocardial in adult obese mice overnourished in early life are associated with higher phosphorylation of GHSR-1a, PI3K and AKT but not with AMPK.

  8. Overexpression of intraislet ghrelin enhances β-cell proliferation after streptozotocin-induced β-cell injury in mice.

    PubMed

    Bando, Mika; Iwakura, Hiroshi; Ariyasu, Hiroyuki; Koyama, Hiroyuki; Hosoda, Kiminori; Adachi, Souichi; Nakao, Kazuwa; Kangawa, Kenji; Akamizu, Takashi

    2013-07-01

    Previously, we reported that exogenous administration of ghrelin ameliorates glucose metabolism in a neonate streptozotocin (STZ)-induced diabetic rat model through enhancement of β-cell proliferation. However, it was not clear whether the observed β-cell proliferation was a direct or indirect effect (e.g., via orexigenic or growth hormone-stimulated pathways) of ghrelin activity. Here, we aimed to investigate whether ghrelin directly impacts β-cell proliferation after STZ-induced injury in mice. Seven-week-old male rat insulin II promoter-ghrelin internal ribosomal sequence ghrelin O-acyltransferase transgenic (RIP-GG Tg) mice, which have elevated pancreatic ghrelin levels, but only minor changes in plasma ghrelin levels when fed a medium-chain triglyceride-rich diet, were treated with STZ. Then, serum insulin, pancreatic insulin mRNA expression, and islet histology were evaluated. We found that the serum insulin levels, but not blood glucose levels, of RIP-GG Tg mice were significantly ameliorated 14 days post-STZ treatment. Pancreatic insulin mRNA expression was significantly elevated in RIP-GG Tg mice, and β-cell numbers in islets were increased. Furthermore, the number of phospho-histone H3⁺ or Ki67⁺ proliferating β-cells was significantly elevated in RIP-GG Tg mice, whereas the apoptotic indexes within the islets, as determined by TUNEL assay, were not changed. These results indicate that ghrelin can directly stimulate β-cell proliferation in vivo after β-cell injury even without its orexigenic or GH-stimulating activities, although it did not have enough impact to normalize the glucose tolerance in adult mice.

  9. Ghrelin and GHRP-6-induced ACTH and cortisol release in thyrotoxicosis.

    PubMed

    Nascif, Sergio Oliva; Molica, Patrícia; Correa-Silva, Silvia Regina; Silva, Marcos Roberto; Lengyel, Ana-Maria Judith

    2009-01-01

    Thyrotoxicosis might alter the hypothalamic-pituitary-adrenal (HPA) axis. We evaluated the effects of ghrelin and GHRP-6 on the HPA axis in 20 hyperthyroid patients and in 9 controls. Mean basal cortisol (microg/dl) and ACTH (pg/ml) levels were higher in hyperthyroidism (cortisol: 10.7 +/- 0.7; ACTH: 21.5 +/- 2.9) compared to controls (cortisol: 8.1 +/- 0.7; ACTH: 13.5 +/- 1.8). In thyrotoxicosis Delta AUC cortisol values (microg/dl.90 min) after ghrelin (484 +/- 80) and GHRP-6 (115 +/- 63) were similar to controls (ghrelin: 524 +/- 107; GHRP-6: 192 +/- 73). A significant increase in Delta AUC ACTH (pg/ml x 90 min) after ghrelin was observed in thyrotoxicosis (4,189 +/- 1,202) compared to controls (1,499 +/- 338). Delta AUC ACTH values after GHRP-6 were also higher, although not significantly (patients: 927 +/- 330; controls: 539 +/- 237). In summary, our results suggest that ghrelin-mediated pathways of ACTH release might be activated by thyroid hormone excess, but adrenocortical reserve is maintained.

  10. Reduced Anticipatory Locomotor Responses to Scheduled Meals in Ghrelin Receptor Deficient Mice

    PubMed Central

    Blum, Ian D.; Patterson, Zack; Khazall, Rim; Lamont, Elaine Waddington; Sleeman, Mark W.; Horvath, Tamas L.; Abizaid, Alfonso

    2009-01-01

    Ghrelin, an orexigenic hormone produced by the stomach, is secreted in anticipation of scheduled meals and in correlation with anticipatory locomotor activity. We hypothesized that ghrelin is directly implicated in stimulating locomotor activity in anticipation of scheduled meals. To test this hypothesis, we observed 24 hr patterns of locomotor activity in mice with targeted mutations of the ghrelin receptor gene (GHSR KO) and wild-type littermates, all given access to food for four hours daily for 14 days. While WT and GHSR KO mice produced increases in anticipatory locomotor activity, anticipatory locomotor activity in GHSR KO mice was attenuated (p.< 0.05). These behavioral measures correlated with attenuated levels of Fos immunoreactivity in a number of hypothalamic nuclei from GHSR KO placed on the same restricted feeding schedule for seven days and sacrificed at ZT4. Interestingly, seven daily intraperitoeneal ghrelin injections mimicked hypothalamic Fos expression patterns to those seen in mice under restricted feeding schedules. These data suggest that ghrelin acts in the hypothalamus to augment locomotor activity in anticipation of scheduled meals. PMID:19666088

  11. Neuroprotective and antioxidant effects of ghrelin in an experimental glaucoma model

    PubMed Central

    Can, Nagehan; Catak, Onur; Turgut, Burak; Demir, Tamer; Ilhan, Nevin; Kuloglu, Tuncay; Ozercan, Ibrahim Hanifi

    2015-01-01

    Damage to retinal ganglion cells due to elevation of intraocular pressure (IOP) is responsible for vision loss in glaucoma. Given that loss of these cells is irreversible, neuroprotection is crucial in the treatment of glaucoma. In this study, we investigated the possible antioxidant and neuroprotective effects of ghrelin on the retina in an experimental glaucoma model. Twenty-one Sprague–Dawley rats were randomly assigned to three groups comprising seven rats each. The rats in the control group were not operated on and did not receive any treatment. In all rats in the other groups, IOP was increased by cauterization of the limbal veins. After creation of the IOP increase, saline 1 mL/kg or ghrelin 40 μg/kg was administered intraperitoneally every day for 14 days in the vehicle control group and ghrelin groups, respectively. On day 14 of the study, the eyes were enucleated. Levels of malondialdehyde (MDA), nitric oxide (NO), and nitric oxide synthase-2 (NOS2) in anterior chamber fluid were measured. The retinas were subjected to immunohistochemistry staining for glial fibrillary acidic protein (GFAP), S-100, and vimentin expression. Mean levels of MDA, NO, and NOS2 in the aqueous humor were higher in the vehicle control group than in the control group (P<0.05). Mean levels of MDA, NO, and NOS2 in the ghrelin group did not show a significant increase compared with levels in the control group (P>0.05). Retinal TUNEL and immunohistochemistry staining in the vehicle control group showed an increase in apoptosis and expression of GFAP, S-100, and vimentin compared with the control group (P<0.05). In the ghrelin group, apoptosis and expression of GFAP, S-100, and vimentin was significantly lower than in the vehicle control group (P<0.05). This study suggests that ghrelin has antioxidant and neuroprotective effects on the retina in an experimental glaucoma model. PMID:26082612

  12. Differential turnover of phospholipid acyl groups in mouse peritoneal macrophages

    SciTech Connect

    Kuwae, T.; Schmid, P.C.; Johnson, S.B.; Schmid, H.H. )

    1990-03-25

    Phospholipid acyl turnover was assessed in mouse peritoneal exudate cells which consisted primarily of macrophages. The cells were incubated for up to 5 h in media containing 40% H218O, and uptake of 18O into ester carbonyls of phospholipids was determined by gas chromatography-mass spectrometry of hydrogenated methyl esters. The uptake was highest in choline phospholipids and phosphatidylinositol, less in ethanolamine phospholipids, and much less in phosphatidylserine. Acyl groups at the sn-1 and sn-2 positions of diacyl glycerophospholipids, including arachidonic and other long-chain polyunsaturated fatty acids, acquired 18O at about the same rate. Acyl groups of alkylacyl glycerophosphocholine exhibited lower rates of 18O uptake, and acyl groups of ethanolamine plasmalogens (alkenylacyl glycerophosphoethanolamines) acquired only minimal amounts of 18O within 5 h, indicating a low average acyl turnover via free fatty acids. Pulse experiments with exogenous 3H-labeled arachidonic acid supported the concept that acylation of alkenyl glycerophosphoethanolamine occurs by acyl transfer from other phospholipids rather than via free fatty acids and acyl-CoA. The 18O content of intracellular free fatty acids increased gradually over a 5-h period, whereas in extracellular free fatty acids it reached maximal 18O levels within the first hour. Arachidonate and other long-chain polyunsaturated fatty acids were found to participate readily in deacylation-reacylation reactions but were present only in trace amounts in the free fatty acid pools inside and outside the cells. We conclude that acyl turnover of macrophage phospholipids through hydrolysis and reacylation is rapid but tightly controlled so that appreciable concentrations of free arachidonic acid do not occur.

  13. High Level QM/MM Modeling of the Formation of the Tetrahedral Intermediate in the Acylation of Wild Type and K73A Mutant TEM-1 Class A β-Lactamase

    NASA Astrophysics Data System (ADS)

    Hermann, Johannes C.; Pradon, Juliette; Harvey, Jeremy N.; Mulholland, Adrian J.

    2009-09-01

    The breakdown of β-lactam antibiotics by β-lactamases is the most important resistance mechanism of Gram negative bacteria against these drugs. The reaction mechanism of class A β-lactamases, the most widespread family of these enzymes, consists of two main steps: acylation of an active site serine by the antibiotic, followed by deacylation and release of the cleaved compound. We have investigated the first step in acylation (the formation of the tetrahedral intermediate) for the reaction of benzylpenicillin in the TEM-1 enzyme using high level combined quantum mechanics/molecular mechanics (QM/MM) methods. Structures were optimized at the B3LYP/6-31+G(d)/CHARMM27 level, with energies for key points calculated up to the ab initio SCS-MP2/aug-cc-pVTZ/CHARMM27 level. The results support a mechanism in which Glu166 removes a proton (via an intervening water molecule) from Ser70, which in turn attacks the β-lactam of the antibiotic. Depending on the method used, the calculated barriers range from 3 to 12 kcal mol-1 for this step, consistent with experimental data. We have also modeled this reaction step in a model of the K73A mutant enzyme. The barrier to reaction in this mutant model is found to be slightly higher: the results indicate that Lys73 stabilizes the transition state, in particular deprotonated Ser70, lowering the barrier by about 1.7 kcal mol-1. This finding may help to explain the conservation of Lys73, in addition to the role we have previously found for it in the later stages of the reaction ( Hermann et al. Org. Biomol. Chem. 2006, 4, 206 - 210 ).

  14. Ghrelin binding to serum albumin and its biological impact.

    PubMed

    Lufrano, Daniela; Trejo, Sebastián A; Llovera, Ramiro E; Salgueiro, Mariano; Fernandez, Gimena; Martínez Damonte, Valentina; González Flecha, F Luis; Raingo, Jesica; Ermácora, Mario R; Perelló, Mario

    2016-11-15

    Ghrelin is an octanoylated peptide hormone that plays a key role in the regulation of the body weight and glucose homeostasis. In plasma, ghrelin circulates bound to larger proteins whose identities are partially established. Here, we used size exclusion chromatography, mass spectrometry and isothermal titration microcalorimetry to show that ghrelin interacts with serum albumin. Furthermore, we found that such interaction displays an estimated dissociation constant (KD) in the micromolar range and involves albumin fatty-acid binding sites as well as the octanoyl moiety of ghrelin. Notably, albumin-ghrelin interaction reduces the spontaneous deacylation of the hormone. Both in vitro experiments-assessing ghrelin ability to inhibit calcium channels-and in vivo studies-evaluating ghrelin orexigenic effects-indicate that the binding to albumin affects the bioactivity of the hormone. In conclusion, our results suggest that ghrelin binds to serum albumin and that this interaction impacts on the biological activity of the hormone.

  15. Ghrelin Suppression and Fat Loss after Left Gastric Artery Embolization in Canine Model

    SciTech Connect

    Bawudun, Dilmurat; Xing Yan; Liu Wenya Huang Yujie; Ren Weixin; Ma Mei; Xu Xiaodong; Teng Gaojun

    2012-12-15

    Purpose: To evaluate the effects of left gastric artery embolization (LGAE) on plasma ghrelin levels, abdominal fat, and body weight in beagles. Methods: The institutional animal care and use committee approved this study. Fifteen healthy adult beagles (12 male and three female animals) were randomly divided into three experimental groups: LGAE was proceeded with mixed emulsion of bleomycin A{sub 5} hydrochloride and lipiodol (group A), and polyvinyl alcohol particles (group B). Transcatheter saline injections in the left gastric artery were performed as a control. Weight and fasting plasma ghrelin levels were obtained at baseline and at weekly intervals for 8 weeks after the procedure in all animals. All animals were scanned and measured by multidetector computed tomography at baseline and at week 8 for evaluation of abdominal fat. Results: In LGAE-treated animals, plasma ghrelin and body weight significantly decreased compared to control animals (group A: P = 0.007 and P = 0.000; group B: P = 0.004 and P = 0.000, respectively). Subcutaneous fat size was also significantly reduced (P = 0.011 and P = 0.027 for groups A and B, respectively). The decreasing percentage in ghrelin levels at week 6 (peak of recovery) of LGAE-treated animals were negatively correlated with the size of area supplied by left gastric artery (r = -0.693, P = 0.026). Conclusion: LGAE could suppress the plasma concentration of ghrelin, which results in subcutaneous fat size reduction and weight loss. Compensatory ghrelin production might occur in the remnant gastric fundus after LGAE.

  16. Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls

    PubMed Central

    Ackerman, Kathryn E.; Slusarz, Katherine; Guereca, Gabriela; Pierce, Lisa; Slattery, Meghan; Mendes, Nara; Herzog, David B.

    2012-01-01

    Amenorrhea is common in young athletes and is associated with low fat mass. However, hormonal factors that link decreased fat mass with altered gonadotropin pulsatility and amenorrhea are unclear. Low levels of leptin (an adipokine) and increased ghrelin (an orexigenic hormone that increases as fat mass decreases) impact gonadotropin pulsatility. Studies have not examined luteinizing hormone (LH) secretory dynamics in relation to leptin or ghrelin secretory dynamics in adolescent and young adult athletes. We hypothesized that 1) young amenorrheic athletes (AA) would have lower LH and leptin and higher ghrelin secretion than eumenorrheic athletes (EA) and nonathletes and 2) higher ghrelin and lower leptin would be associated with lower LH secretion. This was a cross-sectional study. We examined ghrelin and leptin secretory patterns (over 8 h, from 11 PM to 7 AM) in relation to LH secretory patterns in AA, EA, and nonathletes aged 14–21 yr. Ghrelin and leptin were assessed every 20 min and LH every 10 min. Groups did not differ for age, bone age, or BMI. However, fat mass was lower in AA than in EA and nonathletes. AA had lower LH and higher ghrelin pulsatile secretion and AUC than nonathletes and lower leptin pulsatile secretion and AUC than EA and nonathletes. Percent body fat was associated positively with LH and leptin secretion and inversely with ghrelin. In a regression model, ghrelin and leptin secretory parameters were associated independently with LH secretory parameters. We conclude that higher ghrelin and lower leptin secretion in AA related to lower fat mass may contribute to altered LH pulsatility and amenorrhea. PMID:22252944

  17. Ghrelin in the CNS: From hunger to a rewarding and memorable meal?

    PubMed Central

    Olszewski, Pawel K.; Schiöth, Helgi B.; Levine, Allen S.

    2008-01-01

    Ghrelin, the endogenous agonist of the growth hormone secretagogue receptor, has been shown to induce robust feeding responses in numerous experimental models. Although ghrelin comes from both peripheral and central sources, its hyperphagic properties, to a large extent, arise from activity at the brain level. The current review focuses on describing central mechanisms through which this peptide affects consumption. We address the issue of whether ghrelin serves just as a signal of energy needs of the organism or – as suggested by the most recent findings -also affects food intake via other feeding-related mechanisms, including reward and memory. Complexity of ghrelin’s role in the regulation of ingestive behavior is discussed by characterizing its influence on consumption, reward and memory as well as by defining its function within the brain circuitry and interplay with other neuropeptides. PMID:18308399

  18. The different satiating capacity of CHO and fats can be mediated by different effects on leptin and ghrelin systems.

    PubMed

    Sánchez, Juana; Cladera, María Magdalena; Llopis, Marina; Palou, Andreu; Picó, Catalina

    2010-12-01

    Leptin and ghrelin are known to be the main hormones involved in the control of food intake, with opposite effects. Here we aimed to assess whether changes in leptin and ghrelin systems can be involved in the different satiating capacities of carbohydrates (CHO) and fat. Adult male Wistar rats were studied under 24h fasting conditions and after 24h fasting followed by a 12h re-feeding period with 64 kcal of CHO or fat, consisting of a mixture of wheat starch and sucrose or bacon, respectively. Serum levels of leptin and ghrelin, and mRNA levels of leptin and ObRb in the retroperitoneal and inguinal adipose tissue and of NPY, POMC, ObRb and GSHR in the hypothalamus were measured. CHO re-feeding resulted in higher leptin mRNA expression levels in the retroperitoneal adipose tissue and in higher circulating leptin levels compared with those after fat re-feeding. Moreover, circulating ghrelin levels and ghrelin/leptin ratio were significantly higher after fat re-feeding compared with CHO re-feeding, and hypothalamic expression levels of ghrelin receptor increased after fat, but not after CHO, re-feeding. Hence, expression levels of hypothalamic neuropeptides involved in food intake control and regulated by these hormones, particularly the orexigenic NPY and the anorexigenic pro-opiomelanocortin (POMC)-derived alpha-melanocyte-stimulating hormone, were also differently affected by CHO and fat re-feeding, resulting in a significantly lower NPY/POMC ratio after CHO re-feeding than after fat re-feeding. In conclusion, different effects on the leptin and ghrelin systems can account, at least in part, for the lower satiating capacity of fat compared to CHO.

  19. Mechanism of Ghrelin-Induced Gastric Contractions in Suncus murinus (House Musk Shrew): Involvement of Intrinsic Primary Afferent Neurons

    PubMed Central

    Mondal, Anupom; Aizawa, Sayaka; Sakata, Ichiro; Goswami, Chayon; Oda, Sen-ichi; Sakai, Takafumi

    2013-01-01

    Here, we have reported that motilin can induce contractions in a dose-dependent manner in isolated Suncus murinus (house musk shrew) stomach. We have also shown that after pretreatment with a low dose of motilin (10−10 M), ghrelin also induces gastric contractions at levels of 10−10 M to 10−7 M. However, the neural mechanism of ghrelin action in the stomach has not been fully revealed. In the present study, we studied the mechanism of ghrelin-induced contraction in vitro using a pharmacological method. The responses to ghrelin in the stomach were almost completely abolished by hexamethonium and were significantly suppressed by the administration of phentolamine, prazosin, ondansetron, and naloxone. Additionally, N-nitro-l-arginine methylester significantly potentiated the contractions. Importantly, the mucosa is essential for ghrelin-induced, but not motilin-induced, gastric contractions. To evaluate the involvement of intrinsic primary afferent neurons (IPANs), which are multiaxonal neurons that pass signals from the mucosa to the myenteric plexus, we examined the effect of the IPAN-related pathway on ghrelin-induced contractions and found that pretreatment with adenosine and tachykinergic receptor 3 antagonists (SR142801) significantly eliminated the contractions and GR113808 (5-hydroxytryptamine receptor 4 antagonist) almost completely eliminated it. The results indicate that ghrelin stimulates and modulates suncus gastric contractions through cholinergic, adrenergic, serotonergic, opioidergic neurons and nitric oxide synthases in the myenteric plexus. The mucosa is also important for ghrelin-induced gastric contractions, and IPANs may be the important interneurons that pass the signal from the mucosa to the myenteric plexus. PMID:23565235

  20. Acylation of Ferrocene: A Greener Approach

    ERIC Educational Resources Information Center

    Birdwhistell, Kurt R.; Nguyen, Andy; Ramos, Eric J.; Kobelja, Robert

    2008-01-01

    The acylation of ferrocene is a common reaction used in organic laboratories to demonstrate Friedel-Crafts acylation and the purification of compounds using column chromatography. This article describes an acylation of ferrocene experiment that is more eco-friendly than the conventional acylation experiment. The traditional experiment was modified…

  1. Central ghrelin signaling mediates the metabolic response of C57BL/6 male mice to chronic social defeat stress.

    PubMed

    Patterson, Z R; Khazall, R; Mackay, H; Anisman, H; Abizaid, A

    2013-03-01

    Chronic stressors promote metabolic disturbances, including obesity and metabolic syndrome. Ghrelin, a peptide that promotes appetite and the accumulation of adipose tissue, is also secreted in response to stressors to protect the brain and peripheral tissues from the effects of these stressors. Here we demonstrate that elevated ghrelin levels produced by chronic exposure to social stress are associated with increased caloric intake and body weight gain in male C57BL mice. In contrast, stressed mice lacking ghrelin receptors (GHSR KO mice) or C57BL mice receiving chronic intracerebroventricular delivery of the ghrelin receptor antagonist [d-Lys(3)]-GHRP-6 show attenuated weight gain and feeding responses under the same social stress paradigm. Interestingly, stressed GHSR KO mice showed depleted sc and intrascapular brown fat depots, whereas stressed young wild-type mice did not. In old wild-type mice, chronic social defeat increased visceral and intrascapular brown fat depots in association with increases in obesity markers like hyperleptinemia and hyperinsulinemia along with increased hypothalamic expression of neuropeptide Y and Agouti related peptide. Importantly, the elevated expression of these peptides persisted least for 2 weeks after cessation of the stressor regimen. In contrast, old GHSR KO mice did not show these alterations after chronic social defeat. These results suggest that ghrelin plays an important role in the metabolic adaptations necessary to meet the energetic demands posed by stressors, but chronic exposure to stress-induced ghrelin elevations ultimately could lead to long lasting metabolic dysfunctions.

  2. Protective effect of leptin and ghrelin against toxicity induced by amyloid-β oligomers in a hypothalamic cell line.

    PubMed

    Gomes, S; Martins, I; Fonseca, A C R G; Oliveira, C R; Resende, R; Pereira, C M F

    2014-03-01

    In addition to cognitive decline, Alzheimer's disease (AD) patients also exhibit an unexplained weight loss that correlates with disease progression. In young and middle-aged AD patients, large amounts of amyloid-β (Aβ) deposits were observed in the hypothalamus, a brain region involved in the control of feeding and body weight through the action of peripheral metabolic peptides, which have recently been shown to have neuroprotective effects. Moreover, levels of peripheral metabolic peptides, such as leptin and ghrelin, are changed in AD patients. The present study aimed to investigate the role of Aβ peptide in the survival of hypothalamic cells and to explore the receptor-mediated protective effect of leptin and ghrelin against Aβ-induced toxicity in these cells. Using the mHypoE-N42 cell line, we demonstrated for the first time that oligomeric Aβ is toxic to hypothalamic cells, leading to cell death. It was also demonstrated that leptin and ghrelin protect these cells against AβO-induced cell death through the activation of the leptin and ghrelin receptors, respectively. Furthermore, ghrelin and leptin prevented superoxide production, calcium rise and mitochondrial dysfunction triggered by AβO. Taken together, these results suggest that peripheral metabolic peptides, in particular leptin and ghrelin, might be considered as preventive strategies for ameliorating hypothalamic alterations in AD.

  3. Maternal High-Fat Diet during Pregnancy and Lactation Influences Obestatin and Ghrelin Concentrations in Milk and Plasma of Wistar Rat Dams and Their Offspring.

    PubMed

    Słupecka, Monika; Romanowicz, Katarzyna; Woliński, Jarosław

    2016-01-01

    The study aims to establish the effect of a maternal high-fat diet on obestatin concentration, total ghrelin, and ghrelin/obestatin ratio during pregnancy and lactation of Wistar rats and their offspring in the first 21 days of life. On the mating day, females were randomly allocated and fed either a high-fat diet (30% of fat; HF) or breeding diet (5% fat; BD) till the 21st day of lactation. Hormones were analyzed in the blood plasma and milk of rat dams as well as in the blood plasma of their offspring. HF resulted in a significant decrease in obestatin level on the 14th day of lactation and elevation on the 21st day. Plasma obestatin in HFD offspring was significantly higher than in BD ones. HF diet did not significantly affect dam plasma ghrelin until the 21st day of lactation. The ghrelin concentrations in milk after both diets were significantly lower than in blood plasma. Milk ghrelin in HF dams was significantly higher than in the BD ones. Plasma ghrelin from HF offspring was significantly higher than that from BD dams. Our results demonstrate that a maternal HF diet during pregnancy and lactation influences ghrelin and obestatin level in both dams and their offspring.

  4. Ghrelin signalling and obesity: at the interface of stress, mood and food reward.

    PubMed

    Schellekens, Harriët; Finger, Beate C; Dinan, Timothy G; Cryan, John F

    2012-09-01

    The neuronal circuitry underlying the complex relationship between stress, mood and food intake are slowly being unravelled and several studies suggest a key role herein for the peripherally derived hormone, ghrelin. Evidence is accumulating linking obesity as an environmental risk factor to psychiatric disorders such as stress, anxiety and depression. Ghrelin is the only known orexigenic hormone from the periphery to stimulate food intake. Plasma ghrelin levels are enhanced under conditions of physiological stress and ghrelin has recently been suggested to play an important role in stress-induced food reward behaviour. In addition, chronic stress or atypical depression has often demonstrated to correlate with an increase in ingestion of caloric dense 'comfort foods' and have been implicated as one of the major contributor to the increased prevalence of obesity. Recent evidence suggests ghrelin as a critical factor at the interface of homeostatic control of appetite and reward circuitries, modulating the hedonic aspects of food intake. Therefore, the reward-related feeding of ghrelin may reveal itself as an important factor in the development of addiction to certain foods, similar to its involvement in the dependence to drugs of abuse, including alcohol. This review will highlight the accumulating evidence demonstrating the close interaction between food, mood and stress and the development of obesity. We consider the ghrelinergic system as an effective target for the development of successful anti-obesity pharmacotherapies, which not only affects appetite but also selectively modulates the rewarding properties of food and impact on psychological well-being in conditions of stress, anxiety and depression.

  5. Central ghrelin regulates peripheral lipid metabolism in a growth hormone-independent fashion.

    PubMed

    Sangiao-Alvarellos, Susana; Vázquez, María J; Varela, Luis; Nogueiras, Rubén; Saha, Asish K; Cordido, Fernando; López, Miguel; Diéguez, Carlos

    2009-10-01

    GH plays a major role in the regulation of lipid metabolism and alterations in GH axis elicit major changes in fat distribution and mobilization. For example, in patients with GH deficiency (GHD) or in mice lacking the GH receptor, the percentage of fat is increased. In addition to the direct actions of GH on lipid metabolism, current evidence indicates that ghrelin, a stomach-derived peptide hormone with potent GH secretagogue action, increases lipogenesis in white adipose tissue (WAT) through a hypothalamic-mediated mechanism. Still, the mechanism by which GH tone modulates ghrelin actions on WAT remains unclear. Here we investigated the effect of central ghrelin administration on lipid metabolism in lipogenic tissues (liver and WAT) in the absence of GH, by using a model for the study of GHD, namely the spontaneous dwarf rat, which shows increased body fat. Our data demonstrate that central chronic ghrelin administration regulates adipose lipid metabolism, mainly in a GH-independent fashion, as a result of increased mRNA, protein expression, and activity levels of fatty acid metabolism enzymes. On the contrary, central ghrelin regulates hepatic lipogenesis de novo in a GH-independent fashion but lipid mobilization in a GH-dependent fashion because carnitine palmitoyltransferase 1 was decreased only in wild-type Lewis rats. These findings suggest the existence of a new central nervous system-based neuroendocrine circuit, regulating metabolic homeostasis of adipose tissue. Understanding the molecular mechanism underlying the interplay between GH and ghrelin and their effects on lipid metabolism will provide new strategies for the design and development of suitable drugs for the treatment of GHD, obesity, and its comorbidities.

  6. Sequence, genomic organization and expression of two channel catfish, Ictalurus punctatus, ghrelin receptors.

    PubMed

    Small, Brian C; Quiniou, Sylvie M A; Kaiya, Hiroyuki

    2009-12-01

    Two ghrelin receptor (GHS-R) genes were isolated from channel catfish tissue and a bacterial artificial chromosome (BAC) library. The two receptors were characterized by determining tissue distribution, ontogeny of receptor mRNA expression, and effects of exogenous homologous ghrelin administration on target tissue mRNA expression. Analysis of sequence similarities indicated two genes putatively encoding GHS-R1 and GHS-R2, respectively, which have been known to be present in zebrafish. Organization and tissue expression of the GHS-R1 gene was similar to that reported for other species, and likewise yielded two detectable mRNA products as a result of alternative splicing. Expression of both full-length, GHS-R1a, and splice variant, GHS-R1b, mRNA was highest in the pituitary. Gene organization of GHS-R2 was similar to GHS-R1, but no splice variant was identified. Expression of GHS-R2a mRNA was highest in the Brockmann bodies. GHS-R1a mRNA was detected in unfertilized eggs and throughout embryogenesis, whereas GHR-R2a mRNA was not expressed in unfertilized eggs or early developing embryos and was the highest at the time of hatching. Catfish intraperitoneally injected with catfish ghrelin-Gly had greater mRNA expression of GHS-R1a in pituitaries at 2 h and Brockmann bodies at 4 h, and of GHS-R2a in Brockmann bodies at 6 h post injection. Amidated catfish ghrelin (ghrelin-amide) had no observable effect on expression of either pituitary receptor; however, GHS-R1a and GHS-R2a mRNA expression levels were increased 4 h post injection of ghrelin-amide in Brockmann bodies. This is the first characterization of GHS-R2a and suggests regulatory and functional differences between the two catfish receptors.

  7. Effects of ghrelin, growth hormone-releasing peptide-6, and growth hormone-releasing hormone on growth hormone, adrenocorticotropic hormone, and cortisol release in type 1 diabetes mellitus.

    PubMed

    de Sá, Larissa Bianca Paiva Cunha; Nascif, Sergio Oliva; Correa-Silva, Silvia Regina; Molica, Patricia; Vieira, José Gilberto Henriques; Dib, Sergio Atala; Lengyel, Ana-Maria Judith

    2010-10-01

    In type 1 diabetes mellitus (T1DM), growth hormone (GH) responses to provocative stimuli are normal or exaggerated, whereas the hypothalamic-pituitary-adrenal axis has been less studied. Ghrelin is a GH secretagogue that also increases adrenocorticotropic hormone (ACTH) and cortisol levels, similarly to GH-releasing peptide-6 (GHRP-6). Ghrelin's effects in patients with T1DM have not been evaluated. We therefore studied GH, ACTH, and cortisol responses to ghrelin and GHRP-6 in 9 patients with T1DM and 9 control subjects. The GH-releasing hormone (GHRH)-induced GH release was also evaluated. Mean fasting GH levels (micrograms per liter) were higher in T1DM (3.5 ± 1.2) than in controls (0.6 ± 0.3). In both groups, ghrelin-induced GH release was higher than that after GHRP-6 and GHRH. When analyzing Δ area under the curve (ΔAUC) GH values after ghrelin, GHRP-6, and GHRH, no significant differences were observed in T1DM compared with controls. There was a trend (P = .055) to higher mean basal cortisol values (micrograms per deciliter) in T1DM (11.7 ± 1.5) compared with controls (8.2 ± 0.8). No significant differences were seen in ΔAUC cortisol values in both groups after ghrelin and GHRP-6. Mean fasting ACTH values were similar in T1DM and controls. No differences were seen in ΔAUC ACTH levels in both groups after ghrelin and GHRP-6. In summary, patients with T1DM have normal GH responsiveness to ghrelin, GHRP-6, and GHRH. The ACTH and cortisol release after ghrelin and GHRP-6 is also similar to controls. Our results suggest that chronic hyperglycemia of T1DM does not interfere with GH-, ACTH-, and cortisol-releasing mechanisms stimulated by these peptides.

  8. Case Study: The Hunger Pains--Ghrelin, Weight Loss, and Maintenance

    ERIC Educational Resources Information Center

    Diener, Lynn M.

    2013-01-01

    This article presents a case study regarding healthy weight loss and the role of the hormone ghrelin in maintaining a lower body weight. This study was designed specifically for use in an introductory college-level physiology course. It addresses the use of the case study in teaching digestion and metabolism, exploring the role of hormones in…

  9. Characterization of new stable ghrelin analogs with prolonged orexigenic potency.

    PubMed

    Maletínská, Lenka; Pýchová, Miroslava; Holubová, Martina; Blechová, Miroslava; Demianová, Zuzana; Elbert, Tomáš; Železná, Blanka

    2012-03-01

    Ghrelin, the only known peripherally produced and centrally acting peptide that stimulates food intake, is synthesized primarily in the stomach and acts through the growth hormone secretagogue receptor (GHS-R1a). In addition to its orexigenic effect, ghrelin stimulates the release of growth hormone (GH). In this study, we investigated the biological properties of full-length and shortened ghrelin analogs in which octanoylated Ser(3) is replaced with an octanoic acid moiety coupled to diaminopropionic acid (Dpr). Ghrelin analogs stabilized with Dpr(N-octanoyl) in position 3 and noncoded amino acids in position 1 (sarcosine) and/or position 4 (naphthylalanine or cyclohexylalanine) were found to possess affinities similar to those of ghrelin for cell membranes with transfected GHS-R1a. In vivo, the prolonged orexigenic effects of analogs containing Dpr(N-octanoyl)(3) compared with that of ghrelin in adult mice and a similar impact on GH secretion in young mice were found. Full-length [Dpr(N-octanoyl)(3)]ghrelin and its analogs with a noncoded amino acid in position 1 and/or 4 showed significantly prolonged stability in blood plasma compared with that of ghrelin. Ghrelin analogs with a prolonged orexigenic effect are potential treatments for GH deficiency or cachexia that accompanies chronic diseases. Desoctanoylated ghrelin analogs and N-terminal penta- and octapeptides of ghrelin did not show any biological activity.

  10. Current and potential roles of ghrelin in clinical practice.

    PubMed

    Angelidis, G; Valotassiou, V; Georgoulias, P

    2010-12-01

    Ghrelin is a novel GH-releasing peptide, which has been identified as an endogenous ligand for GH-secretagogue receptor. Ghrelin is mainly secreted by the stomach and plays a critical role in a variety of physiological processes including endocrine, metabolic, cardiovascular, immunological, and other actions. Ghrelin stimulates food intake via hypothalamic neurons and causes a positive energy balance and body weight gain by decreasing fat utilization and promoting adiposity. Given the multiple effects of ghrelin, its potential clinical applications have been evaluated in various conditions. Preliminary trials have shown that it may prove valuable in the management of disease-induced cachexia. Ghrelin may improve the wasting syndrome through GH-dependent or GH-independent effects. Moreover, ghrelin may play a role in the management of disorders of gut motility and obesity. Finally, other potential clinical applications of ghrelin include the treatment of patients with diabetes mellitus, infections, rheumatological diseases or GH deficiency and the diagnosis of this hormonal disorder.

  11. Obesity Impairs the Action of the Neuroendocrine Ghrelin System.

    PubMed

    Zigman, Jeffrey M; Bouret, Sebastien G; Andrews, Zane B

    2016-01-01

    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.

  12. The role of ghrelin in drug and natural reward.

    PubMed

    Vengeliene, Valentina

    2013-11-01

    Ghrelin is a protein that has been given special attention in both nutrition and addiction research during the last decade. Consequently, a vast amount of information has been accumulated concerning the role of ghrelin in natural and drug reward. We are now in the position to ask whether the ghrelin system could be targeted to treat maladaptive behaviours such as obesity and drug addiction. Indeed, ghrelin research has demonstrated that blocking the activity of ghrelin receptors may be effective in reducing the consumption of both food and drugs of abuse. This review will give a short overview of our current knowledge about the ghrelin system in the context of drug and natural rewards as well as the possibility of developing potential ghrelin-based treatments.

  13. Involvement of Astrocytes in Mediating the Central Effects of Ghrelin.

    PubMed

    Frago, Laura M; Chowen, Julie A

    2017-03-02

    Although astrocytes are the most abundant cells in the mammalian brain, much remains to be learned about their molecular and functional features. Astrocytes express receptors for numerous hormones and metabolic factors, including the appetite-promoting hormone ghrelin. The metabolic effects of ghrelin are largely opposite to those of leptin, as it stimulates food intake and decreases energy expenditure. Ghrelin is also involved in glucose-sensing and glucose homeostasis. The widespread expression of the ghrelin receptor in the central nervous system suggests that this hormone is not only involved in metabolism, but also in other essential functions in the brain. In fact, ghrelin has been shown to promote cell survival and neuroprotection, with some studies exploring the use of ghrelin as a therapeutic agent against metabolic and neurodegenerative diseases. In this review, we highlight the possible role of glial cells as mediators of ghrelin's actions within the brain.

  14. Psychosocial stressor effects on cortisol and ghrelin in emotional and non-emotional eaters: influence of anger and shame.

    PubMed

    Raspopow, Kate; Abizaid, Alfonso; Matheson, Kimberly; Anisman, Hymie

    2010-09-01

    Food consumption in stressful situations vary as a function of individual difference factors (e.g., emotional vs. non-emotional eating), and may be related to hormonal responses elicited by the stressful event. These hormonal responses may be tied to specific emotions elicited by the stressful event. The present investigation examined the emotional and hormonal (cortisol, ghrelin) responses of high and low emotional eaters following a laboratory stressor (Trier Social Stress Test; TSST). Women (n=48) either high or low in emotional eating status were tested in a TSST or served as controls during which blood samples were taken for analysis of cortisol and ghrelin, both of which have been implicated in eating and in response to stressors. The TSST promoted elevated cortisol levels, being somewhat more pronounced in emotional than in non-emotional eaters. Both shame and anger were provoked by the TSST, and although both these emotions were correlated with cortisol levels, only anger significantly mediated the relationship between the stressor and cortisol levels. As well, baseline ghrelin levels in low emotional eaters exceeded that of high emotional eaters, and increased moderately in response to the stressor situation, irrespective of emotional eating status. Interestingly, when provided with food, ghrelin levels declined in the non-emotional eaters, but not in emotional eaters. The possibility is offered that the lack of a decline of ghrelin in emotional eaters may sustain eating in these individuals.

  15. Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity?

    PubMed

    Zhang, Yong; Li, Fenxia; Liu, Fu-Qiang; Chu, Chao; Wang, Yang; Wang, Dan; Guo, Tong-Shuai; Wang, Jun-Kui; Guan, Gong-Chang; Ren, Ke-Yu; Mu, Jian-Jun

    2016-05-26

    Overweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death. Several epidemiological studies have demonstrated a clear relationship between salt intake and obesity, but the pathophysiologic mechanisms remain unknown. We hypothesized that ghrelin, which regulates appetite, food intake, and fat deposition, becomes elevated when one consumes a high-salt diet, contributing to the progression of obesity. We, therefore, investigated fasting ghrelin concentrations during a high-salt diet. Thirty-eight non-obese and normotensive subjects (aged 25 to 50 years) were selected from a rural community in Northern China. They were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for seven days (3 g/day, NaCl), then a high-salt diet for seven days (18 g/day). The concentration of plasma ghrelin was measured using an immunoenzyme method (ELISA). High-salt intake significantly increased fasting ghrelin levels, which were higher during the high-salt diet (320.7 ± 30.6 pg/mL) than during the low-salt diet (172.9 ± 8.9 pg/mL). The comparison of ghrelin levels between the different salt diets was statistically-significantly different (p < 0.01). A positive correlation between 24-h urinary sodium excretion and fasting ghrelin levels was demonstrated. Our data indicate that a high-salt diet elevates fasting ghrelin in healthy human subjects, which may be a novel underlying mechanism of obesity.

  16. Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity?

    PubMed Central

    Zhang, Yong; Li, Fenxia; Liu, Fu-Qiang; Chu, Chao; Wang, Yang; Wang, Dan; Guo, Tong-Shuai; Wang, Jun-Kui; Guan, Gong-Chang; Ren, Ke-Yu; Mu, Jian-Jun

    2016-01-01

    Overweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death. Several epidemiological studies have demonstrated a clear relationship between salt intake and obesity, but the pathophysiologic mechanisms remain unknown. We hypothesized that ghrelin, which regulates appetite, food intake, and fat deposition, becomes elevated when one consumes a high-salt diet, contributing to the progression of obesity. We, therefore, investigated fasting ghrelin concentrations during a high-salt diet. Thirty-eight non-obese and normotensive subjects (aged 25 to 50 years) were selected from a rural community in Northern China. They were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for seven days (3 g/day, NaCl), then a high-salt diet for seven days (18 g/day). The concentration of plasma ghrelin was measured using an immunoenzyme method (ELISA). High-salt intake significantly increased fasting ghrelin levels, which were higher during the high-salt diet (320.7 ± 30.6 pg/mL) than during the low-salt diet (172.9 ± 8.9 pg/mL). The comparison of ghrelin levels between the different salt diets was statistically-significantly different (p < 0.01). A positive correlation between 24-h urinary sodium excretion and fasting ghrelin levels was demonstrated. Our data indicate that a high-salt diet elevates fasting ghrelin in healthy human subjects, which may be a novel underlying mechanism of obesity. PMID:27240398

  17. The β-cell GHSR and downstream cAMP/TRPM2 signaling account for insulinostatic and glycemic effects of ghrelin

    PubMed Central

    Kurashina, Tomoyuki; Dezaki, Katsuya; Yoshida, Masashi; Sukma Rita, Rauza; Ito, Kiyonori; Taguchi, Masanobu; Miura, Rina; Tominaga, Makoto; Ishibashi, Shun; Kakei, Masafumi; Yada, Toshihiko

    2015-01-01

    Gastric hormone ghrelin regulates insulin secretion, as well as growth hormone release, feeding behavior and adiposity. Ghrelin is known to exert its biological actions by interacting with the growth hormone secretagogue-receptor (GHSR) coupled to Gq/11-protein signaling. By contrast, ghrelin acts on pancreatic islet β-cells via Gi-protein-mediated signaling. These observations raise a question whether the ghrelin action on islet β-cells involves atypical GHSR and/or distinct signal transduction. Furthermore, the role of the β-cell GHSR in the systemic glycemic effect of ghrelin still remains to be defined. To address these issues, the present study employed the global GHSR-null mice and those re-expressing GHSR selectively in β-cells. We here report that ghrelin attenuates glucose-induced insulin release via direct interaction with ordinary GHSR that is uniquely coupled to novel cAMP/TRPM2 signaling in β-cells, and that this β-cell GHSR with unique insulinostatic signaling largely accounts for the systemic effects of ghrelin on circulating glucose and insulin levels. The novel β-cell specific GHSR-cAMP/TRPM2 signaling provides a potential therapeutic target for the treatment of type 2 diabetes. PMID:26370322

  18. Immunomodulatory actions of central ghrelin in diet-induced energy imbalance.

    PubMed

    Stevanovic, Darko; Starcevic, Vesna; Vilimanovich, Urosh; Nesic, Dejan; Vucicevic, Ljubica; Misirkic, Maja; Janjetovic, Kristina; Savic, Emina; Popadic, Dusan; Sudar, Emina; Micic, Dragan; Sumarac-Dumanovic, Mirjana; Trajkovic, Vladimir

    2012-01-01

    We investigated the effects of centrally administered orexigenic hormone ghrelin on energy imbalance-induced inflammation. Rats were subjected for four weeks to three different dietary regimes: normal (standard food), high-fat (standard food with 30% lard) or food-restricted (70%, 50%, 40% and 40% of the expected food intake in 1st, 2nd, 3rd and 4th week, respectively). Compared to normal-weight controls, starved, but not obese rats had significantly higher levels of proinflammatory cytokines (TNF, IL-1β, IFN-γ) in the blood. When compared to normally fed animals, the hearts of starved and obese animals expressed higher levels of mRNAs encoding proinflammatory mediators (TNF, IL-1β, IL-6, IFN-γ, IL-17, IL-12, iNOS), while mRNA levels of the anti-inflammatory TGF-β remained unchanged. Intracerebroventricular (ICV) injection of ghrelin (1 μg/day) for five consecutive days significantly reduced TNF, IL-1β and IFN-γ levels in the blood of starved rats, as well as TNF, IL-17 and IL-12p40 mRNA expression in the hearts of obese rats. Conversely, ICV ghrelin increased the levels of IFN-γ, IL-17, IL-12p35 and IL-12p40 mRNA in the heart tissue of food-restricted animals. This was associated with an increase of immunosuppressive ACTH/corticosterone production in starved animals and a decrease of the immunostimulatory adipokine leptin both in food-restricted and high-fat groups. Ghrelin activated the energy sensor AMP-activated protein kinase (AMPK) in the hypothalamus and inhibited extracellular signal-regulated kinase (ERK) in the hearts of obese, but not starved rats. Therefore, central ghrelin may play a complex role in energy imbalance-induced inflammation by modulating HPA axis, leptin and AMPK/ERK signaling pathways.

  19. Ghrelin Gene Variants Influence on Metabolic Syndrome Components in Aged Spanish Population

    PubMed Central

    Mora, Mireia; Adam, Victoria; Palomera, Elisabet; Blesa, Sebastian; Díaz, Gonzalo; Buquet, Xavier; Serra-Prat, Mateu; Martín-Escudero, Juan Carlos; Palanca, Ana; Chaves, Javier Felipe; Puig-Domingo, Manuel

    2015-01-01

    Background The role of genetic variations within the ghrelin gene on cardiometabolic profile and nutritional status is still not clear in humans, particularly in elderly people. Objectives We investigated six SNPs of the ghrelin gene and their relationship with metabolic syndrome (MS) components. Subjects and Methods 824 subjects (413 men/411 women, age 77.31±5.04) participating in the Mataró aging study (n = 310) and the Hortega study (n = 514) were analyzed. Anthropometric variables, ghrelin, lipids, glucose and blood pressure levels were measured, and distribution of SNPs -994CT (rs26312), -604GA (rs27647), -501AC (rs26802), R51Q (rs34911341), M72L (rs696217) and L90G (rs4684677) of the ghrelin gene evaluated. Genotypes were determined by multiplex PCR and SNaPshot minisequencing. MS (IDF criteria) was found in 54.9%. Results No association between any of the SNPs and levels of total fasting circulating ghrelin levels was found. C/A-A/A genotype of M72L was associated with increased risk of central obesity according to IDF criteria, while G/A-G/G genotypes of -604GA with reduced risk. A/A genotype of -501AC polymorphism was associated to decreased BMI. In relation to lipid profile, the same genotypes of -604GA were associated with increased total cholesterol and LDL-cholesterol and -501AC with reduced triglycerides. There were no associations with systolic or diastolic blood pressure levels or with hypertension, glucose levels or diabetes and ghrelin polymorphisms. However, G/G genotype of -604GA was associated with glucose >100 mg/dL. Haplotype analysis showed that only one haplotype is associated with increased risk of waist circumference and central obesity. The analysis of subjects by gender showed an important and different association of these polymorphisms regarding MS parameters. Conclusion Ghrelin gene variants -604GA, -501AC and M72L are associated with certain components of MS, in particular to BMI and lipid profile in elderly Spanish subjects. PMID

  20. Anti‐ghrelin Spiegelmer NOX‐B11 inhibits neurostimulatory and orexigenic effects of peripheral ghrelin in rats

    PubMed Central

    Kobelt, P; Helmling, S; Stengel, A; Wlotzka, B; Andresen, V; Klapp, B F; Wiedenmann, B; Klussmann, S; Mönnikes, H

    2006-01-01

    Background and aims Ghrelin, the natural ligand of the growth hormone secretagogue receptor 1a, is the most powerful peripherally active orexigenic agent known. In rodents, ghrelin administration stimulates growth hormone release, food intake, and adiposity. Because of these effects, blocking of ghrelin has been widely discussed as a potential treatment for obesity. Spiegelmer NOX‐B11 is a synthetic l‐oligonucleotide, which was previously shown to bind ghrelin. We examined the effects of NOX‐B11 on ghrelin induced neuronal activation and food intake in non‐fasted rats. Methods Animals received various doses of NOX‐B11, inactive control Spiegelmer, or vehicle intravenously. Ghrelin or vehicle was administered intraperitoneally 12 hours later and food intake was measured over four hours. Neuronal activation was assessed as c‐Fos‐like immunoreactivity in the arcuate nucleus. Results Treatment with NOX‐B11 30 nmol suppressed ghrelin induced c‐Fos‐like immunoreactivity in the arcuate nucleus and blocked the ghrelin induced increase in food intake within the first half hour after ghrelin injection (mean 1.13 (SEM 0.59) g/kg body weight; 4.94 (0.63) g/kg body weight versus 0.58 (0.58) g/kg body weight; p<0.0001). Treatment with NOX‐B11 1 nmol or control Spiegelmer had no effect whereas treatment with NOX‐B11 10 nmol showed an intermediate effect on ghrelin induced food intake. Conclusions Spiegelmer NOX‐B11 suppresses ghrelin induced food intake and c‐Fos induction in the arcuate nucleus in rats. The use of an anti‐ghrelin Spiegelmer could be an innovative new approach to inhibit the biological action of circulating ghrelin. This may be of particular relevance to conditions associated with elevated plasma ghrelin, such as the Prader‐Willi syndrome. PMID:15994217